Dissertation Fiona Cleutjens by Cleutjens

䌀伀最渀椀琀椀瘀攀

倀甀氀洀漀渀愀爀礀䐀椀猀攀愀猀攀一攀甀爀漀瀀猀礀挀栀漀氀漀最椀挀愀氀昀甀渀挀琀椀漀渀椀渀最椀渀瀀愀琀椀攀渀琀猀眀椀琀栀䌀伀倀䐀

䘀䤀伀一䄀䌀䰀䔀唀吀䨀䔀一匀

ISBN:

978 94 6159 697 0

Layout and cover: FIONA CLEUTJENS | ohfiona Graphic Design Production: Datawyse | Universitaire Pers Maastricht

UNIVERSITAIRE

PERS MAASTRICHT

The research presented in this thesis was conducted at CIRO, Horn, the Netherlands; and the School for Mental Health and Neurosciences: MHeNS, Maastricht University, Maastricht, the Netherlands. This thesis was financially supported by The Weijerhorst Foundation, Maastricht, the Netherlands. Printing and distribution of this thesis was financially supported by CIRO, Horn, the Netherlands; de Weldadige Stichting Jan de Limpens, Oirsbeek, the Netherlands; Stichting AstmaBestrijding, Amsterdam, The Netherlands; Teva Netherlands B.V., Haarlem, the Netherlands; Lung Foundation Netherlands, Amersfoort, the Netherlands; Boehringer Ingelheim B.V., Alkmaar, the Netherlands; Chiesi Pharmaceuticals B.V., Rijswijk, the Netherlands.

COgnitive-Pulmonary Disease? Neuropsychological functioning in patients with COPD

Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Maastricht, op gezag van de Rector Magnificus, Prof. dr. Rianne M. Letschert, volgens het besluit van het College van Decanen, in het openbaar te verdedigen op vrijdag 16 juni 2017 om 14.00 uur door

Fiona Cleutjens

Promotoren Prof dr. E.F.M. Wouters Prof. dr. R.W.H.M. Ponds

Copromotoren Dr. D.J.A. Janssen, CIRO Horn Dr. J.B. Dijkstra

Beoordelingscommissie Prof. dr. J.M.G.A. Schols (voorzitter) Prof. dr. D.J.H. Deeg, VUmc Amsterdam Prof. dr. C.M. van Heugten Prof. dr. A. von Leupoldt, KU Leuven Prof. dr. F.R.J. Verhey

Aan papa

Table of contents

Chapter 1 General introduction

Chapter 2 Cognitive Functioning in Obstructive Lung Disease: Results from the United Kingdom Biobank

Chapter 3 Presence of brain pathology in deceased subjects with and without COPD

Chapter 4 Sleep quality disturbances and cognitive functioning in elderly patients with COPD

Chapter 5 The COgnitive‐Pulmonary Disease (COgnitive‐PD) study: protocol of a longitudinal observational comparative study on neuropsychological functioning of COPD patients

Chapter 6 Domain‐specific cognitive impairment in patients with COPD and control subjects

103

Chapter 7 Cognitive impairment and clinical characteristics in patients with COPD

135

Chapter 8 The relationship between cerebral small vessel disease, hippocampal volume and cognitive functioning in patients with COPD: an MRI study 161 Chapter 9 The impact of cognitive impairment on efficacy of pulmonary rehabilitation in patients with COPD

177

Chapter 10 General discussion

195

Chapter 11 Summary Samenvatting Valorization Dankwoord Curriculum Vitae Publications

215 221 227 233 239 243

Chapter 1

General introduction Part of the General introduction was published as: Cleutjens FA, Janssen DJ, Ponds RW, Dijkstra JB, Wouters EF. COgnitive-Pulmonary Disease. BioMed Research International. 2014:697825. Reprinted with permission from Hindawi Ltd.

ChapterÂ 1Â

Chronic obstructive pulmonary disease The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines Chronic obstructive pulmonary disease (COPD) as: "a common preventable and treatable disease, characterized by airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases."1 Significant airflow limitation is caused by small airway disease (i.e. obstructive bronchiolitis) and parenchymal destruction (i.e. emphysema). The severity of COPD can be graded according to the degree of airflow limitation, determined by spirometry, into mild, moderate, severe, and very severe. The updated GOLD guidelines distinguish four categories of patients with COPD (GOLD groups A = low risk, fewer symptoms; B = low risk, more symptoms; C = high risk, fewer symptoms; and D = high risk, more symptoms) based on the combination of severity of symptoms, the degree of airflow limitation, and the number of hospital admissions or exacerbations in the past 12 months. The disease is predominantly caused by cigarette smoking, but other factors, such as indoor and outdoor air pollution, occupational dust, infection in childhood, asthma, and genetic factors including alpha-1 antitrypsin deficiency, may also contribute to the development of COPD.1 Smoking cessation may delay disease progression.2 Although COPD is a treatable disease, it cannot be cured. To improve lung function, COPD symptoms, exacerbations, and morbidity and mortality, a combination of pharmacological treatment (e.g. inhaled bronchodilators and glucocorticosteroids) and non-pharmacological interventions (e.g. pulmonary rehabilitation, long-term oxygen therapy, and endoscopic or surgical lung volume reduction) is available for patients with COPD.3 COPD tends to be underdiagnosed and undertreated by healthcare professionals due to limited disease awareness, relatively late presentation of disease, or confusion with other conditions, which may explain a lower estimated prevalence in Europe (4 to 10%)4 and the United States (5 to 14%)5 compared to a prevalence of COPD based on spirometry of 24% in the area of Maastricht.6 Europe-wide data show with 1.1 million hospital admissions and 150.000 deaths per year that COPD has a high socio-economic burden.7

A multisystem disease Although COPD has been traditionally considered as a disease primarily affecting the lungs, its systemic effects have been increasingly recognized with diverse manifestations involving body systems distant from the lung. The characteristic symptoms of COPD include shortness of breath, cough, and excessive sputum production.1 Other symptoms include fatigue and sleeplessness.8 Common comorbidities, or medical conditions alongside COPD, are obstructive sleep

Cognitive functioning Definition of cognitive functioning Cognitive functioning refers to a range of brain functions that include the processes by which an individual perceives, registers, stores, retrieves, and uses information by which our behavior can be adapted to new situations.

Figure 1. Cognitive domains and specific functions

Chapter 1

General introduction apnea, anemia, hypertension, cardiovascular diseases, osteoporosis, atherosclerosis, infections, diabetes mellitus, musculoskeletal disorders, underweight, obesity, and nutritional depletion.1,9 Moreover, neuropsychological problems occur in different extents, such as problems with memory, problem solving, attention, concentration, logical and abstract reasoning, organization, coordination, and planning.10 Further, depression and anxiety are common in COPD,11 and are associated with worse cognition.12 Besides, the vascular complications in COPD are risk factors for brain abnormalities (e.g. white matter abnormalities), and thus, (executive) cognitive functioning problems.13,14,15 Comorbidities are associated with disease burden, reduced survival and higher health care expenditure, and can be found in up to 98% of patients with COPD.9,16 This underlies the importance towards preventive strategies to reduce comorbid risk, to appropriately detect comorbidities and consequently treat patient with COPD and comorbid diseases.1,17

ChapterÂ 1Â Cognitive functioning can be divided into several cognitive domains, such as information processing, attention and concentration, memory, executive functioning and self-control. Each domain contains specific functions, which can be seen as basic capabilities that influence the content and amount of intellectual skills, personal knowledge and competences (Figure 1). These cognitive functions allow us to read, remember a phone number, recognize a human face, drive, and make decisions.18 The executive functions can be seen as the 'higher' cognitive functions, which are involved in the regulation and control of 'lower' cognitive functions. These complex cognitive activities include purposeful, selfregulatory, and future-oriented behaviors that allow us to plan or initiate an activity, and to solve a problem.19 Self-control consists of a subset of self-regulatory processes which aim to prevent yielding to unwanted impulses or urges, such as craving for a cigarette when trying to quit smoking.20 Deficits in one or more cognitive domains or functions are referred to as cognitive impairment.

COPD = COgnitive-Pulmonary Disease? Cognitive impairment in COPD Various studies have investigated the prevalence of cognitive impairment in COPD, showing the prevalence to be higher in COPD patients than in healthy control subjects. For example, Grant and colleagues showed that 42% of the patients with COPD, had moderate to severe cognitive impairment compared to only 14% in controls.21 Mild cognitive impairment, which refers to significant cognitive decline without major functional impacts on activities of daily living, has been found in 36% of patients with COPD compared to 12% of healthy subjects.22 Moreover, in one study the average performance on cognitive tests of patients with COPD was comparable with the performance of patients with vascular dementia,23 although the stage of vascular dementia of the studied subjects was not specified. Yet, the incidence of cognitive impairment in patients with COPD varies in different studies from 12-88%.24 Cognitive impairment may occur either globally or in specific domains of cognitive functioning.10 However, the current literature does not provide a clear picture of the pattern of cognitive impairment in COPD. Discrepancies in the current literature can be explained by several methodological limitations of previous studies, such as unknown or self-reported premorbid cognitive functioning,25 limited neuropsychological assessment and the use of different definitions and diagnostic criteria for cognitive impairment,26 a self-reported diagnosis of COPD or differences in study population (level of hypoxemia, severity of COPD),27 use of control groups that are not matched on potentially important characteristics, for example educational level,28 or only inclusion of patients with COPD without comorbidities.29

General introduction

Etiological factors contributing to cognitive impairment in COPD In recent years the literature on cognitive functioning in COPD has postulated several causes for cognitive impairment. Structural brain abnormalities are assumed to be related to cognitive impairment, either vascular mediated or through cigarette smoke, inflammation, hypoxemia, atherosclerosis, hypercapnia or nocturnal desaturations.13,14,15 Smoking, the major risk factor of COPD, may promote cerebral atherosclerosis and hypoxemia. It may also affect the microstructural integrity of cerebral white matter due to the stimulating effect of nicotine on nicotine receptors and induction of cerebral small vessel disease.15 Lung function has been implicated as a potential mediator of the association between smoking and the adverse neurocognitive consequences. Whilst smoking appears to be an independent factor in cognitive impairment, indices of lung function have been associated with brain changes such as overall brain atrophy and larger white matter hyperintensities, and impairments in cognition, such as lower psychomotor speed and less fine motor dexterity, independent of smoking status.21,30,31 Inflammation associated with COPD may also damage the white matter integrity.25 C-reactive protein has a direct neurotoxic effect and contributes to cerebral atherosclerosis. Further, IL-6, IL-1β, tumor necrosis factor-α and α1antichymotrypsin have been associated with cognitive impairment. 32,33 Hypoxic episodes or chronic hypoxia in the brain, characterized by deprivation of oxygen supply, can lead to the generation of free radicals, an inflammatory mediated neurotoxic effect, and oxygen dependent enzymes, which mediate the neuronal damage.15 Likewise, hypoxemia, which is characterized by low oxygen tension in the arterial blood, can result in a lack of oxygen supply to the brains.34 Furthermore, nocturnal desaturations may affect cognitive functioning. It is assumed that the structural abnormalities in the cerebral cortex and white matter result from cerebral hypoperfusion and microemboli, resulting in hypoxia.35 Thirty years ago it was demonstrated that oxygen supplementation in COPD patients with hypoxemia may have beneficial effects on cognitive functioning.26,36 As hypoxia, hypercapnia (increased carbon dioxide levels in the blood) can also lead to the generation of free radicals and oxygen dependent enzymes which can result in global neuronal injury. Although a correlation has been demonstrated between increased arterial carbon dioxide tension and impaired cognitive functioning in attention and memory,37 not all studies observe a correlation between hypercapnia and cognitive functioning.38 Atherosclerosis, a progressive disease process involving both chronic artery wall inflammation and hypoxia, can lead to partial or complete obstruction of the vasculature in the brain. This may lead to oxygen deprivation of brain cells situated behind the obstructed vessel wall, resulting in decreased brain function or even brain cell death (stroke) which can impair cognitive functioning. In patients with cardiovascular disease, the thickness of the carotid artery, a

Chapter 1

ChapterÂ 1Â measure of atherosclerosis, is associated with reduced results on cognitive tasks related to attention and executive functions.39 COPD is known to facilitate atherosclerosis in blood vessels throughout the body, for example via oxidative stress, hypoxia, hypoxemia and systemic inflammation.40 Age- and disease-related decline in physical activity is also associated with cognitive functioning.41 Physical activity has a positive effect on cognitive functioning in patients with COPD by influencing mediating factors such as anxiety, depression, nutrition and sleep quality.42 During exacerbations, hypoxemia and systemic inflammation increase which may contribute to cognitive impairment in COPD. While one study showed that cognitive functioning did not improve three months after the exacerbation, other studies showed that cognitive functioning is reversible after six months of discharge for exacerbation25,43,44 Although evidence has been found for the above described factors contributing to cognitive impairment in patients with COPD, these factors can only partly explain cognitive impairment.10 To date, it is still unknown which other factors play a role. Previous research has shown that comorbid conditions explain part of the variance in cognitive impairments in patients with COPD and an exacerbation.25 The variance in cognitive impairment in COPD could also be explained by comorbid conditions such as obstructive sleep apnea syndrome, diabetes,45 hypertension,46 and major depressive disorders which also decrease cognitive performance.47,48 Therefore, causes of cognitive impairment in patients with COPD may be multifactorial.

Consequences of cognitive impairment in COPD The extent to which a person experiences difficulties in daily life due to cognitive impairment depends on which cognitive functions are affected. In theory, 'higher' cognitive functions affect the operation of 'lower' cognitive functions. Three consequences of cognitive impairment can be distinguished. First, immediate discomfort for the patient, such as memory problems and problems with attention and concentration occurs.10 Second, cognitive impairment can affect self-management. Third, cognitive functioning may affect the duration and frequency of hospital admissions and mortality.49 It is possible that the relationship works in a vicious circle in which cognitive impairment and consequent discomfort in patients with COPD hamper self-management behaviors, which in turn have a negative impact on the disease and its outcomes. Examples of immediate discomfort for the patient are forgetting the content of conversations with health professionals or family member, the content of the last therapy session, to keep appointments, or where things, such as reading glasses, are put. Moreover, patients may experience difficulties with concentrating, deciding what to pay attention to, and multi-tasking, and consequently feel easily overloaded by information and conversations.50 Furthermore, cognitive impairment is related to limitations in activities of daily living.51 Physical

Aims of the thesis The current available literature shows that cognitive functioning can be impaired in patients with COPD either globally or in specific domains of cognitive 15

Chapter 1

General introduction activity patterns of patients with COPD are usually lower than the patient is expected to be capable of.52 Cognitive impairment may contribute to physical inactivity. Indeed, cognitive impairment limits the ability to initiate activities and understand the importance of activities such as physical exercise. Cognitive impairment also may adversely affect self-management behaviors. Patients with COPD will be advised to stop smoking.53 However, common barriers to quitting smoking include concerns regarding weight gain, cost of medicine, discouragement, disruption of relationships, fear of failure and the loss of perceived psychological benefits of smoking (reward effects, e.g. stress relieve).54,55 The desire to quit smoking is not sufficient to accomplish smoking cessation. The ability to guide our behavior according to our long-term goals requires inhibition and monitoring of ongoing behavior.56 In order to quit smoking, actions should be planned and the determination to implement these actions is crucial. The cognitive domains involved are executive functioning and self-control. These are essential for making a deliberate effort to break habitual and rigid behavioral patterns in order to fulfill the desire to quit smoking. Impairment in executive functioning as seen in older adults has a negative effect on quitting smoking.57 Furthermore, executive function impairments in patients with COPD may lead to improper use of (inhalation) medication, difficulties in dealing with co-morbidities and difficulty handling guidelines. In addition, patients with executive function deficits can seem unmotivated because they do not follow advised guidelines, while they may not have good self-management skills.58 Consequently, cognitive impairment in patients with COPD may adversely affect treatment. Reduced verbal memory may reduce medication compliance. Poor adherence to medication increases the risk of an acute exacerbation, which consequently results in poorer health outcomes.25 A prospective study showed over a three-year period that the coexistence of COPD and cognitive impairment has an additive effect on respiratory-related hospital admissions and mortality.49 A retrospective study showed that patients who were still alive after three years had a better performance on cognitive tests at the start of the study.59 The cause still remains unknown. A possible explanation is that cognitive impairment may be more common in patients with severe COPD, hypoxia, inflammation or comorbidities. Another explanation is that patients with cognitive impairment are more often hospitalized due to insufficient self-management compared to COPD patients without cognitive impairment. The length of hospitalization is also correlated with cognitive functioning.25 However, cognitive functioning is not a part of the current prognostic indices, such as the BODE index.60

ChapterÂ 1Â functioning. Furthermore, it shows that underlying factors of cognitive impairment in patients with COPD may be multifactorial, and the consequences may be widespread. At the start of this study, prevalence rates of domain-specific cognitive impairment were unknown. Moreover, it was unknown whether and to what extent cognitive impairment is associated with demographic characteristics and clinical characteristics, such as disease severity, structural brain abnormalities, sleep disturbances, exercise performance, daily activities, health status and psychological wellbeing of patients with COPD, and the efficacy of and dropout during pulmonary rehabilitation. Aim of this thesis was to increase our understanding of cognitive functioning in patients with COPD. A better understanding of cognitive impairment and possible causes and consequences could help to adjust disease management and pulmonary rehabilitation programs to the needs and capacity of cognitively impaired patients with COPD. A longitudinal observational study (The COgnitive-Pulmonary Disease (COgnitive-PD) Study) was designed to answer the following research questions: 1. Are cognitive performances of prospective memory, fluid cognitive functioning, visuospatial memory, numeric short-term memory, and cognitive processing speed different between persons in the general population with and without obstructive lung disease? 2. Is the presence of neuropathological brain changes, such as vascular, degenerative, and neoplastic brain changes, different between deceased donors with and without COPD? 3. Is cognitive functioning, including copying ability, related to sleep quality disturbances in elderly ambulatory patients with COPD? 4. Is cognitive functioning in the domains psychomotor speed, planning, verbal memory, working memory and cognitive flexibility impaired in patients with COPD entering a pulmonary rehabilitation program, compared to a control group matched on smoking status, age and educational level without COPD? 5. What are the clinical and demographic characteristics of patients with COPD with cognitive impairment? 6. Are structural brain abnormalities (e.g. features of cerebral small vessel disease and hippocampal volume) related to cognitive performance in patients with COPD? 7. Does cognitive impairment affect outcomes of pulmonary rehabilitation (e.g. functional status, health status, psychological wellbeing, the patientâ&#x20AC;&#x2122;s knowledge about COPD and their need for information)?

General introduction

Outline of the thesis In chapter 2 to 4, a first attempt is made to broaden the current knowledge on cognitive functioning in obstructive lung disease (OLD), including COPD, regarding affected cognitive domains, and the relationship with lung function, brain abnormalities, and sleep quality disturbances. Chapter 2 compares different domains of cognitive functioning between persons with and without obstructive lung disease, and analyzed the relationship between the degree of airflow limitation and the severity of cognitive impairment using data from the United Kingdom Biobank.61 Chapter 3 compares the prevalence of neuropathological brain changes between deceased subjects with COPD and deceased controls without COPD using brain autopsy reports from the Dutch Brain Bank.62 Chapter 4 focuses on sleep quality disturbances as a frequent reported symptom of patients with COPD and investigates the association between cognitive functioning and self-reported sleep quality disturbances and disease severity in an elderly COPD population from the Salute Respiratoria nell’Anziano Study.63 A longitudinal observational comparative study was performed in patients with COPD who enter pulmonary rehabilitation at CIRO, Horn, The Netherlands, as reflected in chapter 5 to 9. Chapter 5 describes the methodology of the prospective longitudinal COgnitive-PD Study being performed in this thesis in detail. Chapter 6 demonstrates the prevalence of domain-specific cognitive impairment in patients with COPD and non-COPD controls. Chapter 7 presents the relationship between cognitive impairment and disease severity. Moreover, clinical characteristics, such as exercise performance, problematic daily activities, health status and psychological well-being are studied in patients with and without cognitive impairment. Chapter 8 shows the results of a brain MRI study investigating whether structural brain abnormalities can differentiate patients with COPD with cognitive impairment from those without cognitive impairment. Chapter 9 focuses on pulmonary rehabilitation outcomes and compares changes on functional status, health status, psychological wellbeing, the patient’s knowledge about COPD and their need for information between patients with and without cognitive impairment. Chapter 10 is the general discussion and discusses the clinical implications of this thesis and future directions for research.

Chapter 1

References 1.

4. 5.

6. 7. 8.

10. 11.

12.

13.

14.

15.

16. 17. 18.

Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187(4):347-365. Russell RE. Chronic obstructive pulmonary disease: getting it right. Does optimal management of chronic obstructive pulmonary disease alter disease progression and improve survival? Curr Opin Pulm Med. 2014;20(2):127-131. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, RodriguezRoisin R, van Weel C, Zielinski J, Global Initiative for Chronic Obstructive Lung D. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176(6):532-555. Halbert RJ, Isonaka S, George D, Iqbal A. Interpreting COPD prevalence estimates: what is the true burden of disease? Chest. 2003;123(5):1684-1692. Landis SH, Muellerova H, Mannino DM, Menezes AM, Han MK, van der Molen T, Ichinose M, Aisanov Z, Oh YM, Davis KJ. Continuing to Confront COPD International Patient Survey: methods, COPD prevalence, and disease burden in 2012-2013. Int J Chron Obstruct Pulmon Dis. 2014;9:597-611. Vanfleteren LE, Franssen FM, Wesseling G, Wouters EF. The prevalence of chronic obstructive pulmonary disease in Maastricht, the Netherlands. Respir Med. 2012;106(6):871-874. Gibson GJ, Loddenkemper R, Lundback B, Sibille Y. Respiratory health and disease in Europe: the new European Lung White Book. Eur Respir J. 2013;42(3):559-563. Miravitlles M, Ferrer J, Baro E, Lleonart M, Galera J. Differences between physician and patient in the perception of symptoms and their severity in COPD. Respir Med. 2013;107(12):19771985. Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel VP, Bruijnzeel PL, Rutten EP, Op 't Roodt J, Wouters EF, Franssen FM. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;187(7):728-735. Dodd JW, Getov SV, Jones PW. Cognitive function in COPD. Eur Respir J. 2010;35(4):913-922. Maurer J, Rebbapragada V, Borson S, Goldstein R, Kunik ME, Yohannes AM, Hanania NA, Anxiety AWPo, Depression in C. Anxiety and depression in COPD: current understanding, unanswered questions, and research needs. Chest. 2008;134(4 Suppl):43S-56S. Bierman EJ, Comijs HC, Rijmen F, Jonker C, Beekman AT. Anxiety symptoms and cognitive performance in later life: results from the longitudinal aging study Amsterdam. Aging Ment Health. 2008;12(4):517-523. Lahousse L, Vernooij MW, Darweesh SK, Akoudad S, Loth DW, Joos GF, Hofman A, Stricker BH, Ikram MA, Brusselle GG. Chronic obstructive pulmonary disease and cerebral microbleeds. The Rotterdam Study. Am J Respir Crit Care Med. 2013;188(7):783-788. Zhang H, Wang X, Lin J, Sun Y, Huang Y, Yang T, Zheng S, Fan M, Zhang J. Grey and white matter abnormalities in chronic obstructive pulmonary disease: a case-control study. BMJ Open. 2012;2(2):e000844. Ryu CW, Jahng GH, Choi CW, Rhee HY, Kim MJ, Kim SM, Kim EJ, Choi WS. Microstructural change of the brain in chronic obstructive pulmonary disease: a voxel-based investigation by MRI. COPD. 2013;10(3):357-366. Hillas G, Perlikos F, Tsiligianni I, Tzanakis N. Managing comorbidities in COPD. Int J Chron Obstruct Pulmon Dis. 2015;10:95-109. Vanfleteren LE, Spruit MA, Wouters EF, Franssen FM. Management of chronic obstructive pulmonary disease beyond the lungs. Lancet Respir Med. 2016. Baltes PB, Lindenberger U, Staudinger UM. Life-span theory in developmental psychology. In: Lerner RM, ed. Handbook of child psychology. Vol 1: Theoretical models of human development. 6th ed. New York, NY: Wiley; 2006:569–664.

General introduction

19. Cummings JL, Miller BL. Conceptual and Clinical Aspects of the Frontal Lobes. The Human Frontal Lobes: Functions and Disorders. New York, USA: Guilford; 2007. 20. Hofmann W, Schmeichel BJ, Baddeley AD. Executive functions and self-regulation. Trends Cogn Sci. 2012;16(3):174-180. 21. Grant I, Heaton RK, McSweeny AJ, Adams KM, Timms RM. Neuropsychologic findings in hypoxemic chronic obstructive pulmonary disease. Arch Intern Med. 1982;142(8):1470-1476. 22. Villeneuve S, Pepin V, Rahayel S, Bertrand JA, de Lorimier M, Rizk A, Desjardins C, Parenteau S, Beaucage F, Joncas S, Monchi O, Gagnon JF. Mild cognitive impairment in moderate to severe COPD: a preliminary study. Chest. 2012;142(6):1516-1523. 23. Incalzi RA, Gemma A, Marra C, Muzzolon R, Capparella O, Carbonin P. Chronic obstructive pulmonary disease. An original model of cognitive decline. The American review of respiratory disease. 1993;148(2):418-424. 24. Hynninen KM, Breitve MH, Wiborg AB, Pallesen S, Nordhus IH. Psychological characteristics of patients with chronic obstructive pulmonary disease: a review. Journal of psychosomatic research. 2005;59(6):429-443. 25. Dodd JW, Charlton RA, van den Broek MD, Jones PW. Cognitive dysfunction in patients hospitalized with acute exacerbation of COPD. Chest. 2013;144(1):119-127. 26. Thakur N, Blanc PD, Julian LJ, Yelin EH, Katz PP, Sidney S, Iribarren C, Eisner MD. COPD and cognitive impairment: the role of hypoxemia and oxygen therapy. Int J Chron Obstruct Pulmon Dis. 2010;5:263-269. 27. Hung WW, Wisnivesky JP, Siu AL, Ross JS. Cognitive decline among patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;180(2):134-137. 28. Lezak M. Neuropsychological assessment. 4 ed. New York: Oxford University Press; 2004. 29. Janssen DJ, Spruit MA, Uszko-Lencer NH, Schols JM, Wouters EF. Symptoms, comorbidities, and health care in advanced chronic obstructive pulmonary disease or chronic heart failure. J Palliat Med. 2011;14(6):735-743. 30. Richards M, Strachan D, Hardy R, Kuh D, Wadsworth M. Lung function and cognitive ability in a longitudinal birth cohort study. Psychosom Med. 2005;67(4):602-608. 31. Sachdev PS, Anstey KJ, Parslow RA, Wen W, Maller J, Kumar R, Christensen H, Jorm AF. Pulmonary function, cognitive impairment and brain atrophy in a middle-aged community sample. Dement Geriatr Cogn Disord. 2006;21(5-6):300-308. 32. Warnberg J, Gomez-Martinez S, Romeo J, Diaz LE, Marcos A. Nutrition, inflammation, and cognitive function. Annals of the New York Academy of Sciences. 2009;1153:164-175. 33. Borson S, Scanlan J, Friedman S, Zuhr E, Fields J, Aylward E, Mahurin R, Richards T, Anzai Y, Yukawa M, Yeh S. Modeling the impact of COPD on the brain. International journal of chronic obstructive pulmonary disease. 2008;3(3):429-434. 34. Ortapamuk H, Naldoken S. Brain perfusion abnormalities in chronic obstructive pulmonary disease: comparison with cognitive impairment. Ann Nucl Med. 2006;20(2):99-106. 35. Dardiotis E, Giamouzis G, Mastrogiannis D, Vogiatzi C, Skoularigis J, Triposkiadis F, Hadjigeorgiou GM. Cognitive impairment in heart failure. Cardiology research and practice. 2012:595821. 36. Heaton RK, Grant I, McSweeny AJ, Adams KM, Petty TL. Psychologic effects of continuous and nocturnal oxygen therapy in hypoxemic chronic obstructive pulmonary disease. Archives of internal medicine. 1983;143(10):1941-1947. 37. Parekh PI, Blumenthal JA, Babyak MA, LaCaille R, Rowe S, Dancel L, Carney RM, Davis RD, Palmer S. Gas exchange and exercise capacity affect neurocognitive performance in patients with lung disease. Psychosom Med. 2005;67(3):425-432. 38. Grant I, Prigatano GP, Heaton RK, McSweeny AJ, Wright EC, Adams KM. Progressive neuropsychologic impairment and hypoxemia. Relationship in chronic obstructive pulmonary disease. Archives of general psychiatry. 1987;44(11):999-1006. 39. Haley AP, Forman DE, Poppas A, Hoth KF, Gunstad J, Jefferson AL, Paul RH, Ler AS, Sweet LH, Cohen RA. Carotid artery intima-media thickness and cognition in cardiovascular disease. Int J Cardiol. 2007;121(2):148-154.

Chapter 1

Chapter 1 40. Agusti A. Systemic effects of chronic obstructive pulmonary disease: what we know and what we don't know (but should). Proceedings of the American Thoracic Society. 2007;4(7):522-525. 41. Foglio K, Carone M, Pagani M, Bianchi L, Jones PW, Ambrosino N. Physiological and symptom determinants of exercise performance in patients with chronic airway obstruction. Respir Med. 2000;94(3):256-263. 42. Spirduso W, Poon L, Chodzko-Zajko W. Exercise and its mediating effects on cognition. Champaign, IL US: Human Kinetics; 2008. 43. Ambrosino N, Bruletti G, Scala V, Porta R, Vitacca M. Cognitive and perceived health status in patient with chronic obstructive pulmonary disease surviving acute on chronic respiratory failure: a controlled study. Intensive Care Med. 2002;28(2):170-177. 44. Kirkil G, Tug T, Ozel E, Bulut S, Tekatas A, Muz MH. The evaluation of cognitive functions with P300 test for chronic obstructive pulmonary disease patients in attack and stable period. Clin Neurol Neurosurg. 2007;109(7):553-560. 45. Kodl CT, Seaquist ER. Cognitive dysfunction and diabetes mellitus. Endocr Rev. 2008;29(4):494-511. 46. Reitz C, Tang MX, Manly J, Mayeux R, Luchsinger JA. Hypertension and the risk of mild cognitive impairment. Arch Neurol. 2007;64(12):1734-1740. 47. Damiani MF, Lacedonia D, Resta O. Influence of obstructive sleep apnea on cognitive impairment in patients with COPD. Chest. 2013;143(5):1512. 48. Potter GG, Steffens DC. Contribution of depression to cognitive impairment and dementia in older adults. The neurologist. 2007;13(3):105-117. 49. Chang SS, Chen S, McAvay GJ, Tinetti ME. Effect of coexisting chronic obstructive pulmonary disease and cognitive impairment on health outcomes in older adults. Journal of the American Geriatrics Society. 2012;60(10):1839-1846. 50. Droes RM, van der Roest HG, van Mierlo L, Meiland FJ. Memory problems in dementia: adaptation and coping strategies and psychosocial treatments. Expert Rev Neurother. 2011;11(12):1769-1781. 51. Incalzi RA, Corsonello A, Pedone C, Corica F, Carbonin P, Bernabei R, Investigators G. Construct validity of activities of daily living scale: a clue to distinguish the disabling effects of COPD and congestive heart failure. Chest. 2005;127(3):830-838. 52. Bourbeau J. Activities of life: the COPD patient. COPD. 2009;6(3):192-200. 53. Bourbeau J. Making pulmonary rehabilitation a success in COPD. Swiss Med Wkly. 2010;140:w13067. 54. Ahrens D, Bandi P, Ullsvik J, Moberg DP. Who smokes? A demographic analysis of Wisconsin smokers. WMJ. 2005;104(4):18-22. 55. Smith SS, Beckley T, Fiore MC. Health care provider use of guideline-based smoking cessation interventions: results from the 2003 Wisconsin Tobacco Survey. WMJ. 2005;104(4):28-31. 56. Ridderinkhof KR, Ullsperger M, Crone EA, Nieuwenhuis S. The role of the medial frontal cortex in cognitive control. Science. 2004;306(5695):443-447. 57. Brega AG, Grigsby J, Kooken R, Hamman RF, Baxter J. The impact of executive cognitive functioning on rates of smoking cessation in the San Luis Valley Health and Aging Study. Age and ageing. 2008;37(5):521-525. 58. Schillerstrom JE, Horton MS, Royall DR. The impact of medical illness on executive function. Psychosomatics. 2005;46(6):508-516. 59. Fix AJ, Daughton D, Kass I, Bell CW, Golden CJ. Cognitive functioning and survival among patients with chronic obstructive pulmonary disease. Int J Neurosci 1985;27:13–17. 60. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, Pinto Plata V, Cabral HJ. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(10):1005-1012. 61. Biobank U. UK Biobank. http://www.ukbiobank.ac.uk/. Accessed March 11, 2013. 62. Bank TNB. The Netherlands Brain Bank. http:// www.brainbank.nl. Accessed 10 October, 2013. 63. Bellia V, Pistelli R, Catalano F, Antonelli-Incalzi R, Grassi V, Melillo G, Olivieri D, Rengo F. Quality control of spirometry in the elderly. The SA.R.A. study. SAlute Respiration nell'Anziano = Respiratory Health in the Elderly. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1094-1100.

Chapter 2

Cognitive Functioning in Obstructive Lung Disease: Results from the United Kingdom Biobank

Cleutjens FA, Spruit MA, Ponds RW, Dijkstra JB, Franssen FM, Wouters EF, Janssen DJ. Cognitive functioning in obstructive lung disease: results from the United Kingdom biobank. JAMDA. 2014;15(3):214-219. Reprinted with permission from JAMDA.

CHAPTER 2

Abstract Objectives To compare domains of cognitive functioning between persons with and without obstructive lung disease (OLD) and to analyze the relationship between cognitive functioning and the degree of airow limitation. Design An observational population-based study. Setting: This research was conducted using the United Kingdom Biobank Resource. Participants The study population consisted of 43,039 persons with complete data on cognitive functioning and spirometry. Measurements Cognitive functioning was compared between persons with and without OLD using linear regression analysis. The relationship between impairment in lung function and cognitive impairment was assessed among persons with OLD. Results Persons with OLD had signicantly worse scores than persons without OLD on prospective memory (β=-0.15 (-0.22 to -0.09)), visuospatial memory (β round 1=0.06 (0.03 to 0.10)); β round 2=0.09 (<0.001 to 0.18)), numeric short-term memory (β=-0.05 (-0.10 to <0.001)) and cognitive processing speed (β=4.62 (1.25 to 8.01)) after correction for possible confounders. Impairment in prospective memory (β=0.004 (<0.001 to 0.01)) and numeric short-term memory (β=0.01 (0.003 to 0.01)) were weakly related to FEV1 (adjusted P <0.05). Conclusions Persons with OLD experience cognitive impairment in different domains, which is partially related to airway obstruction. In particular, memory and information processing are affected. Further assessment of the relationship with patientrelated outcomes is needed to optimize patient-oriented treatment.

Cognitive Functioning in Obstructive Lung Disease

Chronic obstructive pulmonary disease (COPD) is a major public health problem. Up to 600 million people are affected worldwide and COPD is one of the leading causes of mortality.1 COPD is characterized by progressive and largely irreversible airflow limitation resulting in dyspnea. Extrapulmonary features such as fatigue, osteoporosis, cardiac failure, and depression are highly prevalent.2 Patients with COPD can have cognitive impairments, either globally or in single cognitive domains.3 Reported incidence ranges from 12% to 88%.4 Cognitive impairment may be associated with the degree of lung function impairment in patients with COPD5 and has been found to predict mortality in hypoxemic COPD.6 Moreover, cognitive impairment may lead to increased dyspnea and fatigue,7 and result in incorrect use of inhaler devices and low compliance with medical treatment as has previously been shown in elderly subjects.8 This might increase the exacerbation risk and could result in worse health outcome.9 To date it remains unknown which domains of cognitive functioning are affected in community-based patients with COPD.10 Insight in cognitive functioning is of great importance in order to optimize self-management programs for patients with COPD. Indeed, for a patient with COPD, it is important to comply with guidelines for a healthier life style (e.g. quit smoking, correct use of medication, and become physically active). Executive functions are evoked for adequate self-management.11 The domain executive functioning is a multifaceted neuropsychological construct, consisting of a set of higher-order neurocognitive processes that contribute to purposeful, goal-directed, and future-oriented behavioral skills, such as organization, planning, problem solving, and reasoning.12 Patients with executive function deficits have difficulties in managing their disease.11 Consequently, cognitive impairments in COPD patients may negatively affect their treatment and in particular the impact of self-management programs. The aims of the present study were to compare different domains of cognitive functioning between persons in the general population with and without obstructive lung disease (OLD) and to analyze the relationship between cognitive functioning and the degree of airflow limitation. A priori, we hypothesized that persons with OLD have worse scores on cognitive function tests than persons without OLD. Moreover, we hypothesised that the degree of airflow limitation is related with the degree of cognitive impairment in persons with OLD.

Methods Design This observational population-based study has been conducted using the United Kingom (UK) Biobank Resource, which is a large prospective study in the UK

Chapter 2

Introduction

CHAPTERÂ 2Â investigating the role of genetic factors, environmental exposures, and lifestyle in major diseases of late and middle age. Details of the rationale and design of this prospective study have been published elsewhere.13

Study population The UK Biobank study population consisted of 502 682 persons between 40 and 70 years from the UK general population. They were recruited in 22 centers in Scotland, England, and Wales and data were collected from 2006 to 2010. All persons provided written informed consent. In the present study, 43 039 persons with complete data on cognitive functioning and spirometry were included. Persons with a fixed ratio of FEV1/FVC < 0.70 are classified as persons with OLD2. OLD is described as a category of respiratory diseases characterized by airway obstruction, including COPD, chronic bronchitis, emphysema, asthma, bronchiectasis, upper airway lesions, bronchiolar diseases, and some interstitial lung diseases.14 The control group consisted of persons with a FEV1/FVC â&#x2030;Ľ 0.70.

Outcomes The following outcomes were recorded: demographic characteristics (e.g, age, race, education, employment); height; medical history; lifestyle and environment (e.g. smoking habits, sleep, and alcohol intake); and psychosocial factors (e.g. depressed mood). Forced Expiratory Volume in the first second (FEV1) and Forced Vital Capacity (FVC) were measured using spirometry (Vitalograph Pneumotrac 6800). The largest FVC and the largest FEV1 were used after examining the data from all of the usable curves to calculate the Tiffeneau index (FEV1/FVC) and FEV1% predicted.15,16 Five cognitive functioning tests were performed using a touch screen system: 1) The prospective memory test assesses prospective memory, which refers to the ability to carry out future intentions at a specific time or in response to a specific event; 2) The fluid intelligence test assesses fluid cognitive functioning, which reflects the capacity to solve problems that require logic and reasoning ability, independent of acquired knowledge; 3) The pairs matching test assesses visual spatial ability and reflects the capacity to understand and remember the spatial relations among objects; 4) The numeric memory test is used to measure numeric short-term memory and assesses the ability to recollect a series of digits. The length of the longest list a person can remember is called the digit span of this person; and 5) The reaction time test gives an indirect index of the cognitive processing speed of a participant. For detailed information, see supplemental information. These tests have been developed and refined through piloting to ensure that they provide wide response distributions. They are easily repeatable within a larger cognitive screening battery, and have associations with future cognitive decline.13

Cognitive Functioning in Obstructive Lung Disease

Analysis included descriptive statistics using frequencies for categorical variables, and means and standard deviations (SD) or medians and interquartile ranges (IQRs) for continuous variables, depending on the variable distribution. Comparison of continuous variables among persons with OLD (FEV1/FVC<0.70)2 and persons without OLD (FEV1/FVC≥0.70) were done using unpaired t-tests or Mann-Whitney U tests, as appropriate. Categorical variables were compared among persons with OLD and persons without OLD using Chi-square tests. Linear regression analysis with robust standard errors was used to compare cognitive functioning between persons with OLD and persons without OLD, after correction for the following possible confounders: sex, age, race, education, employment, current tobacco smoking, alcohol intake, vascular/heart problems, diabetes, and depressed mood in the last two weeks (see supplemental information). Logistic regression analysis was used to compare prospective memory after correction for these confounders. Furthermore, the relationship between lung function and functioning on the different cognitive tests was analyzed by using a Pearson's correlation coefficient or Spearman's rank correlation coefficient, depending on the variable distribution. In addition, we used linear regression analysis with robust standard errors or logistic regression analysis, as appropriate, in order to adjust for the aforementioned possible confounders. Finally, cognitive functioning of persons with OLD with mild airflow limitation (FEV1 ≥80% predicted), moderate airflow limitation (FEV1 50-80% predicted) and persons with severe or very severe airflow limitation (FEV1 <50% predicted)2 was compared using linear regression analysis with robust standard errors or logistic regression analysis as appropriate, while adjusting for the aforementioned possible confounders. Statistics were performed using SPSS 17.0 (SPSS Inc., Chicago, IL). STATA 11.1 (StataCorp LP, College Station, TX) was used for regression analysis. A priori, a two-sided level of significance was set at p ≤0.05.

Results General characteristics of participants In total, 43 039 persons were included. Of these, 5764 persons (13.4%) had a fixed ratio of FEV1/FVC < 0.70 and were classified as persons with OLD. Generally, persons with OLD were older, more often male, more often current smokers, reported less frequently a college or university degree and were less likely to be employed than persons without OLD. Persons with OLD had more often comorbidities such as cardiovascular problems, blood clotting, DVT, bronchitis, emphysema, asthma, rhinitis, eczema, allergies, or cancer (Table 1).

Chapter 2

Statistics

CHAPTER 2 Table 1. Demographic and clinical characteristics Persons with OLD Persons without P Value (n=5764) OLD (n=37 275) Demographics Age (years), mean (SD)

59.0 (7.6)

56.0 (8.3)

<0.005

Male, n (%)

3145 (54.6%)

16 329 (43.8%)

<0.005

Height (cm), mean (SD)

170.3 (9.6)

168.5 (9.2)

<0.005

Caucasian, n (%)

5456 (94.7%)

35 393 (95.0%)

0.360

Paid or self-employment, n (%)

2765 (48.0%)

22 073 (59.2%)

<0.005

College or university degree, n (%)

1687 (29.3%)

12 061 (32.4%)

<0.005

Spirometry FEV1 (liters), mean (SD)

2.4 (0.8)

2.9 (0.8)

<0.005

FEV1/FVC, mean (SD)*

64.0 (6.5)

78.2 (4.3)

<0.005

FEV1 (% predicted), mean (SD)

84.3 (19.2)

103.2 (16.3)

<0.005

FVC (liters), mean (SD)

3.81 (1.1)

3.77 (1.0)

0.009

Current tobacco smoker, n (%)

1077 (18.7%)

3087 (8.3%)

<0.005

Number of daily smoked cigarettes in current smokers, mean (SD)*,†

16.8 (8.3)

14.6 (8.1)

<0.005

Number of currently cigars and pipes smoked daily in 17.3 (11.4) current smokers, mean (SD)*, ‡

16.1 (9.2)

0.807

Alcohol intake (yes), n (%)

5304 (92.0%)

34 621 (92.9%)

0.020

Vascular/heart problems diagnosed by doctor, n (%) 1859 (32.3%)

10 511 (28.8%)

<0.005

Blood clot, DVT, bronchitis, emphysema, asthma, 2389 (41.4%) rhinitis, eczema, allergy diagnosed by doctor, n (%)

11 129 (29.9%)

<0.005

Smoking status and alcohol consumption

Comorbidities

Diabetes diagnosed by doctor, n (%)

272 (4.7%)

1749 (4.7%)

0.955

Cancer diagnosed by doctor, n (%)

503 (8.7%)

2738 (7.3%)

<0.005

Depressed mood in last 2 weeks, n (%)

1373 (23.8%)

8568 (23.0%)

0.167

Sleeplessness/insomnia, n (%)

4347 (75.4%)

28 286 (75.9%)

0.450

DVT, deep vein thrombosis; FEV1, forced expiratory volume in the rst second; FVC, forced vital capacity; OLD, obstructive lung disease; SD, standard deviation. * Nonparametric statistical tests have been used because of skewed data. † OLD: n = 841, non-OLD: n = 2031. ‡ OLD: n = 48, non-OLD: n = 96.

Prospective memory Univariate analysis suggested that persons with OLD had lower (worse) scores on prospective memory (Table 2). This was confirmed by linear regression analysis. After adjustment for possible confounders, prospective memory scores were worse for persons with OLD (β -0.15 (-0.22 to -0.09)) (Table 2 and S1).

Table 2. Cognitive functioning in persons with and without OLD Persons with Persons Unadjusted Standardized Adjusted OLD without OLD P Value Coefficient Beta (β) P Value* (n=5764) (n=37 275) (95% CI)* Prospective memory test (persons with correct recall on first attempt), n (%)

4235 (73.5%)

29 381 (78.8%)

<0.005

-0.15 (-0.22 to -0.09)

<0.005

Fluid intelligence test (number of correctanswers), mean (SD)

5.9 (2.1)‡

6.1 (2.1)

<0.005

-0.05 (-0.11 to 0.003)

0.061

Pairs matching test round 1 (number of mistakes), median (IQR)†

0.0 (0.0-1.0)

0.0 (0.0-1.0) <0.005

0.06 (0.03 to 0.10)

<0.005

Pairs matching test round 2 (number of mistakes), median (IQR)†

4.00 (2.0-6.0) 3.0 (2.0-5.0) <0.005

0.09 (0.00 to 0.18)

0.047

Numeric memory test (longest number correctly recalled), median (IQR)†

7.0 (6.0-8.0)

7.0 (6.0-8.0) <0.005

-0.05 (-0.10 to 0.00)

0.047

555.0 (493.0 Reaction time test (time in milliseconds), to 637.0) median (IQR)†

539.0 (481.0 <0.005 to 615.0)

4.62 (1.25 to 8.01)

0.007

CI, condence interval; IQR, interquartile range; OLD, obstructive lung disease; SD, standard deviation. * Based on linear regression analysis with robust standard errors or logistic regression analysis (only prospective memory was a dichotomous variable) with non-OLD as reference category and after correction for sex, age, race, education, employment, current tobacco smoking, alcohol intake, depressed mood in the last 2 weeks, vascular/heart problems diagnosed by doctor, and diabetes diagnosed by doctor. † Nonparametric statistical tests have been used because of skewed data. ‡ For one person with OLD the uid intelligence test data are missing.

Fluid cognitive functioning Univariate analysis also suggested that persons with OLD had lower scores on fluid cognitive functioning. They had a lower number of correct answers given within the allotted two minute limit (Table 2). This was not confirmed by linear regression analysis (Table S2). After adjustment for possible confounders, fluid cognitive functioning scores were comparable for persons with and without OLD (β -0.05 (-0.11 to 0.003)) (Table 2 and S2).

Visuospatial memory Persons with OLD had lower scores on visuospatial memory. They needed more attempts to touch as many pairs in both rounds with three and six pairs of cards

Chapter 2

Cognitive Functioning in Obstructive Lung Disease

CHAPTER 2 (Table 2). This was confirmed by linear regression analysis. After adjustment for possible confounders, visuospatial memory scores were lower for persons with OLD (round 1, β 0.06 (0.03 to 0.10); round 2, β 0.09 (<0.01 to 0.18)) (Table 2 and S3).

Numeric short-term memory Univariate analysis suggested that persons with OLD had lower scores on numeric short-term memory, and this was confirmed by linear regression analysis (Table 2). After adjustment for confounders, numeric short-term memory scores were worse for persons with than without OLD (β -0.05 (-0.10 to <0.001)) (Table 2 and S4).

Cognitive processing speed Persons with OLD had lower scores on cognitive processing speed. They had a higher mean duration to first press the snap-button summed over rounds in which both cards matched (Table 2). This was confirmed by linear regression analysis after correction for confounders. (β 4.62 (1.25 to 8.01)) (Table 2 and S5).

Relationship between lung function and cognitive functioning Bivariate analysis demonstrated that impairment in prospective memory, fluid cognitive functioning, numeric short-term memory, visuospatial memory, and cognitive processing speed is related with impairment in FEV1 in persons with OLD. However, all correlations were weak (Table 3). The relationship between FEV1 and prospective memory (β 0.004 (<0.001 to 0.01)) and numeric shortterm memory (β 0.01 (0.003 to 0.01)) remained significant after adjustment for confounders (Table 3 and Supplementary Tables 6-10). Bivariate analysis demonstrated that prospective memory, fluid cognitive functioning, numeric short-term memory, visuospatial memory, and cognitive processing are weakly correlated with FVC in persons with OLD (Table 3). The relationship between FVC and fluid cognitive functioning (β 0.14 (0.08 to 0.21)), visuospatial memory in round 2 (β -0.13 (-0.24 to 0.01)), and numeric shortterm memory (β 0.15 (0.10 to 0.21)) remained significant after adjustment for confounders (Table 3 and Supplementary Tables 11-15).

Mild versus moderate versus (very) severe OLD Linear and logistic regression analysis demonstrated that persons with moderate airflow limitation differed from persons with mild airflow limitation on fluid cognitive functioning and numeric short-term memory. Persons with (very) severe airflow limitation differed from persons with mild airflow limitation on numeric short-term memory (Table 4).

Cognitive Functioning in Obstructive Lung Disease

Table 3. Correlations between cognitive functioning and FEV1 and FVC in persons with Correlation P Standardized coëfficiënt value Coefficient Beta(β) (95% CI)* FEV1 Prospective memory test 0.13† <0.005 0.004 (0.00 to 0.01) <0.005 0.003 (0.00 to 0.01) Fluid intelligence test§ 0.18† Pairs matching test round 1 -0.09‡ <0.005 <0.001 (-0.001 to 0.002) <0.005 -0.002 (-0.01 to 0.003) Pairs matching test round 2 -0.07‡ Numeric memory test 0.20‡ <0.005 0.01 (0.003 to 0.01) Reaction time test -0.20‡ <0.005 -0.09 (-0.27 to 0.08) FVC <0.005 0.07 (0.006 to 0.14) Prospective memory test 0.11† Fluid intelligence test§ 0.17† <0.005 0.14 (0.08 to 0.21) Pairs matching test round 1 -0.09‡ <0.005 -0.01 (-0.05 to 0.02) <0.005 -0.13 (-0.24 to 0.01) Pairs matching test round 2 -0.08‡ Numeric memory test 0.19‡ <0.005 0.15 (0.10 to 0.21) Reaction time test -0.19‡ <0.005 -2.82 (-6.22 to 1.65)

OLD Adjusted P Value*

0.028 0.052 0.938 0.376 <0.005 0.288 0.073 <0.005 0.509 0.028 <0.005 0.256

CI, condence interval; FEV1, forced expiratory volume in the rst second; FVC, forced vital capacity; OLD, obstructive lung disease. * Based on linear regression analysis with robust standard errors or logistic regression analysis (only prospective memory was a dichotomous variable) after correction for sex, age, race, education, employment, current tobacco smoking, alcohol intake, depressed mood in the last 2 weeks, vascular/heart problems diagnosed by doctor, and diabetes diagnosed by doctor. † Pearson correlation coefcient. ‡ Spearman rank correlation coefcient. n = 5764. § For one person with OLD the uid intelligence test data are missing. Table 4. Comparison of cognitive functioning between Mean (SD) Cognitive function FEV1 ≥80% pred. (n= 3525) Prospective memory test 0.75 (0.43) Fluid intelligence test 6.04 (2.11)* Pairs matching test round 1 0.55 (1.20) Pairs matching test round 2 4.21 (3.17) Numeric memory test 6.60 (1.71)*,† Reaction time test 575.62 (128.40)

mild, moderate and (very) severe OLD FEV1 50-80% pred. (n= 1980) 0.72 (0.45) 5.77 (2.14) 0.59 (1.20) 4.21 (3.43) 6.32 (1.89) 583.88 (124.952)

FEV1 < 50% pred. (n= 259) 0.67 (0.47) 5.66 (2.24) 0.55 (0.95) 4.62 (3.45) 6.21 (1.96) 594.15 (127.97)

FEV1, forced expiratory volume in the rst second; OLD, obstructive lung disease; SD, standard deviation. *Adjusted P value <.05 compared with FEV1 50%‒80% predicted based on linear regression analyses with robust standard errors after correction for sex, age, race, education, employment, current tobacco smoking, alcohol intake, depressed mood in the last 2 weeks, vascular/heart problems diagnosed by doctor, and diabetes diagnosed by doctor. † Adjusted P value <.05 compared with FEV1 <.05 compared with FEV1 <50% predicted based on linear regression analysis with robust standard errors or logistic regression analysis (only prospective memory was a dichotomous variable) after correction for sex, age, race, education, employment, current tobacco smoking, alcohol intake, depressed mood in the last 2 weeks, vascular/heart problems diagnosed by doctor, and diabetes diagnosed by doctor.

Chapter 2

CHAPTERÂ 2Â

Discussion Key findings The present study showed that in the general population, persons with OLD have worse scores than persons without OLD on cognitive function tests in the domains memory (prospective memory, visuospatial memory, and numeric short-term memory) and information processing (cognitive processing speed), after correcting for confounding variables. The fluid intelligence test was not significantly different between groups after correcting for confounders. There was a weak relationship between FEV1, FVC, and several cognitive domains in persons with OLD. Until now, little research has been done on deficits in specific domains of cognitive functioning. This study demonstrates that persons with OLD have significant lower scores on cognitive measures of prospective memory, visuospatial memory, numeric short-term memory, and cognitive processing speed. This confirms our hypothesis that the results of cognitive functioning of persons with OLD are significantly lower than the results of cognitive functioning of controls. We did not find differences in scores on the fluid intelligence test. This in contrast to the findings of Emery et al. who indicated that FEV1 predicted performance on tests of fluid cognitive functioning.17 They used the digit symbol substitution test, the block design test, and the digit span backward test, to test fluid cognitive functioning. Although these tests can be used to measure fluid cognitive functioning, they also measure cognitive processing speed, visuospatial memory, and numeric short-term memory respectively. This may explain the differences with our findings. Our hypothesis that airflow limitation is associated with cognitive impairment in persons with OLD was confirmed. In line with previous studies who stated that cognitive functioning seems to be positively correlated with increased FEV1 in patients with COPD,18,19 we found a weak correlation between cognitive impairment and FEV1 in persons with OLD. Etnier et al. found that FVC was a significant predictor of working memory storage in older patients with mild to moderate COPD recruited from the community.19 We found a weak, but significant correlation between FVC and numeric short-term memory, fluid cognitive functioning, and visuospatial memory in round 2. Furthermore, persons with mild airflow obstruction had better numeric short-term memory scores than persons with moderate or (very) severe airflow limitation. In addition, persons with mild airflow limitation had better fluid cognitive functioning scores compared to persons with moderate airflow limitation. The relationship between lung function and cognitive functioning may be influenced by other factors such as genetic factors,17 physical activity,20 and smoking.21 Therefore, these should be studied in order to understand the relationship between lung function and cognitive functioning.

Cognitive Functioning in Obstructive Lung Disease Although there is evidence that prospective memory, visuospatial memory, fluid cognitive functioning, and numeric short-term memory require different aspects of executive functioning and processing speed supports many higherorder cognitive domains, no firm conclusions can be made whether and to what extent persons with OLD perform particularly worse on the cognitive domain executive functioning. Fluid cognitive functioning is often described as executive functioning.22 However, these constructs cannot be equated. The correlations between latent factors indicate approximately 50% shared variance between them.23 A more elaborated testing battery that measures the different components of executive functioning might give a better insight in the role of executive functioning in chronic respiratory diseases.

Methodological considerations Several methodological considerations should be considered in interpreting the results. First, the classification OLD was based on the fixed ratio of FEV1/FVC. We were unable to distinguish between asthma, bronchiectasis, bronchitis, and COPD. Comorbidities like blood clot, DVT, bronchitis, emphysema, asthma and rhinitis were grouped in the database and therefore we were unable to split comorbidities within one group for further analysis. Furthermore persons with severe COPD seem to be underrepresented in this study. However, the distribution of airflow limitation in this study is representative of the distribution of COPD in the general population.24,25 Second, all used cognitive tests concerned visual spatial information, which is unelaborated. More detailed neuropsychological assessment is needed to explore other domains of cognitive functioning in OLD and to control for differences such as motor skills or visual difficulties. Nevertheless, previous studies often only used one scale to measure global cognitive functioning (e.g. the Mini-Mental State Examination; MMSE),9,26 while the current study used a concise testing battery to measure five domain-specific cognitive skills. Next to cognitive functioning, other aspects of executive functioning should be investigated in future studies in order to get a better insight in the role of executive functioning in respiratory diseases. Third, no data were available regarding impact of cognitive impairment in various domains on clinically relevant outcomes (e.g. health-related quality of life, exacerbations, and mortality). Also data on other possible confounders, such as hypoxemia, long term oxygen therapy,27,28 obstructive sleep apnea and overlap syndrome29 which may affect cognitive functioning, are lacking. Finally, we adjusted for symptoms of depression assessed by a single touchscreen question instead of the presence of a major depression disorder diagnosed by a clinician.

Chapter 2

CHAPTERÂ 2Â

Clinical implications Previous studies showed adverse consequences of cognitive impairment in general on health status and daily functioning in patients with COPD7,8,26, but offered no insight in the consequences of cognitive impairment in specific cognitive domains in persons with OLD. The effect of deficits in domain-specific cognitive skills like prospective memory, visuospatial memory, numeric short-term memory, and cognitive processing speed have been studied in other populations. For example, prospective memory deficits may lead to intrusive doubts and checking compulsions,30 unemployment,31 and impaired financial capacity and medication management.32 Visuospatial memory deficits may lead to disorientation,33 and a reduction in the amount of slow wave sleep and in sleep efficiency.34 Persons with impairment of cognitive processing speed will take longer to process and respond to verbal, visual or written information.35 Also in patients with COPD, many daily situations could be influenced by impaired cognitive functioning.36 Therefore, our findings highlight the importance for healthcare professionals to be alert to the possible impact of these cognitive difficulties in the self-management, clinical management, and pulmonary rehabilitation of persons with chronic respiratory diseases. Previous studies showed that smoking is associated with prospective memory deficits and the impact of nicotine on long-term prospective memory may be dose dependent.37 Taking into consideration that cigarette smoking is the leading cause of COPD,2 smoking prevention and cessation should be encouraged in order to prevent and improve prospective memory. Etnier and Berry found an association between improved fluid cognitive functioning and aerobic fitness following an exercise intervention for three months in patients with COPD.20 Further research is needed to confirm whether physical activity leads to cognitive gains in a wider population with chronic respiratory diseases. A case-control study of pulmonary rehabilitation suggested that if visuospatial functions were impaired at baseline, they improved after three weeks of treatment.38 Further, short-term visuospatial memory in healthy controls has been shown to be strongly related with executive functioning.39 Therefore the effects of pulmonary rehabilitation on cognitive functioning in specific cognitive domains should further explored. Future studies should focus on interventions for improving cognitive functioning and adjusting treatment programs, such as education and self-management, for cognitively impaired patients with respiratory diseases.

Cognitive Functioning in Obstructive Lung Disease

The present population-based study shows that persons with OLD may experience cognitive impairment in different domains, which could be related to impaired lung function. Therefore, cognitive impairment should be considered as an important extrapulmonary manifestation of COPD. In particular the domains memory and information processing are affected, which can have important consequences for self-management skills. Further assessment of domains of cognitive functioning and the relationship between cognitive impairment and patient-related outcomes is needed in order to optimize patient-oriented treatment and self-management programs for patients with chronic respiratory diseases. Future studies should also assess the effects of pulmonary rehabilitation and lifestyle factors on the relationship between lung function and cognitive functioning in patients with COPD. Hereby it is important to take premorbid ability and longitudinal change in cognitive functioning in persons with OLD into account in order to explore a potentially causal relationship.

Chapter 2

Conclusions

CHAPTERÂ 2Â

References 1.

3. 4.

5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

17.

18.

19.

20. 21.

Schou L, Ostergaard B, Rasmussen LS, Rydahl-Hansen S, Phanareth K. Cognitive dysfunction in patients with chronic obstructive pulmonary disease--a systematic review. Respir Med. 2012;106(8):1071-1081. Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. American journal of respiratory and critical care medicine. 2013;187(4):347-365. Dodd JW, Getov SV, Jones PW. Cognitive function in COPD. The European respiratory journal: official journal of the European Society for Clinical Respiratory Physiology. 2010;35(4):913-922. Hynninen KM, Breitve MH, Wiborg AB, Pallesen S, Nordhus IH. Psychological characteristics of patients with chronic obstructive pulmonary disease: a review. Journal of psychosomatic research. 2005;59(6):429-443. Hung WW, Wisnivesky JP, Siu AL, Ross JS. Cognitive decline among patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;180(2):134-137. Antonelli-Incalzi R, Corsonello A, Pedone C, Trojano L, Acanfora D, Spada A, Izzo O, Rengo F. Drawing impairment predicts mortality in severe COPD. Chest. 2006;130(6):1687-1694. Meek PM, Lareau SC, Anderson D. Memory for symptoms in COPD patients: how accurate are their reports? Eur Respir J. 2001;18(3):474-481. Allen SC, Jain M, Ragab S, Malik N. Acquisition and short-term retention of inhaler techniques require intact executive function in elderly subjects. Age Ageing. 2003;32(3):299-302. Dodd JW, Charlton RA, van den Broek MD, Jones PW. Cognitive dysfunction in patients hospitalized with acute exacerbation of COPD. Chest. 2013;144(1):119-127. Meek PM. Cognitive Function. In: Nici L, ZuWallack R, eds. Chronic Obstructive Pulmonary Disease: Comorbidities and Systemic Consequences. New York: Humana Press; 2012:119-136. Foster ER, Hershey T. Everyday Executive Function Is Associated With Activity Participation in Parkinson Disease Without Dementia. OTJR (Thorofare N J). 2011;31(1):16-22. Suchy Y. Executive functioning: overview, assessment, and research issues for non-neuropsychologists. Ann Behav Med. 2009;37(2):106-116. Collins R. Protocol for a Large-scale Prospective Epidemiological Resource. http://www.ukbiobank.ac.uk/scientists-3/. Ryu JH, Scanlon PD. Obstructive lung diseases: COPD, asthma, and many imitators. Mayo Clin Proc. 2001;76(11):1144-1153. Standardized lung function testing. Official statement of the European Respiratory Society. Eur Respir J Suppl. 1993;16:1-100. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-338. Emery CF, Pedersen NL, Svartengren M, McClearn GE. Longitudinal and genetic effects in the relationship between pulmonary function and cognitive performance. The journals of gerontology Series B, Psychological sciences and social sciences. 1998;53(5):P311-317. Antonelli-Incalzi R, Corsonello A, Trojano L, Pedone C, Acanfora D, Spada A, Izzo O, Rengo F. Screening of cognitive impairment in chronic obstructive pulmonary disease. Dement Geriatr Cogn Disord. 2007;23(4):264-270. Etnier J, Johnston R, Dagenbach D, Pollard RJ, Rejeski WJ, Berry M. The relationships among pulmonary function, aerobic fitness, and cognitive functioning in older COPD patients. Chest. 1999;116(4):953-960. Etnier JL, Berry M. Fluid intelligence in an older COPD sample after short- or long-term exercise. Med Sci Sports Exerc. 2001;33(10):1620-1628. Grant I, Heaton RK, McSweeny AJ, Adams KM, Timms RM. Neuropsychologic findings in hypoxemic chronic obstructive pulmonary disease. Arch Intern Med. 1982;142(8):1470-1476.

Cognitive Functioning in Obstructive Lung Disease

22. Blair C. How similar are fluid cognition and general intelligence? A developmental neuroscience perspective on fluid cognition as an aspect of human cognitive ability. The Behavioral and brain sciences. 2006;29(2):109-125; discussion 125-160. 23. Kane MJ, Hambrick DZ, Conway AR. Working memory capacity and fluid intelligence are strongly related constructs: comment on Ackerman, Beier, and Boyle (2005). Psychological bulletin. 2005;131(1):66-71; author reply 72-65. 24. Hoogendoorn M, Feenstra TL, Schermer TR, Hesselink AE, Rutten-van Molken MP. Severity distribution of chronic obstructive pulmonary disease (COPD) in Dutch general practice. Respir Med. 2006;100(1):83-86. 25. Lindberg A, Bjerg A, Ronmark E, Larsson LG, Lundback B. Prevalence and underdiagnosis of COPD by disease severity and the attributable fraction of smoking Report from the Obstructive Lung Disease in Northern Sweden Studies. Respir Med. 2006;100(2):264-272. 26. Barberger-Gateau P, Commenges D, Gagnon M, Letenneur L, Sauvel C, Dartigues JF. Instrumental activities of daily living as a screening tool for cognitive impairment and dementia in elderly community dwellers. J Am Geriatr Soc. 1992;40(11):1129-1134. 27. Martin SE, Bradley JM, Buick JB, Crossan A, Elborn JS. The effect of hypoxia on cognitive performance in patients with chronic obstructive pulmonary disease. Respir Physiol Neurobiol. 2011;177(1):36-40. 28. Thakur N, Blanc PD, Julian LJ, Yelin EH, Katz PP, Sidney S, Iribarren C, Eisner MD. COPD and cognitive impairment: the role of hypoxemia and oxygen therapy. Int J Chron Obstruct Pulmon Dis. 2010;5:263-269. 29. Damiani MF, Lacedonia D, Resta O. Influence of obstructive sleep apnea on cognitive impairment in patients with COPD. Chest. 2013;143(5):1512. 30. Cuttler C, Sirois-Delisle V, Alcolado GM, Radomsky AS, Taylor S. Diminished confidence in prospective memory causes doubts and urges to check. Journal of behavior therapy and experimental psychiatry. 2013;44(3):329-334. 31. Woods SP, Weber E, Weisz BM, Twamley EW, Grant I. Prospective memory deficits are associated with unemployment in persons living with HIV infection. Rehabilitation psychology. 2011;56(1):77-84. 32. Pirogovsky E, Woods SPW, Filoteo JV, Gilbert PE. Prospective memory deficits are associated with poorer everyday functioning in Parkinson’s disease. Journal of the International Neuropsychological Society. 2012;6:986-995. 33. Iachini I, Iavarone A, Senese VP, Ruotolo F, Ruggiero G. Visuospatial memory in healthy elderly, AD and MCI: a review. Current aging science. 2009;2(1):43-59. 34. Goder R, Boigs M, Braun S, Friege L, Fritzer G, Aldenhoff JB, Hinze-Selch D. Impairment of visuospatial memory is associated with decreased slow wave sleep in schizophrenia. Journal of psychiatric research. 2004;38(6):591-599. 35. Gordon WA. The interface between cognitive impairments and access to information technology. ACM SIGACCESS Accessibility and Computing. Vol 83. New York: ACM; 2005:3-6. 36. Klein M, Gauggel S, Sachs G, Pohl W. Impact of chronic obstructive pulmonary disease (COPD) on attention functions. Respir Med. 2010;104(1):52-60. 37. Heffernan TM, Ling J, Parrott AC, Buchanan T, Scholey AB, Rodgers J. Self-rated everyday and prospective memory abilities of cigarette smokers and non-smokers: a web-based study. Drug Alcohol Depend. 2005;78(3):235-241. 38. Kuo HK, Jones RN, Milberg WP, Tennstedt S, Talbot L, Morris JN, Lipsitz LA. Effect of blood pressure and diabetes mellitus on cognitive and physical functions in older adults: a longitudinal analysis of the advanced cognitive training for independent and vital elderly cohort. Journal of the American Geriatrics Society. 2005;53(7):1154-1161. 39. Miyake A, Friedman NP, Rettinger DA, Shah P, Hegarty M. How are visuospatial working memory, executive functioning, and spatial abilities related? A latent-variable analysis. Journal of experimental psychology General. 2001;130(4):621-640.

Chapter 2

CHAPTER 2

Supplementary data Cognitive functioning tests Prospective memory test. The participant was shown the message ‘At the end of the games we will show you four colored shapes and ask you to touch the Blue Square. However, to test your memory, we want you to actually touch the Orange Circle instead’. This test assesses prospective memory, which refers to the ability to carry out future intentions at a specific time or in response to a specific event. Successful prospective remembering requires that an intention to be remembered is encoded and recalled some time later in response to a cue so that accurate prospective memory task performance has both a prospective component (remembering to remember) and a retrospective component (remembering the content of what is to be remembered).1 Fluid intelligence test. The participant had 2 minutes to complete as many questions as possible from the test. This test assesses fluid cognitive functioning, which can be thought of as the capacity to solve problems that require logic and reasoning ability, independent of acquired knowledge.2 Pairs matching test. This visual spatial ability test provides data on two 'pairs' matching tests. Participants were asked to memorize the position of as many matching pairs of cards as possible. The cards are then turned face down on the screen and the participant is asked to touch as many pairs as possible in the fewest tries. The first test includes 3 pairs of cards, the second 6 pairs of cards.3 Numeric memory test. The participant was shown a 2-digit number to remember. The number then disappeared and after a short while they were asked to enter the number onto the screen. The number became 1-digit longer each time they remembered correctly (up to a maximum of 12 digits). This test is used to measure numeric short-term memory and assesses the ability to recollect a series of digits. The length of the longest list a person can remember is called the digit span of this person.4 Reaction time test. The participant was shown two cards at a time. If both cards are the same, they press a button-box that is on the table in front of them as quickly as possible. During 12 rounds, this test measures the reaction time which is the elapsed time between presentation of two cards (a sensory stimulus) and pressing the button-box (the subsequent behavioral response). It gives an indirect index of the cognitive processing speed of a participant.5

Cognitive Functioning in Obstructive Lung Disease

Analysis included correction for the following confounders, which have been associated with cognitive functioning in previous studies: sex,6-9 age,9-12 race,1315 education,9,10,16 employment,17,18 current tobacco smoking,19,20 alcohol intake,21-23 depressed mood in the last two weeks,24,25 vascular/heart problems diagnosed by doctor,26-28 and diabetes diagnosed by doctor.27,29,30

Additional tables Table S1. Prospective memory test: association with OLD using logistic regression analysis Standardized Coefficient P Value Beta (β) (95% CI) Primary predictor OLD versus non-OLD (ref: non-OLD) -0.15 (-0.22 to -0.09) <0.005 Possible confounders Sex (ref: female) 0.10 (0.05 to 0.14) <0.005 Age -0.04 (-0.04 to -0.03) <0.005 Race (ref: non-Caucasian) 1.20 (1.10 to 1.29) <0.005 Education (ref: less than college or University degree) 0.51 (0.45 to 0.56) <0.005 Employment (non employed) 0.16 (0.11 to 0.22) <0.005 Current tobacco smoking (ref: non-smoking) -0.16 (-0.24 to -0.08) <0.005 Alcohol intake (ref: none) 0.33 (0.25 to 0.41) <0.005 Depressed mood in last 2 weeks (ref: no) 0.04 (-0.02 to 0.09) 0.210 Vascular/heart problems diagnosed by doctor -0.07 (-0.13 to -0.02) 0.006 Diabetes diagnosed by doctor -0.14 (-0.25 to -0.04) 0.007 OLD= Obstructive Lung Disease; 95% CI= 95% confidence interval. n= 43039 R2=0.05, p=<0.005 Table S2. Fluid intelligence test: association with OLD using linear regression analysis Standardized Coefficient Beta (β) (95% CI) Primary predictor OLD versus non-OLD (ref: non-OLD) -0.05 (-0.11 to 0.003) Possible confounders Sex (ref: female) 0.20 (0.16 to 0.23) Age -0.003 (-0.01 to <-0.001) Race (ref: non-Caucasian) 1.27 (1.18 to 1.36) Education (ref: less than college or 1.37 (1.33 to 1.41) University degree) Employment (non employed) 0.15 (0.10 to 0.20) Current tobacco smoking (ref: non-smoking) -0.27 (-0.33 to -0.20) Alcohol intake (ref: none) 0.36 (0.29 to 0.44) Depressed mood in last 2 weeks (ref: no) 0.02 (-0.02 to 0.06) Vascular/heart problems diagnosed by -0.14 (-0.19 to -0.10) doctor Diabetes diagnosed by doctor -0.17 (-0.27 to -0.08)

P Value 0.065 <0.005 0.048 <0.005 <0.005 <0.005 <0.005 <0.005 0.358 <0.005 <0.005

OLD= Obstructive Lung Disease; 95% CI= 95% confidence interval. n= 43039 R2=0.13, p=<0.005. For one person with OLD the fluid intelligence test data are missing.

Chapter 2

Statistics

CHAPTER 2 Table S3. Pairs matching test: association with OLD using Round 1 Standardized Coefficient Beta (β) (95% CI) Primary predictor OLD versus non-OLD (ref: non0.06 OLD) (0.03 to 0.10) Possible confounders Sex (ref: female) -0.05 (-0.07 to -0.03) Age 0.01 (0.01 to 0.01) Race (ref: non-Caucasian) -0.39 (-0.46 to -0.32) Education (ref: less than college -0.13 or University degree) (-0.15 to -0.11) Employment (non employed) -0.01 (-0.04 to 0.01) Current tobacco smoking (ref: 0.04 non-smoking) (0.01 to 0.08) Alcohol intake (ref: none) -0.12 (-0.17 to -0.07) Depressed mood in last 2 weeks -0.01 (ref: no) (-0.04 to 0.01) Vascular/heart problems 0.01 diagnosed by doctor (-0.01 to 0.03) Diabetes diagnosed by doctor 0.06 (<0.001 to 0.11)

linear regression analysis Round 2 P value Standardized Coefficient Beta (β) (95% CI)

P Value

<0.005

0.09 (<0.001 to 0.18)

0.047

<0.005

-0.02 (-0.08 to 0.04) 0.05 (0.05 to 0.06) -1.02 (-1.20 to -0.86) -0.20 (-0.27 to -0.14) -0.12 (-0.20 to -0.05) -0.09 (-0.19 to 0.01) -0.10 (-0.22 to 0.02) 0.01 (-0.06 to 0.08) 0.09 (0.02 to 0.17) -0.04 (-0.20 to 0.11)

0.522

<0.005 <0.005 <0.005 0.283 0.014 <0.005 0.299 0.430 0.034

<0.005 <0.005 <0.005 0.001 0.068 0.116 0.857 0.009 0.587

OLD= Obstructive Lung Disease; 95% CI= 95% confidence interval. n= 43039 R2 round 1=0.02, p=<0.005; R2 round 2=0.03, p=<0.005 Table S4. Numeric memory test: association with OLD using linear regression analysis Standardized Coefficient Beta (β) (95% CI) Primary predictor OLD versus non-OLD (ref: non-OLD) -0.05 (-0.10 to <0.001) Possible confounders Sex (ref: female) 0.16 (0.12 to 0.19) Age -0.01 (-0.01 to <-0.001) Race (ref: non-Caucasian) 0.58 (0.48 to 0.67) Education (ref: less than college or University 0.54 (0.50 to 0.57) degree) Employment (non employed) 0.19 (0.16 to 0.23) Current tobacco smoking (ref: non-smoking) -0.12 (-0.18 to -0.06) Alcohol intake (ref: none) 0.33 (0.26 to 0.40) Depressed mood in last 2 weeks (ref: no) 0.01 (-0.03 to 0.04) Vascular/heart problems diagnosed by doctor -0.06 (-0.10 to -0.03) Diabetes diagnosed by doctor -0.26 (-0.34 to -0.17) OLD= Obstructive Lung Disease; 95% CI= 95% confidence interval. n= 43039 R2=0.05, p=<0.005

P Value

0.047 <0.005 <0.005 <0.005 <0.005 <0.005 <0.005 <0.005 0.677 0.001 <0.005

Cognitive Functioning in Obstructive Lung Disease

Table S5. Reaction time test: association with OLD using linear regression analysis Standardized Coefficient Beta (β) (95% CI) Primary predictor OLD versus non-OLD (ref: non-OLD) 4.62 (1.25 to 8.01) Possible confounders Sex (ref: female) -18.02 (-20.21 to -15.83) Age 4.12 (3.97 to 4.29) Race (ref: non-Caucasian) -55.16 (-61.01 to -49.31) Education (ref: less than college or University -11.78 (-14.03 to -9.54) degree) Employment (non employed) -6.56 (-9.29 to -3.84) Current tobacco smoking (ref: non-smoking) 5.27 (1.80 to 8.73) Alcohol intake (ref: none) -15.90 (-20.47 to -11.34) Depressed mood in last 2 weeks (ref: no) -2.49 (-5.02 to 0.03) Vascular/heart problems diagnosed by doctor 5.98 (3.37 to 8.54) Diabetes diagnosed by doctor 9.78 (4.16 to 15.40)

P Value

Chapter 2

0.007 <0.005 <0.005 <0.005 <0.005 <0.005 0.003 <0.005 0.053 0.001 <0.005

OLD= Obstructive Lung Disease; 95% CI= 95% confidence interval. n= 43039 R2=0.11, p=<0.005 Table S6. Prospective memory test: association with FEV1 using logistic regression analysis Standardized Coefficient P Value Beta (β) (95% CI) Primary predictor FEV1 (% predicted) 0.004 (<0.001 to 0.01) 0.028 Possible confounders Sex (ref: female) 0.17 (0.05 to 0.29) 0.007 Age -0.03 (-0.04 to -0.02) <0.005 Race (ref: non-Caucasian) 1.34 (1.09 to 1.58) <0.005 Education (ref: less than college or University 0.58 (0.43 to 0.73) <0.005 degree) Employment (non employed) 0.34 (0.19 to 0.48) <0.005 Current tobacco smoking (ref: non-smoking) 0.01 (-0.15 to 0.17) 0.915 Alcohol intake (ref: none) 0.32 (0.11 to 0.53) 0.003 Depressed mood in last 2 weeks (ref: no) 0.04 (-0.10 to 0.18) 0.607 Vascular/heart problems diagnosed by doctor -0.09 (-0.22 to 0.05) 0.207 Diabetes diagnosed by doctor -0.12 (-0.39 to 0.16) 0.411 OLD= Obstructive Lung Disease; 95% CI= 95% confidence interval. n= 5764 R2=0.05, p=<0.005

CHAPTER 2 Table S7. Fluid intelligence test: association with FEV1 using linear regression analysis Standardized Coefficient Beta (β) (95% CI) Primary predictor FEV1 (% predicted) 0.003 (<0.001 to 0.01) Possible confounders Sex (ref: female) 0.32 (0.22 to 0.43) Age -0.001 (-0.01 to 0.01) Race (ref: non-Caucasian) 1.43 (1.19 to 1.68) Education (ref: less than college or University 1.43 (1.31 to 1.55) degree) Employment (non employed) 0.25 (0.12 to 0.38) Current tobacco smoking (ref: non-smoking) -0.15 (-0.29 to -0.02) Alcohol intake (ref: none) 0.42 (0.23 to 0.62) Depressed mood in last 2 weeks (ref: no) 0.001 (-0.12 to 0.12) Vascular/heart problems diagnosed by doctor -0.18 (-0.30 to -0.07) Diabetes diagnosed by doctor -0.12 (-0.38 to 0.13)

P Value

0.052 <0.005 0.763 <0.005 <0.005 <0.005 0.023 <0.005 0.983 0.326 <0.005

OLD= Obstructive Lung Disease; 95% CI= 95% confidence interval. n= 5764 R2=0.15, p=<0.005. For one person with OLD the fluid intelligence test data are missing. Table S8. Pairs matching test: association with FEV1 using linear regression analysis Round 1 Round 2 Standardized pStandardized Coefficient Beta value Coefficient Beta (β) (95% CI) (β) (95% CI) Primary predictor FEV1 (% predicted) <0.001 0.938 -0.002 (-0.001 to 0.002) (-0.01 to 0.003) Possible confounders Sex (ref: female) -0.04 0.161 0.01 (-0.11 to 0.02) (-0.15 to 0.18) Age 0.01 <0.005 0.04 (0.01 to 0.02) (0.03 to 0.06) Race (ref: non-Caucasian) -0.37 <0.005 -1.60 (-0.53 to -0.20) (-2.04 to -1.16) Education (ref: less than -0.17 <0.005 -0.22 college or University degree) (-0.23 to -0.10) (-0.41 to -0.04) Employment (non employed) -0.02 0.528 -0.21 (-0.09 to 0.05) (-0.42 to -0.006) Current tobacco smoking (ref: 0.04 0.308 -0.17 non-smoking) (-0.04 to 0.12) (-0.38 to 0.05) Alcohol intake (ref: none) -0.14 0.029 -0.13 (-0.28 to -0.02) (-0.44 to 0.18) Depressed mood in last 2 weeks -0.002 0.969 -0.05 (ref: no) (-0.08 to 0.07) (-0.24 to 0.15) Vascular/heart problems -0.04 0.301 0.01 diagnosed by doctor (-0.11 to 0.03) (-0.19 to 0.29) Diabetes diagnosed by doctor 0.08 0.303 -0.31 (-0.07 to 0.23) (-0.72 to 0.11) OLD= Obstructive Lung Disease; 95% CI= 95% confidence interval. n= 5764 R2 round 1=0.02, p=<0.005; R2 round 2=0.03, p=<0.005

P Value

0.376

0.863 <0.005 <0.005 0.020 0.044 0.130 0.412 0.636 0.944 0.151

Cognitive Functioning in Obstructive Lung Disease

Table S9. Numeric memory test: association with FEV1 using linear regression analysis Standardized Coefficient Beta (β) (95% CI) Primary predictor FEV1 (% predicted) 0.01 (0.003 to 0.01) Possible confounders Sex (ref: female) 0.32 (0.22 to 0.41) Age -0.005 (-0.01 to 0.003) Race (ref: non-Caucasian) 0.83 (0.56 to 1.09) Education (ref: less than college or University 0.63 (0.54 to 0.72) degree) Employment (non employed) 0.30 (0.19 to 0.40) Current tobacco smoking (ref: non-smoking) -0.005 (-0.12 to 0.12) Alcohol intake (ref: none) 0.27 (0.08 to 0.46) Depressed mood in last 2 weeks (ref: no) 0.04 (-0.06 to 0.14) Vascular/heart problems diagnosed by doctor -0.01 (-0.11 to 0.09) Diabetes diagnosed by doctor -0.27 (-0.51 to -0.03)

P Value

Chapter 2

<0.005 <0.005 0.196 <0.005 <0.005 <0.005 0.930 0.005 0.426 0.817 0.030

OLD= Obstructive Lung Disease; 95% CI= 95% confidence interval. n= 5764 R2=0.07, p=<0.005 Table S10. Reaction time test: association with FEV1 using linear regression analysis Standardized Coefficient Beta (β) (95% CI) Primary predictor FEV1 (% predicted) -0.09 (-0.27 to 0.08) Possible confounders Sex (ref: female) -16.09 (-22.52 to -9.66) Age 3.74 (3.27 to 4.21) Race (ref: non-Caucasian) -54.28 (-70.39 to -38.18) Education (ref: less than college or University -12.89 (-19.57 to -6.22) degree) Employment (non employed) -17.45 (-24.87 to -10.04) Current tobacco smoking (ref: non-smoking) 6.75 (-1.31 to 14.82) Alcohol intake (ref: none) -14.10 (-26.91 to -1.29) Depressed mood in last 2 weeks (ref: no) -6.37 (-13.55 to 0.81) Vascular/heart problems diagnosed by doctor 0.23 (-7.10 to 7.55) Diabetes diagnosed by doctor 22.69 (5.78 to 39.60)

P Value

0.288 <0.005 <0.005 <0.005 <0.005 <0.005 0.101 0.031 0.082 0.951 0.009

OLD= Obstructive Lung Disease; 95% CI= 95% confidence interval. n= 5764 R2=0.09, p=<0.005

CHAPTER 2 Table S11. Prospective memory test: association with FVC using logistic regression analysis Standardized Coefficient P Value Beta (β) (95% CI) Primary predictor FVC 0.07 (0.006 to 0.14) 0.073 Possible confounders Sex (ref: female) 0.08 (0. 08 to 0.23) 0.318 Age -0.02 (-0.03 to -0.01) <0.005 Race (ref: non-Caucasian) 1.30 (1.05 to 1.55) <0.005 Education (ref: less than college or University 0.58 (0.43 to 0.72) <0.005 degree) Employment (non employed) 0.34 (0.19 to 0.48) <0.005 Current tobacco smoking (ref: non-smoking) 0.003 (-0.15 to 0.15) 0.966 Alcohol intake (ref: none) 0.32 (0.11 to 0.53) 0.003 Depressed mood in last 2 weeks (ref: no) 0.04 (-0.11 to 0.18) 0.624 Vascular/heart problems diagnosed by doctor -0.09 (-0.22 to 0.05) 0.206 Diabetes diagnosed by doctor -0.12 (-0.39 to 0.16) 0.405 FVC= forced vital capacity; 95% CI= 95% confidence interval. n= 5764 R2=0.05, p=<0.005 Table S12. Fluid intelligence test: association with FVC using linear regression analysis Standardized Coefficient Beta (β) (95% CI) Primary predictor FVC 0.14 (0.08 to 0.21) Possible confounders Sex (ref: female) 0.14 (<-0.001 to 0.27) Age 0.004 (-0.004 to 0.01) Race (ref: non-Caucasian) 1.37 (1.13 to 1.61) Education (ref: less than college or University 1.41 (1.30 to 1.53) degree) Employment (non employed) 0.24 (0.12 to 0.37) Current tobacco smoking (ref: non-smoking) -0.14 (-0.27 to -0.001) Alcohol intake (ref: none) 0.42 (0.22 to 0.61) Depressed mood in last 2 weeks (ref: no) <-0.001 (-0.12 to 0.12) Vascular/heart problems diagnosed by doctor -0.16 (-0.28 to -0.05) Diabetes diagnosed by doctor -0.10 (-0.35 to 0.15) FVC= forced vital capacity; 95% CI= 95% confidence interval. n= 5764 R2=0.15, p=<0.005 For one person with OLD the fluid intelligence test data are missing.

P Value

<0.005 0.051 0.335 <0.005 <0.005 <0.005 0.048 <0.005 0.994 0.006 0.433

Cognitive Functioning in Obstructive Lung Disease

Table S13. Pairs matching test: association with FVC using linear regression analysis Round 1 Round 2 Standardized pStandardized Coefficient Beta value Coefficient Beta (β) (95% CI) (β) (95% CI) Primary predictor FVC -0.01 0.509 -0.13 (-0.05 to 0.02) (-0.24 to 0.01) Possible confounders Sex (ref: female) -0.03 0.469 0.18 (-0.10 to 0.05) (-0. 05 to 0.41) Age 0.01 <0.005 0.04 (0.01 to 0.02) (0.02 to 0.05) Race (ref: non-Caucasian) -0.36 <0.005 -1.55 (-0.53 to -0.19) (-1.99 to -1.10) Education (ref: less than -0.16 <0.005 -0.21 college or University degree) (-0.23 to -0.10) (-0.40 to -0.02) Employment (non employed) -0.02 0.547 -0.21 (-0.09 to 0.05) (-0.42 to -0.001) Current tobacco smoking (ref: 0.04 0.354 -0.19 non-smoking) (-0.04 to 0.12) (-0.41 to 0.03) Alcohol intake (ref: none) -0.14 0.030 -0.12 (-0.27 to -0.01) (-0.44 to 0.19) Depressed mood in last 2 weeks -0.001 0.970 -0.04 (ref: no) (-0.08 to 0.07) (-0.24 to 0.15) Vascular/heart problems -0.04 0.264 -0.01 diagnosed by doctor (-0.11 to 0.03) (-0.21 to 0.18) Diabetes diagnosed by doctor 0.08 0.329 -0.33 (-0.08 to 0.23) (-0.75 to 0.09)

P Value

0.028

0.121 <0.005 <0.005 0.029 0.051 0.091 0.439 0.646 0.891 0.120

FVC= forced vital capacity; 95% CI= 95% confidence interval. n= 5764 R2 round 1=0.02, p=<0.005; R2 round 2=0.03, p=<0.005 Table S14. Numeric memory test: association with FVC using linear regression analysis Standardized Coefficient Beta (β) (95% CI) Primary predictor FVC 0.15 (0.10 to 0.21) Possible confounders Sex (ref: female) 0.11 (-0.01 to 0.23) Age 0.001 (-0.01 to 0.01) Race (ref: non-Caucasian) 0.75 (0.49 to 1.01) Education (ref: less than college or University 0.62 (0.53 to 0.71) degree) Employment (non employed) 0.29 (0.18 to 0.40) Current tobacco smoking (ref: non-smoking) <-0.001 (-0.12 to 0.12) Alcohol intake (ref: none) 0.26 (0.07 to 0.45) Depressed mood in last 2 weeks (ref: no) 0.04 (-0.06 to 0.14) Vascular/heart problems diagnosed by doctor -0.001 (-0.10 to 0.10) Diabetes diagnosed by doctor -0.26 (-0.50 to -0.02)

P Value

<0.005 0.171 0.775 <0.005 <0.005 <0.005 0.994 0.006 0.456 0.980 0.037

FVC= forced vital capacity; 95% CI= 95% confidence interval. n= 5764 R2=0.07, p=<0.005

Chapter 2

CHAPTER 2 Table S15. Reaction time test: association with FVC using linear regression analysis Standardized Coefficient Beta (β) (95% CI) Primary predictor FVC -2.82 (-6.22 to 1.65) Possible confounders Sex (ref: female) -12.99 (-21.04 to -4.94) Age 3.65 (3.15 to 4.15) Race (ref: non-Caucasian) -53.10 (-69.43 to -36.77) Education (ref: less than college or -12.75 (-19.44 to -6.06) University degree) Employment (non employed) -17.39 (-24.81 to -9.97) Current tobacco smoking (ref: non-smoking) 6.73 (-1.31 to 14.78) Alcohol intake (ref: none) -14.04 (-26.83 to -1.24) Depressed mood in last 2 weeks (ref: no) -6.74 (-13.51 to 0.85) Vascular/heart problems diagnosed by 0.11 (-7.25 to 7.46) doctor Diabetes diagnosed by doctor 22.58 (5.61 to 39.55) FVC= forced vital capacity; 95% CI= 95% confidence interval. n= 5764 R2=0.09, p=<0.005

P Value 0.256 0.002 <0.005 <0.005 <0.005 <0.005 0.101 0.032 0.084 0.977 0.009

Cognitive Functioning in Obstructive Lung Disease

1. 2.

4. 5.

6. 7.

10.

11.

12.

13.

14. 15.

16. 17. 18.

McDaniel MA, Scullin MK. Implementation intention encoding does not automatize prospective memory responding. Mem Cognit. 2010;38(2):221-232. Kane MJ, Engle RW. The role of prefrontal cortex in working-memory capacity, executive attention, and general fluid intelligence: an individual-differences perspective. Psychon Bull Rev. 2002;9(4):637-671. Washburn DA, Gulledge JP, James FJ, & Rumbaugh DM. A species difference in visuospatial working memory: Does language link "what" with "where"? International Journal of Comparative Psychology. 2007;20:54-63. Conrad R, Hille BA. The decay theory of immediate memory and paced recall. Can J Psychol. 1958;12(1):1-6. Karia RM, Ghuntla TP, Mehta HB, Gokhale PA, Shah CJ. Effect Of Gender Difference On Visual Reaction Time : A Study On Medical Students Of Bhavnagar Region. IOSR Journal of Pharmacy. 2012;2(3):452-454. Ardila A, Rosselli M, Matute E, Inozemtseva O. Gender differences in cognitive development. Dev Psychol. 2011;47(4):984-990. Crespo-Facorro B, Roiz-Santianez R, Perez-Iglesias R, Mata I, Rodriguez-Sanchez JM, Tordesillas-Gutierrez D, Ortiz-Garcia de la Foz V, Tabares-Seisdedos R, Sanchez E, Andreasen N, Magnotta V, Vazquez-Barquero JL. Sex-specific variation of MRI-based cortical morphometry in adult healthy volunteers: the effect on cognitive functioning. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(2):616-623. Kao YC, Liu YP, Lien YJ, Lin SJ, Lu CW, Wang TS, Loh CH. The influence of sex on cognitive insight and neurocognitive functioning in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;44:193-200. van Hooren SA, Valentijn AM, Bosma H, Ponds RW, van Boxtel MP, Jolles J. Cognitive functioning in healthy older adults aged 64-81: a cohort study into the effects of age, sex, and education. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2007;14(1):40-54. Liu KP, Kuo MC, Tang KC, Chau AW, Ho IH, Kwok MP, Chan WC, Choi RH, Lam NC, Chu MM, Chu LW. Effects of age, education and gender in the Consortium to Establish a Registry for the Alzheimer's Disease (CERAD)-Neuropsychological Assessment Battery for Cantonese-speaking Chinese elders. Int Psychogeriatr. 2011;23(10):1575-1581. Loewenstein DA, Czaja SJ, Bowie CR, Harvey PD. Age-associated differences in cognitive performance in older patients with schizophrenia: a comparison with healthy older adults. Am J Geriatr Psychiatry. 2012;20(1):29-40. Salarirad S, Staff RT, Fox HC, Deary IJ, Whalley L, Murray AD. Childhood intelligence and brain white matter hyperintensities predict fluid intelligence age 78-81 years: a 1921 Aberdeen birth cohort study. Age Ageing. 2011;40(5):562-567. Dotson VM, Kitner-Triolo MH, Evans MK, Zonderman AB. Effects of race and socioeconomic status on the relative influence of education and literacy on cognitive functioning. J Int Neuropsychol Soc. 2009;15(4):580-589. Kennedy SW, Allaire JC, Gamaldo AA, Whitfield KE. Race differences in intellectual control beliefs and cognitive functioning. Exp Aging Res. 2012;38(3):247-264. Schwartz BS, Glass TA, Bolla KI, Stewart WF, Glass G, Rasmussen M, Bressler J, Shi W, BandeenRoche K. Disparities in cognitive functioning by race/ethnicity in the Baltimore Memory Study. Environ Health Perspect. 2004;112(3):314-320. Lee S, Kawachi I, Berkman LF, Grodstein F. Education, other socioeconomic indicators, and cognitive function. Am J Epidemiol. 2003;157(8):712-720. Garcia-Villamisar D, Hughes C. Supported employment improves cognitive performance in adults with Autism. J Intellect Disabil Res. 2007;51(Pt 2):142-150. Gorske TT, Daley DC, Yenerall E, Morrow LA. Neuropsychological function and employment status in a welfare-to-work sample. Appl Neuropsychol. 2006;13(3):141-150.

Chapter 2

References

Â 19. Gons RA, van Norden AG, de Laat KF, van Oudheusden LJ, van Uden IW, Zwiers MP, Norris DG, de Leeuw FE. Cigarette smoking is associated with reduced microstructural integrity of cerebral white matter. Brain. 2011;134(Pt 7):2116-2124. 20. Heffernan TM, Ling J, Parrott AC, Buchanan T, Scholey AB, Rodgers J. Self-rated everyday and prospective memory abilities of cigarette smokers and non-smokers: a web-based study. Drug Alcohol Depend. 2005;78(3):235-241. 21. Lyvers M, Tobias-Webb J. Effects of acute alcohol consumption on executive cognitive functioning in naturalistic settings. Addict Behav. 2010;35(11):1021-1028. 22. Son SJ, Lee KS, Oh BH, Hong CH. The effects of head circumference (HC) and lifetime alcohol consumption (AC) on cognitive function in the elderly. Arch Gerontol Geriatr. 2012;54(2):343-347. 23. Squeglia LM, Schweinsburg AD, Pulido C, Tapert SF. Adolescent binge drinking linked to abnormal spatial working memory brain activation: differential gender effects. Alcohol Clin Exp Res. 2011;35(10):1831-1841. 24. Baker SC, Frith CD, Dolan RJ. The interaction between mood and cognitive function studied with PET. Psychol Med. 1997;27(3):565-578. 25. Halvorsen M, Hoifodt RS, Myrbakk IN, Wang CE, Sundet K, Eisemann M, Waterloo K. Cognitive function in unipolar major depression: a comparison of currently depressed, previously depressed, and never depressed individuals. J Clin Exp Neuropsychol. 2012;34(7):782-790. 26. Ritz K, van Buchem MA, Daemen MJ. The heart-brain connection: mechanistic insights and models. Neth Heart J. 2013;21(2):55-57. 27. Verhaeghen P, Marcoen A, Goossens L. Facts and fiction about memory aging: a quantitative integration of research findings. J Gerontol. 1993;48(4):P157-171. 28. Zheng L, Mack WJ, Chui HC, Heflin L, Mungas D, Reed B, DeCarli C, Weiner MW, Kramer JH. Coronary artery disease is associated with cognitive decline independent of changes on magnetic resonance imaging in cognitively normal elderly adults. J Am Geriatr Soc. 2012;60(3):499-504. 29. Biessels GJ, Deary IJ, Ryan CM. Cognition and diabetes: a lifespan perspective. Lancet Neurol. 2008;7(2):184-190. 30. Biessels GJ, Gispen WH. The impact of diabetes on cognition: what can be learned from rodent models? Neurobiol Aging. 2005;26 Suppl 1:36-41.

Chapter 3

Presence of brain pathology in deceased subjects with and without COPD Cleutjens FA, Spruit MA, Beckervordersandforth J, Franssen FM, Dijkstra JB, Ponds RW, Wouters EF, Janssen DJ. Presence of brain pathology in deceased subjects with and without chronic obstructive pulmonary disease. CRD. 2015 Reprinted with permission from CRD.

ChapterÂ 3Â

Abstract Patients with chronic obstructive pulmonary disease (COPD) have extrapulmonary co-morbidities, such as cardiovascular disease, musculoskeletal wasting, and neuropsychological conditions. To date, it remains unknown whether and to what extent COPD is associated with a higher prevalence of brain pathology. Therefore, the aim of this retrospective study was to compare the prevalence of neuropathological brain changes between deceased donors with and without COPD. Brain autopsy reports of age matched donors with (n=89) and without COPD (n=89) from the Netherlands Brain Bank were assessed for demographics, cause of death, comorbidities and brain pathology. The prevalence of degenerative brain changes was comparable for donors with and without COPD (50.6% versus 61.8%, p > 0.05). Neoplastic brain changes were reported in a minority of the donors (5.6% versus 10.1%, p > 0.05). After correction for CVA or cardiac cause of death, and Charlson comorbidity index score, the prevalence of vascular brain changes was higher among control versus COPD donors (27.0% versus 11.2%, adjusted p = 0.013, odds ratio = 2.98). Brain autopsy reports of donors with and without COPD did not reveal differences in the presence of degenerative or neoplastic brain changes. Vascular brain changes were described more often in controls. Prospective studies including spirometry and structural and functional brain imaging should corroborate our findings.

Brain pathology in deceased subjects with and without COPD

Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation and extrapulmonary co-morbidities that may contribute to the severity of the disease.1 Cardiovascular, musculoskeletal and also neuropsychological conditions are among the most prevalent extrapulmonary features.2 Patients with COPD frequently have clinically significant, but often unrecognized, cognitive deficits, either globally or in specific cognitive domains.3,4 Indeed, the incidence of cognitive impairment in patients with COPD varies in different studies from 12% to 88%.5 Cognitive impairment is correlated with poor selfmanagement skills, for example, improper use of medication, difficulties in dealing with co-morbidities and difficulty in handling guidelines.6 Furthermore, neuropathologic changes may occur in COPD. It might be of great significance to map the presence of brain pathology since neuropathological brain changes may be a possible explanation for cognitive impairment in COPD. Studies using magnetic resonance imaging (MRI) suggested a relationship between COPD and neuropathological changes like reduction of regional grey matter volume,7,8 reduced white matter integrity7,9 and reduced hippocampal volume.10 As pulmonary function deteriorates and the disease progresses, the risk of hypoxaemia and consequent hypoxia in the peripheral organs increases.11 Consequently, decreased oxygen supply may cause neuronal damage in the brains of patients with COPD.12 Frontal and parietal hypoperfusion13–15 and microstructural damage of white matter, such as severe periventricular white matter lesions might be correlated with cognitive impairment.9,16 Indeed, Grant et al. showed a weak correlation between hypoxia and cognitive impairment in patients with COPD.17 However, other authors did not find differences in brain structure between patients with COPD and controls using MRI and neurochemical imaging.18 In order to unravel the discrepancy in the presence of brain pathology in patients with COPD, the aim of this study was to compare the prevalence of neuropathological brain changes between deceased patients with COPD and deceased controls without COPD, one to-one matched for age, using brain autopsy reports. This study investigates the hypothesis that subjects with COPD have more brain pathology compared with subjects without COPD.

Methods Study design This retrospective cross-sectional, observational study has been conducted using the Netherlands Brain Bank (NBB; Netherlands Institute of Neuroscience, Amsterdam, the Netherlands). The NBB is a non-profit organization that collects

Chapter 3

Introduction

Chapter 3 human brain tissue of donors with a variety of neurological and psychiatric disorders and non-diseased donors. The brains of all subjects are neuropathologically investigated in a systematic way. In short, the brains were macroscopically examined and dissected depending on the clinical diagnosis and the actual applications of researchers. The brain tissue was either frozen or formalin fixed for 4 weeks. The formalin-fixed tissue was subdivided into cortex (frontal, temporal, parietal and occipital), hippocampus, locus coeruleus, substantia nigra, caudate nucleus, putamen, pallidum, insula, pons, cerebellum and medulla oblongata. These tissue specimens were embedded in paraffin, sectioned for histological or immunocytochemical stainings and used for microscopic examination by the pathologists of the NBB.19

Study population The computer program of the NBB selected 110 summaries of medical records of donors without dementia with a clinical diagnosis of COPD. Donors with Alzheimer’s disease, frontotemporal dementia, vascular dementia and other types of dementia were excluded. Other exclusion criteria were multiple sclerosis, Parkinson’s disease, progressive supranuclear palsy, schizophrenia and drug abuse. In total, 89 records (80.9%) had complete data on age, gender, cause of death and neuropathological information and were included in the current study. These were age matched with 89 summaries of medical records of donors without dementia and COPD. All patients provided pre-mortem consent for brain autopsy and use of brain material and clinical information for research purposes.

Outcome measures The following outcomes were obtained from the medical records: gender, age at death, cause of death, co-morbid conditions and neuropathological information. Cause of death (respiratory insufficiency, cardiac, cancer, cerebrovascular accident, pneumonia and others) and co-morbid conditions (according to the Charlson Co-morbidity Index)20 were scored independently by two researchers (FAHMC, master of science in mental health and DJAJ, elderly care physician). Consensual classifications were automatically accepted. The researchers discussed discrepancies case-by-case until a consensual agreement was reached. Neuropathological reports were systematically studied by a pathologist with extensive expertise in autopsy neuropathology (JB). All reports were classified into normal brain (no brain pathologies) or brain pathology. The following brain pathologies were scored: vascular brain changes, degenerative brain changes (age-related degeneration and/or neurodegeneration) and neoplastic brain changes (Table 1).

Table 1. Brain pathologies Vascular brain changes Degenerative brain changes

Neoplastic brain changes

• Extensive atherosclerosis • Old or recent ischaemic changes • Senile changes, for example senile plaques and neurofibrillary tangles • Braak and Braak stage21 • Neurodegenerative disorders, for example AD, PD and HD • Tumor (no distinction between primary CNS tumors, meningiomas, Schwannomas or metastasis elsewhere)

AD: Alzheimer’s disease; PD: Parkinson’s disease; HD: Huntington’s disease; CNS: central nervous system.

Statistics Statistics were done using SPSS 17.0 (SPSS Inc., Chicago, Illinois, USA). Descriptive statistics were used to summarize the characteristics of the donors (age, gender, cause of death, co-morbidities and Charlson Co-morbidity Index score) and to present the various brain pathologies. Categorical variables are described as frequencies, whilst continuous variables were tested for normality and are presented as mean and standard deviation. Categorical variables were compared between donors with and without COPD using χ2 tests. Continuous variables were compared between donors with and without COPD using an independent sample t-test. Binary logistic regression analysis was used to compare brain pathology between the two groups after correction for the following possible confounders that might be related with brain pathology: cardiac cause of death, cerebrovascular accident (CVA) as cause of death and Charlson Comorbidity Index score.22–25 A priori, a two-sided level of significance has been set at p≤0.05.

Results The study cohort included 89 donors with COPD and 89 donors without COPD (Table 2). Respiratory insufficiency as cause of death was more prevalent in donors with COPD. Cancer and cardiac cause of death were more prevalent in control donors. The mean Charlson Co-morbidity Index score was significantly higher in COPD donors compared with the control donors. There was no difference in the prevalence of brain abnormalities between the donors with or without COPD (Table 3). The most frequently reported brain changes in both groups were degenerative changes, followed by vascular changes. Neoplastic brain changes were reported in a minority of the patients. Control donors had a higher prevalence of vascular brain changes. This remained significant after correction for a cardiac cause of death, CVA as cause of death and Charlson Co-morbidity Index.

Chapter 3

Brain pathology in deceased subjects with and without COPD

ChapterÂ 3Â Table 2. Donor characteristics.a Demographics Age (years) Male Cause of death Respiratory insufficiency Cardiac cause of death Cancer CVA Pneumonia Otherb Comorbidities Myocardial infarction Congestive heart disease Peripheral vascular disease Cerebrovascular disease Dementia Chronic pulmonary disease Rheumatic disease Peptic ulcer disease Mild liver disease Diabetes Diabetes with chronic complications Hemiplegia or paraplegia Renal disease Any malignancy, including lymphoma and leukemia, except malignant neoplasm of skin Moderate or severe liver disease Metastatic solid tumor AIDS/HIV Charlson comorbidity index Charlson comorbidity index score

COPD donors (n=89)

Control donors (n=89)

p Value

77.1 (10.2) 49 (55.1%)

77.9 (10.9) 44 (49.4%)

0.604 0.548

37 (41.6%) 16 (18.0%) 8 (9.0%) 1 (1.1%) 7 (7.9%) 20 (22.5%)

2 (2.2%) 31 (34.8%) 23 (25.8%) 3 (3.4%) 8 (9.0%) 22 (24.7%)

<0.005 0.017 0.006 0.613 1.000 0.860

28 (31.5%) 41 (46.1%) 41 (46.1%) 16 (18.0%) 0 (0.0%) 89 (100%) 5 (5.6%) 18 (20.2%) 15 (16.9%) 12 (13.5%) 2 (2.2%)

25 (28.1%) 29 (32.6%) 29 (32.6%) 14 (15.7%) 0 (0.0%) 0 (0.0%) 13 (14.6%) 15 (16.9%) 4 (4.5%) 17 (19.1%) 5 (5.6%)

0.743 0.091 0.091 0.841 <0.005 0.082 0.700 0.015 0.417 0.441

3 (3.4%) 17 (19.1%) 28 (31.5%)

0 (0.0%) 12 (13.5%) 14 (15.7%)

0.244 0.417 0.022

0 (0.0%) 18 (20.0%) 0 (0.0%)

2 (2.2%) 24 (27.0%) 0 (0.0%)

0.477 0.377 -

5.2 (2.4)

3.9 (2.4)

<0.005

COPD: chronic obstructive pulmonary disease; CVA: cerebrovascular accident; AIDS: acquired immune deficiency syndrome; HIV: human immunodeficiency virus. a Data reported as n (%) or mean (SD); b Including for example septic syndrome, haematoma, haemorrhage and cachexia. Table 3. Brain pathology.a

Normal brain Abnormal brain Vascular brain changes Degenerative brain changes Age-related degeneration Neurodegeneration Neoplastic brain changes

COPD donors (n=89) 36 (40.4%)

Control donors (n=89) 24 (27.0%)

p Value

Adjusted p Valuea

0.081

0.092

10 (11.2%) 45 (50.6%) 44 (49.4%) 5 (5.6%) 5 (5.6%)

24 (27.0%) 55 (61.8%) 54 (60.7%) 9 (10.1%) 9 (10.1%)

0.013 0.174 0.175 0.404 0.404

0.013 0.228 0.242 0.210 0.113

COPD: chronic obstructive pulmonary disease; CVA: cerebrovascular accident. a Data reported as n (%); b Based on binary logistic regression analysis, adjusted for a cardiac cause of death, CVA as cause of death and Charlson Co-morbidity Index score.

Brain pathology in deceased subjects with and without COPD

Discussion

The current retrospective study is the first to explore the presence of brain pathology in deceased donors with and without COPD. In both groups, only a minority had a normal brain. In contrast to our hypothesis, neuropathological brain changes did not occur more often in deceased donors with COPD. In fact, brain autopsy reports did not reveal a difference in the presence of degenerative or neoplastic brain changes between deceased donors with or without COPD. A statistically significant higher proportion of vascular brain changes was found among donors without COPD. However, the clinical relevance of this finding remains unknown. The brain is a high oxygen-consuming organ, and although it constitutes only a small fraction (2.5%) of the total human body weight in adults, it accounts for about 20% of the body’s oxygen consumption.26 A continuous oxygen supply is essential for proper functioning of the brain cells.27 Earlier studies suggested that hypoxaemia may result in decreased oxygenation of the brain,8 resulting in hypoxic stress.26 Particularly during physical exercise, exacerbations and sleep, COPD patients were suggested to be at risk for prolonged periods of oxygen deprivation.28–30 Van Dijk et al. demonstrated that low oxygen saturation and COPD are associated with more severe white matter periventricular lesions,16 independent of cardiac function, vascular risk factors and haemoglobin concentration, which might be related to reduced mental ability and reduced gait speed.31–33 As mentioned previously, other studies also showed structural brain abnormalities, for example, reduction of white matter integrity, grey matter and hippocampal volume, using MRI in patients with COPD.7–10 These pathologies are often been suggested to be induced by chronic hypoxaemia. In the study of Borson et al., however, no differences could be observed in brain structure between persons with COPD and controls using MRI.18 Our study, using microscopical examination of brain tissue, confirmed the findings of Borson and colleagues. No significant difference in degenerative and neoplastic brain changes could be observed between both groups. COPD patients might be protected against the ischaemic brain changes by increasing blood and oxygen supply to the brain. In fact, increased partial pressure of carbon dioxide and decreased partial pressure of oxygen lead to vasodilatation and increased cerebral blood flow.34 Albayrak et al. demonstrated that total cerebral blood flow volume was increased in COPD patients due to vasodilatation of the bilateral internal carotid artery and vertebral artery, which are the main arteries supplying the brain. In a mouse brain study, during chronic hypoxia, significant vasodilation of the capillary diameter of intracor-

Chapter 3

Key findings

Chapter 3 tical microvasculature was observed, whilst the diameter of penetrating arterioles and emerging veins only demonstrated a tendency to enlarge.35 This suggests that, within the brain, the capillaries are the main actors, which react to chronic hypoxia. Vogiatzis et al. showed that cerebral blood flow at the limit of exercise tolerance in COPD patients without resting hypoxaemia was maintained at significantly greater levels compared with resting conditions, whilst in healthy individuals cerebral blood flow declined towards baseline during exercise at the limit of tolerance.36 Finally, hypoxia leads to lactate production. Previously, lactate was seen as a marker of brain hypoxia, and lactate was suggested to lead to toxicity of neuronal cells. However, a direct relationship between lactate and neuronal cell damage was not proved.37 Moreover, Leverve suggested that lactate has a protective role rather than a detrimental role after brain ischemia. Indeed, lactate is used as an aerobic substrate used for cell recovery after hypoxia. 38 This may explain why this study did not show a relationship between brain changes and COPD. Atherosclerosis is expected to be associated with smoking and COPD.39 Several authors demonstrated increased intima-media thickness, an early phase of atherosclerosis, in COPD patients. In our study, more extensive atherosclerosis was found in the brain of control donors. However, the cause of this discrepancy is unknown. Future studies should explore this issue. In analogy with cardiac ischaemic preconditioning, characterized by brief, repetitive periods of ischaemia reducing the size of a subsequent myocardial infarction,40 COPD might also lead to brain ischaemic preconditioning.41 Recently, Thompson et al. described that ischaemic brain preconditioning leads to an ischaemic-tolerant epigenetic profile.42 Ischaemic preconditioning might also induce a reduction in the vascular changes like atherosclerosis or ischaemic lesions in the COPD brain as observed in this study. Biochemical and molecular biological techniques with fresh brain tissue samples that allow measurement of enzyme activity, (epi)genetic status and expression of cell death proteins, inflammatory cytokines and growth factors might be used in the future to further analyse brain differences between both groups. The pathologies described in the autopsy reports such as age-related brain- and neurodegeneration and neoplastic brain changes are evenly distributed between the deceased COPD and control donors. These data suggest that COPD is not the main contributor in the onset of these brain pathologies. Although evidence has been found for a relationship between neuropathologic alterations and cognitive impairment in COPD,9,13–16 the results of this study do not show a higher prevalence of neuropathologic brain changes in COPD. Other previously hypothesized etiologic factors for cognitive impairment in patients with COPD are smoking, inflammation, atherosclerosis and also decreased physical activity, exacerbations and co-morbid conditions such as obstructive sleep apnoea syndrome and major depressive disorders. Future studies should explore brain abnormalities using structural and functional brain MRI

Brain pathology in deceased subjects with and without COPD scans along with the investigation of cognitive functioning in patients with and without COPD.

A first potential limitation is the retrospective nature of this study with pathological records only. Data collection was dependent on the availability and accuracy of the medical records. No information was available about the lung function, including severity of COPD (i.e. Global Initiative for Chronic Obstructive Lung Disease grading). Therefore, it was unknown whether and to what extent the diagnosis of COPD was confirmed by spirometry. Moreover, the amount of structural brain changes and areas affected in the brain were not consistently described in the medical records and therefore could not be explored in this study. Furthermore, the present study could not explore the causal relationship between impaired lung function and brain pathology. Also data about cognitive functioning, educational level, intelligence, sleep apnoea, smoking history, hypoxaemia, alcohol consumption, medication and long-term oxygen therapy were incomplete or unavailable. Because of the poor characterization of the COPD patients it was impossible to explore the relationship between COPD and the presence of structural brain changes after correction for clinical characteristics such as severity of airflow limitation or hypoxaemia. Second, the donor sample may have been distorted by selection bias, involving persons motivated to make their brain available for brain autopsy. These persons may not be generalizable to the whole population.43 Furthermore, this may explain the deviated distribution of causes of death in this study sample compared with the previously described COPD literature.44

Conclusions The presence of brain pathologies did not differ between deceased persons with and without COPD. Interestingly, vascular brain changes were described more often in the brain autopsy reports of controls. However, the clinical relevance of this finding remains unknown. Longitudinal prospective studies should explore brain abnormalities using structural and functional brain MRI scans along with the investigation of pulmonary function and cognitive functioning in patients with COPD and age-matched controls without COPD.

Chapter 3

Limitations

ChapterÂ 3Â

References 1.

3. 4. 5. 6. 7.

10. 11. 12.

13.

14.

15. 16.

17.

18.

19.

Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187(4):347-365. Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel VP, Bruijnzeel PL, Rutten EP, Op 't Roodt J, Wouters EF, Franssen FM. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;187(7):728-735. Cleutjens F, Spruit M, Ponds R, Dijkstra J, Franssen F, Wouters E, Janssen D. Cognitive Functioning in Obstructive Lung Disease: Results from the UK Biobank. JAMDA. 2014;15(3):214-219. Dodd JW, Getov SV, Jones PW. Cognitive function in COPD. Eur Respir J. 2010;35(4):913-922. Hynninen KM, Breitve MH, Wiborg AB, Pallesen S, Nordhus IH. Psychological characteristics of patients with chronic obstructive pulmonary disease: a review. J Psychosom Res. 2005;59(6):429-443. Schillerstrom JE, Horton MS, Royall DR. The impact of medical illness on executive function. Psychosomatics. 2005;46(6):508-516. Zhang H, Wang X, Lin J, Sun Y, Huang Y, Yang T, Zheng S, Fan M, Zhang J. Grey and white matter abnormalities in chronic obstructive pulmonary disease: a case-control study. BMJ Open. 2012;2(2):e000844. Zhang H, Wang X, Lin J, Sun Y, Huang Y, Yang T, Zheng S, Fan M, Zhang J. Reduced regional gray matter volume in patients with chronic obstructive pulmonary disease: a voxel-based morphometry study. AJNR American journal of neuroradiology. 2013;34(2):334-339. Dodd JW, Chung AW, van den Broek MD, Barrick TR, Charlton RA, Jones PW. Brain structure and function in chronic obstructive pulmonary disease: a multimodal cranial magnetic resonance imaging study. American journal of respiratory and critical care medicine. 2012;186(3):240-245. Li J, Fei GH. The unique alterations of hippocampus and cognitive impairment in chronic obstructive pulmonary disease. Respir Res. 2013;14:140. Kent BD, Mitchell PD, McNicholas WT. Hypoxemia in patients with COPD: cause, effects, and disease progression. Int J Chron Obstruct Pulmon Dis. 2011;6:199-208. Zhang H, Wang X, Lin J, Sun Y, Huang Y, Yang T, Zheng S, Fan M, Zhang J. Reduced regional gray matter volume in patients with chronic obstructive pulmonary disease: a voxel-based morphometry study. AJNR Am J Neuroradiol. 2013;34(2):334-339. Antonelli Incalzi R, Marra C, Giordano A, Calcagni ML, Cappa A, Basso S, Pagliari G, Fuso L. Cognitive impairment in chronic obstructive pulmonary disease--a neuropsychological and spect study. Journal of neurology. 2003;250(3):325-332. Huang C, Wahlund LO, Almkvist O, Elehu D, Svensson L, Jonsson T, Winblad B, Julin P. Voxeland VOI-based analysis of SPECT CBF in relation to clinical and psychological heterogeneity of mild cognitive impairment. Neuroimage. 2003;19(3):1137-1144. Ortapamuk H, Naldoken S. Brain perfusion abnormalities in chronic obstructive pulmonary disease: comparison with cognitive impairment. Annals of nuclear medicine. 2006;20(2):99-106. van Dijk EJ, Vermeer SE, de Groot JC, van de Minkelis J, Prins ND, Oudkerk M, Hofman A, Koudstaal PJ, Breteler MM. Arterial oxygen saturation, COPD, and cerebral small vessel disease. Journal of neurology, neurosurgery, and psychiatry. 2004;75(5):733-736. Grant I, Prigatano GP, Heaton RK, McSweeny AJ, Wright EC, Adams KM. Progressive neuropsychologic impairment and hypoxemia. Relationship in chronic obstructive pulmonary disease. Arch Gen Psychiatry. 1987;44(11):999-1006. Borson S, Scanlan J, Friedman S, Zuhr E, Fields J, Aylward E, Mahurin R, Richards T, Anzai Y, Yukawa M, Yeh S. Modeling the impact of COPD on the brain. Int J Chron Obstruct Pulmon Dis. 2008;3(3):429-434. Bank TNB. Information for tissue applicants. 2014; http://www.brainbank.nl/media/uploads/file/Information%20for%20tissue%20applicants_2013.pdf. Accessed October 10, 2013.

Brain pathology in deceased subjects with and without COPD

20. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383. 21. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-259. 22. D'Hoore W, Sicotte C, Tilquin C. Risk adjustment in outcome assessment: the Charlson comorbidity index. Methods Inf Med. 1993;32(5):382-387. 23. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22(9):391-397. 24. Goldstein LB, Samsa GP, Matchar DB, Horner RD. Charlson Index comorbidity adjustment for ischemic stroke outcome studies. Stroke. 2004;35(8):1941-1945. 25. Taraszewska A, Zelman IB, Ogonowska W, Chrzanowska H. The pattern of irreversible brain changes after cardiac arrest in humans. Folia Neuropathol. 2002;40(3):133-141. 26. Erecinska M, Silver IA. Tissue oxygen tension and brain sensitivity to hypoxia. Respir Physiol. 2001;128(3):263-276. 27. Prayson RA. Neuropathology. 2nd ed. Philadelphia: Elsevier; 2012:96-182. 28. Barbera JA, Roca J, Ferrer A, Felez MA, Diaz O, Roger N, Rodriguez-Roisin R. Mechanisms of worsening gas exchange during acute exacerbations of chronic obstructive pulmonary disease. Eur Respir J. 1997;10(6):1285-1291. 29. Dealberto MJ, Pajot N, Courbon D, Alperovitch A. Breathing disorders during sleep and cognitive performance in an older community sample: the EVA Study. J Am Geriatr Soc. 1996;44(11):1287-1294. 30. Garcia-Rio F, Lores V, Mediano O, Rojo B, Hernanz A, Lopez-Collazo E, Alvarez-Sala R. Daily physical activity in patients with chronic obstructive pulmonary disease is mainly associated with dynamic hyperinflation. Am J Respir Crit Care Med. 2009;180(6):506-512. 31. Baezner H, Blahak C, Poggesi A, Pantoni L, Inzitari D, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Langhorne P, O'Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Hennerici MG. Association of gait and balance disorders with age-related white matter changes: the LADIS study. Neurology. 2008;70(12):935-942. 32. Starr JM, Leaper SA, Murray AD, Lemmon HA, Staff RT, Deary IJ, Whalley LJ. Brain white matter lesions detected by magnetic resonance [correction of resosnance] imaging are associated with balance and gait speed. Journal of neurology, neurosurgery, and psychiatry. 2003;74(1):94-98. 33. Whitman GT, Tang Y, Lin A, Baloh RW. A prospective study of cerebral white matter abnormalities in older people with gait dysfunction. Neurology. 2001;57(6):990-994. 34. Ainslie PN, Ogoh S. Regulation of cerebral blood flow in mammals during chronic hypoxia: a matter of balance. Exp Physiol. 2010;95(2):251-262. 35. Albayrak R, Fidan F, Unlu M, Sezer M, Degirmenci B, Acar M, Haktanir A, Yaman M. Extracranial carotid Doppler ultrasound evaluation of cerebral blood flow volume in COPD patients. Respir Med. 2006;100(10):1826-1833. 36. Vogiatzis I, Louvaris Z, Habazettl H, Andrianopoulos V, Wagner H, Roussos C, Wagner PD, Zakynthinos S. Cerebral cortex oxygen delivery and exercise limitation in patients with COPD. The European respiratory journal. 2013;41(2):295-301. 37. Payen JF, LeBars E, Wuyam B, Tropini B, Pepin JL, Levy P, Decorps M. Lactate accumulation during moderate hypoxic hypoxia in neocortical rat brain. J Cereb Blood Flow Metab. 1996;16(6):1345-1352. 38. Leverve XM. Energy metabolism in critically ill patients: lactate is a major oxidizable substrate. Curr Opin Clin Nutr Metab Care. 1999;2(2):165-169. 39. Rahaghi FN, van Beek EJ, Washko GR. Cardiopulmonary coupling in chronic obstructive pulmonary disease: the role of imaging. J Thorac Imaging. 2014;29(2):80-91. 40. Amsterdam EA, Schaefer S. Ischemic preconditioning in coronary heart disease: a therapeutic golden fleece? J Am Coll Cardiol. 2004;43(9):1515-1516. 41. Liu XQ, Sheng R, Qin ZH. The neuroprotective mechanism of brain ischemic preconditioning. Acta Pharmacol Sin. 2009;30(8):1071-1080.

Chapter 3

ChapterÂ 3Â 42. Thompson JW, Dave KR, Young JI, Perez-Pinzon MA. Ischemic preconditioning alters the epigenetic profile of the brain from ischemic intolerance to ischemic tolerance. Neurotherapeutics. 2013;10(4):789-797. 43. Tsuang D, Simpson KL, Li G, Barnhart RL, Edland SD, Bowen J, McCormick W, Teri L, Nochlin D, Larson EB, Thompson ML, Leverenz JB. Evaluation of selection bias in an incident-based dementia autopsy case series. Alzheimer Dis Assoc Disord. 2005;19(2):67-73. 44. Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: Role of comorbidities. Eur Respir J. 2006;28(6):1245-1257.

Chapter 4

Sleep quality disturbances and cognitive functioning in elderly patients with COPD Cleutjens FA, Pedone C, Janssen DJ, Wouters EF, Incalzi RA. Sleep quality disturbances and cognitive functioning in elderly patients with COPD. ERJ Open Research. 2016;2(3). Reprinted with permission from ERJ Open Research.

ChapterÂ 4Â

Abstract Information about the association between cognitive functions, such as copying function, and sleep disturbances in patients with chronic obstructive pulmonary disease (COPD) is lacking. This cross-sectional observational study aimed to investigate the association between copying function and self-reported sleep quality disturbances and disease severity in an elderly COPD population. Cognitive function performances, assessed using the Mini-Mental State Examination, were compared in 562 ambulatory COPD patients with and without sleep disturbances; assessed using the Established Populations for Epidemiologic Studies of the Elderly questionnaire; and stratified by Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades. Sleep disturbances overall were not correlated with cognitive functioning. A trend was revealed towards worse design copying in patients with sleep disturbances overall. GOLD I patients with difficulties falling asleep and nocturnal awakenings had worse copying ability compared to GOLD I patients without these sleep disturbances. Copying ability was worse for GOLD III than GOLD I, orientation was worse for GOLD II than GOLD I and language was worse for GOLD II and III than GOLD I. To conclude, sleep disturbances seem to be a weak correlate of cognitive functioning, and are not a marker of disease severity.

Sleep quality disturbances and cognition in COPD

In the general population, sleep deprivation has been demonstrated to negatively impact cognitive functions such as attention and working memory.1 Both sleep disturbances2 and cognitive impairment3 are frequently found in patients with chronic obstructive pulmonary disease (COPD). However, knowledge concerning the relationship between sleep and cognition in COPD is scarce. Bellia et al.2 did not find a relationship between sleep disturbances and cognitive impairment in an elderly ambulatory mixed asthma-chronic obstructive pulmonary disease (COPD) population. Nevertheless, asthma patients accounted for about 40% of the sample, and it is well known that cognitive impairment is rare in patients with asthma.4 In contrast, Omachi et al.5 found a relationship between verbal memory and sleep disturbances in patients with COPD. However, confounders potentially affecting cognitive functioning such as comorbid diseases, sensory impairment, and physical functioning were not assessed. In view of these conflicting results, we hypothesize that further insight into the sleep-cognition relationship in COPD might be obtained by focusing on a specific cognitive function, namely copying ability. The rationale for this hypothesis lies in the observation that the insula is involved in the neural circuits underlying the copying function, and at the same time limbic areas such as amygdaloid complexes, hippocampal formation, and anterior cingulate cortex are involved in sleep regulation.6 Even if assessed in the context of a simple screening test such as The Mini-Mental State Examination (MMSE), copying ability has been proved to identify COPD patients at risk of improper use of inhalers,7 and to predict mortality in COPD.8 Furthermore, it has been proved to have important classificatory and prognostic implications in the broad elderly population.8 Thus, it carries information worthy of interest because of its practical application. The present study purposed to verify whether and to which respective extent copying function and the remaining components of MMSE are correlated with self-reported sleep disturbances and with COPD severity in an elderly COPD population.

Methods Study design This observational follow-up study uses data coming from the Salute Respiratoria nell’Anziano (Sa.R.A) Study, a multicenter study of various aspects of clinical and functional conditions and prognostic implications in older home-dwelling subjects with chronic respiratory and nonrespiratory conditions. A detailed

Chapter 4

Introduction

Chapter 4 description of recruitment criteria, studied population and diagnostic procedures is available elsewhere.9

Study population The Sa.R.A. Study population consisted of 1970 participants aged 65 years and older, recruited in 24 geriatric institutions throughout Italy. For this study all patients with COPD were selected from all included individuals in Sa.R.A. Patients were considered to have COPD if they had a pre-bronchodilator FEV1/FVC ratio of <70% predicted, and if there was no evidence of asthma. Patients gave their written consent to participate in the study. The Sa.R.A. Study was approved by the Ethical Committee of the coordinating center (University of Palermo, #276/2012).

Outcome measures The following outcomes were recorded: sociodemographic characteristics (age, gender, years of education); smoking habits (smoking status, pack years); disease-specific health status (St. George Respiratory Questionnaire (SGRQ))10; physical functioning (a single 6-minute walking test (6MWT)11 and the Barthel index12); mood status (15-item version of the Geriatric Depression Scale (GDS)13); pre-bronchodilator spirometry (forced vital capacity (FVC), FVC% predicted, forced expiratory volume in the first second (FEV1), FEV1% predicted, and FEV1/FVC); nocturnal symptoms and early morning symptoms by using selected items of the International Union against Tuberculosis and Lung Disease (IUATLD) Bronchial Symptoms Questionnaire14; and comorbid diseases (ICD9)15. Sleep quality disturbances were evaluated by the index of disturbed sleep from the Established Populations for Epidemiologic Studies of the Elderly questionnaire (EPESE)16 and defined as report of 0=never, 1=rarely (3-4 times per month), 2=sometimes (1-2 days per week), 3=often (3 or more days per week), 4=always on the following questions: (a) trouble falling asleep, (b) frequent awakenings at night, (c) waking up too early in the morning and not being able to fall asleep again, and (d) feeling rested in the morning. A total score ranging from 0 (completely undisturbed sleep) to 16 points (most severely disturbed sleep) was then calculated. Scores on the EPESE domains were dichotomized with a threshold value for each item of 2.2 Cognitive functioning was assessed with the MMSE17, which explores global cognitive functioning (total score 0-30 points) and five specific cognitive functions: orientation (0-10 points), memory (0-6 points), attention and calculation (0-5 points), language (0-8 points), and design copying (0-1 point). In order to be able to compare mean scores per cognitive function, a percentage correct score per MMSE cognitive function was calculated by dividing the patient’s cognitive function score with the total possible points for the items that comprise a specific cognitive function. For dichotomous items, percentage of patients

Sleep quality disturbances and cognition in COPD who failed was calculated. Individual performances on the MMSE total scores were adjusted for age and level of education according to a random sample of 906 persons from the Italian population (see e-Table 2).18

Statistical analysis was performed using the SPSS statistical software package, version 21.0 (SPSS Inc., Chicago, IL, USA). Probability values of p<0.05 were considered to be statistically significant. In descriptive analyses, data are presented as means and standard deviations or number of data items and percentage of the total number of items. Using Chi square tests for categorical variables and ANOVA or Kruskal-Wallis test, as appropriate for continuous variables, patient characteristics were compared between COPD patients across GOLD grades (GOLD I: FEV1 ≥80%; GOLD II: FEV1 ≥50% and <80%; GOLD III: FEV1 ≥30% and <50%; GOLD IV: FEV1 <30%).19 If p<0.05, pairwise comparisons were conducted. Chi-square test or Pearson's r was used to establish whether there was a relationship between the presence of nocturnal symptoms and sleep disturbances and between sleep disturbances and cognitive functioning. An overall outcome for EPESE was defined by dichotomizing the total score on the basis of a threshold value of 8 points.2 MMSE total score was dichotomized as follows: scores ≤24 points indicate cognitive impairment and scores >24 points indicate no cognitive impairment.17 Bar charts were used to summarize and present cognitive performance after stratification for GOLD grade or specific sleep disturbances. Cognitive functions were compared between patients with and without specific sleep disturbances, using independent sample t test or Mann-Whitney U test. To assess the degree to which the effect of sleep disturbances on cognitive functioning changes across GOLD grades, linear regression analysis was used with an interaction term between sleep disturbances and GOLD grade.

Results General characteristics of participants In total, 562 ambulatory patients (77% male) with COPD were included. Of these, 194 patients (34.5%) were classified as GOLD grade I, 232 patients (41.3%) as GOLD grade II, 103 patients (18.3%) as GOLD grade III, and 33 patients (5.9%) as GOLD grade IV. Across GOLD grades, patients differed in age, gender, lung function, smoking habits, BMI, depressive symptoms, disease-specific health status, physical functioning, and comorbid diseases including myocardial infarction and congestive heart failure. (Table 1). Sleep disturbances did not differ across GOLD grades (Table 2). Significant associations were found between nocturnal symptoms and sleep disturbances, but not between early

Chapter 4

Statistics

Chapter 4 morning symptoms and sleep disturbances in the total COPD group. After stratification by GOLD grade, nocturnal symptoms were correlated with sleep disturbances only in GOLD I and III (e-Table 1). Table 1. Patient characteristics of the study population Total COPD GOLD I GOLD II group (n=562) (n=194) (n=232) Sociodemographic characteristics Age (years), mean 73.9 (5.9) (SD) Male, n (%) 433 (77.0) Educational years (years),mean (SD) Spirometry FEV1/FVC, mean (SD) FEV1 (% predicted), mean (SD) Smoking habit Smoker, n (%) Former smoker, n (%) Never smoker, n (%) Packyears (years), mean (SD) Clinical characteristics BMI (kg/m2), mean, (SD) GDS (points), mean (SD) GDS >5 points, n (%) Visual impairment, n (%) Hearing impairment, n (%)

Pvalue†

74.5 (6.2)§ 172 (74.1)§ 6.1 (3.9)

71.9 (5.0) 89 (86.4) 6.0 (3.9)

72.9 (5.8) 29 (87.9) 7.8 (14.3)

0.001

65.1 (4.1)‡§¶ 95.6 (12.8)‡§¶

59.2 (7.6)§¶ 65.9 (8.9)§¶

44.6 (10.3)¶ 40.0 (60.0)¶

36.5 (10.8) 25.7 (2.9)

<0.001

27 (13.9) 112 (57.7) 55 (28.4) 34.8 (25.9)‡§

42 (18.1)

50.1 (35.9)

52.7 (1.8)

6 (18.2) 23 (69.7) 4 (12.2) 50.4 (35.7)

0.005

56 (24.1)

22 (21.4) 72 (69.9) 9 (8.7)

26.1 (4.0)¶ 3.7 (3.2)

28 (12.1)

25.2 (4.5) 4.1 (3.4) 35 (34.0) 4 (3.9)

24.3 (3.3) 5.0 (3.4) 12 (36.4) 3 (9.1)

0.023

51 (9.1)

26.1 (3.5)¶ 2.8 (3.0)‡§¶ 34 (17.5)‡§¶ 16 (8.2)

42 (7.5)

12 (6.2)

2 (9.5)

8 (7.8)

0 (0.0)

0.212

30.0 (21.9)‡

43.6 (23.0)§¶

61.9 (19.6)

62.4 (20.1)

<0.001

45.3 (26.3)§¶ 21.7 (19.8)§ 33.1 (19.8)§¶

61.2 (20.4) 37.0 (19.5)¶ 49.2 (17.3)

73.3 (17.0) 49.7 (24.3) 59.0 (18.5)

<0.001

6.6 (5.1)

57.2 (11.5) 69.1 (24.7)

97 (17.3) 341 (60.7) 124 (22.1) 45.8 (33.8)

25.8 (3.9) 3.5 (3.2) 144 (25.6)

score (points), mean (SD)

GOLD IV (n=33)

74.4 (5.9)§ 143 (73.7)§ 7.2 (4.0)

Disease-specific health status SGRQ symptom 47.2 (24.8)

SGRQ activity score (points), mean (SD) SGRQ impact score (points), mean (SD) SGRQ total score (points), mean (SD)

GOLD III (n=103)

134 (57.8)

63 (27.2)

0.022 0.056

<0.001

<0.001 0.005 0.109

§¶

48.4 (27.5) 26.3 (22.4) 37.1 (22.1)

28.5 (24.5)‡§¶ 13.4 (16.8)‡§¶ 21.2 (18.1)‡§¶

<0.001 <0.001

Sleep quality disturbances and cognition in COPD

Physical functioning 6MWT (meters), mean (SD) 6MWT (% predicted), mean (SD) Barthel index (points), mean (SD) Barthel index <80, n (%)

317.4 (120.2)

341.0 (123.8)¶ 23.3 (36.8)

322.0 (111.1)§¶ 24.4 (36.7)

280.2 (124.1) 26.1 (33.3)

255.6 (100.6) 29.6 (30.4)

<0.001

94.7 (8.9)¶ 7 (3.6)¶

93.1 (9.3)¶ 16 (6.9)¶

91.9 (7.8) 8 (7.8)¶

87.7 (10.2) 9 (27.3)

<0.001

31 (13.4)§

4 (3.9)

30 (12.9)§

3 (2.9)

16 (6.9)

4 (3.9)

4 (12.1) 4 (12.1) 0 (0.0)

0.003

34 (6.0)

66 (5.7)‡ 10 (5.2)‡ 14 (7.2)

22 (3.9)

7 (3.6)

11 (4.7)

4 (3.9)

0 (0.0)

0.612

64 (11.4)

18 (9.3)

31 (13.4)

9 (8.7)

0.264

30 (5.3)

10 (5.2)

17 (7.3)

2 (1.9)

6 (18.2) 1 (3.0)

9 (1.6)

3 (1.5)

4 (1.7)

2 (1.9)

0 (0.0)

0.888

24.6 (35.7) 93.1 (9.1) 40 (7.1)

0.797

<0.001

Myocardial infarction, n (%) Congestive heart failure, n (%) Peripheral vascular disease, n (%) Cerebrovascular disease or ischemic stroke, n (%) Diabetes Mellitus, n (%) Solid or malignant tumors, n (%) Parkinson Disease, n (%)

48 (8.5) 47 (8.4)

0.004 0.292

0.210

Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; GDS, Geriatric Depression Scale; SD, standard deviation; SGRQ, St George’s Respiratory Questionnaire (SGRQ); 6MWT, 6-minute walking test. For the following variables missing variables were present: packyears (24.2%) and SGRQ (34.5%). †, comparisons between patients with COPD in GOLD grades I-IV; ‡, p<0.05 vs. GOLD II; §, p<0.05 vs. GOLD III; ¶, p<0.05 vs. GOLD IV. Table 2. Nocturnal symptoms, early morning symptoms, sleep disturbances, and cognitive functioning in the study population COPD GOLD I GOLD II GOLD III GOLD P(n=562) (n=194) (n=232) (n=103) IV value† (n=33) Nocturnal symptoms IUATLD shortness of 100 (17.8) 10 (5.2)‡§¶ 39 31 20 <0.001 breath (yes), n (%) (16.8)§ ¶ (30.1)¶ (60.6) IUATLD coughing 203 (36.1) 39 80 60 (58.3) 24 <0.001 (yes), n (%) (20.1)‡§¶ (34.5)§ ¶ (72.7) Early morning symptoms Coughing in the 232 (41.3) 35 91 76 30 <0.001 early morning (18.0)‡§¶ (39.2)§ ¶ (73.8)¶ (90.9) (yes), n (%) Expectoration in 264 (47.0) 37 112 88 (85.4) 27 <0.001 the early morning (19.1)‡§¶ (48.3)§ ¶ (81.8) (yes), n (%)

Chapter 4

Comorbid diseases

Chapter 4 Sleep disturbances EPESE (points), mean (SD) EPESE ≥ 8, n (%) EPESE difficulty falling asleep (yes), n (%) EPESE nocturnal awakenings (yes), n (%) EPESE morning tiredness (yes), n (%) EPESE early awakenings (yes), n (%)

Cognitive functioning Age and education adjusted MMSE (points), mean (SD) MMSE ≤24, n (%)

MMSE orientation (percentage correct), mean (SD) MMSE memory (percentage correct), mean (SD) MMSE attention and calculation (percentage correct), mean (SD) MMSE language (percentage correct), mean (SD) MMSE design copying (failed), n (%)

4.2 (4.4)

4.5 (4.5)

4.1 (4.4)

3.7 (4.1)

0.257

23 (22.3)

5.1 (4.6) 12 (36.4) 5 (15.2)

175 (31.1)

64 (33.0)

70 (30.2)

29 (28.2)

97 (17.3)

38 (19.6)

31 (13.4)

171 (30.4)

64 (33.0)

68 (29.3)

31 (30.1)

8 (24.2)

0.720

38 (6.8)

29 (14.9)

38 (16.4)

19 (18.4)

8 (24.2)

0.569

94 (16.7)

14 (7.2)

213 (5.6)

9 (8.7)

2 (6.1)

0.748

0.739 0.160

28.4 (3.7)

28.9 (2.9)

28.4 (4.0)

27.7 (4.6)

28.6 (3.1)

0.064

142 (25.3)

39 (20.1)

68 (29.3)

0.96 (0.09)‡

0.92 (0.16)

11 (33.3) 0.93 (0.14)

0.107

0.93 (0.1)

24 (23.3) 0.92 (0.15)

0.86 (0.2)

0.87 (0.17)

0.86 (0.18)

0.83 (0.20)

0.85 (0.18)

0.228

0.76 (0.3)

0.78 (0.31)

0.75 (0.34)

0.72 (0.36)

0.79 (0.30)

0.462

0.91 (0.1)

0.95 (0.10)‡§

0.91 (0.14)

0.88 (0.19)

0.91 (0.12)

0.001

178 (33.3)

48 (25.3)§

76 (34.5)

41 (43.6)

13 (43.3)

0.001

0.014

Abbreviations: COPD, chronic obstructive pulmonary disease; EPESE, Established Populations for Epidemiologic Studies of the Elderly questionnaire; IUATLD, The International Union against Tuberculosis and Lung Disease Bronchial Symptoms Questionnaire; MMSE, Mini Mental State Examination. †, comparisons between patients with COPD GOLD grade I-IV. ‡, p<0.05 vs. GOLD II; §, p<0.05 vs. GOLD III; ¶, p<0.05 vs. GOLD IV.

Sleep quality disturbances and cognition in COPD

Copying ability and language were worse for GOLD III than GOLD I. Orientation and language were worse for GOLD II than GOLD I. Instead, the prevalence of global cognitive impairment and the adjusted MMSE score did not differ across GOLD grades (Table 2). Sleep disturbances overall did not correlate with global cognitive functioning in the total COPD group (r=0.036, p=0.392), and this relationship was not influenced by COPD severity (interaction term GOLD grade × sleep disturbances in a linear regression model ß=-0.257, p=0.797). Copying ability was comparable between patients with and without sleep disturbances overall in the total COPD group and across GOLD grades, except that a higher percentage of patients in GOLD I with sleep disturbances failed on copying function compared to those without sleep disturbances (41.5% vs. 20.8%, p=0.008) (Figure 1). In the total COPD group, patients with difficulties to fall asleep more often failed on the design copying compared to patients without difficulties to fall asleep (Figure 2). Patients in GOLD I with difficulties to fall asleep and nocturnal awakenings had worse copying ability than those without these specific sleep disturbances (Figure 3). For the remaining cognitive functions, percentage correct scores did not differ between patients with and without specific sleep disturbances (e-Figure 1-3).

Figure 1. Design copying failure (% of patients) (y-axis) in the total COPD group with and without sleep disturbances and after stratification for GOLD grade (x-axis).

Chapter 4

Relationship between cognitive functioning and sleep disturbances

ChapterÂ 4Â

Figure 2. Percentage correct cognitive functioning scores (y-axis) per cognitive function (x-axis) in patients with COPD with and without difficulties to fall asleep (A), nocturnal awakening (B), early awakening (C), and (D) morning tiredness. For the copying ability function, percentages of patient who failed (y-axis) are depicted. P>0.05 unless otherwise indicated.

Figure 3. Percentage correct cognitive functioning scores (y-axis) per cognitive function (x-axis) in patients with COPD GOLD I with and without difficulties to fall asleep (A), nocturnal awakening (B), early awakening (C), and (D) morning tiredness. For the copying ability function, percentages of patient who failed (y-axis) are depicted. P>0.05 unless otherwise indicated.

Sleep quality disturbances and cognition in COPD

Discussion Key findings

Cognitive functioning and sleep disturbances Sleep disturbances were equally distributed across GOLD stages, and our a priori hypothesis that copying ability is associated to sleep disturbances in patients with COPD was confirmed for patients in GOLD I: patients with sleep disturbances overall had worse performance compared to those without sleep disturbances. A trend towards worse copying ability in the total COPD group with sleep disturbances overall compared to those without was observed as well, suggesting that these patients are more prone to impairments in executive and visuospatial functions. In addition, GOLD I patients with difficulties to fall asleep and nocturnal awakenings had worse copying ability. The fact that we disclosed an association between copying ability and sleep disturbances only in mild COPD suggests that factors different from those contributing to GOLD grading account for impairments of sleep and cognition. Indeed, MMSE and EPESE total scores were not correlated in the total COPD group.

Cognitive functioning and disease severity Also a link between COPD severity and copying function, orientation and language was disclosed, but not on the remaining components of the MMSE. This information is important since higher-level cognitive functions may have adverse effects on therapy.20 Some large-scale studies did find a significant, albeit weak, association between cognitive functioning and lung function.21,22 It is possible that this relationship becomes evident after the onset of hypoxemia or consequent hypoxia.23 Hypoxemia increases with disease severity, with over 80% of patients with advanced disease using some form of oxygen therapy.24 Since we included ambulatory patients with mostly mild to moderate COPD, hypoxia might not be highly prevalent in this study population. Yet, depression predates the onset of cognitive impairment,25 and depressive symptoms, measured with the GDS, in fact, were increased in GOLD III and IV compared to GOLD I and II. Also disease-specific health status, which has been shown to be associated with depressive symptoms,26 was worse for GOLD II-IV compared to patients in GOLD I. Moreover, a higher prevalence of myocardial infarction and

Chapter 4

The present study found that global cognitive functioning was not associated with self-reported sleep quality disturbances overall in an elderly COPD population. However, a trend was observed towards worse copying function in patients with sleep disturbances in the total group and in GOLD I. Moreover, higher-level cognitive functions as reflected by the copying function, orientation, and language decreased to some extent with increasing disease severity.

ChapterÂ 4Â congestive heart failure was found in GOLD II patients. Even though these comorbidities, as well as health status, are known to have a close association with both cognitive impairment and sleep disturbances,27 the prevalence of global cognitive impairment and sleep disturbances was comparable across all GOLD grades. Until now, apart from the MMSE total score, no norm scores are available for specific MMSE cognitive function scores. Moreover, the copy function item of the MMSE is a pass or fail item and the clinical significance of its findings have to be further investigated. Nevertheless, the finding of a decrease in copying ability from GOLD I-III seems biologically plausible because defective copying design qualified as a marker of COPD severity and a prognostic marker as well.8,28 Moreover, in the general population, impairments in copying design have been found to identify drivers being more likely to cause a car accident or to adapt their driving by avoiding peak times and keeping to familiar areas.29,30 This is not surprising, since the design copying function reflects both executive and visuospatial functions.8 Nocturnal symptoms and sleep disturbances are suggested to be the effects of COPD related symptoms,31 and recent literature shows that nocturnal symptoms have a distinctive distribution with regard to COPD severity.32 In line with this study, we found that early morning and nocturnal symptoms, but not sleep disturbances, were associated with COPD severity. Sleep disturbances therefore, might reflect a common symptom of the disease which cannot be entirely captured by COPD severity. Indeed, sleep disturbances are reported frequently in this population and might influence cognitive functioning.

Methodological considerations A strength of the study is that data from individual centers were collected prospectively by a coordinating center and the study population thus reflects an unselected cohort of COPD patients. However, this study was a cross-sectional design, and therefore is limited to draw valid conclusions as to causality and the strength of the association between COPD severity, sleep disturbances and cognitive functioning. Another limitation is that no post-bronchodilator spirometry was included, which is a prerequisite for the definition of airflow limitation that is not fully reversible. Additionaly, no data were available regarding medication use. Not only the usage of pulmonary medication (e.g. (oral) corticosteroids, Î˛2-agonists, anticholinergics and theophylline) and non-pulmonary medication (e.g. anticonvulsants, analgesics, antidepressants, beta adrenergic blockers, diuretics, and thyroid preparations) may promote sleep disturbances, but also the discontinuation of these medications.33 Moreover, no data of elderly patients without COPD were included and the prevalence of sleep disturbance and cognitive impairment in normal elderly patients needs to be investigated. Administration of the MMSE was not only performed in a patient subset

Conclusions Sleep disturbances seem to be a weak correlate of cognitive performance in patients with COPD, nor a marker of severity of COPD. Longitudinal studies including hypoxemic patients and using a detailed neuropsychological testing battery in combination with polysomnography are needed to confirm our results.

Chapter 4

Sleep quality disturbances and cognition in COPD being selected for a specific intervention, but as part of routine clinical workup. Indication bias therefore can be excluded. Yet, elderly ambulatory patients from geriatric institutions with only a very minority of COPD patients in GOLD IV who are not likely to have hypoxia were included, so conclusions should be generalized with some caution. Moreover, we have no information about obstructive sleep apnea syndrome, that may be a confounder in the association between sleep disturbances and cognitive deficits34 Further, cognitive assessment was based upon a screening instrument, which is less sensitive than a detailed neuropsychological testing battery. Finally, the IUATLD questionnaire does not provide grading of nocturnal symptoms and qualitative characteristics of sleep disturbances were studied. Objective polysomnographic data should confirm our findings.

Chapter 4

References 1. 2.

3. 4. 5.

6. 7. 8. 9.

10. 11.

12. 13.

14.

15. 16.

17. 18.

19.

20.

Alhola P, Polo-Kantola P. Sleep deprivation: Impact on cognitive performance. Neuropsychiatr Dis Treat. 2007;3(5):553-567. Bellia V, Catalano F, Scichilone N, Incalzi RA, Spatafora M, Vergani C, Rengo F. Sleep disorders in the elderly with and without chronic airflow obstruction: the SARA study. Sleep. 2003;26(3):318-323. Cleutjens FA, Janssen DJ, Ponds RW, Dijkstra JB, Wouters EF. COgnitive-pulmonary disease. Biomed Res Int. 2014;2014:697825. Ray M, Sano M, Wisnivesky JP, Wolf MS, Federman AD. Asthma control and cognitive function in a cohort of elderly adults. J Am Geriatr Soc. 2015;63(4):684-691. Omachi TA, Blanc PD, Claman DM, Chen H, Yelin EH, Julian L, Katz PP. Disturbed sleep among COPD patients is longitudinally associated with mortality and adverse COPD outcomes. Sleep Med. 2012;13(5):476-483. Maquet P. Functional neuroimaging of normal human sleep by positron emission tomography. J Sleep Res. 2000;9(3):207-231. Board M, Allen SC. A simple drawing test to identify patients who are unlikely to be able to learn to use an inhaler. Int J Clin Pract. 2006;60(5):510-513. Antonelli-Incalzi R, Corsonello A, Pedone C, Trojano L, Acanfora D, Spada A, Izzo O, Rengo F. Drawing impairment predicts mortality in severe COPD. Chest. 2006;130(6):1687-1694. Bellia V, Pistelli R, Catalano F, Antonelli-Incalzi R, Grassi V, Melillo G, Olivieri D, Rengo F. Quality control of spirometry in the elderly. The SA.R.A. study. SAlute Respiration nell'Anziano = Respiratory Health in the Elderly. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1094-1100. Meguro M, Barley EA, Spencer S, Jones PW. Development and Validation of an Improved, COPDSpecific Version of the St. George Respiratory Questionnaire. Chest. 2007;132(2):456-463. Holland AE, Spruit MA, Troosters T, Puhan MA, Pepin V, Saey D, McCormack MC, Carlin BW, Sciurba FC, Pitta F, Wanger J, MacIntyre N, Kaminsky DA, Culver BH, Revill SM, Hernandes NA, Andrianopoulos V, Camillo CA, Mitchell KE, Lee AL, Hill CJ, Singh SJ. An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease. Eur Respir J. 2014;44(6):1428-1446. Mahoney FI, Barthel DW. Functional Evaluation: The Barthel Index. Md State Med J. 1965;14:61-65. Sheikh VI, Yesavage VA. The short form of the Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. In: Brink TL, ed. Clinical gerontology: a guide to assessment and intervention. Vol 165-74. New York: Haworth Press; 1986. Burney PG, Laitinen LA, Perdrizet S, Huckauf H, Tattersfield AE, Chinn S, Poisson N, Heeren A, Britton JR, Jones T. Validity and repeatability of the IUATLD (1984) Bronchial Symptoms Questionnaire: an international comparison. Eur Respir J. 1989;2(10):940-945. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45(6):613-619. Cornoni-Huntley J, Ostfeld AM, Taylor JO, Wallace RB, Blazer D, Berkman LF, Evans DA, Kohout FJ, Lemke JH, Scherr PA. Established populations for epidemiologic studies of the elderly: study design and methodology. Aging (Milano). 1993;5(1):27-37. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198. Measso G, Cavarzeran F, Zappalà G, Lebowitz BD, Crook TH, Pirozzolo FJ, Amaducci LA, Massari D, Grigoletto F. The mini-mental state examination: Normativestudy of an Italian random sample. Developmental Neuropsychology. 1993;9(2):77-85. Global initiative for chronic obstructive lung disease: Pocket guide to COPD diagnosis, management, and prevention. Updated 2015. 2015; http://www.goldcopd.org/uploads/users/files/GOLD_Pocket_2015_Feb18.pdf. Becker BW, Thames AD, Woo E, Castellon SA, Hinkin CH. Longitudinal change in cognitive function and medication adherence in HIV-infected adults. AIDS Behav. 2011;15(8):1888-1894.

Sleep quality disturbances and cognition in COPD

21. Cleutjens FA, Spruit MA, Ponds RW, Dijkstra JB, Franssen FM, Wouters EF, Janssen DJ. Cognitive functioning in obstructive lung disease: results from the United Kingdom biobank. J Am Med Dir Assoc. 2014;15(3):214-219. 22. Sachdev PS, Anstey KJ, Parslow RA, Wen W, Maller J, Kumar R, Christensen H, Jorm AF. Pulmonary function, cognitive impairment and brain atrophy in a middle-aged community sample. Dement Geriatr Cogn Disord. 2006;21(5-6):300-308. 23. Thakur N, Blanc PD, Julian LJ, Yelin EH, Katz PP, Sidney S, Iribarren C, Eisner MD. COPD and cognitive impairment: the role of hypoxemia and oxygen therapy. Int J Chron Obstruct Pulmon Dis. 2010;5:263-269. 24. Martinez FJ, Foster G, Curtis JL, Criner G, Weinmann G, Fishman A, DeCamp MM, Benditt J, Sciurba F, Make B, Mohsenifar Z, Diaz P, Hoffman E, Wise R, Group NR. Predictors of mortality in patients with emphysema and severe airflow obstruction. Am J Respir Crit Care Med. 2006;173(12):1326-1334. 25. Jelicic M, Bosma H, Ponds RW, Van Boxtel MP, Houx PJ, Jolles J. Subjective sleep problems in later life as predictors of cognitive decline. Report from the Maastricht Ageing Study (MAAS). Int J Geriatr Psychiatry. 2002;17(1):73-77. 26. Incalzi RA, Bellia V, Catalano F, Scichilone N, Imperiale C, Maggi S, Rengo F, Salute Respiratoria nell-Anziano S. Evaluation of health outcomes in elderly patients with asthma and COPD using disease-specific and generic instruments: the Salute Respiratoria nell'Anziano (Sa.R.A.) Study. Chest. 2001;120(3):734-742. 27. Garcia S, Alosco ML, Spitznagel MB, Cohen R, Raz N, Sweet L, Colbert L, Josephson R, Hughes J, Rosneck J, Gunstad J. Poor sleep quality and reduced cognitive function in persons with heart failure. Int J Cardiol. 2012;156(2):248-249. 28. Antonelli Incalzi R, Corsonello A, Trojano L, Pedone C, Acanfora D, Spada A, D'Addio G, Maestri R, Rengo F, Rengo G. Heart rate variability and drawing impairment in hypoxemic COPD. Brain Cogn. 2009;70(1):163-170. 29. Gallo JJ, Rebok GW, Lesikar SE. The driving habits of adults aged 60 years and older. J Am Geriatr Soc. 1999;47(3):335-341. 30. Johansson K, Bronge L, Lundberg C, Persson A, Seideman M, Viitanen M. Can a physician recognize an older driver with increased crash risk potential? J Am Geriatr Soc. 1996;44(10):1198-1204. 31. Kessler R, Partridge MR, Miravitlles M, Cazzola M, Vogelmeier C, Leynaud D, Ostinelli J. Symptom variability in patients with severe COPD: a pan-European cross-sectional study. Eur Respir J. 2011;37(2):264-272. 32. Miravitlles M, Worth H, Soler Cataluna JJ, Price D, De Benedetto F, Roche N, Godtfredsen NS, van der Molen T, Lofdahl CG, Padulles L, Ribera A. Observational study to characterise 24-hour COPD symptoms and their relationship with patient-reported outcomes: results from the ASSESS study. Respir Res. 2014;15:122. 33. Stege G, Vos PJ, van den Elshout FJ, Richard Dekhuijzen PN, van de Ven MJ, Heijdra YF. Sleep, hypnotics and chronic obstructive pulmonary disease. Respir Med. 2008;102(6):801-814. 34. Bedard MA, Montplaisir J, Malo J, Richer F, Rouleau I. Persistent neuropsychological deficits and vigilance impairment in sleep apnea syndrome after treatment with continuous positive airways pressure (CPAP). J Clin Exp Neuropsychol. 1993;15(2):330-341.

Chapter 4

Supplementary file Tables e-Table 1. Associations between nocturnal and early morning symptoms and sleep disturbances in the study population Nocturnal and early morning symptoms Woken at night Woken at night Coughing in Expectoration by shortness of by coughing the early in the early breath morning morning Sleep disturbances ppppӼ2 Ӽ2 Ӽ2 Ӽ2 value value value value COPD EPESE difficulty 23.7 <0.00 18.1 0.001 5.3 0.255 3.3 0.505 falling asleep 1 EPESE nocturnal 17.5 0.002 15.8 0.003 5.3 0.260 6.0 0.198 awakenings EPESE morning 17.8 0.001 16.6 0.002 8.0 0.092 7.5 0.112 tiredness EPESE early 21.5 <0.00 8.1 0.087 3.2 0.530 3.8 0.430 awakenings 1 EPESE total score 0.13† 0.003 0.16† <0.001 0.03† 0.500 0.03† 0.528 GOLD I EPESE difficulty 17.0 0.002 14.4 0.006 6.1 0.189 12.4 0.014 falling asleep EPESE nocturnal 4.9 0.293 6.3 0.179 1.6 0.809 2.3 0.677 awakenings EPESE morning 3.7 0.445 10.9 0.028 3.9 0.415 5.2 0.268 tiredness EPESE early 7.5 0.113 6.5 0.165 1.4 0.838 2.0 0.735 awakenings EPESE total score 0.18† 0.014 0.18† 0.012 0.03† 0.697 0.09† 0.205 GOLD II EPESE difficulty 6.2 0.186 8.4 0.080 2.2 0.697 4.1 0.394 falling asleep EPESE nocturnal 8.2 0.086 10.6 0.031 6.8 0.149 7.0 0.138 awakenings EPESE morning 8.7 0.070 4.8 0.304 4.3 0.372 2.7 0.616 tiredness EPESE early 5.1 0.281 3.9 0.425 4.6 0.325 3.5 0.482 awakenings EPESE total score 0.11† 0.100 0.16† 0.016 0.00* 0.957 -0.01† 0.926 GOLD III EPESE difficulty 13.6 0.010 14.4 0.006 5.0 0.284 4.5 0.347 falling asleep EPESE nocturnal 13.3 0.010 9.2 0.057 5.4 0.246 5.7 0.219 awakenings EPESE morning 20.9 <0.00 10.5 0.033 2.4 0.663 4.2 0.386 tiredness 1 EPESE early 13.6 0.009 20.3 <0.001 6.9 0.143 3.8 0.432 awakenings EPESE total score 0.24† 0.014 0.28† 0.005 0.22† 0.023 0.16† 0.094

Sleep quality disturbances and cognition in COPD

GOLD IV EPESE difficulty falling asleep EPESE nocturnal awakenings EPESE morning tiredness EPESE early awakenings EPESE total score

3.1

0.546

2.3

0.672

2.8

0.585

6.3

0.177

4.5

0.338

1.6

0.805

2.0

0.736

2.8

0.589

2.9

0.569

4.7

0.528

0.8

0.932

1.9

0.757

2.2

0.696

2.2

0.698

1.4

0.845

3.4

0.486

0.01†

0.974

0.03†

0.862

0.04†

0.833

0.13†

0.457

Abbreviations: COPD, chronic obstructive pulmonary disease; EPESE, Established Populations for Epidemiologic Studies of the Elderly questionnaire. †, Correlation Coefficient (Pearson's r).

Chapter 4

e-Table 2. Adjustment values for the MMSE total score, by age and years of education Age (years) Education (years) 0-3 4-5 6-8 9-13 >13 20-29 0.72 -0.17 -0.81 -1.41 -1.93 30-39 0.91 0.09 -0.58 -1.25 -1.90 40-49 1.10 0.31 -0.38 -1.11 -1.79 50-59 2.24 0.74 -0.03 -1.01 -1.69 60-69 2.99 1.27 0.53 -0.51 -1.54 70-79 5.24 2.03 1.20 -0.14 -1.15 Derived from: Measso G, Cavarzeran F, Zappalà G, Lebowitz BD, Crook TH, Pirozzolo FJ, Amaducci LA, Massari D, Grigoletto F: The mini-mental state examination: Normativestudy of an Italian random sample. Developmental Neuropsychology 1993, 9:77-85. The values were added to the observed MMSE total score of a subject in order to remove the effects of age and education from his or her performance on the test.

Figures

e-Figure 1. Percentage correct cognitive functioning scores (y-axis) per cognitive domain (x-axis) in patients with COPD GOLD II with and without difficulties to fall asleep (A), nocturnal awakening (B), early awakening (C), and (D) morning tiredness. For the domain copying ability, percentages of patient who failed (y-axis) are depicted. P>0.05 unless otherwise indicated.

ChapterÂ 4Â

e-Figure 2. Percentage correct cognitive functioning scores (y-axis) per cognitive domain (x-axis) in patients with COPD GOLD III with and without difficulties to fall asleep (A), nocturnal awakening (B), early awakening (C), and (D) morning tiredness. For the domain copying ability, percentages of patient who failed (y-axis) are depicted. P>0.05 unless otherwise indicated.

e-Figure 3. Percentage correct cognitive functioning scores (y-axis) per cognitive domain (x-axis) in patients with COPD GOLD IV with and without difficulties to fall asleep (A), nocturnal awakening (B), early awakening (C), and (D) morning tiredness. For the domain copying ability, percentages of patient who failed (y-axis) are depicted. P>0.05 unless otherwise indicated.

Chapter 5

The COgnitive-Pulmonary Disease (COgnitive-PD) study: protocol of a longitudinal observational comparative study on neuropsychological functioning of COPD patients Cleutjens FA, Wouters EF, Dijkstra JB, Spruit MA, Franssen FM, Vanfleteren LE, Ponds RW, Janssen DJ. The COgnitive-Pulmonary Disease (COgnitive-PD) study: protocol of a longitudinal observational comparative study on neuropsychological functioning of patients with COPD. BMJ Open. 2014;4(3):e004495. Reprinted with permission from BMJ Publishing Group Ltd.

ChapterÂ 5Â

Abstract Introduction Intact cognitive functioning is necessary for patients with chronic obstructive pulmonary disease (COPD) to understand the value of healthy lifestyle guidelines, to make informed decisions and subsequently act on it. Nevertheless, brain abnormalities and cognitive impairment have been found in patients with COPD. To date, it remains unknown which cognitive domains are affected and what the possible consequences are of cognitive impairment. Therefore, objectives of the study described are to determine neuropsychological functioning in patients with COPD, and its influence on health status, daily functioning and pulmonary rehabilitation outcome. Furthermore, structural and functional brain abnormalities and the relationship with cognitive and daily functioning will be explored. Methods and analysis A longitudinal observational comparative study will be performed in 183 patients with COPD referred for pulmonary rehabilitation and in 90 healthy control participants. Demographic and clinical characteristics, activities of daily living and knowledge about COPD will be assessed. Baseline cognitive functioning will be compared between patients and controls using a detailed neuropsychological testing battery. An MRI substudy will be performed to compare brain abnormalities between 35 patients with COPD with cognitive impairment and 35 patients with COPD without cognitive impairment. Patients will be recruited between November 2013 and November 2015. Ethics and dissemination The study has been approved by the Medical Ethics Committee of the University Hospital Maastricht and Maastricht University (NL45127.068.13/METC13-3-035) and is registered in the Dutch trial register. All participants will provide written informed consent and can withdraw from the study at any point in time. Assessment and home visit data material will be managed anonymously. The results obtained can be used to optimize patient-oriented treatment for cognitively impaired patients with COPD. The findings will be disseminated in international peer reviewed journals and through research conferences.

The COgnitive‐PD study

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease of the lungs, that is usually progressive.1 It is a major course of morbidity and mortality worldwide.2 Patients with COPD often suffer from extrapulmonary features, such as cardiovascular disease, exercise intolerance, osteoporosis and psychological symptoms.1,3–5 Patients with COPD may suffer from cognitive impairment.6 The incidence of cognitive impairment in patients with COPD varies in different studies from 12% to 88%.7 It may lead to increased dyspnoea and fatigue,8 incorrect use of inhaler devices and low compliance with medicaltreatment.9 This might increase the exacerbation risk and could result in worse health outcomes.10 Indeed, cognitive impairment has been found to predict mortality in hypoxaemic patients with COPD.11 A recent review article indicates a specic pattern of cognitive impairment in patients with COPD.12 This suggests that COPD is associated with specic abnormalities in brain structure. However, cognitive functioning has mostly been studied with broad-scale measurements, which do not separate specic cognitive functions, such as psychomotor speed, memory, cognitive exibilityandplanning.13 Therefore, no clear statement can be made about the incidence and clinical implications of cognitive impairment in specic cognitive domains in patients with COPD. Insight in cognitive functioning is of great importance in order to optimize self-management skills of patients with COPD. Indeed, cognitive decits may lead to difculties in managing their disease and negatively affect their treatment and, in particular, the efcacy of a pulmonary rehabilitation programme.14 Therefore, the aim of this study is to compare cognitive functioning in patients with COPD referred for pulmonary rehabilitation and participants without COPD. More specic objectives of the present study are to: 1. Examine whether and to what extent cognitive functioning is impaired in patients with COPD referred for pulmonary rehabilitation, compared with a control group matched on smoking status, age and educational level without COPD in the following domains: psychomotor speed, memory, cognitive exibility and planning; 2. Investigate clinical and demographic characteristics of patients with COPD with cognitive impairment; 3. Explore whether and to what extent cognitive functioning of patients with COPD referred for pulmonary rehabilitation is related to problems in daily functioning;

Chapter 5

Background

Chapter 5 4. Examine whether and to what extent cognitive functioning affects outcomes of pulmonary rehabilitation (general psychological functioning, knowledge about COPD, need for information, daily functioning and functional exercise capacity); 5. Determine the presence of functional and structural brain abnormalities in patients with COPD with and without cognitive dysfunction. We hypothesize that patients with COPD with more severe airow limitation have worse cognitive functioning on all of the aforementioned domains, compared with patients with less severe disease. Moreover, patients with COPD have worse cognitive functioning compared with healthy controls. Furthermore, patients with COPD with cognitive impairments will potentially have worse clinical characteristics, experience more often limitations in daily functioning and have worse outcomes of pulmonary rehabilitation compared with patients with COPD without cognitive impairment. Finally, patients with COPD with brain abnormalities are suspected to have more often cognitive impairments and to experience more often limitations in daily functioning.

Methods and analysis Study design A longitudinal observational comparative study will be performed. Patients who enter pulmonary rehabilitation at CIRO+ will be recruited between November 2013 and November 2015. They are referred to CIRO+ for interdisciplinary assessment when they are symptomatic or they report having decreased daily lifeactivity at outpatient consultation with their chest physician, even if receiving optimum drug treatment. During the 3-day assessment at CIRO+, centre of expertise for chronic organ failure,15 patients will be invited to participate in the study. The 3-day assessment includes as part of the clinical routine the evaluation of physical functioning, psychosocial functioning, coexisting morbidities, exercise capacity, daily functioning and health status, as published before.5,16 Before the start of the pulmonary rehabilitation programme, the patient will be visited at home for neuropsychological examination. After completion of the pulmonary rehabilitation programme, all patients will undergo an outcome assessment. Baseline test will be repeated and the results of initial and outcome assessments will be available for the study in the electronic patient’s record. As part of an MRI substudy, a subgroup of the patients with COPD will undergo MRI of the brain to determine the presence of brain abnormalities in patients with COPD with and without cognitive impairment. MRI will be performed after the 3-day assessment and before the start of the pulmonary rehabilitation programme (see gure 1).

The COgnitive‐PD study

Chapter 5

Figure 1. Study design

Study population In total, the study will include 183 patients with clinically stable COPD, based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) document,1 referred for pulmonary rehabilitation. Participants with clinically unstable COPD in the past 4 weeks, participants with a diagnosis of dementia in their medical history and/or participants who do not master the Dutch language sufciently will not be eligible to participate. To develop a representative control group, 90 controls will be included. Controls will be matched with a patient with COPD on smoking status (non-smoker, ex-smoker or smoker), age (SD=10 years) and education (SD=1) level according to the scoring system of the Central Bureau of Statistics (CBS) Dutch educational system.17 Control participants with a diagnosis of COPD, asthma or dementia in their medical history are ineligible to participate, as well as participants who have Dutch language difculties. A subgroup of 35 patients with COPD and cognitive impairment and 35 without cognitive impairment will be included in the MRI substudy. Participants are excluded when they suffer from claustrophobia or when they have a cardiac pacemaker, cochlear implant, neurostimulator, metal fragments in the eyes and/or other electronic or metal implants.

Measures Table 1 gives an overview of the variables assessed and instruments used.

Chapter 5 Table 1. Primary and secondary outcomes in de COgnitive-PD study Instrument Primary outcome Cognitive functioning

Secondary outcomes Demographic characteristics Age Educational level Marital status Clinical characteristics General psychological functioning Anxiety and depression symptoms Personality Psychopathology Coping style Disease-specific health status

Other clinical characteristics Information needs Arterial blood gases including PaO2, PaCO2 and SaO2 Medical history Resting transcutaneous oxygen saturation, lung function (FEV1 and FVC), and DLCO Use of inhaled and systemic corticosteroids, diagnosis of OSAS, oxygen therapy Smoking behaviour Height, weight and BMI Functional exercise capacity Fatigue Dyspnea

Cognitive Failure Questionnaire18 ‘Groninger Intelligentie Test’ (vocabulary, mental rotation, figure discovery, doing sums, analogies and fluency)20 Concept Shifting Test21 Stroop Color-Word Interference test22,23 Letter Digit Substitution Test24 15-word learning task25 Behavioural Assessment of the Dysexecutive Syndrome (key-search and zoo-map test)26 Mini-Mental State Examination27 Wechsler Adult Intelligence Scale III (digit span)30

N.A. CBS Dutch educational system17

T1A

T1B

X X

X X X X X

X X

X X X

Hospital Anxiety and Depression scale40 Beck Depression Inventory41 Dutch Personality Questionnaire42 Symptom Checklist-9043 Utrecht Coping List44 St George Respiratory Questionnaire45; COPD assessment test46

X X

X P

Lung Information Needs Questionnaire47 Arterial blood gas P Charlson comorbidity index48

P X

6-minute walk test49 Borg scale49 Borg scale49

X X X X X

The COgnitive‐PD study

Problem areas in daily functioning Knowledge about the lung disease Brain abnormalities Brain atrophy White matter lesions Hippocampal volume Vascular abnormalities Structural connectivity Functional connectivity

Canadian Occupational Performance Measure31 CIROPD

P Traditional MRI Traditional MRI Traditional MRI Traditional MRI Diffusion tensor imaging Resting state functional MRI

P P P P P P P

Primary outcome Our primary outcome, cognitive functioning, consists of four compound performance indices, namely psychomotor speed, memory, cognitive exibility and planning. These will be measured with a detailed neuropsychological testing battery consisting of the following subtests: A. A validated Dutch translation of the CFQ18 which is a 25-item self-report inventory and comprises four main subscales: absent-mindedness, social interactions, names and words and orientation.19 Participants are asked to indicate on a ve-point scale how often they experience subjective cognitive failures. The scale ranges from ‘never (0)’, ‘very rarely (1)’, ‘occasionally (2)’, ‘quite often (3)’, to ‘very often (4)’. Total scores range between 0 and 100, with a higher scores indicating more subjectively experienced cognitive failures. B. A shortened form of the Groninger Intelligence Test (GIT)20 will be used to determine general intelligence. Six subtasks will be administered: (1) vocabulary: measures verbal comprehension. In this subtest, 20 words of increasing difculty are presented of which the participant has to choose the synonym out of ve alternatives. The total score ranges between 0 and 20, with higher scores reecting higher level of verbal intelligence. (2) Mental rotation: measures visualisation. This subtest requires participants to decide which of several smaller geometric shapes from a larger set are needed to ll a larger geometric gure. Total scores range between 0 and 20 with higher scores reecting higher level of visuospatial performance. (3) Figure discovery: measures perceptual intelligence. In

Chapter 5

CBS, Central Bureau of Statistics; COgnitive-PD, COgnitive-Pulmonary Disease; COPD, chronic obstructive pulmonary disease; DLCO, diffusing capacity; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; NA, not applicable; OSAS, obstructive sleep apnoea syndrome; P, patient group only; PaCO2, partial pressure of carbon dioxide; PaO2, partial pressure of oxygen; SaO2, oxygen saturation; T0, 3-day assessment; T1, before pulmonary rehabilitation; T1A, home visit; T1B, MRI of the brains; T2, 2-day outcome assessment; X, instrument used in both patients and controls (however, in patients assessments take place in 1 day at a single visit to the pulmonary rehabilitation centre).

Chapter 5 this subtest, the participant is shown 20 cards with silhouettes of incomplete pictures of familiar objects or animals and then has to estimate what the picture depicts. The total score ranges between 0 and 20, with higher scores reecting higher level of perceptual intelligence. (4) Doing sums: measures numeracy. This subtest requires the participants to complete as many adding sums as possible within a time period of 1 min. The total score ranges between 0 and 32, with higher scores reecting higher level of numeracy. (5) Analogies: measures reasoning. In this subtest, the participant has to choose one from ve possibilities that correctly completes a 3×2 matrix of logical semantic relations (eg, black–white, high– low, hot...?). The total score ranges between 0 and 20, with higher scores reecting higher level of reasoning. (6) Fluency: measures word uency. The Animal Naming Task and the Profession Naming Task are used to assess semantic verbal uency. These tasks require patients to generate as many names as possible within 60 seconds of animals respectively professions. Scores are determined by summing correct responses and reect strategy driven retrieval of information from semantic memory. C. The Concept Shifting Test (CST)21 which is a simple pen-and-paper test, measures concept shifting and executive functioning. This test consists of three subtasks. On each test sheet, 16 small circles are grouped in a larger circle. The small circles contain numbers, letters or both, appearing in a xed random order. Participants are requested to cross out the items in the right order. In the nal part of the test, they have to alternate between numbers (1–8) and letters (A–H). The time needed to complete each subtask and errors will be recorded. Finally, participants are presented with a condition to control for basic motor speed in which empty circles have to be marked as fast as possible in a clockwise manner. The difference between the score for the last part, corrected for basic motor speed, and the mean score for the rst and second parts also corrected for basic motor speed, represent the time needed for cognitive shifting. Cognitive shifting (or mental set shifting) is considered to be part of executive functioning.21 D. The Stroop Colour-Word Test (SCW)22,23 will be used to assess cognitive exibility and is composed of three trials using word, colour and interference cards. The rst card shows names of colours, printed in black, which have to be read out loud. The second card shows patches of colours, which have to be named. The last card shows names of colours printed in incongruously coloured ink and participants are instructed to name the colour of the ink in the printed words. Errors, self-corrected errors and time of completion for all trials will be recorded. The time needed for the last card will be subtracted from the mean score for the rst and second cards to obtain an interference score. This interference

The COgnitive‐PD study score can be regarded as a measure of inhibition of a habitual response (reading) which is part of the domain of executive functioning. E. The Letter Digit Substitution Test (LDST)24 will be used as a measure of information processing speed. A code is presented at the top of the test form, with 10 digit/letter combinations. Participants ll in digits in blank squares indexed with a letter using the code key. The key and the stimuli are the same for the oral and written versions of the LDST. The written LDST version will be administered rst, immediately followed by the oral version. The number of correct substitutions made in 60 s is the dependent variable for both test versions. F. The 15-word learning task (WLT-15)25 visual version will be used to measure memory and verbal learning. In this test, 15 words are visually presented, one after the other, at 2 s intervals. The participants are then asked to recall as many words as possible, in a random order. This procedure will be repeated ve times. When the fth trial is completed, a xed battery of other cognitive tests will be administered for about 20 min. After the delay, unexpectedly for the participant, the instruction will be given to recall the words learned (delayed recall). This will be followed immediately by a recognition test, involving yes/no recognition of the 15 words intermixed with 15 non-target words. Dependent variables are the total number of recalled words in the rst three trials, the number of words recalled after 20 min and the number of words recognised in the recognition trial. G. The key search of the Behavioural Assessment of the Dysexecutive Syndrome will be used as a measure of executive functioning.26 It is claimed that this test assesses ability to plan a strategy to solve a problem (nding a key lost in a eld). The score is based on a number of criteria, including whether the rater believes the strategy to be systematic, efcient and likely to be effective. A penalty is imposed for lack of speed. H. The zoo-map test of the Behavioural Assessment of the Dysexecutive Syndrome as a measure of executive functions.26 This is a test to assess ability independently to formulate and implement a plan (high demand condition) and to follow a preformulated plan (low demand condition). It involves plotting or following a route through a map that does not contravene a set of rules. The score is based on the successful implementation of the plan. Penalties are imposed for rule breaks and lack of speed. I. Global cognitive functioning was assessed with the Mini-Mental State Examination (MMSE)27 as a brief screening for global cognitive functioning. This test consists of questions on orientation to time and place, registration, attention and calculation, recall, language, and visual construction

Chapter 5

Chapter 5 to measure global cognitive functioning. The MMSE consists of 20 questions and the maximum score to achieve is 30 points, with a higher score indicating a better cognitive performance. A score of 26–30 indicates ‘normal cognitive functioning’, a score of 24 or 25 ‘borderline normal cognitive functioning’, a score below 24 ‘cognitive impairment’,28 and a score below 18 ‘severe cognitive impairment’.29 J. Digit span from the Wechsler Adult Intelligence Scale III (WAIS-III)30 as a measure of short-term memory. This test consists of two parts, namely orally presented digits forward and digits backwards. Participants are required to repeat 3–9 digits forward and 2–9 digits backwards. There are two trials at each series length, and the test continues until both trials of a series length are failed. One point is awarded for each correct trial.

Secondary outcomes Age, educational level and marital status will be obtained from the patient records. Psychological factors may inuence cognitive functioning. Therefore, symptoms of anxiety and depression, personality, psychopathology, coping style and disease-specic health status will be measured using the questionnaires mentioned in table 1. Problems in daily functioning will be measured by the Canadian Occupational Performance Measure’s (COPM) semistructured interview.31 The COPM is an outcome measure designed for use by occupational therapists to assess client outcomes in the areas of self-care, productivity and leisure.32 The CIROPD, a knowledge questionnaire developed by CIRO+, Horn will assess what persons know about COPD. The CIROPD is available from authors on request. Conventional MRI will be analysed on brain atrophy, white matter lesions, hippocampal volume and vascular abnormalities by skilled laboratory technicians. In addition, resting state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI) will be used. In diffusion-weighted imaging (DWI), the MR signal is made sensitive to tissue water diffusion in a certain direction. In DTI, for each voxel, the diffusion-weighted signal is evaluated in several directions to which a diffusion tensor is tted. Because in white matter the voxel diffusion coefcient is maximal in the direction parallel to the bre orientation within that voxel, DTI is a technique to study white matter architecture.33 fMRI specically visualises neuronal activity-related changes in cerebral perfusion and thus provides unique insights into the localisation of cognitive functions. In rs-fMRI, no cognitive challenge is presented and the spontaneous uctuation of neuronal activity is assessed. Brain areas that show synchronised activity over time are functionally connected.34 In conventional MRI, the signal intensity of a brain region reects the local composition of the brain tissue. In connectivity studies, the signal intensity of a brain region will also provide information of the structural (DTI) and functional connections (rs-fMRI).

The COgnitive‐PD study

To answer objective 1, cross-sectional analyses will be used to evaluate differences in cognitive functioning in specic domains between 90 patients with COPD (stratied into GOLD stages for severity of COPD) and their matched controls. Student t test will be used for parametric distributed continuous data, Mann-Whitney U test for non-parametric distributed ordinal data and χ2 test for categorical variables. Multivariate analyses will be used to correct for possible confounders, including comorbidities. To limit the number of dependent variables and to improve the robustness of the underlying cognitive construct, the raw test scores will be clustered in four compound performance indices, namely psychomotor speed, memory, cognitive exibility and planning. For all participants, the raw scores will be transformed into Z-scores (Z= {x−mean}/SD).35 36 By transforming raw scores to Zscores, performances can be compared and individual test performances can be classied. This enables us to distinguish between impaired and non-impaired performances on the neuropsychological testing battery. Z-scores from tests that were included in each compound performance index will be averaged. The factor, psychomotor speed, which refers to the speed at which different cognitive operations can be executed, will be created from performance indices on the Stroop Colour-Word Test (initial condition), CST (the time required for the initial condition) and the Letter Digit Substitution Test (raw scores). The memory score will be derived from the total score, the maximum score and delayed recall score of the 15-WLT and the maximum score on the Digit span. The cognitive exibility score will include the time required for the third condition of the CST (alternating letter/digit cancellation) and the time required for subtask 3 of the SCWI. Finally, planning will consist of total scores on the key research and the total scores on the rst condition of the Zoo-map test. In addition, the total score of the MMSE will be used as a general cognitive measure. The sum of the six standardised subscale scores of the GIT will be multiplied by 9/6, yielding an estimate of the complete test score. This estimate will be converted into an IQ score. The sum score of the Cognitive Failure Questionnaire (CFQ) will be used as a measure of subjective cognitive functioning. To answer objective 2, two COPD groups will be created: ‘worst scoring patients with COPD differ −1 SD on the overall compound scores of the neuropsychological testing battery compared with the overall compound scores of the MAAS study and the best scoring patients with COPD differ +1 SD on the overall compound scores of the neuropsychological testing battery compared with the overall compound scores of the MAAS study.37 Clinical characteristics (such as results of blood gases, lung function, etc) and demographic characteristics will be compared between these two groups using univariate and multivariate analyses.

Chapter 5

Planned statistical analyses

Chapter 5 To answer objectives 2–4, correlation analysis/multivariate regression analysis will be used. Potential predictors are dened as variables with a marginally signicant association (p<0.10) with the outcome variable. Only these variables will be included in the subsequent regression analyses to determine the most important predictors. In general, effects with a two-tailed <0.05 are considered statistically signicant. To answer objective 5, cross-sectional analyses will be used to evaluate differences in brain abnormalities between patients with COPD with and without cognitive impairment. Correlation analysis/multivariate regression analysis will be used to assess the relationship between brain abnormalities and cognitive and daily functioning. Signicant correlations will be included in the subsequent regression analyses. Participants who successfully complete initial assessment and the home visit will be assessed for the rst three objectives. Participants who do not complete the outcome assessment will be excluded for the fourth objective. Missing data will be processed without imputation. Post hoc tests with Bonferroni correction will be used to increase the validity of the research and to correct p values in large quantities of statistical tests. Furthermore, the data will be adjusted for gender and pack years.

Sample size and power calculation A sample size calculation with a power of 95%, effect size=0.25 and α=0.05 showed that 175 participants are needed to answer our rst objective. Therefore, 90 patients and 90 matched controls will be included. Our secondary objectives are based on a four-point difference on the St. George’s Respiratory Questionnaire. Because this concerns a clinically relevant difference, we expect greater differences on our secondary objectives, compared with our main aim. Therefore, we opted for a power of 80%. With regard to an expected dropout rate of 10%, the sample size includes 183 patients and 90 controls.

Monitoring The study will be monitored once a year by independent healthcare professionals from CIRO+, according to the guidelines of the Dutch Federation of University Medical Centres (NFU) and will be conducted in accordance with the Medical Research Involving Human Subjects Act (WMO).

The COgnitive‐PD study

Ethics and dissemination Ethical considerations The study is based on informed written consent, and participants can withdraw from the study at any point in time. The study is non-invasive and imposes no signicant risks. Data material will be managed condentially and anonymously.

Dissemination Results will be disseminated through regional, national and international research conferences and in articles published in international peer-reviewed journals.

The COgnitive-PD study has several strengths and methodological considerations which are discussed below.

Strengths The approach of our project differs considerably from other studies on neuropsychological factors in COPD by its predominant focus on cognitive functioning in specic domains. So far, in previous studies, cognitive functioning was often assessed using a single scale to measure global cognitive functioning (eg, MMSE).10,38 The COgnitive-PD study uses a comprehensive neuropsychological testing battery and novel imaging techniques. Therefore, cognitive functioning in specic domains in patients with COPD can be adequately pictured. Next to the local composition of the brain tissue, rs-fMRI and DTI will give information of the structural connections (DTI) and functional connections (rs-fMRI). Furthermore, recruitment of participants in a pulmonary rehabilitation centre allows us to further explore the effects of domain-specic cognitive skills on pulmonary rehabilitation outcomes and daily functioning in patients with COPD. Insight in the incidence and clinical implications of cognitive impairment will help to adjust disease-management programmes and pulmonary rehabilitation to the patient’s needs and capacity.

Methodological considerations Confounding factors may inuence the comparison between groups. However, we will use matching on smoking status, age and educational level as a technique to create similar groups of participants. The data will also be adjusted for confounding factors such as bronchodilator drugs, IQ level and gender. Audio and visual functions must be intact in patients with COPD and controls to obtain

Chapter 5

Discussion

ChapterÂ 5Â reliable measurements. However, whether the participant has impairment in hearing and vision will be assessed during the home visit. Furthermore, recruitment in a rehabilitation centre will provide, in particular, patients with COPD experiencing moderate to very severe limitations in daily life activities, 32,39 which may decrease the generalisability of the results to the general population of patients with COPD. Finally, due to the cross-sectional assessment of cognitive functioning, we are not able to set conclusions about causal relationships, for example, between comorbidities and cognitive functioning. Conclusions In conclusion, the COgnitive-PD study ď&#x192;&#x17E;ndings will give more insight into neuropsychological functioning in patients with COPD and shed light on the impact of cognitive impairment on pulmonary rehabilitation. This could help to adjust disease management and pulmonary rehabilitation programmes to the needs and capacity of cognitively impaired patients with COPD.

The COgnitive‐PD study

3. 4.

8. 9. 10. 11. 12. 13. 14.

15. 16.

17. 18. 19. 20. 21.

Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187(4):347-365. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006;367(9524):1747-1757. Graat-Verboom L, Wouters EF, Smeenk FW, van den Borne BE, Lunde R, Spruit MA. Current status of research on osteoporosis in COPD: a systematic review. Eur Respir J. 2009;34(1):209-218. Spruit MA, Pennings HJ, Janssen PP, Does JD, Scroyen S, Akkermans MA, Mostert R, Wouters EF. Extra-pulmonary features in COPD patients entering rehabilitation after stratification for MRC dyspnea grade. Respir Med. 2007;101(12):2454-2463. Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel VP, Bruijnzeel PL, Rutten EP, Op 't Roodt J, Wouters EF, Franssen FM. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;187(7):728-735. Schou L, Ostergaard B, Rasmussen LS, Rydahl-Hansen S, Phanareth K. Cognitive dysfunction in patients with chronic obstructive pulmonary disease--a systematic review. Respir Med. 2012;106(8):1071-1081. Hynninen KM, Breitve MH, Wiborg AB, Pallesen S, Nordhus IH. Psychological characteristics of patients with chronic obstructive pulmonary disease: a review. Journal of psychosomatic research. 2005;59(6):429-443. Meek PM, Lareau SC, Anderson D. Memory for symptoms in COPD patients: how accurate are their reports? Eur Respir J. 2001;18(3):474-481. Allen SC, Jain M, Ragab S, Malik N. Acquisition and short-term retention of inhaler techniques require intact executive function in elderly subjects. Age Ageing. 2003;32(3):299-302. Dodd JW, Charlton RA, van den Broek MD, Jones PW. Cognitive Dysfunction in Patients Hospitalized with Acute Exacerbation of Chronic Obstructive Pulmonary Disease (COPD). Chest. 2013. Antonelli-Incalzi R, Corsonello A, Pedone C, Trojano L, Acanfora D, Spada A, Izzo O, Rengo F. Drawing impairment predicts mortality in severe COPD. Chest. 2006;130(6):1687-1694. Dodd JW, Getov SV, Jones PW. Cognitive function in COPD. The European respiratory journal: official journal of the European Society for Clinical Respiratory Physiology. 2010;35(4):913-922. Meek PM. Cognitive Function. In: Nici L, ZuWallack R, eds. Chronic Obstructive Pulmonary Disease: Comorbidities and Systemic Consequences. New York: Humana Press; 2012:119-136. Dijkstra JB, Strik JJ, Lousberg R, Prickaerts J, Riedel WJ, Jolles J, van Praag HM, Honig A. Atypical cognitive profile in patients with depression after myocardial infarction. Journal of affective disorders. 2002;70(2):181-190. Spruit MA, Vanderhoven-Augustin I, Janssen PP, Wouters EF. Integration of pulmonary rehabilitation in COPD. Lancet. 2008;371(9606):12-13. Sillen MJ, Franssen FM, Delbressine JM, Uszko-Lencer NH, Vanfleteren LE, Rutten EP, Wouters EF, Spruit MA. Heterogeneity in clinical characteristics and co-morbidities in dyspneic individuals with COPD GOLD D: findings of the DICES trial. Respir Med. 2013;107(8):1186-1194. CBS. Standaard Beroepenclassificatie 1992 – editie 2001. Den Haag: SDU; 2001. Merckelbach H, Muris P, Nijman H, de Jong PJ. Self-reported cognitive failures and neurotic symptomatoloy. Pers Indiv Differ. 1996;20(6):715-724. Wallace JC, Kass SJ, Stanny CJ. The cognitive failures questionnaire revisited: dimensions and correlates. J Gen Psychol. 2002;129(3):238-256. Luteijn F, Barelds, D.P.F. GIT-2: Groninger Intelligentie Test 2. Handleiding. Amsterdam: Pearson Assessment and Information B.V. Van der Elst W, Van Boxtel MP, Van Breukelen GJ, Jolles J. The Concept Shifting Test: adult normative data. Psychol Assess. 2006;18(4):424-432.

Chapter 5

References

Chapter 5 22. Van der Elst W, Van Boxtel MP, Van Breukelen GJ, Jolles J. The Stroop color-word test: influence of age, sex, and education; and normative data for a large sample across the adult age range. Assessment. 2006;13(1):62-79. 23. Stroop J. Studies of interference in serial verbal reactions. Journal of Experimental Psychology. 1935;18:20. 24. van der Elst W, van Boxtel MP, van Breukelen GJ, Jolles J. The Letter Digit Substitution Test: normative data for 1,858 healthy participants aged 24-81 from the Maastricht Aging Study (MAAS): influence of age, education, and sex. J Clin Exp Neuropsychol. 2006;28(6):998-1009. 25. Van der Elst W, van Boxtel MP, van Breukelen GJ, Jolles J. Rey's verbal learning test: normative data for 1855 healthy participants aged 24-81 years and the influence of age, sex, education, and mode of presentation. J Int Neuropsychol Soc. 2005;11(3):290-302. 26. Wilson BA, Aldermann, N., Burgess, B.W. Behavioural assessment of the dysexecutive syndrome. Bury St Edmunds: Thames Valley Test Co; 1998. 27. Cockrell JR, Folstein MF. Mini-Mental State Examination (MMSE). Psychopharmacol Bull. 1988;24(4):689-692. 28. Coyle JT. Use it or lose it--do effortful mental activities protect against dementia? N Engl J Med. 2003;348(25):2489-2490. 29. Ball K, Berch DB, Helmers KF, Jobe JB, Leveck MD, Marsiske M, Morris JN, Rebok GW, Smith DM, Tennstedt SL, Unverzagt FW, Willis SL. Effects of cognitive training interventions with older adults: a randomized controlled trial. JAMA. 2002;288(18):2271-2281. 30. Wechsler D. Wechsler Adult Intelligence Scale—Revised. San Antonio, TX: The Psychological Corporation; 1981. 31. Law M, Baptiste S, McColl M, Opzoomer A, Polatajko H, Pollock N. The Canadian occupational performance measure: an outcome measure for occupational therapy. Can J Occup Ther. 1990;57(2):82-87. 32. Annegarn J, Meijer K, Passos VL, Stute K, Wiechert J, Savelberg HH, Schols AM, Wouters EF, Spruit MA, Ciro+ Rehabilitation N. Problematic activities of daily life are weakly associated with clinical characteristics in COPD. J Am Med Dir Assoc. 2012;13(3):284-290. 33. Basser PJ, Pajevic S, Pierpaoli C, Duda J, Aldroubi A. In vivo fiber tractography using DT-MRI data. Magn Reson Med. 2000;44(4):625-632. 34. Rogers BP, Morgan VL, Newton AT, Gore JC. Assessing functional connectivity in the human brain by fMRI. Magn Reson Imaging. 2007;25(10):1347-1357. 35. van Boxtel MP, Buntinx F, Houx PJ, Metsemakers JF, Knottnerus A, Jolles J. The relation between morbidity and cognitive performance in a normal aging population. J Gerontol A Biol Sci Med Sci. 1998;53(2):M147-154. 36. de Groot JC, de Leeuw FE, Oudkerk M, van Gijn J, Hofman A, Jolles J, Breteler MM. Cerebral white matter lesions and cognitive function: the Rotterdam Scan Study. Ann Neurol. 2000;47(2):145-151. 37. Jolles J, van Boxtel MP, Ponds RW, Metsemakers JF, Houx PJ. [The Maastricht aging study (MAAS). The longitudinal perspective of cognitive aging]. Tijdschr Gerontol Geriatr. 1998;29(3):120-129. 38. Barberger-Gateau P, Commenges D, Gagnon M, Letenneur L, Sauvel C, Dartigues JF. Instrumental activities of daily living as a screening tool for cognitive impairment and dementia in elderly community dwellers. Journal of the American Geriatrics Society. 1992;40(11):1129-1134. 39. Vaes AW, Wouters EF, Franssen FM, Uszko-Lencer NH, Stakenborg KH, Westra M, Meijer K, Schols AM, Janssen PP, Spruit MA. Task-related oxygen uptake during domestic activities of daily life in patients with COPD and healthy elderly subjects. Chest. 2011;140(4):970-979. 40. Zigmond AS SR. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67:10. 41. Beck AT WC, Mendelson M, Mock J, Erbaugh, J. An inventory for measuring depression. . Archives of General Psychiatry. 1961;4:11. 42. Luteijn F SJ, Van Dijk H. . Eerste herziene NPV handleiding. Lisse: Swets & Zeitlinger; 1985. 43. Derogatis LR LR, Covi L. SCL-90: an outpatient psychiatric rating scalepreliminary report. Psychopharm Bull. 1973;9:16.

100

The COgnitive‐PD study

Chapter 5

44. Schreurs PJG, Van de Willige G, Brosschot JF, Tellegen B. De Utrechtse Coping Lijst: UCLhandleiding. Lisse: Swets & Zeitlinger; 1987. 45. Jones PW QF, Baveystock CM, Littlejohns P. A selfcomplete measure of health status for chronic airflow limitation. Am Rev Respir Dis. 1992(145):7. 46. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J. 2009;34(3):648-654. 47. Hyland ME, Jones RC, Hanney KE. The Lung Information Needs Questionnaire: Development, preliminary validation and findings. Respir Med. 2006;100(10):1807-1816. 48. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383. 49. Hernandes NA, Wouters EF, Meijer K, Annegarn J, Pitta F, Spruit MA. Reproducibility of 6minute walking test in patients with COPD. Eur Respir J. 2010.

101

Chapter 6

Domain-specific cognitive impairment in patients with COPD and control subjects Cleutjens FA, Franssen FM, Spruit MA, Vanfleteren LE, Gijsen C, Dijkstra JB, Ponds RW, Wouters EF, Janssen DJ. Domain-specific cognitive impairment in patients with COPD and control subjects. International Journal of COPD. 2017;12:1-11. Reprinted with permission from International Journal of COPD.

103

ChapterÂ 6Â

Abstract Impaired cognitive function is increasingly recognized in COPD. Yet, the prevalence of cognitive impairment in specific cognitive domains in COPD has been poorly studied. The aim of this cross-sectional observational study was to compare the prevalence of domain-specific cognitive impairment between patients with COPD and non-COPD controls. A neuropsychological assessment was administered in 90 stable COPD patients and 90 non-COPD controls with comparable smoking status, age, and level of education. Six core tests from the Maastricht Aging Study were used to assess general cognitive impairment. By using Z-scores, compound scores were constructed for the following domains: psychomotor speed, planning, working memory, verbal memory, and cognitive flexibility. General cognitive impairment and domain-specific cognitive impairment were compared between COPD patients and controls after correction for comorbidities using multivariate linear and logistic regression models. General cognitive impairment was found in 56.7% of patients with COPD and in 13.3% of controls. Deficits in the following domains were more often present in patients with COPD after correction for comorbidities: psychomotor speed (17.8% vs 3.3%; P<0.001), planning (17.8% vs 1.1%; P<0.001), and cognitive flexibility (43.3% vs 12.2%; P<0.001). General cognitive impairment and impairments in the domains psychomotor speed, planning, and cognitive flexibility affect the COPD patients more than their matched controls.

104

Domain‐specific cognitive impairment in COPD

Cognitive impairment has been reported in patients with COPD.1–4 The prevalence rates of general cognitive impairment in COPD vary widely, ranging from 5.5% in a large sample of adults with COPD, measured with the Mini-Mental State Examination (MMSE),5 up to 77.0% in patients with both COPD and hypoxemia, measured with multiple cognitive tests.6 Increasing age is the most significant determinant of cognitive impairment,7 besides a history of tobacco smoking8 and a low educational level.9 Although the exact pathogenesis of cognitive impairment in COPD remains unknown, vascular-mediated brain pathology, oxidative stress, hypoxemia, systemic inflammation, and comorbidities are proposed pathways to cognitive impairment.1,2,10,11 Several domains of cognitive functioning can be distinguished.1 Psychomotor speed and information processing assess cognitively demanding information processing tasks, reaction time, and basic manual motor activity.12 Memory is the ability to elaborate, store, retrieve, and use information and is defined according to its function, duration, and content.13 Executive functioning includes complex cognitive activities such as planning and cognitive flexibility. Planning assesses the ability to set goals and to develop appropriate steps or strategies to effectively and efficiently achieve a desired outcome.14 Cognitive flexibility assesses the ability to shift concepts and problem-solving strategies. 15 The importance of examining domain-specific cognition in COPD patients entering pulmonary rehabilitation (PR) is supported by associations between cognitive impairment in specific domains and poor adherence to therapies in HIVinfected adults,16 decreased levels of smoking cessation in community-dwelling older persons,17 and negative rehabilitation outcomes in elderly patients recovering from a hip fracture.18 The prevalence of domain-specific cognitive impairment in COPD patients has been poorly studied, and the pre-rehabilitation assessment does not include cognitive functioning tests. To date, studies assessing specific cognitive domains1–3 lack a clear theoretical and operational definition of domain-specific cognitive impairment and do not provide prevalence rates. Moreover, an adequate control group matched for age, educational level, and smoking history was lacking.3 The aim of this study was to compare general and domain-specific cognitive impairments (ie, psychomotor speed, planning, working memory, verbal memory, and cognitive flexibility) between patients with COPD entering PR and non-COPD control subjects with comparable age, educational level, and smoking history. We hypothesized that patients with COPD have a higher prevalence of cognitive impairment compared to controls and that the higher-order cognitive functions, including planning and cognitive flexibility, are more often affected.

105

Chapter 6

Introduction

ChapterÂ 6Â

Methods Study design The current study includes cross-sectional data of the COgnitive-PD study, a longitudinal study on neuropsychological functioning in patients with COPD entering PR. The detailed methodology of this study has been published before.19 The study is registered in the Dutch Trial Registry (NTR 4215).

Participants Based on a previous sample size calculation, the study sample included a total of 90 patients with clinically stable COPD, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 strategic document,20 and 90 non-COPD control participants. Patients were referred for an interdisciplinary three-day assessment in a tertiary referral center in the Netherlands before the start of a comprehensive interdisciplinary inpatient (8 weeks) or outpatient (16 weeks) PR program, in line with the latest American Thoracic Society/European Respiratory Society (ATS/ERS) Statement on PR. Participants were excluded if they had an exacerbation in the past 4 weeks, insufficient comprehension of the Dutch language, or a diagnosis of dementia. Non-COPD control participants were recruited from within the COPD community, and included care partners, family members, or friends of clinical participants, and via advertisements in local newspapers requesting volunteers from the general population. Information regarding smoking status, age, and education was obtained. If possible, the control participant was one-to-one matched with a COPD patient of the COgnitive-PD study population (n=183) on smoking status (smoker, former smoker, or never smoker), age (standard deviation [SD] <10 years), and educational level (SD <1) according to the Dutch Standard Classification of Education (CBS).21 If not, the control participant was put on a voluntary waiting list to be contacted after inclusion of a COPD patient with matching criteria of the control participant. Exclusion criteria for control participants were as follows: a diagnosis of COPD or asthma, dementia in their medical history, and Dutch language difficulties. All participants gave written informed consent. The Medical Ethics Committee of the University Hospital Maastricht approved this study (NL45127.068.13).

Procedures Home visits were performed from November 2013 up to June 2015, between the three-day assessment and the first day of PR, excluding the potential effect of PR on cognitive functioning. The following characteristics were assessed: age, gender, educational level, marital status, visual and hearing impairment, handedness, and intelligence quotient (IQ, by using a shortened version of the

106

Statistical analysis All analyses were performed using SPSS 21.0 (SPSS Inc., Chicago, IL, USA). A Pvalue <0.01 was considered to be statistically significant. Analysis of cognitive performance included descriptive statistics using frequencies for categorical variables, and mean and standard deviation (SD) for continuous variables. Reference data were derived from the Maastricht Aging Study (MAAS), a large Dutch longitudinal study examining the determinants of cognitive aging in a large group of cognitively intact people aged 24–81 years.27 For the DS and BADS, normative data in scoring were used. Raw scores on neuropsychological tests were transformed into a standardized Z-score (Z={x−mean}/SD) based on its mean and SD calculated from the reference group, and were adjusted for age, gender, and educational level. Six core subtests used in MAAS28 were used to assess general cognitive impairment (Table S2). General cognitive impairment was defined as a Z-score less than 1.0 SD29 below the age-, gender-, and education-specific mean of the MAAS study population for at least two of the six core tests.28 Individual cognitive measures were grouped into the following specific cognitive domains: psychomotor speed, planning, working memory, verbal memory, and cognitive flexibility (Table S3). Within each domain, scaled Z-scores were summed and averaged to

107

Chapter 6

Domain‐specific cognitive impairment in COPD 22 Groninger Intelligence Test), and smoking behavior. The Charlson comorbidity index23 was used to quantify self-reported comorbidities. During the three-day assessment, data on body mass index (BMI), functional exercise capacity (measured with two six-minute walk distance [6MWD]) tests according to ERS/ATS guidelines),24 spirometry (forced vital capacity [FVC], FVC% predicted, forced expiratory volume in 1 second [FEV1], FEV1% predicted, and FEV1/FVC), previous self-reported diagnosis of obstructive sleep apnea syndrome (OSAS), neurological disease (eg, cerebrovascular accident, hernia, concussion, migraine, or Parkinson), or psychiatric disease (eg, major depressive disorder, post-traumatic stress disorder, or schizophrenia), physician-diagnosed hypertension, and psychological well-being (using the Hospital Anxiety and Depression Scale [HADS]25 and the Beck Depression Inventory)26 were collected as part of the clinical routine. The neuropsychological assessment comprised a detailed testing battery consisting of the following subtests: MMSE, the Stroop Color-Word Test, the Concept Shifting Test, the Letter Digit Substitution Test, the Visual Verbal Learning Task, the Digit Span (DS) from the Wechsler Adult Intelligence Scale III (WAIS-III) and a shortened version of the Behavioral Assessment of the Dysexecutive Syndrome (BADS) including subtasks Key Search and Zoo-map. A validated Dutch translation of the Cognitive Failure Questionnaire (CFQ) was used as a subjective measure of cognitive failure. Subscores, subtests, and parameter measures are described in Table S1. For detailed information, see the section “Supplementary materials”.

Chapter 6 yield one compound Z-score per cognitive domain. Cognitive impairment in a specific domain was defined as a compound Z-score of less than 1.0 SD below the age-, gender-, and education-specific mean of the MAAS study population.29 Global cognitive impairment was defined as a score of 24 or below on the MMSE.30 A comparison of raw scores and compound Z-scores among COPD patients and control participants was made using an independent sample t-test or Mann–Whitney U-test, as appropriate. Proportions of patients and control participants with general and domain-specific cognitive impairment were calculated and compared with chi-square tests. Multivariate linear or logistic regression models were performed to adjust for the comorbidities, with a significantly higher prevalence rate found in patients than in controls: myocardial infarction, peripheral vascular disease, hemiplegia, clinically relevant symptoms of depression, and clinically relevant symptoms of anxiety. A post hoc analysis was performed in order to compare neuropsychological measures between COPD patients and controls without comorbidities on the Charlson comorbidity index using chi-square tests for categorical variables and independent sample t-test or Mann–Whitney U-test, as appropriate for continuous variables.

Results General characteristics of participants The current sample is comparable with the total COgnitive-PD study sample regarding age, gender, lung function, and IQ (all P>0.05). In addition to a reduced lung function, patients with COPD had a lower functional exercise capacity and IQ, compared to non-COPD controls, while Charlson comorbidity index score was increased. Myocardial infarction, peripheral vascular disease, hemiplegia, and symptoms of anxiety and depression were more often reported by patients with COPD. Moreover, patients with COPD more often reported the use of antidepressants (Table 1). Table 1. Characteristics of the study populations Characteristic COPD patients (n=90) Demographics 63.7 (8.8) Age, mean (SD) 49 (54.4) Male, n (%) 38 (42.2) Lower general or vocational education, n 54 (60.0) (%) Married, n (%) Spirometry 41.9 (15.1) FEV a 54.5 (23.7) 1/FVC, mean (SD) FEV1 (% predicted), mean (SD)a

108

Controls (n=90)

P-value

62.3 (7.4) 45 (50.0) 25 (27.8) 62 (68.9)

0.260 0.327 0.187 0.706

77.8 (4.7) 116.3 (18.2)

<0.001 <0.001

Domain‐specific cognitive impairment in COPD Clinical characteristics Visual impairment, n (%) Hearing impairment, n (%) Right-handed by nature, n (%) BMI (kg/m2), mean, (SD) 6MWD (meters), mean (SD)a 6MWD (% predicted), mean (SD) PaO2, mean (SD) PaCO2, mean (SD) Oxygen therapy, n (%) IQ, mean (SD) Anxiolytics and/or hypnotics, n (%) Antidepressants, n (%) Alcohol intake and smoking behavior ≥ 1 Alcohol units per day, n (%) Current smoker, n (%) Former smoker, n (%) Never smoker, n (%) Comorbidities Charlson comorbidity index score, points, mean (SD)a Myocardial infarction, n (%) Congestive heart failure, n (%) Peripheral vascular disease, n (%) Cerebrovascular disease, n (%) Connective tissue disease, n (%) Peptic ulcer disease, n (%) Mild, moderate or severe liver disease, n (%) Diabetes Mellitus, n (%) Hemiplegia, n (%) Moderate to severe chronic kidney disease, n (%) Solid or malignant tumors, n (%) Hypertension, n (%) OSAS, n (%) Neurological disease, n (%) Psychiatric disease, n (%) Psychological wellbeing HADS Anxiety score (points), mean (SD)a HADS Anxiety score >10 points, n (%) HADS Depression score (points), mean (SD)a HADS Depression score >10 points, n (%) BDI score score (points), mean (SD)a

17 (18.9) 19 (21.1) 72 (80.0) 27.3 (6.6) 426.0 (102.4) 67 (15) 9.8 (1.6) 5.1 (0.9) 18 (20.0) 84.2 (15.8) 7 (7.8) 26 (28.9)

11 (12.2) 23 (25.6) 70 (77.8) 27.3 (4.2) 633.5 (96.8) 95 (28) 0 (0.0) 99.2 (14.6) 1 (1.1) 2 (2.2)

0.152 0.299 0.214 0.987 <0.001 <0.001 <0.001 0.032 <0.001

30 (38.6) 12 (13.3) 75 (83.3) 3 (3.3)

12 (13.3) 75 (83.3) 3 (3.3)

1.000

3.0 (1.8)

0.9 (1.5)

<0.001

16 (17.8) 10 (11.1) 23 (25.6) 11 (12.2) 14 (15.6) 11 (12.2) 2 (2.2) 15 (16.7) 10 (11.1) 4 (4.4) 15 (16.7) 70 (77.8) 13 (14.4) 20 (22.0) 11 (12.2)

5 (5.6) 2 (2.2) 9 (10.0) 4 (4.4) 16 (17.8) 6 (6.7) 1 (1.1) 10 (11.1) 1 (1.1) 0 (0.0) 7 (7.8) 7 (7.8) 9 (10.0) 4 (4.4)

0.009 0.016 0.005 0.052 0.421 0.154 0.500 0.195 0.005 0.341 0.055 0.118 0.021 0.052

8.3 (4.5) 28 (31.1) 7.7 (3.9) 19 (21.1) 16.3 (8.8)

3.9 (3.1) 5 (5.6) 2.2 (2.5) 2 (2.2) 5.1 (5.9)

<0.001 <0.001 <0.001 <0.001 <0.001

Notes: a, Nonparametric statistical tests have been used because of skewed data; ‘–’ indicates no data. Abbreviations: BDI, Beck Depression Inventory; BMI, body mass index; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HADS, Hospital Anxiety and Depression Scale; IQ, intelligence quotient; OSAS, obstructive sleep apnea syndrome; PaO2 , arterial partial pressure of oxygen; PaCO2, arterial partial pressure of carbon dioxide; SD, standard deviation; 6MWD, 6-minute walk distance.

109

Chapter 6

Prevalence of general cognitive impairment According to the MMSE, global cognitive impairment did not differ between the COPD patients and non-COPD controls (Table 2). The prevalence rate of general cognitive impairment, as assessed with the COgnitive-PD neuropsychological assessment, was 56.7% in the current sample of patients with COPD compared to 13.3% for controls. Raw mean scores on all core tests were significantly worse in patients with COPD compared to controls (Table 2). Table 2. Raw unadjusted means on neuropsychological measures and compound z-scores in patients with COPD and controls Outcome measure COPD Controls PAdjusted patients (n=90) value P-valuea (n=90) Global cognitive functioning MMSE, mean (SD)b 27.4 (2.3) 28.1 (1.6) 0.017 0.016 Global cognitive impairment (MMSE ≤24), n 7 (7.8) 2 (2.2) 0.084 0.243 (%) Domain-specific cognition Psychomotor speed (compound z-score), mean -0.5 (1.1) 0.3 (0.7) <0.001 <0.001 (SD) SCWT card I, mean (SD)b 19.1 (5.6) 17.0 (2.6) 0.003 0.010 CST-A, mean (SD) 28.1 (15.8) 21.2 (5.6) <0.001 <0.001 LDST 60 sec written, mean (SD) 25.2 (7.2) 31.7 (5.7) <0.001 <0.001 LDST 60 sec oral, mean (SD) 31.1 (7.5) 37.1 (6.5) <0.001 <0.001 Planning (compound z-score), mean (SD) -0.3 (0.8) 0.3 (0.6) <0.001 <0.001 BADS key search, mean (SD) 2.2 (1.5) 3.1 (1.2) <0.001 0.002 BADS zoo map, mean (SD)b 2.2 (0.8) 2.7 (0.7) <0.001 <0.001 Working memory (compound z-score), mean -0.6 (0.8) -0.2 (0.8) 0.004 0.035 (SD) VVLT trial 1, mean (SD) 4.4 (1.9) 5.5 (2.1) <0.001 0.001 DS backward, mean (SD) 3.0 (1.1) 3.1 (1.2) 0.556 0.961 Verbal memory (compound z-score), mean -0.5 (1.1) 0.0 (1.0) 0.001 0.002 (SD) VVLT total recall 1–5, mean (SD) 40.2 (10.8) 47.3 <0.001 <0.001 (10.2) VVLT delayed recall, mean (SD) 7.3 (3.5) 9.1 (3.2) 0.001 0.002 VVLT retention max, mean (SD)b 0.6 (0.3) 0.7 (0.2) 0.020 0.030 Cognitive flexibility (compound z-score), -1.2 (1.6) -0.0 (0.8) <0.001 <0.001 mean (SD) SCWT card III, mean (SD)b 60.9 (26.7) 43.0 (13.0) <0.001 <0.001 CST-C, mean (SD) 51.1 (26.3) 35.3 (11.6) <0.001 <0.001 General cognitive impairment (2 out of 6 51 (56.7) 12 (13.3) <0.001 <0.001 subtest Z scores -1SD), n (%) Cognitive complaints CFQ absent-mindedness, mean (SD) CFQ social interactions, mean (SD) CFQ names and words, mean (SD) CFQ orientation, mean (SD) CFQ total score, mean (SD)

110

8.2 (5.4) 5.7 (3.3) 5.7 (2.6) 2.7 (2.6) 31.8 (17.3)

7.1 (3.6) 4.9 (2.2) 4.9 (2.0) 2.3 (1.7) 27.3 (11.0)

0.112 0.042 0.021 0.352 0.038

0.619 0.855 0.081 0.638 0.987

Domain‐specific cognitive impairment in COPD

Notes: a, Adjusted for myocardial infarction, peripheral vascular disease, hemiplegia, clinically relevant symptoms of depression, and clinically relevant symptoms of anxiety; b, nonparametric statistical tests have been used because of skewed data. Abbreviations: BADS, Behavioral Assessment of the Dysexecutive Syndrome; CFQ, Cognitive Failure Questionnaire; CST-A, Concept Shifting Test part A; CST-C, Concept Shifting Test part C; DS, Digit Span; LDST, Letter Digit Substitution Test; MMSE, Mini-Mental State Examination; SCWT, Stroop Color-Word Test; SD, standard deviation; VVLT, Visual Verbal Learning Test.

Prevalence of domain-specific cognitive impairment

Chapter 6

The prevalence of cognitive impairment across the five cognitive domains was significantly higher among the included patients with COPD than among controls, except for working memory. Multivariate analyses confirmed a higher prevalence of impairments across all domains, except for working memory (Figure 1).

Figure 1. Domain-specific cognitive impairment after correcting for myocardial infarction, peripheral vascular disease, hemiplegia, clinically relevant symptoms of depression, and clinically relevant symptoms of anxiety. Proportion of patients with COPD and controls with impairments in the domains psychomotor speed (17.8 vs 3.3%; p<0.001;), planning (17.8 vs 1.1%; p<0.001), working memory (32.3 vs 14.4%; p=0.035), verbal memory (33.3 vs 12.2%; p=0.002), and cognitive flexibility (43.3 vs 12.2%; p<0.001). COPD: chronic obstructive pulmonary disease.

Results remained the same when the matching variables age, education, and smoking status, in addition to the comorbidities, were included in the multivariate model (Table S4). Patients with and without oxygen therapy did not significantly differ on general cognitive impairment or any of the cognitive domains (all P-values >0.01; Table S5). The same was true when comparing COPD pa-

111

ChapterÂ 6Â tients with clinically relevant symptoms of depression or anxiety (HADS depression or anxiety score >10 points) and those without clinically relevant symptoms of depression or anxiety (all P-values >0.01; Tables S6 and S7).

Cognitive complaints The CFQ total score and subscores did not differ between patients with COPD and non-COPD controls (Table 2). These results were confirmed by multivariate analyses.

Cognitive impairment in COPD patients and controls without comorbidities In total, 18 patients with COPD reported no other disease than COPD on the Charlson Index and 43 non-COPD controls reported no comorbidities on the Charlson Index and were included in a post hoc analysis (Table 3).

Figure 2. Domain-specific cognitive impairment in patients with COPD and controls without comorbidities. Proportion of patients with COPD and controls with impairments in the domains psychomotor speed (16.7 vs 0.0%; p=0.039;), planning (16.7 vs 0.0%; p<0.001), working memory (38.9 vs 14.0%; p=0.140), verbal memory (22.2 vs 16.3%; p=0.262), and cognitive flexibility (44.4 vs 11.6%; p<0.001). COPD: chronic obstructive pulmonary disease.

The prevalence of general cognitive impairment did not differ significantly between patients and controls without comorbidities (50% and 18.6%, respec-

112

Table 3. Characteristics of the selected study population without comorbidities Characteristic COPD patients Controls P-value (n=18) (n=43) Demographics 61.9 (8.8) 60.3 (7.5) 0.477 Age, mean (SD) 9 (50.0) 22 (51.2) 0.578 Male, n (%) 10 (23.3) 0.176 Lower general or vocational education, n 7 (38.9) 7 (38.9) 34 (79.1) 0.003 (%) Married, n (%) Spirometry 42.1 (13.3) 77.3 (4.6) <0.001 FEV1/FVC, mean (SD) FEV1 (% predicted), mean (SD) 59.3 (28.0) 113.8 (10.7) <0.001 Clinical characteristics Visual impairment, n (%) 3 (16.7) 1 (2.3) 0.073 Hearing impairment, n (%) 2 (11.1) 13 (30.2) 0.101 Right-handed by nature, n (%) 11 (61.1) 33 (76.7) 0.236 BMI (kg/m2), mean, (SD) 25.3 (6.5) 27.0 (4.2) 0.219 459.0 (131.20 661.1 (106.8) <0.001 6MWD (meters), mean (SD) 71.4 (18.3) 94.2 (39.0) <0.001 6MWD (% predicted), mean (SD)a 10.1 (1.6) PaO2, mean (SD) 5.1 (0.6) PaCO2, mean (SD)a Oxygen therapy, n (%) 2 (11.1) IQ, mean (SD) 84.6 (13.9) 100.9 (15.6) <0.001 Hypertension, n (%) 2 (11.1) OSAS, n (%) 0 (0.0) 4 (9.3) Alcohol intake and smoking behavior ≥ 1 Alcohol units per day, n (%)b 8 (47.1) Current smoker, n (%) 2 (11.1) 6 (14.0) 0.606 Former smoker, n (%) 16 (88.9) 35 (81.4) Never smoker, n (%) 0 (0.0) 2 (4.7) Psychological wellbeing <0.001 3.4 (2.5) 8.4 (4.5) HADS Anxiety score (points), mean (SD)a <0.001 1 (2.3) 7 (38.9) HADS Anxiety score >8 points, n (%) <0.001 1.7 (1.8) 7.5 (4.7) HADS Depression score (points), mean <0.001 0 (0.0) 8 (44.4) (SD) <0.001 3.9 (4.0) 17.8 (11.4) HADS Depression score >8 points, n (%) BDI score score (points), mean (SD)a Notes: a, Nonparametric statistical tests have been used because of skewed data; b, n=17; ‘–’ indicates no data. Abbreviations: BDI, Beck Depression Inventory; BMI, body mass index; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HADS, Hospital Anxiety and Depression Scale; IQ, intelligence quotient; OSAS, obstructive sleep apnea syndrome; PaO2 , arterial partial pressure of oxygen; PaCO2, arterial partial pressure of carbon dioxide; SD, standard deviation; 6MWD, 6-minute walk distance.

113

Chapter 6

Domain‐specific cognitive impairment in COPD tively). Global cognitive impairment, general cognitive impairment, and cognitive impairment in the domains psychomotor speed, working memory, and verbal memory did not differ between both groups. Patients with COPD more often reported complaints on the CFQ subscale words and names (Table 4). The prevalence of cognitive impairment was higher for patients with COPD without comorbidities than for controls without comorbidities in the domains planning and cognitive flexibility (Figure 2).

Chapter 6 Table 4. Raw unadjusted means on neuropsychological measures and compound z-scores in patients with COPD and controls without comorbidities Outcome measure COPD patients Controls P(n=18) (n=43) value Global cognitive functioning MMSE, mean (SD) 28.1 (1.4) 28.1 (1.3) 0.824 Global cognitive impairment (MMSE ≤24), n (%) 0.0 (0.0) 0.0 (0.0) Domain-specific cognition Psychomotor speed (compound z-score), mean -0.2 (1.0) 0.3 (0.5) 0.039 (SD) SCWT card I, mean (SD) 18.4 (4.0) 16.9 (2.3) 0.079 CST-A, mean (SD) 24.7 (8.2) 20.5 (5.3) 0.019 LDST 60 sec written, mean (SD) 28.4 (7.4) 31.8 (5.1) 0.044 LDST 60 sec oral, mean (SD) 32.3 (6.8) 37.1 (6.2) 0.011 Planning (compound z-score), mean (SD) -0.4 (0.9) 0.4 (0.5) <0.001 BADS key search, mean (SD) 1.9 (1.4) 3.1 (1.0) 0.002 BADS zoo map, mean (SD) 2.2 (1.2) 2.8 (0.6) 0.042 Working memory (compound z-score), mean (SD) -0.6 (0.7) -0.3 (0.8) 0.140 VVLT trial 1, mean (SD) 4.7 (2.3) 5.4 (2.0) 0.218 DS backward, mean (SD) 2.8 (1.3) 3.1 (1.1) 0.262 Verbal memory (compound z-score), mean (SD) -0.5 (1.2) -0.0 (1.1) 0.153 VVLT total recall 1–5, mean (SD) 40.5 (11.7) 46.7 (10.6) 0.049 VVLT delayed recall, mean (SD) 7.6 (3.7) 8.9 (3.3) 0.155 VVLT retention max, mean (SD)a 0.7 (0.2) 0.7 (0.2) 0.716 Cognitive flexibility (compound z-score), mean -1.1 (1.5) -0.2 (0.7) <0.001 (SD) SCWT card III, mean (SD)a 56.3 (15.9) 42.2 (12.3) 0.001 CST-C, mean (SD)a 48.7 (24.3) 33.6 (11.2) 0.029 General cognitive impairment (2 out of 6 subtest 9 (50.0) 8 (18.6) 0.016 Z scores -1SD), n (%) Cognitive complaints CFQ absent-mindedness, mean (SD) 7.2 (4.0) 6.5 (3.4) 0.480 CFQ social interactions, mean (SD) 5.8 (2.4) 4.6 (2.1) 0.044 CFQ names and words, mean (SD) 6.1 (2.1) 4.4 (2.0) 0.005 CFQ orientation, mean (SD) 2.5 (2.3) 2.3 (1.9) 0.662 CFQ total score, mean (SD) 30.6 (10.9) 25.4 (10.5) 0.084 Notes: a, Nonparametric statistical tests have been used because of skewed data. ‘–’ indicates a pvalue cannot be calculated since both patients and controls do not meet the criteria for global cognitive impairment. Abbreviations: BADS, Behavioral Assessment of the Dysexecutive Syndrome; CFQ, Cognitive Failure Questionnaire; CST, Concept Shifting Test; DS, Digit Span; LDST, Letter Digit Substitution Test; MMSE, Mini-Mental State Examination; SCWT, Stroop Color-Word Test; SD, standard deviation; VVLT, Visual Verbal Learning Test.

114

Domain‐specific cognitive impairment in COPD

Discussion Key findings This cross-sectional observational study showed a prevalence rate of 56.7% for cognitive impairment in a cohort of patients with COPD referred for PR by applying a comprehensive neuropsychological assessment. This prevalence was four times higher compared to matched non-COPD controls. Moreover, cognitive impairment in the domains planning and cognitive flexibility was more prevalent in patients with COPD than controls after correction for comorbidities.

Differences in study populations (such as level of hypoxemia and severity of COPD), methodology, sample size, the use of different definitions, and diagnostic criteria for cognitive impairment may explain the wide range of prevalence rates of cognitive impairment in COPD.5,6,31 We observed a prevalence rate of 56.7% for general cognitive impairment, which is within the range of previous studies. In accordance with Singh et al.29 Z-scores below −1.0 SD were considered as being impaired. The relatively low Z-score cutoff of −1.0 SD may explain why impairments in some non-COPD controls were present as well. Nevertheless, the use of a control group enhances our understanding of the cognitive profile for patients with COPD by showing that general cognitive impairment is four times more common in patients with COPD compared to controls and that domain-specific cognitive impairment occurs two to sixteen times more often in patients with COPD compared to controls. These differences are less clear when only patients and controls without comorbidities are analyzed. Indeed, abnormal planning was observed in 16.7% of patients without comorbidities but in none of the controls without comorbidities, and abnormal cognitive flexibility was observed in 44.4% and 11.6% of patients and controls without comorbidities, respectively. Global cognitive impairment, as assessed with the MMSE, did not differ between patients with COPD (7.8%) and non-COPD controls (2.2%). Moreover, the prevalence rate of global cognitive impairment is lower compared to that of general cognitive impairment. Both can be explained by methodological factors. The six core tests to assess general cognitive impairment might be more sensitive to detect relatively small impairments in specific areas of cognitive functioning that together may not lead to poor performance on a screening test such as the MMSE. In fact, the MMSE is used to detect dementia, which was an exclusion criterion in the current study, but is not sensitive enough to detect mild cognitive deficits.

115

Chapter 6

Prevalence of cognitive impairment

ChapterÂ 6Â

Domain-specific cognitive impairment Cognitive domains that have been shown to be affected in patients with COPD are memory, learning, attention, concentration, verbal and letter fluency, information processing speed, coordination, intelligence, and mental and cognitive flexibility.3,32 In the current study, one out of five patients with COPD showed impairments in the domain psychomotor speed. This may explain clinical features such as a decreased ability to comprehend lengthy, detailed, and fast instructions during therapies or to engage in educational sessions without losing attention. Second, two out of five patients with COPD were impaired in the domain planning. Owing to the inability to transfer previous knowledge to new events, patients with COPD may be hampered in their self-management because of difficulties in handling new problems and situations, and initiating any kind of health behavior change, which is the key component for effective self-management of patients with COPD.33 Third, over 30.0% of patients with COPD showed working memory impairments, which consequently may lead to problems with maintaining given educational information. Fourth, one out of three patients with COPD showed impairments in the domain verbal memory. Patients may seem unmotivated if they forget or ignore given guidelines, requests, or instructions. These clinical features may be a consequence of verbal memory impairment. Finally, over 40% of patients with COPD showed impairments in the domain cognitive flexibility. These may be related to difficulties in flexible thinking, alternating attention without losing focus, choosing appropriate behavioral responses according to the situation, and initiating behavioral and motor plans and activity, which all together may hamper attempts to adapt lifestyle (eg, quit smoking and become physically active).14,15

The role of comorbidities After exclusion of patients and controls with comorbidities, differences in the domains psychomotor speed, working memory, and verbal memory between patients and controls waned. COPD is a multimorbid disease,34,35 and it is likely that selected comorbidities explain part of the cognitive impairment in COPD. For example, myocardial infarction and hemiplegia may lead to hypoxia-induced brain cell death and possible cognitive deficits.36 Moreover, symptoms of depression and anxiety were increased in patients with COPD, which might explain part of the effect on memory.37 Nevertheless, in the current study, we did not find differences in general or domain-specific cognitive impairment when comparing COPD patients with and without symptoms of depression or anxiety. This might be explained by the fact that we used a generic scale to assess symptoms of anxiety and depression instead of a structured psychiatric interview to diagnose a major depressive disorder or anxiety disorder. It is possible that COPD patients with and without a major depressive disorder differ in their cognitive performances. Indeed, deficits in cognitive performances are

116

Clinical consequences Patients with cognitive impairment may be labeled as unmotivated and uncooperative because of problems with treatment adherence, treatment attrition, or negative treatment outcomes. Moreover, patients with COPD may be stigmatized as resistant, unmotivated, and in denial.42 However, rather than misattributing such problems as poor motivation to a character trait, cognitive impairment may be the culprit. For example, a recent study shows that cognitive functioning as assessed with the Montreal Cognitive Assessment is able to distinguish COPD patients with poor adherence to inhaler therapy from those with frequent errors in inhaler use technique.43 Therefore, a comprehensive

117

Chapter 6

Domain‐specific cognitive impairment in COPD 38 found in major depressive disorders. Moreover, the higher prevalence of antidepressant use may partly account for the higher prevalence of cognitive impairment in patients compared to controls due to its sedative and anticholinergic effects. The dose, time since last administration, and plasma concentration of the drug, however, determine the extent to which cognitive performance is affected.39 A post hoc analysis in which we compared neuropsychological measures between COPD patients and controls without any comorbidities on the Charlson index revealed that the domains cognitive flexibility and planning were more often affected in patients with COPD. Despite a difference in group sizes between patients and controls, which might distort the results, our results are in line with the idea that higher executive functions are more related to COPDspecific factors, compared to lower cognitive functions. Since hypertension and OSAS, both of which impact cognition and are common in COPD, are not integrated in the Charlson index, these comorbidities may also account for a higher prevalence of cognitive impairment in COPD patients compared to controls. Moreover, 9% of the total COPD study population without a diagnosis of diabetes on the Charlson comorbidity index had a blood glucose level of 7 mmol/L or above, and 47% of patients without physician-diagnosed hypertension had an elevated systolic blood pressure (≥140 mmHg) or elevated diastolic blood pressure of (≥90 mmHg) and were referred for further diagnosis. These underreported comorbidities may also partly account for the high prevalence of cognitive impairment in COPD. COPD patients had significantly lower 6MWD and IQ scores compared to non-COPD controls, which may also explain impairments in complex, higher-order cognitive functions (eg, executive functioning).40,41 Physical exercise has been suggested to enhance cognitive vitality of older adults, and therefore it is possible that patients with a lower baseline physical exercise pattern have lower cognitive performances.40 Yet, we cannot identify causal relationships, and it remains difficult to draw safe conclusions about the reasons for the presence of domain-specific cognitive impairments in patients with COPD.

Chapter 6 assessment of cognitive functioning and accurately distinguishing cognitive impairment among multiple cognitive domains might become more important, as more specific therapy interventions can be developed by taking into account the possible consequences of domain-specific cognitive impairment. Moreover, in patients with brain injuries, Alzheimer disease, and multiple sclerosis, cognitive training strategies, which aim to improve cognitive functioning and consequently reduce functional and psychological problems, have already been applied.44,45 To our knowledge, no study has been conducted to explore the effect of cognitive training strategies on cognitive performance in patients with COPD. Even though we demonstrated that cognitive impairment is more common in patients with COPD compared to controls, subjectively reported memory complaints on the CFQ were within the normal range of 21–43 in both groups.46 It is possible that impairments in cognition may gradually grow into deficits so that they are not easily recognized by the patient. Moreover, the burden of COPD may outflank the seriousness of self-experienced cognitive impairments and hence the recognition of daily cognitive difficulties.

Future research The high prevalence of general and domain-specific cognitive impairment in our study population raises questions about its consequences. Longitudinal followup studies are needed to assess whether cognitive impairment in specific domains affects the educational components, behavior change interventions, and other outcomes of PR. Moreover, it might be worthwhile to assess whether cognitive training strategies are able to slow down or prevent cognitive decline, or whether it has a beneficial effect on a PR trajectory and its sustained effects.

Methodological considerations By using an extensive neuropsychological assessment, we were able to estimate the prevalence of general and domain-specific cognitive impairment in patients with COPD and matched controls. The major determinants of cognitive impairment include a history of cigarette smoking, increasing age, and educational level.7–9 Therefore, the inclusion of a matched comparison group, a major strength of this study, might rule out the effect of smoking, age, and education on cognitive functioning. Although we did not match for gender and IQ, there were no significant differences in gender between both groups, and Z-scores were adjusted for educational level, age, and gender. Despite these strengths, this study has some limitations. Patients and controls were not matched for comorbidities, and data on arterial blood gases, alcohol intake, and hypertension in controls were not available. However, a post hoc analysis was performed in order to compare cognitive functioning between patients and controls without comorbidities. The sample size of the post hoc analysis was small, and therefore this analysis might be underpowered. However, extrapulmonary

118

Domain‐specific cognitive impairment in COPD comorbidities are common and significant in COPD, and therefore our study sample is representative of the COPD population. Yet, we included patients from a tertiary referral center, which may limit the generalizability of the results because, in general, patients with more advanced COPD are being referred. Nevertheless, these data are of significant importance for COPD patients who follow a PR program. Because of multiple comparisons, and to decrease the numbers of false negatives, a p-value ≤0.01 was used instead of the common used p-value of ≤0.05. Also selection bias may reduce the generalizability of our results. Patients and controls with subjective complaints of cognitive functioning might avoid participation due to anxiety or worry, or may have been more willing to participate in the present study due to personal interest.

The results of this study underline that general cognitive impairment and cognitive impairment in specific domains, namely psychomotor speed, planning, and cognitive flexibility, affect a higher proportion of patients with COPD than their matched controls. Comorbid diseases in COPD are likely to affect cognitive performance in COPD. Yet, impairments in executive functions may be more related to COPD-specific factors. The identification of domain-specific cognitive impairment is necessary for further optimizing therapies (eg, smoking cessation, self-management programs, and PR) for patients with COPD. Longitudinal follow-up of our participants will enable us to examine the effects of cognitive impairment in specific domains on PR outcomes, such as functional status, health status, psychological wellbeing, and the patient’s knowledge about COPD and their need for information.

119

Chapter 6

Conclusions

Chapter 6

References 1. 2. 3.

4. 5.

6. 7. 8. 9.

10. 11. 12.

13.

14. 15. 16. 17.

18.

19.

20.

21. 22.

120

Cleutjens FA, Janssen DJ, Ponds RW, Dijkstra JB, Wouters EF. COgnitive-pulmonary disease. Biomed Res Int. 2014;2014:697825. Dodd JW, Getov SV, Jones PW. Cognitive function in COPD. Eur Respir J. 2010;35(4):913-922. Schou L, Ostergaard B, Rasmussen LS, Rydahl-Hansen S, Phanareth K. Cognitive dysfunction in patients with chronic obstructive pulmonary disease--a systematic review. Respir Med. 2012;106(8):1071-1081. Shrikrishna D, Hopkinson NS. Chronic obstructive pulmonary disease: consequences beyond the lung. Clin Med (Lond). 2012;12(1):71-74. Thakur N, Blanc PD, Julian LJ, Yelin EH, Katz PP, Sidney S, Iribarren C, Eisner MD. COPD and cognitive impairment: the role of hypoxemia and oxygen therapy. Int J Chron Obstruct Pulmon Dis. 2010;5:263-269. Grant I, Heaton RK, McSweeny AJ, Adams KM, Timms RM. Neuropsychologic findings in hypoxemic chronic obstructive pulmonary disease. Arch Intern Med. 1982;142(8):1470-1476. Barnes JN. Exercise, cognitive function, and aging. Adv Physiol Educ. 2015;39(2):55-62. Anstey KJ, von Sanden C, Salim A, O'Kearney R. Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies. Am J Epidemiol. 2007;166(4):367-378. Evans DA, Beckett LA, Albert MS, Hebert LE, Scherr PA, Funkenstein HH, Taylor JO. Level of education and change in cognitive function in a community population of older persons. Ann Epidemiol. 1993;3(1):71-77. Cleutjens FA, Janssen DJ, Gijsen C, Dijkstra JB, Ponds RW, Wouters EF. [Cognitive impairment in patients with COPD: a review]. Tijdschr Gerontol Geriatr. 2014;45(1):1-9. Lahousse L, Tiemeier H, Ikram MA, Brusselle GG. Chronic obstructive pulmonary disease and cerebrovascular disease: A comprehensive review. Respir Med. 2015;109(11):1371-1380. Kochunov P, Coyle T, Lancaster J, Robin DA, Hardies J, Kochunov V, Bartzokis G, Stanley J, Royall D, Schlosser AE, Null M, Fox PT. Processing speed is correlated with cerebral health markers in the frontal lobes as quantified by neuroimaging. Neuroimage. 2010;49(2):1190-1199. Marchetta ND, Hurks PP, Krabbendam L, Jolles J. Interference control, working memory, concept shifting, and verbal fluency in adults with attention-deficit/hyperactivity disorder (ADHD). Neuropsychology. 2008;22(1):74-84. Miller D. Best practices in school neuropsychology: Guidelines for effective practice, assessment, and evidenced-based intervention. Hoboken, NJ: John Wiley and Sons. Leber AB, Turk-Browne NB, Chun MM. Neural predictors of moment-to-moment fluctuations in cognitive flexibility. Proc Natl Acad Sci U S A. 2008;105(36):13592-13597. Becker BW, Thames AD, Woo E, Castellon SA, Hinkin CH. Longitudinal change in cognitive function and medication adherence in HIV-infected adults. AIDS Behav. 2011;15(8):1888-1894. Brega AG, Grigsby J, Kooken R, Hamman RF, Baxter J. The impact of executive cognitive functioning on rates of smoking cessation in the San Luis Valley Health and Aging Study. Age Ageing. 2008;37(5):521-525. Lenze EJ, Munin MC, Dew MA, Rogers JC, Seligman K, Mulsant BH, Reynolds CF, 3rd. Adverse effects of depression and cognitive impairment on rehabilitation participation and recovery from hip fracture. Int J Geriatr Psychiatry. 2004;19(5):472-478. Cleutjens FA, Wouters EF, Dijkstra JB, Spruit MA, Franssen FM, Vanfleteren LE, Ponds RW, Janssen DJ. The COgnitive-Pulmonary Disease (COgnitive-PD) study: protocol of a longitudinal observational comparative study on neuropsychological functioning of patients with COPD. BMJ Open. 2014;4(3):e004495. Global initiative for chronic obstructive lung disease: Pocket guide to COPD diagnosis, management, and prevention. Updated 2015. 2015; http://www.goldcopd.org/uploads/users/files/GOLD_Pocket_2015_Feb18.pdf. C.B.S. Standaard Beroepenclassificatie 1992 – editie 2001. Den Haag: SDU; 2001. Luteijn F, Barelds, D.P.F. GIT-2: Groninger Intelligentie Test 2. Handleiding. Amsterdam: Pearson Assessment and Information B.V.

Domain‐specific cognitive impairment in COPD

23. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373383. 24. Holland AE, Spruit MA, Troosters T, Puhan MA, Pepin V, Saey D, McCormack MC, Carlin BW, Sciurba FC, Pitta F, Wanger J, MacIntyre N, Kaminsky DA, Culver BH, Revill SM, Hernandes NA, Andrianopoulos V, Camillo CA, Mitchell KE, Lee AL, Hill CJ, Singh SJ. An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease. Eur Respir J. 2014;44(6):1428-1446. 25. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta psychiatrica scandinavica. 1983; 67(6):361-370. 26. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561-571. 27. Jolles J, van Boxtel MP, Ponds RW, Metsemakers JF, Houx PJ. [The Maastricht aging study (MAAS). The longitudinal perspective of cognitive aging]. Tijdschr Gerontol Geriatr. 1998;29(3):120-129. 28. Burgmans S, van Boxtel MP, Smeets F, Vuurman EF, Gronenschild EH, Verhey FR, Uylings HB, Jolles J. Prefrontal cortex atrophy predicts dementia over a six-year period. Neurobiol Aging. 2009;30(9):1413-1419. 29. Singh B, Parsaik AK, Mielke MM, Roberts RO, Scanlon PD, Geda YE, Pankratz VS, Christianson T, Yawn BP, Petersen RC. Chronic obstructive pulmonary disease and association with mild cognitive impairment: the Mayo Clinic Study of Aging. Mayo Clin Proc. 2013;88(11):1222-1230. 30. Cockrell JR, Folstein MF. Mini-Mental State Examination (MMSE). Psychopharmacol Bull. 1988;24(4):689-692. 31. Dulohery MM, Schroeder DR, Benzo RP. Cognitive function and living situation in COPD: is there a relationship with self-management and quality of life? International Journal of Chronic Obstructive Pulmonary Disease. 2015(10):1883-1889. 32. Dal Negro RW, Bonadiman L, Bricolo FP, Tognella S, Turco P. Cognitive dysfunction in severe chronic obstructive pulmonary disease (COPD) with or without Long-Term Oxygen Therapy (LTOT). Multidiscip Respir Med. 2015;10(1):17. 33. Bucknall CE, Miller G, Lloyd SM, Cleland J, McCluskey S, Cotton M, Stevenson RD, Cotton P, McConnachie A. Glasgow supported self-management trial (GSuST) for patients with moderate to severe COPD: randomised controlled trial. BMJ. 2012;344:e1060. 34. Paterniti S, Dufouil C, Bisserbe JC, Alperovitch A. Anxiety, depression, psychotropic drug use and cognitive impairment. Psychol Med. 1999;29(2):421-428. 35. Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel VP, Bruijnzeel PL, Rutten EP, Op 't Roodt J, Wouters EF, Franssen FM. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;187(7):728-735. 36. Cardiogenic brain embolism. Cerebral Embolism Task Force. Arch Neurol. 1986;43(1):71-84. 37. Fan VS, Meek PM. Anxiety, depression, and cognitive impairment in patients with chronic respiratory disease. Clin Chest Med. 2014;35(2):399-409. 38. Lam RW, Kennedy SH, McLntyre RS, Khullar A. Cognitive dysfunction in major depressive disorder: effects on psychosocial functioning and implications for treatment. Can J Psychiatry. 2014;59(12):649-654. 39. Amado-Boccara I, Gougoulis N, Poirier Littre MF, Galinowski A, Loo H. Effects of antidepressants on cognitive functions: a review. Neurosci Biobehav Rev. 1995;19(3):479-493. 40. Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: a metaanalytic study. Psychol Sci. 2003;14(2):125-130. 41. Friedman NP, Miyake A, Corley RP, Young SE, Defries JC, Hewitt JK. Not all executive functions are related to intelligence. Psychol Sci. 2006;17(2):172-179. 42. Boer LM, Daudey L, Peters JB, Molema J, Prins JB, Vercoulen JH. Assessing the stages of the grieving process in chronic obstructive pulmonary disease (COPD): validation of the Acceptance of Disease and Impairments Questionnaire (ADIQ). Int J Behav Med. 2014;21(3):561-570.

121

Chapter 6

ChapterÂ 6Â 43. Sulaiman I, Cushen B, Greene G, Seheult J, Seow D, Rawat F, MacHale E, Mokoka M, Moran CN, Sartini Bhreathnach A, MacHale P, Tappuni S, Deering B, Jackson M, McCarthy H, Mellon L, Doyle F, Boland F, Reilly RB, Costello RW. Objective Assessment of Adherence to Inhalers by COPD Patients. Am J Respir Crit Care Med. 2016. 44. Finlayson M. Multiple Sclerosis Rehabilitation: From Impairment to Participation. Boca Raton, FL: CRC Press; 2012. 45. Fleming JM, Shum D, Strong J, Lightbody S. Prospective memory rehabilitation for adults with traumatic brain injury: a compensatory training programme. Brain Inj. 2005;19(1):1-10. 46. Merckelbach H, Muris P, Nijman H, de Jong PJ. Self-reported cognitive failures and neurotic symptomatoloy. Pers Indiv Differ. 1996;20(6):715-724.

122

Domain‐specific cognitive impairment in COPD

Supplementary material Neuropsychological assessment

(a) A shortened form of the Groninger Intelligence Test (GIT) will be used to determine general intelligence. Six subtasks will be administered: (1) Vocabulary: measures verbal comprehension. In this subtest 20 words of increasing difficulty are presented of which the participant has to choose the synonym out of five alternatives. The total score ranges between 020, with higher scores reflecting higher level of verbal intelligence; (2) Mental rotation: measures visualization. This subtest requires participants to decide which of several smaller geometric shapes from a larger set are needed to fill a larger geometric figure. Total scores ranges between 0-20, with higher scores reflecting higher level of visuo-spatial performance; (3) Figure Discovery: measures perceptual intelligence. In this subtest the subject is shown 20 cards with silhouettes of incomplete pictures of familiar objects or animals and then has to estimate what the picture depicts. The total score ranges between 0-20, with higher scores reflecting higher level of perceptual intelligence; (4) Doing sums: measures numeracy. This subtest requires participants to complete as many adding sums as possible within a time period of 1 minute. The total score ranges between 0-32, with higher scores reflecting higher level of numeracy; (5) Analogies: measures reasoning. In this subtest the subject has to choose 1 from 5 possibilities that correctly completes a 3 x 2 matrix of logical semantic relations (e.g., black-white, high-low, hot-?). The total score ranges between 0-20, with higher scores reflecting higher level of reasoning; (6) Fluency: measures word fluency. The Animal Naming Task and the Profession Naming Task are used to assess semantic verbal fluency and require patients to generate the names of as many animals respectively professions as possible within 60 seconds. Scores are determined by summing correct responses and reflect strategy-driven retrieval of information from semantic memory.1 (b) Global cognitive functioning was assessed with the Mini-Mental State Examination (MMSE) as a brief screening for global cognitive functioning. This test consists of questions on orientation to time and place, registration, attention and calculation, recall, language, and visual construction to measure global cognitive functioning. The MMSE consists of 20 questions and the maximum score to achieve is 30 points, with a higher score indicating a better cognitive performance. A score of 26-30 indicates ‘normal cognitive functioning’, a score of 24 or 25 ‘borderline normal

123

Chapter 6

Our primary outcome, cognitive functioning, was measured with a detailed neuropsychological assessment consisting of the following subtests:

Chapter 6 cognitive functioning’, a score below 24 ‘cognitive impairment’ and a score below 18 ‘severe cognitive impairment’.2 (c) The Stroop Colour-Word Test (SCW) will be used to assess cognitive flexibility and is composed of three trials using word, color, and interference cards. The first card shows names of colors, which have to be read out loud, printed in black. The second card shows patches of colors, which have to be named. The last card shows names of colors printed in incongruously colored ink and participants are instructed to name the color of the ink in the printed words. Errors, self-corrected errors, and time of completion for all trials will be recorded. The time needed for the last card will be subtracted from the mean score for the first and second cards to obtain an interference score. This interference score can be regarded as a measure of inhibition of a habitual response (reading) which is part of the domain of executive functioning.3 (d) The Concept Shifting Test (CST) which is a simple pen-and-paper test which measures concept shifting and executive functioning. This test consists of three subtasks. On each test sheet, 16 small circles are grouped in a larger circle. The small circles contain numbers, letters, or both, appearing in a fixed random order. Participants are requested to cross out the items in the right order. In the final part of the test, they have to alternate between numbers (1–8) and letters (A–H). The time needed to complete each subtask and errors will be recorded. Finally, participants are presented with a condition to control for basic motor speed in which empty circles have to be marked as fast as possible in a clockwise manner. The difference between the score for the last part, corrected for basic motor speed, and the mean score for the first and second parts also corrected for basic motor speed, represent the time needed for cognitive shifting. Cognitive shifting (or mental set shifting) is considered to be part of executive functioning.4 (e) The Letter Digit Substitution Test (LDST) will be used as a measure of information processing speed. A code is presented at the top of the test form, with 10 digit/letter combinations. The participants fill in digits in blank squares indexed with a letter using the code key. The key and the stimuli are the same for the oral and written versions of the LDST. The written LDST version will be administered first, immediately followed by the oral version. The number of correct substitutions made in 60 seconds is the dependent variable for both test versions.5 (f) The visual verbal learning task (VVLT) visual version, will be used in order to measure memory and verbal learning. In this test, 15 words are visually presented, one after the other, at 2-s intervals. The participants are then

124

Domain‐specific cognitive impairment in COPD asked to recall as many words as possible, in a random order. This procedure will be repeated five times. When the fifth trial has completed, a fixed battery of other cognitive tests will be administered for about 20 minutes. After the delay, unexpectedly for the participant, the instruction will be given to recall the words learned (delayed recall). This will be followed immediately by a recognition test, involving yes/no recognition of the fifteen words intermixed with fifteen nontarget words. Dependent variables are the total number of recalled words in the first three trials, the number of words recalled after 20 minutes and the number of words recognized in the recognition trial.6 (g) Digit span from the Wechsler Adult Intelligence Scale III (WAIS-III) as a measure of short-term memory. This test consists of two parts, namely orally presented digits forward and digits backwards. Subjects are required to repeat 3 - 9 digits forward and 2 - 9 digits backwards. There are two trials at each series length, and the test continues until both trials of a series length are failed. One point is awarded for each correct trial.7 (h) The key-search of the Behavioural Assessment of the Dysexecutive Syndrome will be used as a measure of executive functioning. It is claimed that this test assesses ability to plan a strategy to solve a problem (finding a key lost in a field). The score is based on a number of criteria, including whether the rater believes the strategy to be systematic, efficient and likely to be effective. A penalty is imposed for lack of speed. (i) The zoo-map test of the Behavioural Assessment of the Dysexecutive Syndrome as a measure of executive functions. This is a test to assess ability independently to formulate and implement a plan (high demand condition) and to follow a pre-formulated plan (low demand condition). It involves plotting or following a route through a map that does not contravene a set of rules. The score is based on the successful implementation of the plan. Penalties are imposed for rule breaks and lack of speed.8 (j) A validated Dutch translation of the Cognitive Failure Questionnaire (CFQ) which is a 25-item self-report inventory and comprises four main subscales: absent-mindedness, social interactions, names and words, and orientation. Participants are asked to indicate on a 5-point scale how often they experience subjective cognitive failures. The scale ranges from ‘never (0)’, ‘very rarely (1)’, ‘occasionally (2)’, ‘quite often (3)’, to ‘very often (4)’. Total scores range between 0-100, with a higher scores indicating more subjectively experienced cognitive failures.9

125

Chapter 6

ChapterÂ 6Â

Additional tables Table S1. Neuropsychological outcome measures Test name Subscore or subtest Objective measures Groninger Subtests: vocabulary, Intelligence Test mental rotation, figure (GIT) discovery, doing sums, analogies, fluency Mini-Mental State Subscore: total score Examination (MMSE) Stroop Color-Word Subtests: Card I, card II, Test (SCWT) card III, interference

Concept Shifting Test (CST)

Subtests: CST-A, CST-B, CST-C, CST interference

Letter Digit Substitution Test (LDST) Visual Verbal Learning Test (VVLT), direct and delayed recall Digit Span (DS) from the WAIS-R Behavioural Assessment of the Dysexecutive Syndrome (BADS) Subjective measures Cognitive Failure Questionnaire (CFQ)

Subtests: written, oral, motor

Parameter measures Verbal comprehension, visualisation, perceptual intelligence, numeracy, reasoning, word fluency, and intelligence quotient (IQ) Global cognitive functioning (Selective) attention, general information processing speed, inhibition, and interference susceptibility (Divided) attention, information processing speed, simple motor speed, visual conceptual and visuomotor tracking, and mental flexibility Attention, information processing speed, psychomotor speed

Subscores: Trial 1, 2, 3, 4, and 5, total, delayed recall, recognition, retention Subtests: Forward, backward, total Subtests: Key search, zoo map

Verbal learning and memory

Subscores: absentmindedness, social interactions, names and words and orientation, and total score

Cognitive failures in daily life

Verbal immediate memory, working memory, and general auditory attention Planning and priority setting

Abbreviations: BADS, Behavioural Assessment of the Dysexecutive Syndrome; CFQ, Cognitive Failure Questionnaire; CST, Concept Shifting Test; DS, Digit Span; GIT, Groninger Intelligence Test, LDST, Letter Digit Substitution Test; MMSE, Mini-Mental State Examination; SCWT, Stroop Color-Word Test; VVLT, Visual Verbal Learning Test.

126

Domain‐specific cognitive impairment in COPD

Table S2. Neuropsychological tests for the evaluation of general cognitive impairment Test Subscore or subtest Parameter measures name GIT-II Animal naming (number of animal Semantic fluency names)* SCWT Card III (time in seconds)† Attentional inhibition of a dominant response CST CST-C (time in seconds)† Alternating attention 60 Sec (number correct: 0-125)‡ Psychomotor speed and speed of information LDST processing VVLT Total recall (number correct: 0-75)‡ Overall verbal learning Verbal memory after an interval Delayed recall (number correct: 015)‡

Table S3. Neuropsychological tests for the evaluation of compound performance indices Test name Subscore or subtest Parameter measures Psychomotor speed SCWT Card I (time in seconds)* Reading speed CST CST-A (time in seconds)* Simple motor speed LDST 60 Sec written and oral (number correct: Psychomotor speed and 0-125)† speed of information processing Planning BADS Key search (profile score: 0-4)† Planning and priority setting Zoo map (profile score: 0-4)† Working memory VVLT Trial 1 (number correct: 0-15)† Immediate verbal span DS Backward (span: 0-7)† Working memory Verbal memory VVLT Total recall (number correct: 0-75)† Overall verbal learning and Delayed recall (number correct: 0-15)† verbal memory after an Retention (percentage of words that interval were retained from the immediate to the delayed score)† Cognitive flexibility SCWT Card III (time in seconds)* Attentional inhibition of a dominant response CST CST-C (time in seconds)* Alternating attention Abbreviations: SCWT, Stroop Color-Word Test; CST, Concept Shifting Test; LDST, Letter Digit Substitution Test; BADS, Behavioural Assessment of the Dysexecutive Syndrome; VVLT, Visual Verbal Learning Test; DS, Digit Span. *, Higher scores indicate worse performance. Score or scale ranges are in parentheses. †, Higher scores indicate better performance.

127

Chapter 6

At least 2 out of 6 subtest Z scores should be –1SD for the patients with COPD with general cognitive impairment. Abbreviations: CST, Concept Shifting Test; GIT, Groninger Intelligence Test; LDST, Letter Digit Substitution Test; SCWT, Stroop Color-Word Test; VVLT, Visual Verbal Learning Test. *, Indicates score has no upper limit; †, Higher scores indicate worse performance; ‡, Higher scores indicate better performance; Score or scale ranges are in parentheses

Chapter 6 Table S4. Raw unadjusted means on neuropsychological measures, compound z-scores, and P-values adjusted for matching variables and comorbidities in patients with COPD and controls Outcome measure COPD patients Controls Adjusted (n=90) (n=90) P-value* Global cognitive functioning MMSE, mean (SD)† 27.4 (2.3) 28.1 (1.6) 0.068 Global cognitive impairment (MMSE ≤24), n (%) 7 (7.8) 2 (2.2) 0.356 Domain-specific cognition Psychomotor speed (compound z-score), mean (SD) -0.5 (1.1) 0.3 (0.7) <0.001 SCWT card I, mean (SD)† 19.1 (5.6) 17.0 (2.6) 0.035 CST-A, mean (SD) 28.1 (15.8) 21.2 (5.6) 0.003 LDST 60 sec written, mean (SD) 25.2 (7.2) 31.7 (5.7) <0.001 LDST 60 sec oral, mean (SD) 31.1 (7.5) 37.1 (6.5) <0.001 Planning (compound z-score), mean (SD) -0.3 (0.8) 0.3 (0.6) <0.001 BADS key search, mean (SD) 2.2 (1.5) 3.1 (1.2) 0.004 BADS zoo map, mean (SD)† 2.2 (0.8) 2.7 (0.7) <0.001 Working memory (compound z-score), mean (SD) -0.6 (0.8) -0.2 (0.8) 0.087 VVLT trial 1, mean (SD) 4.4 (1.9) 5.5 (2.1) 0.003 DS backward, mean (SD) 3.0 (1.1) 3.1 (1.2) 0.485 Verbal memory (compound z-score), mean (SD) -0.5 (1.1) 0.0 (1.0) 0.004 VVLT total recall 1–5, mean (SD) 40.2 (10.8) 47.3 (10.2) <0.001 VVLT delayed recall, mean (SD) 7.3 (3.5) 9.1 (3.2) 0.011 VVLT retention max, mean (SD)† 0.6 (0.3) 0.7 (0.2) 0.060 Cognitive flexibility (compound z-score), mean (SD) -1.2 (1.6) -0.0 (0.8) <0.001 SCWT card III, mean (SD)† 60.9 (26.7) 43.0 (13.0) <0.001 CST-C, mean (SD) 51.1 (26.3) 35.3 (11.6) <0.001 General cognitive impairment (2 out of 6 subtest Z 51 (56.7) 12 (13.3) 0.128 scores -1SD), n (%) Cognitive complaints CFQ absent-mindedness, mean (SD) CFQ social interactions, mean (SD) CFQ names and words, mean (SD) CFQ orientation, mean (SD) CFQ total score, mean (SD)

8.2 (5.4) 5.7 (3.3) 5.7 (2.6) 2.7 (2.6) 31.8 (17.3)

7.1 (3.6) 4.9 (2.2) 4.9 (2.0) 2.3 (1.7) 27.3 (11.0)

0.615 0.685 0.028 0.638 0.843

Abbreviations: BADS, Behavioural Assessment of the Dysexecutive Syndrome; CFQ, Cognitive Failure Questionnaire; CST, Concept Shifting Test; DS, Digit Span; LDST, Letter Digit Substitution Test; MMSE, Mini-Mental State Examination; SCWT, Stroop Color-Word Test; SD, standard deviation; VVLT, Visual Verbal Learning Test. *, Adjusted for matching variables age, educational level, and smoking status, and comorbidities (myocardial infarction, peripheral vascular disease, hemiplegia, clinically relevant symptoms of depression, and clinically relevant symptoms of anxiety). †, Nonparametric statistical tests have been used because of skewed data.

128

Domain‐specific cognitive impairment in COPD

Table S5. Raw unadjusted means on neuropsychological measures and compound z-scores tients with COPD with and without oxygen therapy Outcome measure COPD patients with COPD patients without oxygen therapy (n=18) oxygen therapy (n=72) Global cognitive functioning MMSE, mean (SD)* 27.3 (2.9) 27.4 (2.1) Global cognitive impairment (MMSE 2 (11.1) 5 (6.9) ≤24), n (%) Domain-specific cognition Psychomotor speed (compound z-0.6 (1.4) -0.4 (0.9) score), mean (SD)* SCWT card I, mean (SD)* 19.4 (8.6) 19.1 (4.6) 31.9 (29.1) 27.2 (10.2) CST-A, mean (SD)* LDST 60 sec written, mean (SD) 24.1 (8.1) 25.5 (6.9) LDST 60 sec oral, mean (SD) 31.3 (8.9) 31.1 (7.2) Planning (compound z-score), mean -0.0 (0.8) -0.3 (0.7) (SD) BADS key search, mean (SD)* 2.8 (1.5) 2.1 (1.5) BADS zoo map, mean (SD) 2.2 (0.8) 2.2 (0.8) Working memory (compound z-0.4 (0.9) -0.6 (0.7) score), mean (SD) VVLT trial 1, mean (SD)* 4.9 (2.1) 4.2 (1.8) 2.9 (1.1) 3.0 (1.1) DS backward, mean (SD)* Verbal memory (compound z-score), -0.3 (1.1) -0.5 (1.1) mean (SD) VVLT total recall 1–5, mean (SD) 41.7 (12.5) 39.9 (10.4) VVLT delayed recall, mean (SD) 7.8 (3.9) 7.2 (3.4) VVLT retention max, mean (SD) * 0.7 (0.3) 0.6 (0.3) -1.3 (1.8) -1.1 (1.5) Cognitive flexibility (compound zscore), mean (SD)* SCWT card III, mean (SD) * 61.1 (33.4) 60.8 (25.0) CST-C, mean (SD)* 59.1 (39.6) 49.0 (21.8) General cognitive impairment (2 out 9 (50.0) 42 (58.3) of 6 subtest Z scores -1SD), n (%) Cognitive complaints CFQ absent-mindedness, mean (SD)* 9.2 (5.9) 8.0 (5.3) CFQ social interactions, mean (SD) 5.9 (3.7) 5.7 (3.2) CFQ names and words, mean (SD) 5.8 (3.1) 5.6 (2.5) CFQ orientation, mean (SD)* 2.7 (3.4) 2.6 (2.4) CFQ total score, mean (SD)* 34.0 (21.0) 31.2 (16.4)

in paP-value

0.620 0.426

0.912 0.443 0.972 0.479 0.911 0.200 0.071 0.753 0.350 0.158 0.941 0.418 0.535 0.529 0.904 0.793 0.493 0.259 0.353

0.268 0.823 0.840 0.656 0.668

129

Chapter 6

Chapter 6 Table S6. Raw unadjusted means on neuropsychological measures and compound z-scores in patients with COPD with and without clinically relevant symptoms of depression Outcome measure COPD patients COPD patients P-value with symptoms without symptoms of depression of depression (n=19) (n=71) Global cognitive functioning MMSE, mean (SD)* 27.9 (1.7) 27.2 (2.4) 0.321 Global cognitive impairment (MMSE ≤24), 1 (5.3) 6 (8.5) 0.542 n (%) Domain-specific cognition -0.4 (0.9) -0.5 (1.1) 0.925 Psychomotor speed (compound z-score), mean (SD)* SCWT card I, mean (SD)* 18.9 (4.6) 19.2 (5.8) 0.953 CST-A, mean (SD)* 25.9 (6.7) 28.7 (17.4) 0.707 LDST 60 sec written, mean (SD) 25.2 (7.8) 25.2 (7.0) 0.983 LDST 60 sec oral, mean (SD) 30.8 (6.4) 31.2 (7.8) 0.867 Planning (compound z-score), mean (SD) -0.3 (0.7) -0.2 (0.8) 0.559 2.0 (1.6) 2.3 (1.5) 0.507 BADS key search, mean (SD)* BADS zoo map, mean (SD) 2.2 (0.6) 2.2 (0.9) 0.945 Working memory (compound z-score), -0.6 (0.5) -0.6 (0.8) 0.919 mean (SD) VVLT trial 1, mean (SD)* 4.8 (2.3) 4.3 (1.8) 0.440 DS backward, mean (SD)* 2.7 (1.0) 3.1 (1.1) 0.277 Verbal memory (compound z-score), mean -0.3 (0.9) -0.5 (1.1) 0.465 (SD) VVLT total recall 1–5, mean (SD) 43.0 (8.7) 39.5 (11.2) 0.213 VVLT delayed recall, mean (SD) 8.0 (2.4) 7.1 (3.7) 0.335 VVLT retention max, mean (SD)* 0.7 (0.2) 0.6 (0.3) 0.498 Cognitive flexibility (compound z-score), -1.3 (1.3) -1.2 (1.6) 0.409 mean (SD)* SCWT card III, mean (SD)* 62.3 (17.7) 60.5 (28.7) 0.134 50.0 (20.1) 51.3 (27.9) 0.839 CST-C, mean (SD)* General cognitive impairment (2 out of 6 13 (68.4) 38 (53.5) 0.184 subtest Z scores -1SD), n (%) Cognitive complaints CFQ absent-mindedness, mean (SD)* 11.1 (6.7) 7.4 (4.8) 0.013 CFQ social interactions, mean (SD) 6.8 (3.8) 5.4 (3.1) 0.097 CFQ names and words, mean (SD) 5.6 (2.9) 5.7 (2.5) 0.947 CFQ orientation, mean (SD)* 3.5 (3.4) 2.4 (2.4) 0.109 39.4. (22.3) 29.7 (15.3) 0.054 CFQ total score, mean (SD)* Abbreviations: see table S4. *, Nonparametric statistical tests have been used because of skewed data.

130

Domain‐specific cognitive impairment in COPD

Table S7. Raw unadjusted means on neuropsychological measures and compound z-scores in patients with COPD with and without clinically relevant symptoms of anxiety Outcome measure COPD patients COPD patients P-value with symptoms without of anxiety symptoms of (n=28) anxiety (n=62) Global cognitive functioning MMSE, mean (SD)* 27.3 (2.5) 27.4 (2.2) 0.891 Global cognitive impairment (MMSE ≤24), n 3 (10.7) 4 (6.5) 0.376 (%) Domain-specific cognition -0.4 (1.0) -0.5 (1.1) 0.889 Psychomotor speed (compound z-score), mean (SD)* SCWT card I, mean (SD)* 19.0 (5.1) 19.2 (5.8) 0.747 CST-A, mean (SD)* 25.8 (7.7) 29.2 (18.3) 0.403 LDST 60 sec written, mean (SD) 25.6 (8.2) 25.0 (6.7) 0.689 LDST 60 sec oral, mean (SD) 30.9 (7.5) 31.2 (7.6) 0.885 Planning (compound z-score), mean (SD) -0.3 (0.7) -0.2 (0.8) 0.631 2.0 (1.5) 2.3 (1.5) 0.416 BADS key search, mean (SD)* BADS zoo map, mean (SD) 2.3 (0.7) 2.2 (0.9) 0.629 Working memory (compound z-score), -0.6 (0.7) -0.5 (0.8) 0.618 mean (SD) VVLT trial 1, mean (SD)* 4.8 (2.1) 4.2 (1.7) 0.232 DS backward, mean (SD)* 2.6 (1.0) 3.1 (1.1) 0.036 Verbal memory (compound z-score), mean -0.4 (1.0) -0.5 (1.1) 0.448 (SD) VVLT total recall 1–5, mean (SD) 43.2 (10.6) 38.9 (10.7) 0.083 VVLT delayed recall, mean (SD) 8.0 (3.2) 7.0 (3.6) 0.325 VVLT retention max, mean (SD)* 0.7 (0.2) 0.6 (0.3) 0.427 Cognitive flexibility (compound z-score), -1.2 91.5) -1.2 (1.6) 0.428 mean (SD)* SCWT card III, mean (SD) * 61.8 (24.8) 60.5 (27.7) 0.491 49.5 (17.7) 51.7 (29.5) 0.679 CST-C, mean (SD)* General cognitive impairment (2 out of 6 18 (64.3) 33 (53.2) 0.227 subtest Z scores -1SD), n (%) Cognitive complaints CFQ absent-mindedness, mean (SD)* 9.6 (6.1) 7.6 (5.0) 0.113 CFQ social interactions, mean (SD) 6.4 (3.4) 5.4 (3.2) 0.202 CFQ names and words, mean (SD) 5.4 (2.9) 5.8 (2.5) 0.503 CFQ orientation, mean (SD)* 3.2 (3.0) 2.4 (2.4) 0.223 35.4 (19.9) 30.1 (15.9) 0.255 CFQ total score, mean (SD)* Abbreviations: see table S4. *, Nonparametric statistical tests have been used because of skewed data.

131

Chapter 6

References 1. 2. 3.

4. 5.

7. 8. 9.

132

Luteijn F, Barelds, D.P.F. GIT-2: Groninger Intelligentie Test 2. Handleiding. Amsterdam: Pearson Assessment and Information B.V. Cockrell JR, Folstein MF. Mini-Mental State Examination (MMSE). Psychopharmacol Bull. 1988;24(4):689-692. Van der Elst W, Van Boxtel MP, Van Breukelen GJ, Jolles J. The Stroop color-word test: influence of age, sex, and education; and normative data for a large sample across the adult age range. Assessment. 2006;13(1):62-79. Van der Elst W, Van Boxtel MP, Van Breukelen GJ, Jolles J. The Concept Shifting Test: adult normative data. Psychol Assess. 2006;18(4):424-432. van der Elst W, van Boxtel MP, van Breukelen GJ, Jolles J. The Letter Digit Substitution Test: normative data for 1,858 healthy participants aged 24-81 from the Maastricht Aging Study (MAAS): influence of age, education, and sex. J Clin Exp Neuropsychol. 2006;28(6):998-1009. Van der Elst W, van Boxtel MP, van Breukelen GJ, Jolles J. Rey's verbal learning test: normative data for 1855 healthy participants aged 24-81 years and the influence of age, sex, education, and mode of presentation. J Int Neuropsychol Soc. 2005;11(3):290-302. Wechsler D. Wechsler Adult Intelligence Scale—Revised. San Antonio, TX: The Psychological Corporation; 1981. Wilson BA, Aldermann, N., Burgess, B.W. Behavioural assessment of the dysexecutive syndrome. Bury St Edmunds: Thames Valley Test Co; 1998. Merckelbach H, Muris P, Nijman H, de Jong PJ. Self-reported cognitive failures and neurotic symptomatoloy. Pers Indiv Differ. 1996;20(6):715-724.

Chapter 7

Cognitive impairment and clinical characteristics in patients with COPD Cleutjens FAHM, Spruit MA, Ponds RWHM, Vanfleteren LEGW, Franssen FME, Gijsen C, Dijkstra JB, Wouters EFM, Janssen DJA (in press). Cognitive impairment and clinical characteristics in patients with COPD. CRD.

135

Chapter 7

Abstract Introduction Cognitive impairment (CI) is common in patients with chronic obstructive pulmonary disease (COPD). We aimed to investigate 1) the relationship between CI and disease severity; and 2) potential differences in exercise performance, daily activities, health status and psychological wellbeing between patients with and without CI. Methods Clinically stable COPD patients, referred for pulmonary rehabilitation, underwent a neuropsychological examination. Functional exercise capacity (six-minute walk test (6MWT)), daily activities (Canadian Occupational Performance Measure (COPM)), health status (COPD Assessment Test (CAT)) and St George’s Respiratory Questionnaire-COPD specific (SGRQ-C)), and psychological wellbeing (Hospital Anxiety and Depression Scale (HADS), Beck Depression Inventory (BDI), Symptom Checklist 90 (SCL-90)) were compared between patients with and without CI. Results Out of 183 COPD patients (mean age 63.6 (9.4) years, FEV1 54.8 (23.0)% predicted), 76 patients (41.5%) had CI. The prevalence was comparable across GOLD grades 1-4 (44.8%, 40.0%, 41.0%, 43.5% respectively, p=0.97) and GOLD groups A-D (50.0%, 44.7%, 33.3%, 40.2% respectively, p=0.91). Patients with and without CI were comparable for demographics, smoking status, FEV1% predicted, mMRC, 6MWT, COPM, CAT, HADS, BDI, and SCL-90 scores. Conclusion Clinical characteristics of COPD patients with and without CI are comparable. Assessment of CI in COPD requires an active case finding approach.

136

Cognitive impairment and clinical characteristics in COPD

Chronic obstructive pulmonary disease (COPD) is primarily a pulmonary disease characterized by a (usually) progressive, largely irreversible, airflow limitation.1 Although defined by an abnormal spirometry, COPD is well recognized as more than a respiratory disease. Indeed, extrapulmonary features and comorbidities occur frequently in patients with COPD, and include for example decreased muscle mass, cardiovascular disease, anemia, and osteoporosis.2 Furthermore, psychological problems, such as symptoms of depression and anxiety, and cognitive impairment (CI) are common in patients with COPD. 2 3 Patients with COPD can have either global impairment or deficits in specific cognitive domains, such as memory or cognitive flexibility.3 Impairment in memory and cognitive flexibility may lead to problems with adherence to treatment, educational achievement, self-management, and smoking abstinence,4-7 which are components of pulmonary rehabilitation.8 Conventional COPD classification is mainly based on airflow limitation. In the Global initiative for chronic Obstructive Lung Disease (GOLD) document, the severity of airflow limitation is classified in four grades.1 Until now, the prevalence of CI among these traditional GOLD grades remains unknown. The updated COPD GOLD strategy 20141 recommend to grade disease severity into risk groups, based on symptoms and exacerbation risk. Also, the prevalence of CI among the GOLD groups remains unknown. Moreover, the relationship between CI and other patient-related outcomes is unknown. Nevertheless, identifying factors associated with CI in COPD patients can help clinicians to detect patients with possible CI for further cognitive assessment. Therefore, the first aim of this study was to study the relationship between CI and the severity of airflow limitation. The second aim was to compare functional status, diseasespecific health status and psychological wellbeing between COPD patients with and without CI. Because CI may be of special interest in educational components and behavior change interventions of PR, the current study focuses specifically on patients with COPD who are to start a comprehensive interdisciplinary PR program. A priori, we hypothesized that CI is most prevalent in GOLD grades 3-4 and in GOLD group D, having high risk and more symptoms. Furthermore, we hypothesized that functional status, disease-specific health status and psychological wellbeing are worse in patients with CI compared to patients without CI.

Methods Design This cross-sectional observational study is part of a longitudinal study (COgnitive-PD study) concerning neuropsychological functioning in patients with

137

Chapter 7

Introduction

ChapterÂ 7Â COPD. Details of the methodology of this study and data concerning cognitive functioning have been published before.9 Moreover, 90 patients were part of a previous publication on the prevalence of general and domain-specific CI between patients with COPD and non-COPD controls.3

Study sample Patients with clinically stable COPD were included. Diagnosis of COPD was based on GOLD criteria.1 All patients were admitted to CIRO, a tertiary referral center, for a 3-day assessment before the start of a comprehensive interdisciplinary PR program.10 Exclusion criteria were: an exacerbation within the previous four weeks, insufficient comprehension of the Dutch language, or having a diagnosis of dementia. All participants gave informed consent. The Medical Ethics Committee of the University Hospital Maastricht and Maastricht University approved this study (NL45127.068.13).

Measures Age, gender, educational level (according to The Dutch Standard Classification of Education (CBS)11), marital status, visual and hearing impairment, handedness, smoking behavior, and self-reported comorbidities (Charlson Comorbidity Index)12 were recorded. The patient medical record was used to collect data on body mass index (BMI), long-term oxygen therapy, modified Medical Research Council (mMRC) dyspnoea scale, BODE (Body mass index, airflow Obstruction, Dyspnea and Exercise capacity) index,13 post-bronchodilator spirometry (forced vital capacity (FVC), FVC% predicted, forced expiratory volume in the first second (FEV1), FEV1% predicted, and FEV1/FVC), exacerbation history, arterial blood gases, including arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), and arterial oxygen saturation (SaO2)), and single breath carbon monoxide diffusing capacity (DLCO% predicted), and level of hypoxemia (mild: PaO2 60-79 mmHg; moderate: PaO2 40-59 mmHg; and severe: PaO2 <40 mmHg). Neuropsychological examination comprised a detailed neuropsychological testing battery from the Cognitive-PD study, namely: the Concept Shifting Test (CST); the Letter Digit Substitution Test (LDST); the Stroop Color-Word Test (SCWT); and the visual verbal learning task (VVLT); and a shortened version of the Groninger Intelligence Test (GIT) including subtasks vocabulary, mental rotation, figure discovery, doing sums, analogies, and fluency. For detailed information of the neuropsychological testing battery see the Cognitive-PD study protocol.9 Two six-minute walk tests (6MWT) were performed according to ERS/ATS guidelines to measure functional exercise capacity.14 The best 6MWT was expressed in percentage of predicted values. The Canadian Occupational Performance Measure (COPM) was used to assess the performance of daily activities

138

Statistics All statistics were done using SPSS 21.0 (SPSS Inc. Chicago, IL). Because of multiple comparisons a p-value ≤0.01 was considered as statistically significant. Categorical variables are described as frequencies, while continuous variables were tested for normality and are presented as mean and standard deviation (SD) or median and interquartile range (IQR). Raw test scores on the neuropsychological testing battery were transformed into age, gender, and education corrected Z-scores based on normative data from the Maastricht Aging Study (MAAS). 22 Six core tests used in MAAS to probe different cognitive domains23: verbal memory (VVLT total, VVLT recall), verbal fluency (GIT animal naming); psychomotor speed (LDST 60 sec) and information processing (CST-C and SCWT card III), were used to distinguish between COPD patients with CI and COPD patients without CI (see table E1). In accordance with Singh et al.24 Z-scores below −1.0 SD were considered as being impaired. Therefore, patients with general CI have a score less than 1.0 SD below the age-, gender-, and education-specific mean of the MAAS study population for at least two core tests.

139

Chapter 7

Cognitive impairment and clinical characteristics in COPD 15 and satisfaction with daily activities, as described before. Problematic ADLs were categorized into four COPM domains (problems / no problems): ‘selfcare,’ ‘productivity’, ‘leisure’ and ‘mobility’.16 To assess disease-specific health status, participants completed the COPD Assessment Test (CAT) and the St George’s Respiratory Questionnaire-COPD specific (SGRQ-C). The CAT contains eight items with a final single score ranging from 0 (mild) to 40 points (very severe).17 The SGRQ-C provides a total score and three domain scores: symptoms, activities and impact (ranging from 0 (best) to 100 points (worst)).18 Symptoms of anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS). The HADS is comprised of a Depression and Anxiety subscale. Scores per subscale range from 0-21 points. Scores of 0-7 points indicate normal levels of anxiety and depression; 8-10 points indicate borderline abnormal anxiety and depression levels; 11-21 points suggest abnormal levels of anxiety and depression.19 The Beck Depression Inventory (BDI) was used to measure the intensity, severity, and depth of depression. The questionnaire consists of 21 items. Total score ranges from 0 to 63 points (0-9 points indicate that a person is not depressed; 10–18 points indicate mild-moderate depression; 19-29 points indicate moderate-severe depression; 30–63 points indicate severe depression).20 Psychological symptom intensity was measured using the Symptom Checklist 90 (SCL-90), a self-report inventory consisting of 90 items divided in 9 subscales. Items are scored on a five-point Likert scale (ranging from 0 ‘not at all’ to 4 points ‘extremely’), indicating the rate of occurrence of the symptom during the time reference.21

Chapter 7 Individual cognitive test measures were grouped into the following specific cognitive domains: psychomotor speed (SCWT card I, CST-A, LDST 60 sec), planning (BADS key search and zoo map), working memory (VVLT trial 1, and DS backward), verbal memory (VVLT total recall, delayed recall, and retention), and cognitive flexibility (SCWT card III and CST-C). Within each cognitive domain, the scaled test Z scores were summed and averaged into one compound Z score. In each cognitive domain, a compound Z score of less than 1.0 SD below the age-, gender-, and education-specific mean of the MAAS study population was considered as impaired.24 Patients were categorized in severity grades 1-4 using spirometry (GOLD I: FEV1 ≥80%; GOLD II: FEV1 ≥50% and <80%; GOLD III: FEV1 ≥30% and <50%; GOLD IV: FEV1 <30%). Additionally, patients were categorized into GOLD groups A-D combining symptom assessment by CAT (<10 or ≥10 points) and exacerbation risk (either by GOLD severity grades (1-2 or 3-4) or the number of exacerbations in the previous 12 months (≤1 or >1)) according to the 2011 GOLD strategy.1 The prevalence of general and domain-specific CI was compared between GOLD grades and GOLD groups using Chi square tests. A post hoc analysis was performed in order to compare clinical characteristics between COPD patients with and without impairments in the cognitive domains psychomotor speed, planning, working memory, verbal memory, and cognitive flexibility using independent sample t-test or Mann–Whitney U-test, as appropriate. Furthermore, the relationship between FEV1 and the five cognitive domains and it’s individual cognitive test measures was analyzed by using a Pearson’s correlation coefcient or Spearman’s rank correlation coefcient, depending on the variable distribution. Patient characteristics, functional status, disease-specific health status and psychological wellbeing were compared between COPD patients with and without CI using Chi square tests for categorical variables and independent sample t test or Mann-Whitney U test, as appropriate for continuous variables.

Results Patient characteristics In total, 183 patients (53% men) with mild to very severe COPD were included (table 1). In total 29 patients (15.8%) were classified as GOLD grade 1, 70 patients (38.3%) as GOLD grade 2, 61 patients (33.3%) as GOLD grade 3, and 23 patients (12.6%) as GOLD grade 4. Furthermore, 6 patients were classified in GOLD group A, 47 patients (25.7%) in GOLD group B, 3 patients (1.6%) in GOLD group C, and 127 patients (69.4%) in GOLD group D. A majority of the patients had a lower general or vocational education level, were positioned in quartile I (0-2 points) of the BODE index, and a majority were non-smokers (table 1).

140

Cognitive impairment and clinical characteristics in COPD

Prevalence of cognitive impairment in different GOLD grades

Table 1. Patient characteristics of the study population Total Patients with group cognitive (n=183) impairment (n=76) Demographics Age, years 63.3 (9.4) 62.7 (8.7) Male, n (%) 97 (53.0) 46 (60.5) Lower general or 100 (54.6) 42 (55.3) vocational education, n (%) IQ, mean (SD) 85.5 (14.9) 77.5 (13.4) Married, n (%) 111 (60.7) 48 (63.2) Clinical characteristics Visual impairment, n (%) 31 (16.9) 12 (15.8) Hearing impairment, n (%) 45 (24.6) 17 (22.4) Right-handed by nature, n 149 (81.4) 63 (82.9) (%) BMI (kg/m2), mean, (SD) 27.1 (6.1) 27.5 (7.2) Oxygen therapy, n (%) 37 (20.2) 15 (19.7) mMRC (points), mean (SD) 2.2 (1.0) 2.2 (1.0) Bode Index 0-2 points, n (%) 107 (58.5) 47 (61.8) 2-3 points, n (%) 27 (14.8) 9 (11.8) 4-5 points, n (%) 33 (18.0) 16 (21.1) 6-10 points, n (%) 16 (8.7) 4 (5.3) Exacerbation history in the previous 12 months 0 exacerbations, n (%) 50 (27.9) 23 (30.3) 1 exacerbation, n (%) 32 (17.9) 13 (17.3) 2 exacerbations, n (%) 30 (16.8) 10 (13.3) 3 exacerbations, n (%) 21 (11.7) 5 (6.7) 4 ≥ exacerbations, n (%) 46 (25.7) 24 (32.0) Smoking behavior Current smoker, n (%) 24 (13.1) 14 (18.4) Former smoker, n (%) 156 (85.2) 62 (81.6) Never smoker, n (%) 3 (1.6) 0 (0.0)

Patients without cognitive impairment (n=107)

Pvalue

63.7 (9.9) 51 (47.7) 58 (54.2)

0.51 0.09 0.89

91.2 (13.2) 63 (58.9)

<0.01 0.56

19 (17.8%) 28 (26.2) 86 (80.4)

0.73 0.56 0.13

26.8 (5.3) 22 (20.6) 2.3 (1.0)

0.45 0.98 0.53

60 18 17 12

(56.1) (16.8) (15.9) (11.2)

0.33

27 19 20 16 22

(26.0) (18.3) (19.2) (15.4) (21.2)

0.19

10 (9.3) 94 (87.9) 3 (2.8)

0.08

141

Chapter 7

The prevalence of general CI did not differ between COPD patients in GOLD grades 1-4 and GOLD groups A-D (Figure 1). Also impairments in specific cognitive domains (psychomotor speed, planning, working memory, verbal memory, and cognitive flexibility) did not differ between COPD patients in GOLD grades 1-4 (Figure 2) and GOLD groups A-D (Figure 3). Moreover, correlations between cognitive measures and FEV1 were weak (Table S1). Demographic and clinical characteristics, including smoking behavior, lung function, and results of arterial blood gases were comparable between patients with and without CI (table 1). COPD patients with CI had a lower IQ compared to those without CI (table 1).

ChapterÂ 7Â Spirometry and arterial blood gases 42.3 (14.8) FEV1/FVC, mean (SD) 54.8 (23.0) FEV1 (% predicted), mean (SD) 94.6 (92.8SaO2 (%), median (IQR) 96.0)a 9.7 (1.6)a PaO2 (kPa), mean (SD) PaCO2 (kPa), mean (SD) 5.2 (0.8)a 49.3 (41.0DLCO (% predicted), 61.7)d median (IQR) Comorbidities Charlson comorbidity index 2.8 (1.8) score, mean, (SD)

43.7 (15.9) 55.3 (24.8)

41.3 (14.0) 54.4 (21.7)

94.4 (93.0-95.8)b 9.7 (1.5)b 5.3 (0.9)b

94.8 (92.8-96.0)c 9.7 (1.6)c 5.1 (0.6)c

48.3 (40.8-62.4)e

49.6 (41.7-61.1)f

2.9 (1.8)

2.7 (1.9)

0.28 0.79 0.98 0.97 0.05 0.61

0.44

Abbreviations: COPD, chronic obstructive pulmonary disease; SD, standard deviation; IQR, interquartile range; BMI, body mass index; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; SaO2, oxygen saturation; PaO2, arterial oxygen partial pressure; PaCO2, arterial partial pressure of carbon dioxide; DLCO, single breath carbon monoxide diffusing capacity;. a, n = 181; b, n = 75; c, n =106; d, n = 174; e, n = 73; f, n =101

Figure 1. The prevalence of cognitive impairment in patients with COPD, stratified for GOLD grades (A) and GOLD groups (B). GOLD: The Global Initiative for Chronic Obstructive Lung Disease guidelines.

142

Cognitive impairment and clinical characteristics in COPD

Figure 2. Domain-specific cognitive impairment. Proportion of patients in GOLD grades 1-4 with impairments in the domains psychomotor speed (17,2%, 8,6%, 8,2%, and 8,7% respectively; p=0.544), planning (10,3%, 11,4%, 8,2%, and 17,4% respectively; p=0.686), working memory (34,5%, 28,6%, 19,7%, and 21,7% respectively; p=0.419), verbal memory (24,1%, 28,6%, 26,2%, and 39,1% respectively; p=0.636), and cognitive flexibility (37,9%, 28,6%, 27,9%, and 13,0% respectively; p=0.262) COPD: chronic obstructive pulmonary disease.

143

Chapter 7

Figure 3. Domain-specific cognitive impairment. Proportion of patients in GOLD groups A-D with impairments in the domains psychomotor speed (0,0%, 17,0%, 33,3%, and 7,1% respectively; p=0.096), planning (0,0%, 12,8%, 33,3%, and 10,2% respectively; p=0.474), working memory (33,3%, 29,8%, 33,3%, and 23,6% respectively; p=0.808), verbal memory (50,0%, 25,5%, 66,7%, and 27,6% respectively; p=0.287), and cognitive flexibility (50,0%, 34,0%, 33,3%, and 24,4% respectively; p=0.369) COPD: chronic obstructive pulmonary disease.

Functional status, disease-specific health status, and psychological wellbeing in patients with and without cognitive impairment Functional exercise capacity measured with the 6MWT was comparable between patients with and without CI (table 2). The COPM domain ‘mobility’ was most frequently scored followed by ‘productivity’, ‘leisure’ and ‘self-care’. The proportion of COPD patients scoring problematic ADLs within the COPM domains did not differ between patients with and without CI (table 2). Also, performance of daily activities and satisfaction with performance of daily activities were comparable between the groups. Finally, patients with and without CI did not differ in diseases-specific health status or psychological well-being (table 2). When comparing COPD patients with and without impairments in specific cognitive domains, functional exercise capacity was worse in those with verbal memory impairments compared to those without verbal memory impairments (400.2 (111.1)) meters vs. 443.9 (110.1) meters, p=0.018) (Table S5). Regarding daily functioning patients with impairments in psychomotor speed, planning,

144

Cognitive impairment and clinical characteristics in COPD and cognitive flexibility had lower satisfaction scores on specific domains of the COPM (Tables S2, S3, and S6) Patients with and without domain-specific CI did not differ in diseases-specific health status. As to psychological wellbeing, impairments in psychomotor speed, planning, and cognitive flexibility were related to somatization, and impairments in planning, working memory, verbal memory, cognitive flexibility to symptoms of depression (Tables S2-S6). Moreover, patients with impairments in the domain cognitive flexibility had higher (worse) scores on the insufficiency (28.3 (9.2) and 25.4 (7.7) respectively) and psychoneuroticism (160.6 (44.1) and 143.9 (40.8) respectively) items of the SCL-90 compared to patients without impairments in this cognitive domain) (Table S6). Pvalue

0.30 0.14 0.16 0.27 0.66 0.59 0.66 0.63 0.65 0.76 0.78 0.65 0.39 0.33 0.04

Chapter 7

Table 2. Functional status, disease-specific health status, and psychological wellbeing Total group Patients with Patients without (n=183) cognitive cognitive impairment impairment (n=76) (n=107) Functional status Functional exercise capacity 6MWT (meters) 432 (111.8) 421.8 (112.2) 439.2 (111.5) 6MWT (% predicted) 68.3 (16.6) 66.1 (16.7) 69.8 (16.4) 6MWT <350 meters, n (%) 45 (24.6) 22 (28.9) 23 (21.5) Daily activities COPM mobility domain, n (%) 147 (80.3) 64 (84.2) 83 (77.6) Performance score (points) 3.8 (1.5) 3.7 (1.7) 3.8 (1.4) Satisfaction score (points) 2.8 (1.7) 2.7 (1.9) 2.9 (1.7) COPM productivity domain, n (%) 117 (63.9) 50 (65.8) 67 (62.6) Performance score (points) 3.9 (1.5) 3.8 (1.5) 3.9 (1.5) Satisfaction score (points) 3.3 (1.8) 3.4 (1.9) 3.2 (1.8) COPM leisure domain, n (%) 94 (51.4) 38 (50.0) 56 (52.3) Performance score (points) 3.4 (1.6) 3.5 (1.5) 3.4 (1.7) Satisfaction score (points) 2.8 (1.6) 2.7 (1.6) 2.9 (1.7) COPM self-care domain, n (%) 87 (47.5) 39 (51.3) 48 (44.9) Performance score (points) 4.2 (1.6) 4.3 (1.5) 4.0 (1.6) 3.2 (1.8) 3.6 (1.9) 2.7 (1.6) Satisfaction score (points) Disease-specific health status CAT score (points) 22.0 (6.5) 22.7 (6.1) 21.6 (6.7) SGRQ-C symptom score (points) 61.1 (19.9) 60.1 (19.7) 61.9 (20.1) SGRQ-C activity score (points) 80.5 (16.2) 82.8 (14.0) 78.9 (17.5) SGRQ-C impact score (points) 50.1 (19.0) 53.2 (18.4) 48.0 (19.3) SGRQ-C total score (points) 61.4 (15.4) 63.5 (14.7) 59.9 (15.8)

0.27 0.55 0.11 0.07 0.13

145

ChapterÂ 7Â Psychological wellbeing HADS Depression score (points) HADS Anxiety score (points) BDI score score (points) SCL-90 Anxiety score (points) SCL-90 Agoraphobia score (points) SCL-90 Depression score (points) SCL-90 Somatization score (points) SCL-90 Insufficiency score (points) SCL-90 Sensitivity score (points) SCL-90 Hostility score (points) SCL-90 Insomnia score (points) SCL-90 Psychoneuroticism score (points)

7.4 (4.0) 8.0 (4.5) 15.5 (9.6) 16.2 (6.2) 10.1 (4.2)

7.9 (4.0) 8.7 (4.7) 17.2 (9.6) 16.5 (5.6) 10.8 (4.2)

6.9 (7.4) 7.4 (4.3) 14.3 (9.5) 16.0 (6.6) 9.6 (4.2)

0.10 0.06 0.05 0.54 0.06

28.0 (10.7)

28.7 (10.5)

27.5 (10.8)

0.46

23.4 (7.6)

24.0 (8.0)

23.0 (7.2)

0.40

17.9 (5.9)

18.9 (6.3)

17.2 (5.4)

0.05

26.2 (8.2) 7.7 (2.3) 6.6 (2.9) 148.6 (42.3)

27.2 (9.0) 7.8 (2.3) 13.2 (4.5) 153.9 (42.7)

25.4 (7.5) 7.7 (2.3) 12.2 (3.9) 144.8 (41.8)

0.15 0.69 0.24 0.15

Data shown as mean (SD) or as n (%). Abbreviations: 6MWT. 6-min walk distance; BDI Beck Depression Inventory; COPM. Canadian Occupational Performance Measure; HADS. Hospital Anxiety and Depression Scale; SCL-90 Symptom Checklist 90; SGRQ-C. COPD-specific version of the St. George respiratory questionnaire.

Discussion In contrast to our hypotheses we found a comparable prevalence of CI across traditional and revised GOLD grades. Additionally, patients with CI did not have worse functional status, disease-specific health status or psychological wellbeing compared to patients without CI.

Cognitive impairment in different GOLD grades The equal distribution of CI across GOLD grades demonstrates that CI is prevalent in COPD patients, independent of severity of airflow limitation. This is in line with the findings of Antonelli-Incalzi and colleagues who show that indexes of health status assessing cognitive status, affective status and quality of sleep did not differ across GOLD gradesp.25 Additionally, the prevalence of CI did not differ across GOLD groups, which shows that CI is prevalent in all symptom groups and risk groups of COPD. Yet, due to the inclusion of patients entering PR, only a small number of patients in the low-symptom categories (GOLD A and C) were included. Moreover, FEV1% predicted did not differ significantly between patients with and without CI. Although the DS backward test and the domain cognitive flexibility correlated with FEV1, all correlations between domain-specific cognitive functioning, individual cognitive test measures, and FEV1 were weak. This is in line with the idea that complex, higher-order cognitive functions, as reflected by cognitive flexibility are more related to COPD specific factors, such as lung function, than less complex cognitive functions.

146

Cognitive impairment and clinical characteristics in COPD Indeed, in COPD patients without any comorbidities on the Charlson index compared to controls without COPD and other comorbidities on the Charlson index, worse scores for cognitive flexibility and planning, but not for lower-order cognitive functions such as psychomotor speed and memory, have been demonstrated.3 However, another study, using a large sample size, did find an association between cognition and lung function, although associations were weak26 and no association has been found between lung function and cognitive decline over time.27 Therefore, CI should be actively screened for in COPD patients admitted to PR, irrespective of airflow limitation. CI may provide additional clinical relevant information in order to optimize therapy which cannot be predicted from other clinical determinants.

No significant differences in clinical and patient-related outcomes were found between COPD patients with and without CI. For example, we found no statistical significant or clinically relevant difference14 in 6MWT. Similarly, Schure and colleagues found no association between cognitive impairment and decreased 6MWT after adjusting for disease severity, comorbidities, psychological functioning, and demographic characteristics.28 Moreover, Ozyemisci-Taskiran did not find an association between CI and functional capacity during an exacerbation of COPD.29 Yet, exacerbations itself have been shown to be correlated with cognitive decline30, nevertheless cognitive performances improved after discharge from hospital following exacerbation.31 The proportion of patients reporting to experience problems in the four COPM domains did not differ between patients with and without CI. It has been shown to be problematic to use the COPM in patients with poor self-awareness.32 The self-reported nature of the COPM may lead to biased outcomes by lack of insight of the patient with COPD. Moreover, we did not find a difference in disease-specific health status between patients with and without CI. This is in contrast to Antonelli-Incalzi and colleagues33 who demonstrated a weak correlation between global cognitive functioning and domain scores of the SGRQ in 230 COPD patients. Also Roncero and colleagues found an association between cognitive functioning, as measured with the MMSE, and health-related quality of life.34 This discrepancy may be explained by methodological differences. Our study used a more sensitive battery of cognitive tests, compared to the MMSE, a brief screening tool, of which the accuracy in detecting CI has been shown to have suboptimal specificity.35 Although CI is known to be associated with several psychopathological characteristics such as anxiety36 and depression,37 we did not find differences in anxiety and depression between patients with and without CI. Discrepancies

147

Chapter 7

Functional status, disease-specific health status, and psychological wellbeing in patients with and without cognitive impairment

ChapterÂ 7Â may be explained by the fact that we assessed anxiety and depression symptoms by subjective questionnaires instead of the presence of an anxiety or major depression disorder diagnosed by a psychologist. Clinical characteristics and patient-related outcomes are not related to CI. Consequently, clinical characteristics of COPD patients are not able to differentiate COPD patients with and without CI. However, functional exercise capacity, satisfaction scores regarding daily activities such as productivity and self-care, and symptoms of somatization, depression, and insufficiency as assessed during a 3-day assessment before the start of a comprehensive interdisciplinary PR program might be leads for clinicians to know whether or not they are dealing with COPD patients with domainspecific cognitive impairments. Consequently they are warned for possible specific consequences during the PR program. For example, it is possible that a worse functional exercise capacity might be related to a tendency to ignore more often given guidelines, requests, or instructions because we found that COPD patients with verbal memory impairments had lower 6MWT scores compared to those without. This needs to be verified in future research.

Potential clinical consequences Previous studies showed that CI challenges adherence to complex medication regimens.5 38 Especially learning and memory were associated with changes in medication adherence.39 Moreover, memory impairment is associated with poorer adherence to self-care practices and educational participation and achievement. For example, heart failure patients with CI reported poorer selfmanagement behaviors such as recognizing symptoms of worsening compared to patients without CI.6 CI in executive functions among elderly has been associated with decreased levels of smoking cessation.4 CI also was predictive of negative outcomes in rehabilitation from hip fracture in elderly.7 The proportion of patients with CI varies in different studies due to differences in study population and neuropsychological assessment methods, ranging up to almost 80% in COPD patients.38 40 41 In non-COPD controls, matched for age, smoking status and education, the prevalence rate of CI was 13.3%.3 Several facts underline the importance of active case finding of patient with COPD and CI. First, two out of five COPD patients entering PR have CI. Second, CI is prevalent irrespective of disease severity and clinical outcomes. Third, and finally, CI may occur with above mentioned clinical consequences. Yet, Dodd and colleagues42 did not find an association between executive functions and frequency of hospitalization, and a recent study showed no correlation between cognitive functioning and exacerbations, emergency room visits, hospitalizations, self-management skills or quality of life.43 They conclude that an active screening approach for CI in COPD may not be indicated. However, due to the cross-sectional study design, the possible impact of CI on health or therapy outcomes could not

148

Cognitive impairment and clinical characteristics in COPD be assessed in this study. In view of this, we believe that detecting patients with CI may improve overall care processes, by for example including cognitive training strategies which can be divided into restorative and compensatory strategies.44 Restorative strategies attempt to improve functioning in specific cognitive domains or domains of functioning, such as ADLs, social skills, and behavioural disturbances. Compensatory cognitive strategies, such as incorporating daily routines with fewer tasks and/or pacing tasks, and providing the patient with electronic notes, reminders, calendars or planners to keep track of activities and appointments,45 can be used to minimize functional and psychological problems experienced by patients. Health care professionals should be aware of cognitive deficits in order to tailor clinical interventions to the individual patient and to determine the required type of assistance and environmental modification. Compensatory strategies have been applied in other patients, such as Alzheimer, multiple sclerosis, and patients with brain injuries.45 46 Evaluation of these cognitive training strategies in COPD is needed to explore which are beneficial and should be incorporated in the overall care.

A major strength of this study is the use of an extensive neuropsychological testing battery, which provides objective measures to target general and domain-specific CI. However, a comprise neuropsychological examination is timeconsuming. Future studies should assess how many neuropsychological tests are needed to do a first cognitive screening in clinical practice with a comparable sensitivity in order to detect both general and domain-specific CI. A further advantage of this study is the well-characterized study sample. Yet, in depth analyses are needed to assess the impact of hypoxemia on cognitive impairment since hypoxemia30 has been proposed to be a factor, amongst multiple others, connecting COPD and cognitive impairment. Then again, the inclusion of patients from a tertiary referral center, including a majority of patients in highsymptom categories (GOLD B and D) and a minority in low-symptom categories (GOLD A and C), may limit the generalizability of our results. Performance and satisfaction of problematic activities of daily life were assessed with the COPM, which relies on the self-perception of the patient. It is possible that patients with CI less frequently report decreased performance of daily activities due to difficulties in seeing the relevance of daily life activities and problems with initiating activities. Instead of the COPM, The Perceive, Recall, Plan & Perform (PRPP) System of Task Analysis,47 The Arnadóttir OT-ADL Neurobehavioral Evaluation (A-ONE),48 or The Assessment of Motor and Process Skills (AMPS)49 can be administered in order to observe and analyze occupational activities. Specifically, the A-ONE directly links functional performance to cognitive-perceptual impairments, such as agnosia, body neglect, decreased organization, motor apraxia, and spatial neglect. Selection bias may have played a role in this study.

149

Chapter 7

Methodological considerations

ChapterÂ 7Â Patients with subjective complaints of cognitive functioning might avoid participation due to anxiety or worry, or may have been more willing to participate in the present study due to personal interest. Also, patients with severe CI or a diagnosis of dementia most likely will not be referred for PR. Future studies should include a test in order to detect poor testing motivation. Since we found that patients with COPD have a lower IQ compared to those without cognitive impairment, and an intellectually stimulating atmosphere may boost cognitive performance, longitudinal studies are needed to assess pre morbid cognitive ability and to incorporate cognitive reserve and cognitive loss over time in relation to clinical characteristics of this study population.

Conclusions CI in patients with COPD is prevalent, irrespective of clinical characteristics. Clinical characteristics are not able to differentiate patients with COPD with and without CI. An active case finding approach is required to assess CI in patients with COPD who are about to start a PR program. Future research should investigate whether and to what extent CI influences medication adherence, educational achievement, self-management, smoking cessation, and outcomes of PR in patients with COPD.

150

Cognitive impairment and clinical characteristics in COPD

6. 7.

10. 11. 12.

13.

14.

15.

Global initiative for chronic obstructive lung disease: Pocket guide to COPD diagnosis, management, and prevention. Updated 2015. 2015; http://www.goldcopd.org/uploads/users/files/GOLD_Pocket_2015_Feb18.pdf. Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel VP, Bruijnzeel PL, Rutten EP, Op 't Roodt J, Wouters EF, Franssen FM. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;187(7):728-735. Cleutjens FA, Franssen FM, Spruit MA, Vanfleteren LE, Gijsen C, Dijkstra JB, Ponds RW, Wouters EF, Janssen DJ. Domain-specific cognitive impairment in patients with COPD and control subjects. Int J Chron Obstruct Pulmon Dis. 2017;12:1-11. Brega AG, Grigsby J, Kooken R, Hamman RF, Baxter J. The impact of executive cognitive functioning on rates of smoking cessation in the San Luis Valley Health and Aging Study. Age Ageing. 2008;37(5):521-525. Campbell NL, Boustani MA, Skopelja EN, Gao S, Unverzagt FW, Murray MD. Medication adherence in older adults with cognitive impairment: a systematic evidence-based review. Am J Geriatr Pharmacother. 2012;10(3):165-177. Hajduk AM, Lemon SC, McManus DD, Lessard DM, Gurwitz JH, Spencer FA, Goldberg RJ, Saczynski JS. Cognitive impairment and self-care in heart failure. Clin Epidemiol. 2013;5:407-416. Lenze EJ, Munin MC, Dew MA, Rogers JC, Seligman K, Mulsant BH, Reynolds CF, 3rd. Adverse effects of depression and cognitive impairment on rehabilitation participation and recovery from hip fracture. Int J Geriatr Psychiatry. 2004;19(5):472-478. Spruit MA, Singh SJ, Garvey C, ZuWallack R, Nici L, Rochester C, Hill K, Holland AE, Lareau SC, Man WD, Pitta F, Sewell L, Raskin J, Bourbeau J, Crouch R, Franssen FM, Casaburi R, Vercoulen JH, Vogiatzis I, Gosselink R, Clini EM, Effing TW, Maltais F, van der Palen J, Troosters T, Janssen DJ, Collins E, Garcia-Aymerich J, Brooks D, Fahy BF, Puhan MA, Hoogendoorn M, Garrod R, Schols AM, Carlin B, Benzo R, Meek P, Morgan M, Rutten-van Molken MP, Ries AL, Make B, Goldstein RS, Dowson CA, Brozek JL, Donner CF, Wouters EF, Rehabilitation AETFoP. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med. 2013;188(8):e13-64. Cleutjens FA, Wouters EF, Dijkstra JB, Spruit MA, Franssen FM, Vanfleteren LE, Ponds RW, Janssen DJ. The COgnitive-Pulmonary Disease (COgnitive-PD) study: protocol of a longitudinal observational comparative study on neuropsychological functioning of patients with COPD. BMJ Open. 2014;4(3):e004495. Spruit MA, Vanderhoven-Augustin I, Janssen PP, Wouters EF. Integration of pulmonary rehabilitation in COPD. Lancet. 2008;371(9606):12-13. C.B.S. Standaard Beroepenclassificatie 1992 – editie 2001. Den Haag: SDU; 2001. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, Pinto Plata V, Cabral HJ. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(10):1005-1012. Holland AE, Spruit MA, Troosters T, Puhan MA, Pepin V, Saey D, McCormack MC, Carlin BW, Sciurba FC, Pitta F, Wanger J, MacIntyre N, Kaminsky DA, Culver BH, Revill SM, Hernandes NA, Andrianopoulos V, Camillo CA, Mitchell KE, Lee AL, Hill CJ, Singh SJ. An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease. Eur Respir J. 2014;44(6):1428-1446. Law M, Baptiste S, McColl M, Opzoomer A, Polatajko H, Pollock N. The Canadian occupational performance measure: an outcome measure for occupational therapy. Can J Occup Ther. 1990;57(2):82-87.

151

Chapter 7

References

Chapter 7 16. Annegarn J, Meijer K, Passos VL, Stute K, Wiechert J, Savelberg HH, Schols AM, Wouters EF, Spruit MA, Ciro+ Rehabilitation N. Problematic activities of daily life are weakly associated with clinical characteristics in COPD. J Am Med Dir Assoc. 2012;13(3):284-290. 17. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J. 2009;34(3):648-654. 18. Meguro M, Barley EA, Spencer S, Jones PW. Development and Validation of an Improved, COPDSpecific Version of the St. George Respiratory Questionnaire. Chest. 2007;132(2):456-463. 19. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361-370. 20. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561-571. 21. Derogatis LR, Lipman RS, Covi L. SCL-90: an outpatient psychiatric rating scale--preliminary report. Psychopharmacol Bull. 1973;9(1):13-28. 22. Jolles J, van Boxtel MP, Ponds RW, Metsemakers JF, Houx PJ. De Maastricht Aging Study (MAAS). Het longitudinaal perspectief van cognitieve veroudering. [The Maastricht aging study (MAAS). The longitudinal perspective of cognitive aging]. Tijdschr Gerontol Geriatr. 1998;29(3):120-129. 23. Burgmans S, van Boxtel MP, Smeets F, Vuurman EF, Gronenschild EH, Verhey FR, Uylings HB, Jolles J. Prefrontal cortex atrophy predicts dementia over a six-year period. Neurobiol Aging. 2009;30(9):1413-1419. 24. Singh B, Parsaik AK, Mielke MM, Roberts RO, Scanlon PD, Geda YE, Pankratz VS, Christianson T, Yawn BP, Petersen RC. Chronic obstructive pulmonary disease and association with mild cognitive impairment: the Mayo Clinic Study of Aging. Mayo Clin Proc. 2013;88(11):1222-1230. 25. Antonelli-Incalzi R, Imperiale C, Bellia V, Catalano F, Scichilone N, Pistelli R, Rengo F, Sa RAI. Do GOLD stages of COPD severity really correspond to differences in health status? Eur Respir J. 2003;22(3):444-449. 26. Cleutjens FA, Spruit MA, Ponds RW, Dijkstra JB, Franssen FM, Wouters EF, Janssen DJ. Cognitive functioning in obstructive lung disease: results from the United Kingdom biobank. J Am Med Dir Assoc. 2014;15(3):214-219. 27. Pathan SS, Gottesman RF, Mosley TH, Knopman DS, Sharrett AR, Alonso A. Association of lung function with cognitive decline and dementia: the Atherosclerosis Risk in Communities (ARIC) Study. Eur J Neurol. 2011;18(6):888-898. 28. Schure MB, Borson S, Nguyen HQ, Trittschuh EH, Thielke SM, Pike KC, Adams SG, Fan VS. Associations of cognition with physical functioning and health-related quality of life among COPD patients. Respir Med. 2016;114:46-52. 29. Ozyemisci-Taskiran O, Bozkurt SO, Kokturk N, Karatas GK. Is there any association between cognitive status and functional capacity during exacerbation of chronic obstructive pulmonary disease? Chron Respir Dis. 2015;12(3):247–255. 30. Zhang X, Cai X, Shi X, Zheng Z, Zhang A, Guo J, Fang Y. Chronic Obstructive Pulmonary Disease as a Risk Factor for Cognitive Dysfunction: A Meta-Analysis of Current Studies. J Alzheimers Dis. 2016;52(1):101-111. 31. Lopez-Torres I, Valenza MC, Torres-Sanchez I, Cabrera-Martos I, Rodriguez-Torres J, MorenoRamirez MP. Changes in Cognitive Status in COPD Patients Across Clinical Stages. COPD. 2015:1-6. 32. Wressle E, Marcusson J, Henriksson C. Clinical utility of the Canadian Occupational Performance Measure--Swedish version. Can J Occup Ther. 2002;69(1):40-48. 33. Incalzi RA, Bellia V, Catalano F, Scichilone N, Imperiale C, Maggi S, Rengo F, Salute Respiratoria nell-Anziano S. Evaluation of health outcomes in elderly patients with asthma and COPD using disease-specific and generic instruments: the Salute Respiratoria nell'Anziano (Sa.R.A.) Study. Chest. 2001;120(3):734-742. 34. Roncero C, Campuzano AI, Quintano JA, Molina J, Perez J, Miravitlles M. Cognitive status among patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2016;11:543-551.

152

Cognitive impairment and clinical characteristics in COPD

35. Hoops S, Nazem S, Siderowf AD, Duda JE, Xie SX, Stern MB, Weintraub D. Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease. Neurology. 2009;73(21):1738-1745. 36. Bierman EJ, Comijs HC, Rijmen F, Jonker C, Beekman AT. Anxiety symptoms and cognitive performance in later life: results from the longitudinal aging study Amsterdam. Aging Ment Health. 2008;12(4):517-523. 37. Gotlib IH, Joormann J. Cognition and depression: current status and future directions. Annu Rev Clin Psychol. 2010;6:285-312. 38. Sulaiman I, Cushen B, Greene G, Seheult J, Seow D, Rawat F, MacHale E, Mokoka M, Moran CN, Sartini Bhreathnach A, MacHale P, Tappuni S, Deering B, Jackson M, McCarthy H, Mellon L, Doyle F, Boland F, Reilly RB, Costello RW. Objective Assessment of Adherence to Inhalers by COPD Patients. Am J Respir Crit Care Med. 2016. 39. Becker BW, Thames AD, Woo E, Castellon SA, Hinkin CH. Longitudinal change in cognitive function and medication adherence in HIV-infected adults. AIDS Behav. 2011;15(8):1888-1894. 40. Cleutjens FA, Janssen DJ, Ponds RW, Dijkstra JB, Wouters EF. COgnitive-pulmonary disease. Biomed Res Int. 2014;2014:697825. 41. Grant I, Heaton RK, McSweeny AJ, Adams KM, Timms RM. Neuropsychologic findings in hypoxemic chronic obstructive pulmonary disease. Arch Intern Med. 1982;142(8):1470-1476. 42. Dodd JW, Novotny P, Sciurba FC, Benzo RP, Group NR. Executive Function, Survival, and Hospitalization in Chronic Obstructive Pulmonary Disease. A Longitudinal Analysis of the National Emphysema Treatment Trial (NETT). Ann Am Thorac Soc. 2015;12(10):1473-1481. 43. Dulohery MM, Schroeder DR, Benzo RP. Cognitive function and living situation in COPD: is there a relationship with self-management and quality of life? International Journal of Chronic Obstructive Pulmonary Disease. 2015(10):1883-1889. 44. Sitzer DI, Twamley EW, Jeste DV. Cognitive training in Alzheimer's disease: a meta-analysis of the literature. Acta Psychiatr Scand. 2006;114(2):75-90. 45. Fleming JM, Shum D, Strong J, Lightbody S. Prospective memory rehabilitation for adults with traumatic brain injury: a compensatory training programme. Brain Inj. 2005;19(1):1-10. 46. Finlayson M. Multiple Sclerosis Rehabilitation: From Impairment to Participation. Boca Raton, FL: CRC Press; 2012. 47. Aubin G, Chapparo C, Gelinas I, Stip E, Rainville C. Use of the Perceive, Recall, Plan and Perform System of Task Analysis for persons with schizophrenia: a preliminary study. Aust Occup Ther J. 2009;56(3):189-199. 48. Gardarsdottir S, Kaplan S. Validity of the Arnadottir OT-ADL Neurobehavioral Evaluation (AONE): performance in activities of daily living and neurobehavioral impairments of persons with left and right hemisphere damage. Am J Occup Ther. 2002;56(5):499-508. 49. Asayama K. [Assessment of motor and process skills (AMPS)]. Nihon Rinsho. 2004;62 Suppl 4:17-23.

153

Chapter 7

Supplementary file Additional table Table S1. Correlations between domain-specific cognitive functioning, individual cognitive test measures, and FEV1 in patients with COPD FEV1

Correlation coefficient

P-value

Domain-specific cognition Psychomotor speed (compound z-score) -0.136a 0.066 SCWT card I 0.046a 0.532 CST-A 0.034a 0.649 0.475 LDST 60 sec written -0.053b LDST 60 sec oral -0.112b 0.132 Planning (compound z-score) 0.056b 0.455 0.210 BADS key search -0.093b BADS zoo map 0.022a 0.766 Working memory (compound z-score) -0.111b 0.136 VVLT trial 1 -0.002b 0.982 0.017 DS backward -0.176b Verbal memory (compound z-score) -0.032b 0.663 VVLT total recall 1–5 -0.003b 0.663 0.469 VVLT delayed recall -0.054b VVLT retention max -0.053a 0.475 Cognitive flexibility (compound z-score) -0.170b 0.021 0.430 SCWT card III 0.059a CST-C 0.101a 0.175 Abbreviations: BADS, Behavioural Assessment of the Dysexecutive Syndrome; CST, Concept Shifting Test; DS, Digit Span; LDST, Letter Digit Substitution Test; SCWT, Stroop Color-Word Test; SD, standard deviation; VVLT, Visual Verbal Learning Test. a, Spearman’s rank correlation coefcient; b, Pearson’s correlation coefcient

154

Cognitive impairment and clinical characteristics in COPD

Table S2. Clinical characteristics in COPD patients with and without impairments in psychomotor speed Patients with Patients without Pimpairments in impairments in value psychomotor psychomotor speed speed (n=18) (n=165) FUNCTIONAL STATUS Functional exercise capacity 6MWT (meters) 440.0 (122.1) 431.1 (111.0) 0.750 6MWT (% predicted) 66.7 (16.6) 68.4 (16.6) 0.668 Daily activities 0.9 (0.3) 0.339 COPM mobility domain, n (%) 0.8 (0.4) Performance score (points) 3.8 (1.9) 3.8 (1.5) 0.921 Satisfaction score (points) 3.3 (2.0) 2.8 (1.7) 0.347 COPM productivity domain, n (%) 0.8 (0.4) 0.6 (0.5) 0.200 Performance score (points) 4.2 (1.5) 3.8 (1.5) 0.393 Satisfaction score (points) 4.2 (1.8) 3.1 (1.8) 0.050 COPM leisure domain, n (%) 0.4 (0.5) 0.5 (0.5) 0.539 Performance score (points) 3.1 (1.7) 3.5 (1.6) 0.572 Satisfaction score (points) 1.8 (1.0) 2.9 (1.6) 0.126 COPM self-care domain, n (%) 0.4 (0.5) 0.5 (0.5) 0.442 4.7 (1.4) 4.1 (1.6) 0.421 Performance score (points) Satisfaction score (points) 3.6 (1.1) 3.1 (1.9) 0.563 DISEASE-SPECIFIC HEALTH STATUS 0.739 CAT score (points) 22.5 (5.8) 22.0 (6.6) SGRQ-C symptom score (points) 59.3 (16.2) 61.7 (20.0) 0.632 SGRQ-C activity score (points) 75.7 (13.8) 77.2 (14.2) 0.677 SGRQ-C impact score (points) 50.6 (12.6) 45.8 (17.1) 0.258 SGRQ-C total score (points) 59.9 (10.9) 58.2 (14.2) 0.635 PSYCHOLOGICAL WELLBEING 0.180 HADS Depression score (points) 8.6 (3.4) 7.2 (4.0) HADS Anxiety score (points) 9.6 (4.9) 7.8 (4.4) 0.117 BDI score score (points) 17.7 (5.6) 16.0 (6.3) 0.272 SCL-90 Anxiety score (points) 11.6 (4.5) 9.9 (4.2) 0.102 SCL-90 Agoraphobia score (points) 30.8 (9,2) 27.6 (10.8) 0.229 SCL-90 Depression score (points) 26.4 (10.6) 23.1 (7.1) 0.078 SCL-90 Somatization score (points) 22.0 (7.0) 17.5 (5.6) 0.002 SCL-90 Insufficiency score (points) 27.6 (8.0) 26.0 (8.3) 0.456 SCL-90 Sensitivity score (points) 8.1 (1.7) 7.7 (2.3) 0.432 SCL-90 Hostility score (points) 6.9 (2.3) 6.5 (3.0) 0.621 SCL-90 Insomnia score (points) 14.2 (5.0) 12.4 (4.1) 0.082 SCL-90 Psychoneuroticism score (points) 165.3 (34.0) 146.8 (42.8) 0.077 Data shown as mean (SD) or as n (%). Abbreviations: 6MWT. 6-min walk distance; BDI Beck Depression Inventory; COPM. Canadian Occupational Performance Measure; HADS. Hospital Anxiety and Depression Scale; SCL-90 Symptom Checklist 90; SGRQ-C. COPD-specific version of the St. George respiratory questionnaire.

155

Chapter 7

Chapter 7 Table S3. Clinical characteristics in COPD patients with and without impairments in planning Patients with Patients without Pimpairments in impairments in value planning (n=20) planning (n=163) FUNCTIONAL STATUS Functional exercise capacity 6MWT (meters) 392.3 (93.2) 436.9 (113.2) 0.092 6MWT (% predicted) 64.2 (15.1) 68.8 (16.7) 0.241 Daily activities 0.8 (0.4) 0.8 (0.4) COPM mobility domain, n (%) 0.969 Performance score (points) 3.9 (1.6) 3.7 (1.6) 0.678 Satisfaction score (points) 3.3 (1.9) 2.8 (1.7) 0.253 COPM productivity domain, n (%) 0.8 (0.4) 0.6 (0.5) 0.277 Performance score (points) 4.5 (1.2) 3.8 (1.6) 0.101 Satisfaction score (points) 4.0 (1.8) 3.1 (1.8) 0.088 COPM leisure domain, n (%) 0.5 (0.5) 0.5 (0.5) 0.898 Performance score (points) 3.4 (1.6) 3.4 (1.6) 0.902 Satisfaction score (points) 3.7 (1.6) 2.7 (1.6) 0.111 COPM self-care domain, n (%) 0.5 (0.5) 0.5 (0.5) 0.817 Performance score (points) 4.4 (1.8) 4.1 (1.6) 0.693 Satisfaction score (points) 4.4 (0.6) 3.0 (1.8) 0.045 DISEASE-SPECIFIC HEALTH STATUS CAT score (points) 21.8 (6.6) 22.1 (6.5) 0.867 SGRQ-C symptom score (points) 57.0 (18.7) 62.0 (19.8) 0.293 SGRQ-C activity score (points) 81.6 (14.3) 76.5 (14.0) 0.137 SGRQ-C impact score (points) 52.5 (14.8) 45.5 (16.9) 0.088 SGRQ-C total score (points) 62.4 (11.9) 57.9 (14.1) 0.185 PSYCHOLOGICAL WELLBEING HADS Depression score (points) 9.1 (3.3) 7.2 (4.0) 0.049 HADS Anxiety score (points) 8.1 (3.7) 8.0 (4.6) 0.926 BDI score score (points) 16.5 (5.6) 16.2 (6.3) 0.844 SCL-90 Anxiety score (points) 10.1 (3.5) 10.0 (4.3) 0.960 SCL-90 Agoraphobia score (points) 29.1 (11.7) 27.8 (10.6) 0.613 SCL-90 Depression score (points) 23.9 (8.4) 23.3 (7.5) 0.781 SCL-90 Somatization score (points) 20.7 (8.0) 17.6 (5.5) 0.025 SCL-90 Insufficiency score (points) 8.0 (2.8) 26.0 (8.0) 0.367 SCL-90 Sensitivity score (points) 7.0 (3.1) 7.7 (2.2) 0.547 SCL-90 Hostility score (points) 8.0 (2.8) 6.5 (2.9) 0.482 SCL-90 Insomnia score (points) 12.7 (3.8) 12.6 (4.3) 0.897 SCL-90 Psychoneuroticism score (points) 155.7 (45.2) 147.7 (42.0) 0.430 Data shown as mean (SD) or as n (%). Abbreviations: 6MWT. 6-min walk distance; BDI Beck Depression Inventory; COPM. Canadian Occupational Performance Measure; HADS. Hospital Anxiety and Depression Scale; SCL-90 Symptom Checklist 90; SGRQ-C. COPD-specific version of the St. George respiratory questionnaire.

156

Cognitive impairment and clinical characteristics in COPD

Table S4. Clinical characteristics in COPD patients with and without impairments in working memory Patients with Patients without Pimpairments in impairments in value working memory working memory (n=47) (n=136) FUNCTIONAL STATUS Functional exercise capacity 6MWT (meters) 426.3 (426.3) 434.0 (109.0) 0.686 6MWT (% predicted) 67.6 (17.0) 68.5 (16.5) 0.741 Daily activities COPM mobility domain, n (%) 0.8 (0.4) 0.8 (1.6) 0.750 Performance score (points) 3.6 (1.5) 3.8 (1.6) 0.575 Satisfaction score (points) 2.6 (1.7) 2.9 (1.8) 0.368 COPM productivity domain, n (%) 0.7 (0.5) 0.6 (0.5) 0.301 Performance score (points) 4.0 (1.5) 3.8 (1.6) 0.510 Satisfaction score (points) 3.4 (1.7) 3.2 (1.9) 0.696 COPM leisure domain, n (%) 0.5 (0.5) 0.5 (0.5) 0.701 Performance score (points) 3.1 (1.4) 3.6 (1.6) 0.208 Satisfaction score (points) 2.8 (1.4) 2.8 (1.7) 0.991 COPM self-care domain, n (%) 0.4 (0.5) 0.5 (0.5) 0.430 Performance score (points) 4.6 (1.4) 4.0 (1.6) 0.152 Satisfaction score (points) 3.7 (1.1) 3.0 (2.0) 0.168 DISEASE-SPECIFIC HEALTH STATUS CAT score (points) 22.0 (6.4) 22.0 (6.6) 0.984 SGRQ-C symptom score (points) 60.8 (21.1) 61.7 (19.2) 0.803 SGRQ-C activity score (points) 78.0 (14.9) 76.7 (13.9) 0.608 SGRQ-C impact score (points) 48.5 (1.9) 45.6 (16.0) 0.316 SGRQ-C total score (points) 59.7 (15.2) 57.9 (13.4) 0.455 PSYCHOLOGICAL WELLBEING HADS Depression score (points) 7.8 (4.0) 7.2 (4.0) 0.387 HADS Anxiety score (points) 8.9 (4.5) 7.7 (4.4) 0.110 BDI score score (points) 16.8 (5.7) 16.0 (6.4) 0.447 SCL-90 Anxiety score (points) 11.1 (4.4) 9.7 (4.1) 0.053 SCL-90 Agoraphobia score (points) 29.9 (10.5) 27.3 (10.7) 0.158 SCL-90 Depression score (points) 23.9 (7.7) 23.2 (7.5) 0.593 SCL-90 Somatization score (points) 19.5 (6.6) 17.4 (5.5) 0.038 SCL-90 Insufficiency score (points) 28.4 (9.3) 25.4 (7.7) 0.034 SCL-90 Sensitivity score (points) 7.9 (2.3) 7.6 (2.3) 0.475 SCL-90 Hostility score (points) 7.2 (3.4) 6.3 (2.8) 0.079 SCL-90 Insomnia score (points) 13.1 (4.4) 12.4 (4.1) 0.345 SCL-90 Psychoneuroticism score (points) 157.7 (42.7) 145.4 (41.9) 0.087 Data shown as mean (SD) or as n (%). Abbreviations: 6MWT. 6-min walk distance; BDI Beck Depression Inventory; COPM. Canadian Occupational Performance Measure; HADS. Hospital Anxiety and Depression Scale; SCL-90 Symptom Checklist 90; SGRQ-C. COPD-specific version of the St. George respiratory questionnaire.

157

Chapter 7

Chapter 7 Table S5. Clinical characteristics in COPD patients with and without impairments in verbal memory Patients with Patients without Pimpairments in impairments in value verbal memory verbal memory (n=50) (n=133) FUNCTIONAL STATUS Functional exercise capacity 6MWT (meters) 400.2 (111.1) 443.9 (110.1) 0.018 6MWT (% predicted) 64.1 (17.1) 69.8 (16.2) 0.035 Daily activities 0.629 COPM mobility domain, n (%) 0.8 (0.4) 0.8 (0.4) Performance score (points) 3.8 (1.7) 3.8 (1.5) 0.850 Satisfaction score (points) 2.8 (1.9) 2.8 (1.7) 0.998 COPM productivity domain, n (%) 0.6 (0.5) 0.6 (0.5) 0.740 Performance score (points) 3.9 (1.5) 3.9 (1.6) 0.926 Satisfaction score (points) 3.5 (1.9) 3.2 (1.8) 0.453 COPM leisure domain, n (%) 0.5 (0.5) 0.5 (0.5) 0.579 Performance score (points) 3.5 (1.5) 3.4 (1.7) 0.841 Satisfaction score (points) 2.9 (1.6) 2.8 (1.6) 0.775 COPM self-care domain, n (%) 0.5 (0.5) 0.5 (0.5) 0.799 Performance score (points) 4.2 (1.8) 4.2 (1.5) 0.991 Satisfaction score (points) 3.4 (2.2) 3.1 (1.6) 0.444 DISEASE-SPECIFIC HEALTH STATUS 0.322 CAT score (points) 21.2 (6.9) 22.3 (6.4) SGRQ-C symptom score (points) 59.0 (22.3) 62.3 (18.7) 0.320 SGRQ-C activity score (points) 79.4 (13.0) 76.2 (14.4) 0.193 SGRQ-C impact score (points) 48.4 (18.2) 45.5 (16.2) 0.310 SGRQ-C total score (points) 59.8 (15.1) 57.8 (13.4) 0.399 PSYCHOLOGICAL WELLBEING 0.932 HADS Depression score (points) 7.4 (3.8) 7.3 (4.0) HADS Anxiety score (points) 7.8 (4.8) 8.0 (4.4) 0.790 BDI score score (points) 15.8 (10.1) 15.4 (0.5) 0.139 SCL-90 Anxiety score (points) 15.1 (5.2) 16.6 (6.5) 0.605 SCL-90 Agoraphobia score (points) 10.3 (4.1) 10.0 (4.3) 0.404 SCL-90 Depression score (points) 26.9 (9.4) 28.4 (11.1) 0.008 SCL-90 Somatization score (points) 21.0 (6.1) 24.3 (7.9) 0.447 SCL-90 Insufficiency score (points) 17.4 (5.6) 18.1 (6.0) 0.344 SCL-90 Sensitivity score (points) 25.2 (7.5) 26.5 (8.5) 0.535 SCL-90 Hostility score (points) 7.5 (2.0) 7.8 (2.4) 0.949 SCL-90 Insomnia score (points) 6.5 (3.3) 6.6 (2.8) 0.806 SCL-90 Psychoneuroticism score (points) 142.4 (38.7) 150.9 (43.5) 0.229 Data shown as mean (SD) or as n (%). Abbreviations: 6MWT. 6-min walk distance; BDI Beck Depression Inventory; COPM. Canadian Occupational Performance Measure; HADS. Hospital Anxiety and Depression Scale; SCL-90 Symptom Checklist 90; SGRQ-C. COPD-specific version of the St. George respiratory questionnaire.

158

Cognitive impairment and clinical characteristics in COPD

Table S6. Clinical characteristics in COPD patients with and without impairments in cognitive flexibility Patients with Patients without Pimpairments in impairments in value cognitive cognitive flexibility (n=51) flexibility (n=132) FUNCTIONAL STATUS Functional exercise capacity 6MWT (meters) 434.0 (107.9) 431.2 (113.7) 0.881 6MWT (% predicted) 68.1 (15.1) 68.3 (17.2) 0.916 Daily activities 0.8 (0.4) 0.8 (0.4) COPM mobility domain, n (%) 0.989 Performance score (points) 3.8 (1.8) 3.8 (1.5) 0.949 Satisfaction score (points) 2.9 (1.9) 2.8 (1.7) 0.937 COPM productivity domain, n (%) 0.6 (0.5) 0.6 (0.5) 0.893 Performance score (points) 4.0 (1.5) 3.9 (1.6) 0.750 Satisfaction score (points) 3.6 (1.7) 3.1 (1.9) 0.240 COPM leisure domain, n (%) 0.5 (0.5) 0.5 (0.5) 0.294 Performance score (points) 3.3 (1.5) 3.5 (1.6) 0.611 Satisfaction score (points) 2.8 (1.5) 2.9 (1.7) 0.942 COPM self-care domain, n (%) 0.5 (0.5) 0.5 (0.5) 0.565 Performance score (points) 4.6 (1.3) 4.0 (1.7) 0.109 Satisfaction score (points) 3.8 (1.7) 2.8 (1.8) 0.022 DISEASE-SPECIFIC HEALTH STATUS CAT score (points) 22.5 (6.2) 21.8 (6.6) 0.544 SGRQ-C symptom score (points) 58.8 (18.8) 62.5 (20.0) 0.268 SGRQ-C activity score (points) 78.6 (14.0) 76.5 (14.2) 0.31 SGRQ-C impact score (points) 49.2 (16.2) 45.2 (17.0) 0.154 SGRQ-C total score (points) 59.9 (13.7) 57.8 (13.9) 0.348 PSYCHOLOGICAL WELLBEING HADS Depression score (points) 8.1 (3.7) 7.1 (4.1) 0.145 HADS Anxiety score (points) 8.6 (4.3) 7.7 (4.5) 0.283 BDI score score (points) 17.3 (6.1) 15.8 (6.2) 0.151 SCL-90 Anxiety score (points) 10.8 (4.3) 9.8 (4.2) 0.160 SCL-90 Agoraphobia score (points) 29.9 (10.8) 27.2 (10.6) 0.133 SCL-90 Depression score (points) 25.4 (9.1) 22.6 (6.8) 0.025 SCL-90 Somatization score (points) 20.7 (6.6) 16.9 (5.2) <0.001 SCL-90 Insufficiency score (points) 28.3 (9.2) 25.4 (7.7) 0.030 SCL-90 Sensitivity score (points) 8.2 (2.4) 7.5 (2.2) 0.098 SCL-90 Hostility score (points) 6.8 (3.0) 6.5 (2.9) 0.424 SCL-90 Insomnia score (points) 13.4 (4.3) 12.3 (4.1) 0.098 SCL-90 Psychoneuroticism score (points) 160.6 (44.1) 143.9 (40.8) 0.016 Data shown as mean (SD) or as n (%). Abbreviations: 6MWT. 6-min walk distance; BDI Beck Depression Inventory; COPM. Canadian Occupational Performance Measure; HADS. Hospital Anxiety and Depression Scale; SCL-90 Symptom Checklist 90; SGRQ-C. COPD-specific version of the St. George respiratory questionnaire.

159

Chapter 7

Chapter 8

The relationship between cerebral small vessel disease, hippocampal volume and cognitive functioning in patients with COPD: an MRI study Cleutjens FAHM, Ponds RWHM, Spruit MA, Burgmans S, Jacobs HIL, Gronenschild EHBM, Staals J, Franssen FME, Dijkstra JB, Vanfleteren LEGW, Hofman PA, Wouters EFM, Janssen DJA. The relationship between cerebral small vessel disease, hippocampal volume and cognitive functioning in patients with COPD: an MRI study. Frontiers in Aging Neuroscience. 2017;9(88). Reprinted with permission from Frontiers in Aging Neuroscience.

161

ChapterÂ 8Â

Abstract The neural correlates of cognitive impairment in chronic obstructive pulmonary disease (COPD) are not yet understood. Structural brain abnormalities could possibly be associated with the presence of cognitive impairment through cigarette smoke, inflammation, vascular disease, or hypoxemia in these patients. This study aimed to investigate whether macrostructural brain Magnetic Resonance Imaging (MRI) features of cerebral small vessel disease (SVD) and hippocampal volume (HCV) are related to cognitive performance in patients with COPD. A subgroup of cognitively high and low-performing COPD patients of the COgnitive-PD study, underwent a brain 3T MRI. SVD as a marker of vascular damage was assessed using qualitative visual rating scales. HCV as a marker of neurodegeneration was assessed using the learning embedding for atlas propagation (LEAP) method. Features of SVD and HCV were compared between cognitively high and low-performing individuals using Mann Whitney U tests and independent samples t-tests, respectively. No group differences were reported between 25 high-performing (mean age 60.3 (SD 9.7) years; 40.0% men; FEV1 50.1% predicted) and 30 low-performing patients with COPD (mean age 60.6 (SD 6.8) years; 53.3% men; FEV1 55.6% predicted) regarding demographics, clinical characteristics, comorbidities, and the presence of the SVD features and HCV. To conclude, the current study does not provide evidence for a relationship between cerebral SVD and HCV and cognitive functioning in patients with COPD. Additional studies will be needed to determine other possible mechanisms of cognitive impairment in patients with COPD, including microstructural brain changes and inflammatory-, hormonal-, metabolic- and (epi)genetic factors.

162

Vascular damage, neurodegeneration, and cognitive impairment in COPD

Chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic disease which is primarily characterized by progressive airflow limitation.1 Beyond respiratory impairment, patients with COPD often suffer from a variety of comorbid and biological conditions.2,3 These biological changes may have adverse effects on the brain leading to cognitive impairment. General cognitive impairment is four times more likely to occur in patients with COPD than in non-COPD controls and involves several cognitive domains, such as psychomotor speed, planning, memory, and cognitive flexibility.4 Impairments in working and verbal memory have been found in one out of three patients with COPD.4 Although the pathogenesis of cognitive impairment in COPD has been searched in oxidative stress, hypoxemia, systemic inflammation, and comorbidities, the exact pathways remain unknown.5-7 Structural brain abnormalities are considered an important cause of cognitive impairment, especially decreased hippocampal volume (HCV), which has been associated with decreased memory,8-10 and features of cerebral small vessel disease (SVD).11 SVD refers to pathological processes affecting the small arteries, arterioles, venules and capillaries of the brain. For example, chronic hypoperfusion can occur, whereby the supply of oxygen and nutrients to the brain tissue is slowly cut.11 Hypoxemia is thought to act in an additive manner in the development of structural brain abnormalities.12 Structural brain abnormalities associated with SVD can be seen on MRI as white matter hyperintensities (WMHs), lacunes, cerebral microbleeds, and perivascular spaces (PVS). The main risk factors for SVD are increased age and hypertension. In comparison to control participants, COPD patients showed smaller HCV,13 reduced white matter integrity and regional grey matter density.14,15 periventricular white matter lesions 16, disturbed functional activation of gray matter,14 and a higher prevalence of cerebral microbleeds.17 Possible mechanisms, common in COPD, which may contribute to brain abnormalities and cognitive impairment are cigarette smoke, inflammation, vascular disease, and hypoxemia.6 Yet, the relationship between structural brain abnormalities, especially HCV and features of SVD and cognitive functioning in COPD remains unexplored. In order to verify whether SVD and HCV may explain the level of cognitive functioning in patients with COPD, this study aimed to assess whether and to what extent SVD and HCV differ between COPD patients with high and low cognitive performance. A priori, we hypothesized that COPD patients with low cognitive performances are characterized by a higher SVD load, and smaller HCV compared to COPD patients with high cognitive performances.

163

Chapter 8

Introduction

Chapter 8

Material and methods Design This cross sectional study is part of a longitudinal study (COgnitive-PD study) aimed at mapping and understanding neuropsychological functioning in patients with COPD. Details of the methodology of this study and data concerning cognition have been described before.4 18

Study population For this study, we selected the first 30 cognitively low-performing and the first 25 high-performing patients with COPD during inclusion of the COgnitive-PD study (n=183) who were willing to undergo brain MRI. Six core tests of the detailed neuropsychological test battery from the Cognitive-PD study (Table 1) were used to distinguish cognitively high-performing individuals from low-performing individuals19 (for details about the tests, please see the Cognitive-PD study protocol18). In addition to the exclusion criteria of the COgnitive-PD study,18 patients were not eligible if they had contraindications to undergo a brain MRI (claustrophobia, a cardiac pacemaker, a cochlear implant, a neurostimulator, or other metal implants in the body). The study was approved by the Medical Ethics Committee of the Maastricht University Medical Centre (NL45127.068.13). All patients provided written informed consent to participate in the study. Table 1. Cognitive performance per core subtest on the COgnitive-PD Study neuropsychological test battery High-performing Low-performing COPD COPD patients patients (n=30) (n=25) Outcome measure Mean (SD) Z≤-1 Mean (SD) Z≤-1 VVLT Total recall (number correct: 0-75)* 54.4 (8.6) 0.0% 35.4 (9.1) 50.0% VVLT Delayed recall (number correct: 0-15)* 11.3 (2.8) 4.0% 6.3 (2.8) 56.7% 25.5 (5.1) 0.0% 19.2 (5.6) 30.0% GIT-II Animal naming (number of animal names)‡ LDST 60 Sec written (number correct: 0-125)*§ 33.8 (6.1) 0.0% 23.4 (6.1) 50.0% CST-C (time in seconds)† 32.1 (11.0) 4.0% 50.1 (18.0) 36.7% 46.7 (43.4) 16.0% 63.3 (21.9) 80.0% SCWT Card III (time in seconds)† Abbreviations: CST, Concept Shifting Test; GIT, Groningen Intelligence Test; LDST, Letter Digit Substitution Test; SD, standard deviation; SCWT, Stroop Colour-Word Test; VVLT, Visual Verbal Learning Test; Z ≤ -1, percentage of patients with a Z score of -1 or lower. *, Higher scores indicate better performance; ‡, indicates score has no upper limit; §, At least one of out the two LDST 60 subtests had to be scored with a score less than 1.0 SD below the age-, gender-, and educationspecific mean of the MAAS study population to have an impaired score on the LDST subtest; †, Higher scores indicate worse performance.

164

Vascular damage, neurodegeneration, and cognitive impairment in COPD

Brain MRI acquisition Patients had brain MRI on a research-dedicated 3-T MRI scanner (Siemens, the Netherlands) operated by research-dedicated technical staff in the Maastricht University Medical Center. Sequences included T1-weighted sagittal sequence (TR = 8.14 ms, TE = 3.72 ms, FA = 8°, FOV = 256 x 256 x 155 mm, acquisition matrix = 256 x 256, number of slices = 155, voxel size = 1.00 mm isotropic), T2weighted transversal sequence (TR = 3000 ms, TE = 80 ms, FA = 90°, FOV = 230 x 230 x 154 mm, acquisition matrix = 512 x 512, number of slices = 28, slice gap = 0.50 mm, voxel size = 0.45 x 0.45 x 5.5 mm), fluid-attenuated inversion recovery (FLAIR) sagittal sequence (TR = 4800 ms, TE = 275 ms, TI = 1650 ms, FOV = 250 x 250 x 154 mm, acquisition matrix = 240 x 240, number of slices = 275, slice gap = 0.56 mm, voxel size = 1.04 x 1.04 x 0.56 mm), and T2*-weighted transversal sequence (TR = 844 ms, TE = 16 ms, FA = 18°, FOV = 230 x 230 x 154 mm, acquisition matrix = 512 x 512, number of slices = 28, slice gap = 0.50 mm, voxel size = 0.45 x 0.45 x 5.5 mm).

All MRIs were analyzed blinded to patient’s cognitive status. WMHs (Figure 1A) were classified as periventricular WMHs (PVWMHs; localized around the lateral ventricles) or deep WMHs (DWMHs; localized within the deep WM) on the Fazekas scale ranging from 0 to 3, using FLAIR and T2-weighted images.20 Additionally, the age-related white matter changes (ARWMC) scale was applied to rate WMHs more specifically per brain region.21 PVS (Figure 2) were defined as small, linear or pointy structures of cerebrospinal fluid intensity measuring <3 mm in size and following the course of the vessels, at the level of the basal ganglia and in the centrum semiovale. T2-weighted images were used in order to rate PVS on a qualitative scale.22 Microbleeds (Figure 1B) and lacunes (Figure 1C) were rated using T2*, T2, and FLAIR images. Microbleeds were defined as small (<5 mm), homogeneous, round foci of low signal intensity on T2* in the cerebellum, brainstem, basal ganglia, white matter, or cortico-subcortical junction, differentiated from vessel flow voids and mineral depositions in the globi pallidi.23 Lacunes were defined as rounded or ovoid lesions with diameters from 3 to 20 mm located in the basal ganglia, internal capsule, centrum semiovale, or brainstem and carefully distinguished from WMH and PVS.24 An SVD compound score, expressing the level of cerebral SVD load, was calculated according to the method of Staals et al.25 WMHs and PVS were rated by two trained raters. In a random sample of one third of the brain scans, the agreement between raters was high with intraclass correlation coefficient (ICC) greater than 0.80 for the Fazekas scale (both PVWMH and DWMH); ICC greater than 0.75 for the ARWMC except for the basal ganglia and the infratentorial area; ICC greater than 0.80 regarding PVS in the basal ganglia and greater than 0.65 in the cen-

165

Chapter 8

MRI analysis

Chapter 8 trum semiovale. Microbleeds and lacunes, were rated by an experienced neurologist (JS). Since one single MRI scanner performed all measurements no intervariability study was performed. HCV was measured on T1-weighted images using the Learning Embeddings Atlas Propagation (LEAP) method.26 HCV was normalized by multiplying the native space volume with the affine scaling factor (ASF), also derived with LEAP. An ASF value of >1 indicated expansion and a value <1 contraction required to register each individual’s brain to the atlas template.27 LEAP data were provided by R. Wolz (Ixico Ltd. and Imperial College, London).

Figure 1. (A): FLAIR brain MRI scan showing periventricular WMHs and deep WMHs in both hemispheres. WMH, = white matter hyperintensities; R, = right. (B): T2*-weighted brain MRI scan showing a microbleed located within the right white matter. R, = right. (C): FLAIR brain MRI scan showing a lacune located in the deep grey matter. R, = right.

Figure 2. T2-weighted brain MRI scans showing symmetric extensive PVS at the level of the basal ganglia (A) and in the centrum semiovale (B). PVS, = perivascular spaces ; R, = right.

166

Vascular damage, neurodegeneration, and cognitive impairment in COPD

Other measures Age, gender, educational level (according to The Dutch Standard Classification of Education (CBS)28), marital status, visual and hearing impairment, handedness, smoking behavior, and self-reported hypertension and comorbidities (Charlson Comorbidity Index)29 were recorded. Moreover, data on body mass index (BMI), long-term oxygen therapy, modified Medical Research Council (mMRC) dyspnea scale,30 post-bronchodilator spirometry (forced vital capacity (FVC), FVC% predicted, forced expiratory volume in the first second (FEV1), FEV1% predicted, and FEV1/FVC), resting arterial blood gases (PaO2, PaCO2, and SaO2), and single breath carbon monoxide diffusing capacity (DLCO% predicted) were collected.

All statistical analyses were done using SPSS 21.0 (SPSS Inc. Chicago, IL). A pvalue <0.05 was considered as statistically significant. Categorical variables are described as frequencies, while continuous variables were tested for normality and are presented as mean and standard deviation (SD) or median and interquartile range (IQR). Raw test scores on the neuropsychological test battery were transformed into age, gender, and education corrected Z-scores based on normative data from the Maastricht Aging Study (MAAS). Cognitively low-performing individuals had a score less than 1.0 SD below the age-, gender-, and education-specific mean of the MAAS study population for at least two core tests and high-performing individuals had a score more than 1.0 SD above the age-, gender-, and educationspecific mean of the MAAS study population for at least two core tests (Table 1).31 Patient characteristics were compared between the groups using Chi-square tests for categorical variables and independent sample t-test or Mann-Whitney U test, as appropriate for continuous variables. Mann Whitney U tests were performed in order to compare high and low-performing individuals based on features of SVD. HCV were compared using independent samples t-tests. The pvalues were adjusted using the Benjamini-Hochberg correction32 for multiple tests, with a false discovery rate of 5%.

Results Patient characteristics Cognitively low-performing patients had significantly worse mean scores on all core tests of the COgnitive-PD test battery compared to high-performing patients (Table 1). Demographic and clinical characteristics, including smoking behavior, FEV1, arterial blood gases, and diffusion capacity were comparable

167

Chapter 8

Statistical analyses

Chapter 8 between cognitively high and low-performing patients. The groups did not differ on reported comorbidities (Table 2). Table 2. Characteristics of the study population Characteristic

Demographics Age, years Male, n (%) Lower education, n (%) Exacerbation history in the previous 12 months 0-1 exacerbations, n (%) 2 ≥ exacerbations, n (%) Health condition Visual impairment, n (%) Hearing impairment, n (%) BMI (kg/m2), mean, (SD) Oxygen therapy, n (%) mMRC (grade), mean (SD) Smoking behavior Current smoker, n (%) Former smoker, n (%) Never smoker, n (%) Spirometry and arterial blood gases FEV1/FVC, mean (SD) FEV1 (% predicted), mean (SD) SaO2 (%), mean (SD) SaO2 before 6MWT (%), mean (SD) SaO2 after 6MWT (%), mean (SD) PaO2 (kPa), mean (SD) PaO2 off-oxygen (kPa), mean (SD) PaCO2 (kPa), mean (SD) PaCO2 off-oxygen (kPa), mean (SD) DLCO (% predicted), mean (SD) Comorbidities Charlson comorbidity index score, mean, (SD) Myocardial infarction, n (%) Congestive heart failure, n (%) Peripheral vascular disease, n (%) Cerebrovascular disease, n (%) Connective tissue disease, n (%) Peptic ulcer disease, n (%) Mild, moderate or severe liver disease, n (%) Diabetes Mellitus, n (%) Hemiplegia, n (%) Moderate to severe chronic kidney disease, n (%) Solid or malignant tumors, n (%) Obstructive sleep apnea, n (%) Hypertension, n (%) HADS Anxiety score, mean (SD) HADS Anxiety >10 points, n (%) HADS Depression score (points)

168

High-performing COPD patients (n=25)

Low-performing COPD patients (n=30)

BenjaminiHochberg P-value

60.3 (9.7) 10 (40.0) 8 (32.0)

60.6 (6.8) 16 (53.3) 7 (23.3)

0.941 0.476 0.497

10 (40.0) 15 (60.0)

10 (33.3) 20 (66.7)

0.408

4 (16.0) 6 (24.0) 25.1 (5.2) 6 (24.0) 2.1 (2.0)

7 (23.3) 6 (20.0) 27.5 (7.7) 3 (10.0) 2.6 (2.0)

0.524 0.612 0.458 0.458 0.458

3 (12.0) 20 (80.0) 2 (8.0)

7 (23.3) 23 (76.7) 0 (0.0)

0.458

37.7 (13.5) 50.1 (20.1) 93.7 (2.7)* 94.5 (2.5) 87.8 (7.1) 9.3 (1.4)* 9.3 (1.1)‡ 5.8 (1.8)* 5.8 (2.0)‡ 49.7 (18.6)*

47.0 (14.6) 55.6 (20.0) 94.0 (2.6) 94.3 (2.1) 88.3 (6.5) 9.6 (1.5) 9.7 (1.6)§ 6.4 (2.2) 6.2 (2.1)§ 49.6 (17.4)

0.272 0.497 0.844 0.771 0.770 0.458 0.361 0.497 0.534 0.988

2.6 (1.6) 2 (8.0) 2 (8.0) 4 (16.0) 3 (12.0) 6 (24.0) 4 (16.0) 2 (8.0) 3 (12.0) 2 (8.0) 1 (4.0) 3 (12.0) 3 (12.0) 2 (8.0) 6.9 (4.7) 5 (20.0) 7.0 (4.6)

3.5 (2.0) 10 (33.3) 5 (16.7) 9 (30.0) 6 (20.0) 8 (26.7) 4 (13.3) 0 (0.0) 8 (26.7) 2 (6.7) 1 (3.3) 6 (20.0) 7 (23.3) 11 (36.7) 9.1 (4.2) 11 (36.7) 7.9 (3.5)

0.425 0.272 0.497 0.458 0.497 0.631 0.631 0.458 0.458 0.705 0.775 0.497 0.476 0.272 0.425 0.458 0.553

Vascular damage, neurodegeneration, and cognitive impairment in COPD HADS Depression >10 points, n (%)

5 (20.0)

8 (26.7)

0.523

Abbreviations: 6MWT, six-minute walking test; BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in first second; FVC, forced vital capacity; FEV1/FVC, Tiffeneau index; HADS, Hospital Anxiety Depression Scale; IQR, interquartile range; PaCO2, arterial partial pressure of carbon dioxide; PaO2, arterial oxygen partial pressure; SaO2, oxygen saturation; SD, standard deviation. *, n = 24; ‡, n=18; §, n=27.

Structural brain abnormalities in high and low-performing patients with COPD

Table 3. SVD and (normalized) hippocampal volume High-performing COPD patients (n=25) SVD WMH Fazekas scale PVH, median (IQR) 1.0 (0.0-1.5) DWMH, median (IQR) 1.0 (1.0-1.0) WMH ARWMC total, median (IQR) 4.0 (4.0-6.0) Frontal, median Left 1.0 (0.5-1.0) (IQR) Right 1.0 (1.0-1.0) Parietal Left 1.0 (0.5-1.0) occipital, Right 1.0 (1.0-1.0) median (IQR) Temporal, Left 0.0 (0.0-0.5) median (IQR) Right 0.0 (0.0-1.0) Basal ganglia, Left 0.0 (0.0-0.0) median (IQR) Right 0.0 (0.0-0.0) Infratentorial, Left 0.0 (0.0-0.0) median (IQR) Right 0.0 (0.0-0.0) PVS Basal ganglia, median (IQR) 0.0 (0.0-1.0) Centrum Semiovale, median (IQR) 1.0 (0.0-1.0) Lacunes, n (%) 5 (20.0) Microbleeds, n (%) 2 (8.0) Total SVD score, median (IQR) 1.0 (0.0-2.0) Hippocampal volume 2813.7 (328.1) Left HCV (mm3), mean (SD) Right HCV (mm3) , mean (SD) 2834.3 (264.6)

Low-performing COPD patients (n=30)

BenjaminiHochberg Pvalue

1.0 (0.0-2.0) 1.0 (1.0-2.0) 6.0 (3.8-10.0) 1.0 (1.0-1.0) 1.0 (1.0-1.0) 1.0 (1.0-2.0) 1.0 (1.0-2.0)

0.509 0.329 0.329 0.329 0.702 0.329 0.386

0.0 0.0 0.0 0.0 0.0 0.0

(0.0-1.0) (0.0-1.0) (0.0-0.0) (0.0-0.0) (0.0-1.0) (0.0-1.0)

0.329 0.509 0.643 0.509 0.329 0.329

0.0 (0.0-1.0) 1.0 (0.0-2.0) 5 (17.0) 1 (3.3) 0.0 (0.0-2.0)

0.985 0.329 0.792 0.603 0.761

2648.8 (328.2) 2751.2 (243.0)

0.329 0.418

Chapter 8

No differences were seen on the DWMH and PVWMH Fazekas subscales (Table 3). WMHs mapped specifically per brain region did not differ between low and high-performing patients. PVS in basal ganglia or centrum semiovale did not differ between the groups. There was no difference in presence of lacunes or microbleeds. The level of cereberal SVD load was comparable between the two groups. No significant difference was found between low and high-performing individuals regarding the left and right HCV (Table 3).

Abbreviations: ARWMC, the age-related white matter changes scale; COPD, chronic obstructive pulmonary disease; DWMH, deep white matter hyperintensity; HCV, hippocampal volume; PVS, enlarged perivascular spaces; IQR, interquartile range; PVH, periventricular hyperintensity; SD, standard deviation; SVD, small vessel disease.

169

Chapter 8

Discussion Key findings The goal of the current brain MRI study was to assess whether differences in SVD features and/or HCV are related to the level of cognitive functioning in patients with COPD. In contrast to our hypothesis that COPD patients with low cognitive performances are characterized by a higher SVD load, and smaller HCV compared to COPD patients with high cognitive performances, we found that structural brain changes were comparable between COPD patients with low or high cognitively performance. We did not find a difference in the compound score of SVD between high and low-performing COPD patients. Indeed, SVD may also be found in individuals with normal cognitive performance33 and the exact pathophysiological link between SVD features and cognitive impairment remains not completely understood. It is suggested that individuals with normal cognitive performance have a greater cognitive reserve by which they are able to compensate certain brain pathologies better than others.34 However, the low and high-performing groups in our study were comparable for educational level, which is considered to be one on of the best indicators for cognitive reserve. Although not significant, we observed a trend towards more hypertension, one of the main risk factors for SVD,35 in cognitively low-performing patients. 34.5% of patients without physician-diagnosed hypertension had an elevated systolic blood pressure (≥140) or elevated diastolic blood pressure of (≥90). Yet, the percentage of patients with elevated systolic or diastolic blood pressure did not differ between the low and high-performing group. When we mapped WMHs specifically per brain region, these structural brain abnormalities were not able to differentiate both groups. A population-based study reported that COPD patients had more severe PVWMHs than persons without COPD.16 Characteristics of the control group were not reported. Our results show no difference in DWMHs between low and high-performing patients. Contradictory findings on the differential impact of PVWMHs and DWMHs on cognition exist, probably due to varying terminology and definitions for PVWMHs and DWMHs.36 Soriano-Raya and colleagues37 suggested that only DWMHs, not PVWMHs, are related to cognitive impairments in middle-aged individuals. De Groot and colleagues38 showed that PVWMHs are associated with cognition and DWMHs with depression. High and low cognitively performing COPD patients did not differ on symptoms of depression. Van Dijk and colleagues16 did not find an association between COPD and lacunes. In addition, our study showed no difference in the incidence of lacunes between high and low-performing COPD patients. In a large population-based study, a higher prevalence of cerebral microbleeds was associated with COPD.17 Our study did not find differences in the presence of microbleeds between high

170

171

Chapter 8

Vascular damage, neurodegeneration, and cognitive impairment in COPD and low-performing COPD patients. It might be that patients with COPD are at risk for microbleeds due to comorbid processes, such as systemic inflammation39 without specific cognitive consequences. Finally, no differences in the extent of PVS were found between high and low-performing patients. The exact causes of PVS are uncertain but abnormalities at the blood brain interface and inflammation have been associated with PVS.40,41 Studies suggest that smoking and reduced lung function cause inflammation and that both variables might act in an additive manner.42,43 Our groups were comparable for lung function and smoking status which might explain the absence of differences in the extent of PVS. MRI markers of SVD including WMHs, lacunes, and microbleeds have been related to cognitive performance in population-based44 and stroke cohorts45,46 Yet, effect sizes have been small across studies.47,48 The relatively weak or inconsistent correlations may be explained by the fact that it is not the individual lesions that determine the impact on cognitive performance, but the cumulative effect of these small, spatially distributed lesions. This is in line with findings of Schneider and colleagues49 who demonstrated multiple brain pathologies in cases with dementia using autopsy. Rates of hippocampal atrophy are sensitive features of neurodegeneration. In normal aging50 and in several neurological disorders, including AD,51 temporal lobe epilepsy,52 and depressed elderly,53 measurements of volumes of the hippocampus already have been shown to be positively correlated with impaired performances on neuropsychological tests, especially in the memory domain. Also in COPD, HCV may be a proximity marker for cognitive (memory) impairment. Yet, no differences were observed in left and right HCV between cognitively low and high-performing COPD patients. Indeed, compared to cross-sectional studies, effect sizes are stronger across longitudinal studies.54 Alternate mechanisms than structural brain abnormalities may explain cognitive performances are probably multifactorial. First, worse cognitive performance in the low-performing COPD group might be explained by damage caused by oxidative stress, like oxidized proteins, glycated products, and lipid peroxidation which lead to degeneration of neurons and impairments in cognitive functioning.55 Second, although not significant, the high-performing group more often received supplemental oxygen. Regular use of supplemental oxygen therapy has been shown to decrease the risk for cognitive impairment in patients with COPD.56 Third, it is possible that the low-performing group had more comorbidities associated with cognition, other than mentioned in the Charlson comorbidity index (e.g. osteoporosis and Major Depressive Disorder) compared to the high-performing group. Fourth, mitochondrial dysfunction in COPD affects tissues with high energetic demands such as skeletal muscle, cardiac muscle, and the central nervous system accompanied by cognitive deficits.57

ChapterÂ 8Â

Limitations Although we used a 3-T MRI scanner, the prevalence of detected SVD features was rather low. Furthermore, the number of patients investigated in this study was small and therefore we might have a low power to detect group differences in the outcome of interest. However, the group was relatively homogeneous with regard to demographical and clinical characteristics. Nevertheless, selection bias cannot be excluded, because, for instance, patients with personal interest are more willing to participate. We used visual rating scales, and although validated, these have some limitations, such as non-linearity of data, lack of sensitivity to small changes, and subjective assessment. By using nonparametric tests and calculating an ICC, we tried to compensate for these limitations. Moreover, Z scores below -1.0 SD and above +1 SD were considered as low and high cognitive performance, respectively. These score cutoff scores may not have been able to differentiate both groups sufficiently. Yet, Singh and colleagues31 considered a Z scores below -1.0 SD as being impaired in a COPD population. Though not the goal of this study, future inclusion of a control group could provide more insight into COPD specific brain-cognition correlations. Additionally, this cross-sectional study can only determine associations, no causal relationships nor the sequence of the development of cognitive impairment. Therefore, future studies should assess cognitive impairment at various stages of the disease, taking into account varying degrees of hypoxemia.

Conclusions Using macrostructural MRI features of SVD and HCV, we found no differences between cognitively low and high-performing patients with COPD. This suggests that SVD and HCV are not related to cognitive performance in patients with COPD. Additional studies will be needed to get a better understanding of the mechanisms leading to cognitive impairment in COPD patients, including inflammatory factors, hormonal responses, metabolic disturbances, (epi)genetic or lifestyle factors, or microstructural brain changes using Diffusion Tensor Imaging.

172

Vascular damage, neurodegeneration, and cognitive impairment in COPD

5. 6. 7. 8.

10.

11. 12. 13. 14.

15.

16.

17.

18.

Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187(4):347-365. Divo M, Cote C, de Torres JP, Casanova C, Marin JM, Pinto-Plata V, Zulueta J, Cabrera C, Zagaceta J, Hunninghake G, Celli B, Group BC. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186(2):155-161. Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel VP, Bruijnzeel PL, Rutten EP, Op 't Roodt J, Wouters EF, Franssen FM. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;187(7):728-735. Cleutjens FA, Franssen FM, Spruit MA, Vanfleteren LE, Gijsen C, Dijkstra JB, Ponds RW, Wouters EF, Janssen DJ. Domain-specific cognitive impairment in patients with COPD and control subjects. Int J Chron Obstruct Pulmon Dis. 2017;12:1-11. Cleutjens FA, Janssen DJ, Ponds RW, Dijkstra JB, Wouters EF. COgnitive-pulmonary disease. Biomed Res Int. 2014;2014:697825. Dodd JW, Getov SV, Jones PW. Cognitive function in COPD. Eur Respir J. 2010;35(4):913-922. Lahousse L, Tiemeier H, Ikram MA, Brusselle GG. Chronic obstructive pulmonary disease and cerebrovascular disease: A comprehensive review. Respir Med. 2015;109(11):1371-1380. Schuff N, Woerner N, Boreta L, Kornfield T, Shaw LM, Trojanowski JQ, Thompson PM, Jack CR, Jr., Weiner MW, Alzheimer's Disease Neuroimaging I. MRI of hippocampal volume loss in early Alzheimer's disease in relation to ApoE genotype and biomarkers. Brain. 2009;132(Pt 4):1067-1077. Soininen HS, Partanen K, Pitkanen A, Vainio P, Hanninen T, Hallikainen M, Koivisto K, Riekkinen PJ, Sr. Volumetric MRI analysis of the amygdala and the hippocampus in subjects with ageassociated memory impairment: correlation to visual and verbal memory. Neurology. 1994;44(9):1660-1668. Wolz R, Heckemann RA, Aljabar P, Hajnal JV, Hammers A, Lotjonen J, Rueckert D, Alzheimer's Disease Neuroimaging I. Measurement of hippocampal atrophy using 4D graph-cut segmentation: application to ADNI. Neuroimage. 2010;52(1):109-118. Cai Z, Wang C, He W, Tu H, Tang Z, Xiao M, Yan LJ. Cerebral small vessel disease and Alzheimer's disease. Clin Interv Aging. 2015;10:1695-1704. Miyamoto O, Auer RN. Hypoxia, hyperoxia, ischemia, and brain necrosis. Neurology. 2000;54(2):362-371. Li J, Fei GH. The unique alterations of hippocampus and cognitive impairment in chronic obstructive pulmonary disease. Respir Res. 2013;14:140. Dodd JW, Chung AW, van den Broek MD, Barrick TR, Charlton RA, Jones PW. Brain structure and function in chronic obstructive pulmonary disease: a multimodal cranial magnetic resonance imaging study. Am J Respir Crit Care Med. 2012;186(3):240-245. Zhang H, Wang X, Lin J, Sun Y, Huang Y, Yang T, Zheng S, Fan M, Zhang J. Grey and white matter abnormalities in chronic obstructive pulmonary disease: a case-control study. BMJ Open. 2012;2(2):e000844. van Dijk EJ, Vermeer SE, de Groot JC, van de Minkelis J, Prins ND, Oudkerk M, Hofman A, Koudstaal PJ, Breteler MM. Arterial oxygen saturation, COPD, and cerebral small vessel disease. J Neurol Neurosurg Psychiatry. 2004;75(5):733-736. Lahousse L, Vernooij MW, Darweesh SK, Akoudad S, Loth DW, Joos GF, Hofman A, Stricker BH, Ikram MA, Brusselle GG. Chronic obstructive pulmonary disease and cerebral microbleeds. The Rotterdam Study. Am J Respir Crit Care Med. 2013;188(7):783-788. Cleutjens FA, Wouters EF, Dijkstra JB, Spruit MA, Franssen FM, Vanfleteren LE, Ponds RW, Janssen DJ. The COgnitive-Pulmonary Disease (COgnitive-PD) study: protocol of a longitudinal observational comparative study on neuropsychological functioning of patients with COPD. BMJ Open. 2014;4(3):e004495.

173

Chapter 8

References

Chapter 8 19. Burgmans S, van Boxtel MP, Smeets F, Vuurman EF, Gronenschild EH, Verhey FR, Uylings HB, Jolles J. Prefrontal cortex atrophy predicts dementia over a six-year period. Neurobiol Aging. 2009;30(9):1413-1419. 20. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. AJR Am J Roentgenol. 1987;149(2):351-356. 21. Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjogren M, Wallin A, Ader H, Leys D, Pantoni L, Pasquier F, Erkinjuntti T, Scheltens P, European Task Force on Age-Related White Matter C. A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke. 2001;32(6):1318-1322. 22. Potter G, Morris Z, Wardlaw J. Enlarged perivascular spaces (EPVS): a visual rating scale and user guide. 23. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, Lindley RI, O'Brien JT, Barkhof F, Benavente OR, Black SE, Brayne C, Breteler M, Chabriat H, Decarli C, de Leeuw FE, Doubal F, Duering M, Fox NC, Greenberg S, Hachinski V, Kilimann I, Mok V, Oostenbrugge R, Pantoni L, Speck O, Stephan BC, Teipel S, Viswanathan A, Werring D, Chen C, Smith C, van Buchem M, Norrving B, Gorelick PB, Dichgans M, nEuroimaging STfRVco. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12(8):822-838. 24. Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 2013;12(5):483-497. 25. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Neurology. 2014;83:1228-1234. 26. Wolz R, Aljabar P, Hajnal JV, Hammers A, Rueckert D. LEAP: learning embeddings for atlas propagation. Neuroimage. 2010;49(2):1316-1325. 27. Buckner RL, Head D, Parker J, Fotenos AF, Marcus D, Morris JC, Snyder AZ. A unified approach for morphometric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: reliability and validation against manual measurement of total intracranial volume. Neuroimage. 2004;23(2):724-738. 28. C.B.S. Standaard Beroepenclassificatie 1992 – editie 2001. Den Haag: SDU; 2001. 29. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373383. 30. Surveillance for respiratory hazards in the occupational setting [American Thoracic Society]. Am Rev Respir Dis. 1982;126(5):952-956. 31. Singh B, Parsaik AK, Mielke MM, Roberts RO, Scanlon PD, Geda YE, Pankratz VS, Christianson T, Yawn BP, Petersen RC. Chronic obstructive pulmonary disease and association with mild cognitive impairment: the Mayo Clinic Study of Aging. Mayo Clin Proc. 2013;88(11):1222-1230. 32. Benjamini Y, Hochberg Y. Controlling the false discovery rate—A practical and powerful approach to multiple testing. J Roy Stat Soc Series B-Methodological. 1995(57):289–300. 33. Duning T, Kugel H, Knecht S. Excellent cognitive performance despite massive cerebral white matter changes. Neuroradiology. 2005;47(10):749-752. 34. Stern Y, Habeck C, Moeller J, Scarmeas N, Anderson KE, Hilton HJ, Flynn J, Sackeim H, van Heertum R. Brain networks associated with cognitive reserve in healthy young and old adults. Cereb Cortex. 2005;15(4):394-402. 35. Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: a review. Stroke. 1997;28(3):652-659. 36. Kim KW, MacFall JR, Payne ME. Classification of white matter lesions on magnetic resonance imaging in elderly persons. Biol Psychiatry. 2008;64(4):273-280. 37. Soriano-Raya JJ, Miralbell J, Lopez-Cancio E, Bargallo N, Arenillas JF, Barrios M, Caceres C, Toran P, Alzamora M, Davalos A, Mataro M. Deep versus periventricular white matter lesions and cognitive function in a community sample of middle-aged participants. J Int Neuropsychol Soc. 2012;18(5):874-885. 38. de Groot JC, de Leeuw FE, Oudkerk M, van Gijn J, Hofman A, Jolles J, Breteler MM. Cerebral white matter lesions and cognitive function: the Rotterdam Scan Study. Ann Neurol. 2000;47(2):145-151.

174

Vascular damage, neurodegeneration, and cognitive impairment in COPD

39. Maclay JD, MacNee W. Cardiovascular disease in COPD: mechanisms. Chest. 2013;143(3):798807. 40. Wardlaw JM, Doubal F, Armitage P, Chappell F, Carpenter T, Munoz Maniega S, Farrall A, Sudlow C, Dennis M, Dhillon B. Lacunar stroke is associated with diffuse blood-brain barrier dysfunction. Ann Neurol. 2009;65(2):194-202. 41. Wuerfel J, Haertle M, Waiczies H, Tysiak E, Bechmann I, Wernecke KD, Zipp F, Paul F. Perivascular spaces--MRI marker of inflammatory activity in the brain? Brain. 2008;131(Pt 9):2332-2340. 42. Gan WQ, Man SFP, Sin DD. THe interactions between cigarette smoking and reduced lung function on systemic inflammation*. Chest. 2005;127(2):558-564. 43. Pelegrino NR, Tanni SE, Amaral RA, Angeleli AY, Correa C, Godoy I. Effects of active smoking on airway and systemic inflammation profiles in patients with chronic obstructive pulmonary disease. Am J Med Sci. 2013;345(6):440-445. 44. Prins ND, van Dijk EJ, den Heijer T, Vermeer SE, Jolles J, Koudstaal PJ, Hofman A, Breteler MM. Cerebral small-vessel disease and decline in information processing speed, executive function and memory. Brain. 2005;128(Pt 9):2034-2041. 45. Gregoire SM, Charidimou A, Gadapa N, Dolan E, Antoun N, Peeters A, Vandermeeren Y, Laloux P, Baron JC, Jager HR, Werring DJ. Acute ischaemic brain lesions in intracerebral haemorrhage: multicentre cross-sectional magnetic resonance imaging study. Brain. 2011;134(Pt 8):2376-2386. 46. Patel B, Lawrence AJ, Chung AW, Rich P, Mackinnon AD, Morris RG, Barrick TR, Markus HS. Cerebral microbleeds and cognition in patients with symptomatic small vessel disease. Stroke. 2013;44(2):356-361. 47. Kloppenborg RP, Nederkoorn PJ, Geerlings MI, van den Berg E. Presence and progression of white matter hyperintensities and cognition: a meta-analysis. Neurology. 2014;82(23):2127-2138. 48. van der Vlies AE, Goos JD, Barkhof F, Scheltens P, van der Flier WM. Microbleeds do not affect rate of cognitive decline in Alzheimer disease. Neurology. 2012;79(8):763-769. 49. Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69(24):2197-2204. 50. Ystad MA, Lundervold AJ, Wehling E, Espeseth T, Rootwelt H, Westlye LT, Andersson M, Adolfsdottir S, Geitung JT, Fjell AM, Reinvang I, Lundervold A. Hippocampal volumes are important predictors for memory function in elderly women. BMC Med Imaging. 2009;9:17. 51. Laakso MP, Soininen H, Partanen K, Helkala EL, Hartikainen P, Vainio P, Hallikainen M, Hanninen T, Riekkinen PJ, Sr. Volumes of hippocampus, amygdala and frontal lobes in the MRIbased diagnosis of early Alzheimer's disease: correlation with memory functions. J Neural Transm Park Dis Dement Sect. 1995;9(1):73-86. 52. Kilpatrick C, Murrie V, Cook M, Andrewes D, Desmond P, Hopper J. Degree of left hippocampal atrophy correlates with severity of neuropsychological deficits. Seizure. 1997;6(3):213-218. 53. Steffens DC, McQuoid DR, Payne ME, Potter GG. Change in hippocampal volume on magnetic resonance imaging and cognitive decline among older depressed and nondepressed subjects in the neurocognitive outcomes of depression in the elderly study. Am J Geriatr Psychiatry. 2011;19(1):4-12. 54. Raz N, Rodrigue KM, Kennedy KM, Acker JD. Vascular health and longitudinal changes in brain and cognition in middle-aged and older adults. Neuropsychology. 2007;21(2):149-157. 55. Popa-Wagner A, Mitran S, Sivanesan S, Chang E, Buga AM. ROS and brain diseases: the good, the bad, and the ugly. Oxid Med Cell Longev. 2013;2013:963520. 56. Thakur N, Blanc PD, Julian LJ, Yelin EH, Katz PP, Sidney S, Iribarren C, Eisner MD. COPD and cognitive impairment: the role of hypoxemia and oxygen therapy. Int J Chron Obstruct Pulmon Dis. 2010;5:263-269. 57. Mancuso M, Calsolaro V, Orsucci D, Carlesi C, Choub A, Piazza S, Siciliano G. Mitochondria, cognitive impairment, and Alzheimer's disease. Int J Alzheimers Dis. 2009;2009.

175

Chapter 8

Chapter 9

The impact of cognitive impairment on efficacy of pulmonary rehabilitation in patients with COPD Cleutjens FAHM, Spruit MA, Ponds RWHM, Vanfleteren LEGW, Franssen FME, Dijkstra JB, Gijsen C, Wouters EFM, Janssen DJA. The impact of cognitive impairment on efficacy of pulmonary rehabilitation in patients with COPD. JAMDA. 2017. Reprinted with permission from JAMDA.

177

Chapter 9

Abstract Objectives To compare changes in pulmonary rehabilitation (PR) dropout and outcomes between chronic obstructive pulmonary disease (COPD) patients with and without cognitive impairment. Design A cross-sectional observational study. Setting Patients with COPD were recruited from a PR centre in the Netherlands Participants The study population consisted of 157 patients with clinically stable COPD who were referred for and completed PR. Measurements A comprehensive neuropsychological examination before start of PR was administered. Changes from baseline to PR completion in functional exercise capacity (six-minute walk test (6MWT)), disease-specific health status (COPD Assessment Test (CAT) and St George’s Respiratory Questionnaire-COPD specific (SGRQ-C)), psychological wellbeing (Hospital Anxiety and Depression Scale (HADS)), COPDrelated knowledge, and their need for information (Lung Information Needs Questionnaire (LINQ)) were compared between patients with and without cognitive impairment using independent samples t-tests or Mann Whitney U tests. Results Out of 157 patients with COPD (mean age 62.9 (9.4) years, FEV1 54.6 (22.9)% predicted), 24 patients (15.3%) did not complete PR. The dropout rate was worse in patients with cognitive impairment compared to those without cognitive impairment (23.3% and 10.3%, p=0.03). Mean changes in PR outcomes after PR did not differ between completers with and without cognitive impairment. The proportion of patients with a clinical relevant improvement in 6MWT, CAT, SGRQ-C, HADS, and LINQ scores was comparable for patients with and without cognitive impairment. Conclusion PR is an effective treatment for patients with COPD and cognitive impairment. Yet, patients with cognitive impairment are at increased risk for not completing the PR program.

178

Cognitive impairment on outcomes of pulmonary rehabilitation in COPD

Introduction Pulmonary rehabilitation (PR) is an integral component in the treatment of patients with chronic obstructive pulmonary disease (COPD) who remain symptomatic despite optimal medical therapy. PR is a comprehensive intervention aiming to improve the physical and psychological condition of patients with chronic respiratory disease and to promote long-term adherence to health-enhancing behaviors.1 PR consists of a thorough patient assessment and patienttailored therapy, including supervised exercise training, education, and behavior change. PR has been clearly demonstrated to optimize exercise capacity and quality of life, and to reduce dyspnea in patients with COPD.1,2 Generally, adequate cognitive functioning is needed to understand the challenges associated with the disease, to follow guidelines, to uptake information properly, to integrate feedback, to keep scheduled appointments, and to monitor performance.3 The presence of cognitive impairment (CI) may have a negative impact on patients' adherence and compliance to their PR program. Earlier, we found that 41.5% of patients with stable COPD entering PR experience overall CI.4 Unknown is to what extent CI affects attrition rates and whether patients with CI can benefit from PR to the same extent as patients without CI. Therefore, we aimed to compare changes on outcomes of PR between patients with and without CI. Based on the association between CI and higher levels of attrition,5 poor adherence to medication regimens,6,7 less effective self-management behaviors,8 and lower education participation and achievement,9 we hypothesize that patients with COPD with CI more often dropout from PR, show less improvement in functional exercise capacity, health status, psychological wellbeing, knowledge about the disease and need for information after PR.

Methods

The current analysis was based on data collected as part of the COgnitive-PD study, a longitudinal study on neuropsychological functioning in patients with COPD. The methodology of this study and baseline cognitive functioning have been published before. 4,10

Study population Patients with clinically stable COPD, based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) document,11 were recruited at CIRO, a tertiary referral center in Horn, the Netherlands. Patients with clinically unstable COPD in the past 4 weeks, patients with a diagnosis of dementia in their medical

179

Chapter 9

Study design

Chapter 9 history and/or patients who did not master the Dutch language sufficiently were not eligible to participate. All participating patients gave written informed consent. The study is registered in the Dutch trial register (NTR4215). The Medical Ethics Committee of the University Hospital Maastricht approved this study (NL45127.068.13).

Measures The following outcomes were assessed: demographics, educational level (according to The Dutch Standard Classification of Education (CBS)12), marital status, visual and hearing impairment, handedness, smoking behavior, current self-reported comorbidities using the Charlson Comorbidity Index,13 body mass index (BMI), long-term oxygen therapy, dyspnea using the modified Medical Research Council (mMRC) Dyspnoea Scale, post-bronchodilator spirometry (FVC, FEV1, and FEV1% predicted), resting arterial blood gases (oxygen partial pressure (PaO2), partial pressure of carbon dioxide (PaCO2), and oxygen saturation (SaO2)), single breath carbon monoxide diffusing capacity (DLCO% predicted), and self-reported diagnosis of obstructive sleep apnea syndrome (OSAS). Outcome measures, including functional status (six-minute walk tests (6MWT14), disease-specific health status (COPD Assessment Test (CAT15 and the St George’s Respiratory Questionnaire-COPD specific (SGRQ-C16), and psychological wellbeing (Hospital Anxiety and Depression Scale (HADS17), were obtained before and after PR. COPD-related knowledge was assessed using 34 statements related to COPD, with each item having “correct”, “wrong”, and “I don’t know” options. Patients completed the Lung Information Needs Questionnaire (LINQ), which provides data on what areas of information have and have not been provided to patients. The LINQ provides a total score and six domain scores: disease knowledge, medicines, self-management, exercise, diet, and smoking. Higher total scores in the LINQ define a greater information need.18 Six core tests of the Cognitive-PD neuropsychological assessment were used to distinguish patients with general CI from those without, namely: the total learning score on the Visual Verbal Learning Test (VVLT), the delayed recall subscore on the VVVLT recall, the animal naming subtask of the Groninger Intelligence Test, the Letter Digit Substitution Test 60 sec, subtest C of the Concept Shifting Test, and Stroop Color-Word Test card III19 (for details about the test, please see the Cognitive-PD study protocol10). Moreover, the Mini-Mental State Examination (MMSE)20, as a measure of global CI, and compound scores for the cognitive domains psychomotor speed, planning, working memory, verbal memory, and cognitive flexibility were used in the current study (details about the tests and calculation have been published before).4

180

Cognitive impairment on outcomes of pulmonary rehabilitation in COPD

Statistics Raw test scores on the neuropsychological test battery were transformed into age, gender, and education corrected Z-scores based on normative data from the Maastricht Aging Study (MAAS).21 Patients with general CI had a score less than 1.0 SD below the age-, gender-, and education-specific mean of the MAAS study population for at least two core tests.22 Demographics, clinical characteristics, including exacerbations in the past 12 months, smoking status, spirometry and arterial blood gases, comorbidities, global cognitive functioning (MMSE total score ≤24 points),20 general CI, and cognitive domain compound scores (within each domain, scaled Z scores were summed and averaged to yield one compound Z score per cognitive domain) were compared between dropouts and completers of PR using Chi square tests for categorical variables and independent sample t test or Mann-Whitney U test, as appropriate, for continuous variables. Data before and after PR were evaluated with descriptive statistics and patients with and without CI were compared using paired samples t-tests or Wilcoxon signed-rank tests as appropriate. The difference in PR outcomes was calculated (Δ) and compared between patients with and without CI using independent samples t-tests or Mann Whitney U tests as appropriate. Moreover, the percentage of patients with a minimal clinically important difference (MCID) on the 6MWT (30 meters),23 CAT (-2 points),24 SGRQ (-4 points),25 HADS (-1.5 points),26 and LINQ (-1 point)18 was calculated and compared between patients with and without CI using Chi square tests. A p-value < 0.05 was interpreted as statistically significant. All statistical analyses were performed using SPSS 21.0 (SPSS Inc. Chicago, IL).

Results Baseline characteristics

Dropout Twenty-four patients (15.3%) dropped out from the program because of different reasons (Figure 1). Four patients died (causes of death: stroke, heart failure, and two patients due to respiratory failure). At baseline, patients who did and did not complete PR were comparable for demographics, clinical characteristics, exacerbations in the past 12 months, smoking status, spirometry, arterial blood gases, and comorbidities (table 1). Dropouts had a significantly

181

Chapter 9

In total, 157 patients (85.8% of the original study sample) were included in this study (Figure 1). In general, they were mostly men, slightly overweight, had moderate to severe airflow limitation, and 38.2% had general CI (Table 1).

Chapter 9 lower mean MMSE score, and more frequently global, general, and domain-specific CI (Table 1). The dropout rate was worse in patients with CI at baseline compared to those without CI at baseline (23.3% and 10.3%, p=0.025). Table 1. Patient characteristics of the study population and drop outs Total group Completers (n=157) (n=133) Demographics 62.4 (8.7) 62.9 (9.4) Age, years 65 (48.9) 79 (50.3) Male, n (%) 68 (51.1) 82 (52.2) Lower general or vocational education, n (%) 85 (63.9) 98 (62.4) Married, n (%) Clinical characteristics 28 (17.8) Visual impairment, n (%) 22 (16.5) 42 (26.8) Hearing impairment, n (%) 38 (28.6) 131 (83.4) Right-handed by nature, n (%) 110 (82.7) 27.1 (6.2) BMI (kg/m2), mean, (SD) 26.7 (6.1) Oxygen therapy, n (%) 33 (21.0) 30 (22.6) mMRC (points), mean (SD) 2.2 (1.0)n=156 2.2 (0.9) DLCO (% predicted), median (IQR) 49.5 (41.749.2 (41.361.5)n=125 60.6)n=149 Exacerbation history in the previous 12 months 0-1 exacerbations, n (%) 74 (47.1) 60 (45.1) 2 ≥ exacerbations, n (%) 83 (52.9) 73 (54.9) Smoking behavior Current smoker, n (%) 18 (11.5) 13 (9.8) Former smoker, n (%) 137 (87.3) 118 (88.7) Never smoker, n (%) 2 (1.3) 2 (1.5) Spirometry FEV1/FVC, mean (SD) 42.3 (14.9) 41.6 (14.4) 54.6 (22.9) 54.0 (22.5) FEV1 (% predicted), mean (SD) Arterial blood gases SaO2 (%), median (IQR) 94.8 (92.894.8 (92.896.0)n=131 96.0)n=155 9.7 (1.5)n=155 9.7 PaO2 (kPa), mean (SD) (1.5)n=131 PaCO2 (kPa), median (IQR) 5.1 (4.75.1 (4.75.6)n=131 5.6)n=155 Comorbidities Charlson comorbidity index score, 2.8 (1.9) 2.8 (1.9) mean, (SD) Cognitive functioning MMSE, mean (SD) 27.7 (1.9) 27.9 (1.6) Global cognitive impairment (MMSE 9 (5.7) 3 (2.3) ≤24), n (%)

182

Drop outs (n=24)

P-value

66.1 (12.2) 14 (58.3) 14 (58.3)

0.072 0.265 0.335

13 (54.2)

0.247

6 (25.0) 4 (16.7) 21 (87.5) 28.9 (7.1) 3 (12.5) 2.4 (1.0)n=23 48.3 (36.154.2)

0.233 0.169 0.742 0.118 0.204 0.426 0.239

14 (58.3) 10 (41.7)

0.166

5 (20.8) 19 (79.2) 0 (0.0)

0.254

46.2 (17.3) 57.5 (25.1)

0.164 0.491

95.5 (91.896.6) 9.8 (1.9)

0.501

5.0 (4.65.3)

0.287

2.8 (1.7)

0.988

26.5 (2.8) 6 (25.0)

0.001 <0.001

0.624

Cognitive impairment on outcomes of pulmonary rehabilitation in COPD General cognitive impairment (2 out of 6 subtest Z scores -1SD), n (%) CST-C (time in seconds), mean (SD)* GIT Animal naming (number of animal names), mean (SD)† LDST 60 Sec (number correct: 0-125), mean (SD)‡ SCWT Card III (time in seconds), mean (SD)* VVLT Total recall (number correct: 075), mean (SD)‡ VVLT Delayed recall (number correct: 0-15), mean (SD)‡ Domain-specific cognition Psychomotor speed (compound zscore), mean (SD) Planning (compound z-score), mean (SD) Working memory (compound zscore), mean (SD) Verbal memory (compound z-score), mean (SD) Cognitive flexibility (compound zscore), mean (SD)

60 (38.2)

46 (34.6)

14 (58.3)

0.025

42.7 (16.8) 22.4 (6.7)

41.9 (16.8) 22.9 (6.3)

47.5 (16.3) 20.0 (7.9))

0.135 0.049

27.7 (7.1)

28.4 (7.3)

20.0 (7.9)

0.004

54.6 (21.5)

53.2 (20.8)

62.4 (24.0)

0.053

42.5 (10.9)

43.9 (10.6)

34.4 (8.8)

<0.001

8.1 (3.5)

8.6 (3.4)

5.3 (2.7)

<0.001

(0.8)

0.1 (0.8)

-0.4 (1.0)

0.012

-0.0 (0.7)

0.0 (0.7)

-0.4 (0.6)

0.017

-0.4 (0.7)

-0.3 (0.7)

-0.8 (0.7)

0.005

-0.2 (1.1)

-0.0 (1.1)

-1.2 (0.8)

<0.001

-0.5 (1.3)

-0.5 (1.2)

-1.0 (1.6)

0.049

Chapter 9

Abbreviations: COPD, chronic obstructive pulmonary disease; CST, Concept Shifting Test; DLCO, single breath carbon monoxide diffusing capacity BMI, body mass index; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; GIT, Groninger Intelligence Test; IQR, interquartile range; LDST, Letter Digit Substitution Test; SaO2, oxygen saturation; PaO2, arterial oxygen partial pressure; PaCO2, arterial partial pressure of carbon dioxide; PR, pulmonary rehabilitation; SCWT, Stroop Color-Word Test; SD, standard deviation; VVLT, Visual Verbal Learning Test. *, Higher scores indicate worse performance; †, Indicates score has no upper limit; ‡, Higher scores indicate better performance. P-value compares completers vs. dropouts.

Figure 1. Flow-chart of patient inclusion. CI: cognitive impairment; COPD: chronic obstructive pulmonary disease; PR: pulmonary rehabilitation.

183

Table 2. Functional status, health status, psychological wellbeing, knowledge about the disease, and and after PR Total group (n=133) Patients with cognitive impairment (n=46) Before After PR PBefore After PR Δ PPR value PR value Functional exercise capacity 6MWT (meters) 441.8 459.6 <0.001 432.1 453.8 21.7 0.003 (112.4) (121.3) (113.8) (112.2) (47.2) mMRC dyspnea scale 2.2 1.7 <0.001 2.2 1.6 -0.6 0.013 (0.9)* (0.9)* (0.9)† (0.8)† (1.3)† Health status 17.9 <0.001 22.2 18.4 -3.8 <0.001 CAT score (points) 21.9 (6.2) (6.5) (5.9) (6.7) (5.8) SGRQ-C symptom 60.5 52.2 <0.001 58.4 50.2 -8.2 0.005 score (points) (20.0) (19.4) (19.7) (19.5) (18.6) SGRQ-C activity score 80.5 73.9 <0.001 84.2 76.5 -7.6 0.001 (points) (16.1) (19.3) (13.1) (17.9) (14.9) SGRQ-C impact score 48.4 35.7 <0.001 50.6 38.4 -12.2 <0.001 (points) (18.8) (19.0) (17.9) (19.7) (18.3) SGRQ-C total score 60.4 50.3 <0.001 62.3 52.2 -10.1 <0.001 (points) (15.4) (16.2) (14.2) (16.1) (13.9) Psychological wellbeing HADS Depression 7.3 5.1 <0.001 7.8 5.7 -2.1 <0.001 score (points) (3.9) (3.4) (4.0) (3.7) (3.6) HADS Anxiety score 7.9 5.9 <0.001 8.6 6.4 -2.2 <0.001 (points) (4.4) (3.8) (4.6) (4.1) (3.2) Knowledge about the lung disease Statements COPD 24.1 26.6 <0.001 24.1 26.5 2.4 <0.001 knowledge (number (3.8) (3.5) (4.1) (3.5) (2.8) of good answers), mean (SD)a

184 After PR

462.7 (126.4) 1.7 (0.9)‡ 17.7 (6.5) 53.2 (19.4) 72.5 (19.9) 34.4 (18.6) 49.4 (16.2) 4.8 (3.2) 5.7 (3.6) 26.7 (3.5)

Before PR 447.0 (112.1) 2.2 (1.0)‡ 21.8 (6.3) 61.7 (20.2) 78.6 (17.3) 47.3 (19.3) 59.4 (15.9) 7.0 (3.8) 7.6 (4.3) 24.2 (3.6)

2.5 (3.4)

-2.2 (3.9) -1.9 (3.5)

-4.1 (6.3) -8.5 (18.9) -6.1 (14.9) -13.0 (17.2) -10.1 (13.3)

15.7 (57.8) -0.4 (0.9)‡

0.990

<0.001

0.842

0.627

0.825

<0.001

0.587

<0.001

0.825

0.929

<0.001

0.806

0.415

<0.001

0.549

Δ Pvalue

0.013

Pvalue

Patients without cognitive impairment (n=87)

information needs in completers or PR at baseline

Chapter 9

LINQ overall score (points), mean (SD)

Information needs LINQ disease knowledge (points), mean (SD) LINQ medicine (points), mean (SD)§ LINQ self-management (points), mean (SD) LINQ smoking (points), mean (SD)§ LINQ exercise (points), mean (SD) LINQ diet (points), mean (SD)

1.4 (0.7) 0.7 (1.1) 2.9 (1.6) 0.3 (0.9) 2.0 (1.1) 1.2 (1.1) 8.5 (3.3)

0.8 (0.7) 0.2 (0.5) 2.0 (1.4) 0.1 (0.2) 1.1 (0.7) 1.2 (0.7) 5.3 (2.3) <0.001

0.849

<0.001

0.001

<0.001

1.5 (0.7) 0.7 (1.1) 2.9 (1.7) 0.5 (1.1) 1.8 (0.9) 1.3 (1.0) 8.6 (3.1)

0.9 (0.7) 0.2 (0.6) 2.2 (1.6) 0.1 (0.3) 1.0 (0.8) 1.2 (0.7) 5.6 (2.5)

-0.6 (0.9) -0.5 (0.9) -0.7 (1.8) -0.4 (1.1) -0.8 (1.2) -0.1 (1.3) -3.0 (3.0)

<0.001

0.492

<0.001

0.008

0.019

0.001

<0.001

1.4 (0.8) 0.7 (1.0) 2.9 (1.6) 0.2 (0.7) 2.1 (1.3) 1.1 (0.7) 8.5 (3.4)

0.7 (0.7) 0.2 (0.4) 1.9 (1.4) 0.0 (0.2) 1.1 (0.7) 1.1 (1.1) 5.1 (2.3)

-0.7 (0.8) -0.6 (1.0) -1.0 (1.9) -0.1 (0.6) -1.0 (1.3) 0.0 (1.4) -3.3 (3.5)

<0.001

0.820

<0.001

0.033

<0.001

0.647

0.509

0.353

0.041

0.292

0.602

0.664

Chapter 9

Abbreviations: 6MWT, six-minute walk test; CAT, COPD Assessment Test; HADS, Hospital Anxiety and Depression Scale; LINQ, Lung Information Needs Questionnaire; mMRC, Modified Medical Research Council; PR, pulmonary rehabilitation; SD, standard deviation; SGRQ-C, St George’s Respiratory Questionnaire-COPD specific. Δ, Changes after PR. *, n=91; †, n=29; ‡, n=62; §, Nonparametric statistical tests have been used because of skewed data.

Cognitive impairment on outcomes of pulmonary rehabilitation in COPD

185

ChapterÂ 9Â

Efficacy of pulmonary rehabilitation Generally, 6-min walk distance, health status and psychological wellbeing improved significantly compared to baseline. Moreover, disease knowledge enriched, and information needs lowered from baseline to completion of PR (all p<0.05), except for the LINQ diet subscale (Table 2). After stratification for the presence/absence of CI at baseline, no significant differences in mean responses were found, except for the LINQ smoking subscore. Patients with CI showed a significant decrease in information needs regarding smoking compared to those without CI (Table 2). The percentage of patients with a MCID (improvement) was comparable for patients with and without CI for 6MWT, CAT, SGRQ-C, HADS, and LINQ scores (Figure 2).

Figure 2. Percentage of patients with COPD with and without cognitive impairment with a MCID (improvement) on the 6MWT (39.1 and 29.9% respectively, p=0.188), CAT (65.2 and 65.5% respectively, p=0.560), SGRQ-C (54.3 and 70.1% respectively, p=0.053), HADS depression (52.2 and 52.9% respectively, p=0.542) and anxiety subscales (54.3 and 52.9% respectively, p=0.509), and the LINQ overall score (78.3 and 83.9% respectively, p=0.282).

Discussion The present study demonstrated that patients with CI are at risk for dropout during PR. However, those who complete the program do benefit from PR to the same extent as patients without CI in functional status, health status, psychological wellbeing, disease knowledge, and information needs.

Dropout A higher dropout rate in patients with COPD and CI compared to those without CI was demonstrated. Moreover, dropouts more often had global CI, general CI,

186

Cognitive impairment on outcomes of pulmonary rehabilitation in COPD and domain-specific CI in all domains than patients who completed PR. This suggests that CI could impede a patient’s ability to complete PR. Moreover, attrition has been related to CI in several other populations.27-29 In the Kungsholmen Study,5 CI in older adults was a predictor of refusal to participate in at least one part of the medical examination. In elderly patients recovering from a hip fracture, CI was predictive of negative outcomes in rehabilitation and this effect was mediated by rehabilitation participation.30 Completing a PR program for patients with COPD, which involves analyzing, thinking ahead, planning, and controlling impulses, therefore might be hampered by CI. It is also likely that patients with CI are more often patients with frailty and frailty might also contribute to a higher dropout.31

Lautenschlager and colleagues32 reported that better cognitive functioning motivates participation in exercise activity, suggesting that better cognitive functioning has beneficial effects in terms of functional exercise capacity. The current study demonstrated that functional exercise capacity increased after PR in the total COPD group and both subgroups with and without CI. Moreover, the percentage of patients with a clinically relevant difference33 in 6MWT and delta 6MWT did not differ between patients with and without CI. Therefore, CI in patients with COPD does not influence whether patients progress on functional exercise capacity from baseline to PR completion. This can be explained by the fact that a PR program includes intensive counseling and structured training and education, requiring low demand of cognitive functions.1,2 Yet, it is possible that intact (higher-order) cognitive functioning is necessary for initiating and maintaining participation in PR activities such as physical activity,34 which in turn is important for sustained PR effects. For patients with more significant CI, caregiving family and peers who can assist them to identify and remember how to perform physical activities safely and consistently in a less-structured home environment might be required after PR completion. Patients with and without CI showed comparable improvement in diseasespecific health status after PR. Moreover, the mean change in SGRQ-C in both patients with and without CI was more than twice the MCID, and PR thus seems to be effective with respect to disease-specific health status in both groups. Symptoms of depression and anxiety decreased significantly after PR in both groups, and delta HADS scores and percentage of patients with a MCID were not significantly different between patients with and without CI. Yet, it is wellknown that depression35 and anxiety36 are associated with cognitive functioning. Our study also shows high baseline HADS scores in patients with CI, but also a mean decrease larger than the MCID in these patients. Positive effects of psychological treatments on symptoms of anxiety and depression have also been

187

Chapter 9

Pulmonary rehabilitation efficacy

ChapterÂ 9Â shown in dementia.37 Whether the (long-term) effects of psychological treatment differ between COPD patients with and without CI remains unknown. Despite the fact that the educational content of a PR program is not adapted to the level of cognitive functioning of patients with COPD, PR was as effective in patients with and without CI in increasing disease knowledge and reducing information needs after PR. The mean change in overall LINQ score in both patients with and without CI was more than three times the MCID. The current results do not support tailoring education to patients with CI. Yet, it remains arguable whether a mean change of 1 on statements of COPD knowledge is clinically significant.

Clinical implications Taken together, CI should not be barrier for patients to be referred for PR. Nevertheless, patients with CI may be more susceptible to dropping out before completing PR and interventions should focus on reducing PR dropout in patients with CI. It is important to make the patient feel at ease, comfortable and safe with healthcare providers and other patients. Moreover, the disease perception and management may have some impact.38,39 It is more likely that patients complete PR when rehabilitation makes common sense in relation to their disease beliefs. These perceptions are influenced by the patient-provider interaction,40 which in fact may profit from motivational interviewing to create positive, yet realistic, expectations of PR.41,42 Finally, empathic understanding of healthcare providers and the involvement of informal caregivers may enhance patient adherence.43 PR itself already has been shown to have the potential to improve cognitive functioning with better cognitive performance in complex attention,44 verbal fluency,45 visual attention and semantic fluency,46 and components of fluid intelligence.47 Future research would benefit from assessing the efficacy of cognitive training, which aims to improve performance in one or more cognitive domains through a standard set of cognitive tasks,48 during PR in COPD. Although improvements in cognitive performance have been shown after cognitive training programs, they often do not exceed those seen in control conditions.49 Nevertheless, it would be interesting to investigate whether cognitive training in COPD is able to slow down or prevent cognitive decline, to minimize dropout and increase benefits and maintenance of behavior change after PR. Studies that have followed patients longer than six months after completing PR show that benefits regarding smoking cessation, weight loss, or exercise adherence tend to diminish after about one year.50-53 Even though it remains unknown whether patients with and without CI differ in long-term outcomes, relapse rates, and maintenance of behavior change, our results support the idea that CI is not a contraindication for PR.

188

Cognitive impairment on outcomes of pulmonary rehabilitation in COPD

Methodological considerations To our knowledge, this is the first study among patients with COPD that compared efficacy of PR between patients with and without CI. Some methodological issues should be considered in interpreting the results. Selection bias might have affected the results. Patients with subjective complaints of CI might avoid participation due to anxiety or worry, or may have been more willing to participate in the present study because of personal interest. Moreover, CI was not assessed after PR and finally, the effect of CI on remaining benefits of rehabilitation after completion of a PR program remains unknown.

Conclusions

Chapter 9

The current study suggests that CI could impede the ability of patients with COPD to complete a PR program. However, a PR program is as effective for completers of the program without CI as it is for completers with CI regarding functional status, health status, psychological wellbeing, knowledge about the disease and the need for information after PR. CI therefore is not a contraindication for PR in patients with COPD. However, future studies are needed to investigate whether incorporating cognitive strategies could lead to higher percentage of PR completion, as well as improved cognitive functioning.

189

Chapter 9

References 1. 2.

3. 4.

6. 7.

8. 9. 10.

11.

12. 13. 14. 15. 16. 17. 18. 19.

190

Spruit MA, Vanderhoven-Augustin I, Janssen PP, Wouters EF. Integration of pulmonary rehabilitation in COPD. Lancet. 2008;371(9606):12-13. Spruit MA, Singh SJ, Garvey C, ZuWallack R, Nici L, Rochester C, Hill K, Holland AE, Lareau SC, Man WD, Pitta F, Sewell L, Raskin J, Bourbeau J, Crouch R, Franssen FM, Casaburi R, Vercoulen JH, Vogiatzis I, Gosselink R, Clini EM, Effing TW, Maltais F, van der Palen J, Troosters T, Janssen DJ, Collins E, Garcia-Aymerich J, Brooks D, Fahy BF, Puhan MA, Hoogendoorn M, Garrod R, Schols AM, Carlin B, Benzo R, Meek P, Morgan M, Rutten-van Molken MP, Ries AL, Make B, Goldstein RS, Dowson CA, Brozek JL, Donner CF, Wouters EF, Rehabilitation AETFoP. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med. 2013;188(8):e13-64. Glisky EL. Changes in cognitive function in human aging. In: Riddle DR, ed. Brain Aging: Models, Methods, and Mechanisms. Boca Raton: CRC Press; 2007. Cleutjens FAHM, Franssen FME, Spruit MA, Vanfleteren LEGW, Gijsen C, Dijkstra JB, Ponds RWHM, Wouters EFM, Janssen DJA. Domain-specific cognitive impairment in patients with COPD and control subjects. Int J Chron Obstruct Pulmon Dis. 2017;12:1-11. von Strauss E, Fratiglioni L, Jorm AF, Viitanen M, Winblad B. Attitudes and participation of the elderly in population surveys: data from a longitudinal study on aging and dementia in Stockholm. J Clin Epidemiol. 1998;51(3):181-187. Becker BW, Thames AD, Woo E, Castellon SA, Hinkin CH. Longitudinal change in cognitive function and medication adherence in HIV-infected adults. AIDS Behav. 2011;15(8):1888-1894. Campbell NL, Boustani MA, Skopelja EN, Gao S, Unverzagt FW, Murray MD. Medication adherence in older adults with cognitive impairment: a systematic evidence-based review. Am J Geriatr Pharmacother. 2012;10(3):165-177. Hajduk AM, Lemon SC, McManus DD, Lessard DM, Gurwitz JH, Spencer FA, Goldberg RJ, Saczynski JS. Cognitive impairment and self-care in heart failure. Clin Epidemiol. 2013;5:407-416. Bellon K, Malec JF, Kolakowsky-Hayner SA. Mayo-Portland Adaptability Inventory-4. J Head Trauma Rehabil. 2012;27(4):314-316. Cleutjens FA, Wouters EF, Dijkstra JB, Spruit MA, Franssen FM, Vanfleteren LE, Ponds RW, Janssen DJ. The COgnitive-Pulmonary Disease (COgnitive-PD) study: protocol of a longitudinal observational comparative study on neuropsychological functioning of patients with COPD. BMJ Open. 2014;4(3):e004495. Global initiative for chronic obstructive lung disease: Pocket guide to COPD diagnosis, management, and prevention. Updated 2015. 2015; http://www.goldcopd.org/uploads/users/ files/GOLD_Pocket_2015_Feb18.pdf. C.B.S. Standaard Beroepenclassificatie 1992 – editie 2001. Den Haag: SDU; 2001. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383. Laboratories ATSCoPSfCPF. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111-117. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J. 2009;34(3):648-654. Meguro M, Barley EA, Spencer S, Jones PW. Development and Validation of an Improved, COPDSpecific Version of the St. George Respiratory Questionnaire. Chest. 2007;132(2):456-463. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361-370. Hyland ME, Jones RC, Hanney KE. The Lung Information Needs Questionnaire: Development, preliminary validation and findings. Respir Med. 2006;100(10):1807-1816. Burgmans S, van Boxtel MP, Smeets F, Vuurman EF, Gronenschild EH, Verhey FR, Uylings HB, Jolles J. Prefrontal cortex atrophy predicts dementia over a six-year period. Neurobiol Aging. 2009;30(9):1413-1419.

Cognitive impairment on outcomes of pulmonary rehabilitation in COPD

20. Cockrell JR, Folstein MF. Mini-Mental State Examination (MMSE). Psychopharmacol Bull. 1988;24(4):689-692. 21. Jolles J, van Boxtel MP, Ponds RW, Metsemakers JF, Houx PJ. [The Maastricht aging study (MAAS). The longitudinal perspective of cognitive aging]. Tijdschr Gerontol Geriatr. 1998;29(3):120-129. 22. Singh B, Parsaik AK, Mielke MM, Roberts RO, Scanlon PD, Geda YE, Pankratz VS, Christianson T, Yawn BP, Petersen RC. Chronic obstructive pulmonary disease and association with mild cognitive impairment: the Mayo Clinic Study of Aging. Mayo Clin Proc. 2013;88(11):1222-1230. 23. Singh SJ, Puhan MA, Andrianopoulos V, Hernandes NA, Mitchell KE, Hill CJ, Lee AL, Camillo CA, Troosters T, Spruit MA, Carlin BW, Wanger J, Pepin V, Saey D, Pitta F, Kaminsky DA, McCormack MC, MacIntyre N, Culver BH, Sciurba FC, Revill SM, Delafosse V, Holland AE. An official systematic review of the European Respiratory Society/American Thoracic Society: measurement properties of field walking tests in chronic respiratory disease. Eur Respir J. 2014;44(6):1447-1478. 24. Kon SS, Canavan JL, Jones SE, Nolan CM, Clark AL, Dickson MJ, Haselden BM, Polkey MI, Man WD. Minimum clinically important difference for the COPD Assessment Test: a prospective analysis. Lancet Respir Med. 2014;2(3):195-203. 25. Jones PW. St. George's Respiratory Questionnaire: MCID. COPD. 2005;2(1):75-79. 26. Puhan MA, Frey M, Buchi S, Schunemann HJ. The minimal important difference of the hospital anxiety and depression scale in patients with chronic obstructive pulmonary disease. Health Qual Life Outcomes. 2008;6:46. 27. Deeg DJ, van Tilburg T, Smit JH, de Leeuw ED. Attrition in the Longitudinal Aging Study Amsterdam. The effect of differential inclusion in side studies. J Clin Epidemiol. 2002;55(4):319-328. 28. Matthews FE, Chatfield M, Brayne C, Medical Research Council Cognitive F, Ageing S. An investigation of whether factors associated with short-term attrition change or persist over ten years: data from the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). BMC Public Health. 2006;6:185. 29. Van Beijsterveldt CE, van Boxtel MP, Bosma H, Houx PJ, Buntinx F, Jolles J. Predictors of attrition in a longitudinal cognitive aging study: the Maastricht Aging Study (MAAS). J Clin Epidemiol. 2002;55(3):216-223. 30. Lenze EJ, Munin MC, Dew MA, Rogers JC, Seligman K, Mulsant BH, Reynolds CF, 3rd. Adverse effects of depression and cognitive impairment on rehabilitation participation and recovery from hip fracture. Int J Geriatr Psychiatry. 2004;19(5):472-478. 31. Robertson DA, Savva GM, Kenny RA. Frailty and cognitive impairment--a review of the evidence and causal mechanisms. Ageing Res Rev. 2013;12(4):840-851. 32. Lautenschlager NT, Cox KL, Flicker L, Foster JK, van Bockxmeer FM, Xiao J, Greenop KR, Almeida OP. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA. 2008;300(9):1027-1037. 33. Holland AE, Spruit MA, Troosters T, Puhan MA, Pepin V, Saey D, McCormack MC, Carlin BW, Sciurba FC, Pitta F, Wanger J, MacIntyre N, Kaminsky DA, Culver BH, Revill SM, Hernandes NA, Andrianopoulos V, Camillo CA, Mitchell KE, Lee AL, Hill CJ, Singh SJ. An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease. Eur Respir J. 2014;44(6):1428-1446. 34. Teri L, Logsdon RG, McCurry SM. Exercise interventions for dementia and cognitive impairment: the Seattle Protocols. J Nutr Health Aging. 2008;12(6):391-394. 35. Austin MP, Mitchell P, Goodwin GM. Cognitive deficits in depression: possible implications for functional neuropathology. Br J Psychiatry. 2001;178:200-206. 36. Sinoff G, Werner P. Anxiety disorder and accompanying subjective memory loss in the elderly as a predictor of future cognitive decline. Int J Geriatr Psychiatry. 2003;18(10):951-959. 37. Orgeta V, Qazi A, Spector A, Orrell M. Psychological treatments for depression and anxiety in dementia and mild cognitive impairment: systematic review and meta-analysis. Br J Psychiatry. 2015;207(4):293-298. 38. Garrod R, Marshall J, Barley E, Jones PW. Predictors of success and failure in pulmonary rehabilitation. Eur Respir J. 2006;27(4):788-794.

191

Chapter 9

ChapterÂ 9Â 39. Young P, Dewse M, Fergusson W, Kolbe J. Respiratory rehabilitation in chronic obstructive pulmonary disease: predictors of nonadherence. Eur Respir J. 1999;13(4):855-859. 40. Arnold E, Bruton A, Ellis-Hill C. Adherence to pulmonary rehabilitation: A qualitative study. Respir Med. 2006;100(10):1716-1723. 41. Fischer MJ, Scharloo M, Abbink JJ, van 't Hul AJ, van Ranst D, Rudolphus A, Weinman J, Rabe KF, Kaptein AA. Drop-out and attendance in pulmonary rehabilitation: the role of clinical and psychosocial variables. Respir Med. 2009;103(10):1564-1571. 42. Petrie KJ, Cameron LD, Ellis CJ, Buick D, Weinman J. Changing illness perceptions after myocardial infarction: an early intervention randomized controlled trial. Psychosom Med. 2002;64(4):580-586. 43. Bjoernshave B, Korsgaard J, Nielsen CV. Does pulmonary rehabilitation work in clinical practice? A review on selection and dropout in randomized controlled trials on pulmonary rehabilitation. Clin Epidemiol. 2010;2:73-83. 44. Emery CF, Leatherman NE, Burker EJ, MacIntyre NR. Psychological outcomes of a pulmonary rehabilitation program. Chest. 1991;100(3):613-617. 45. Emery CF, Schein RL, Hauck ER, MacIntyre NR. Psychological and cognitive outcomes of a randomized trial of exercise among patients with chronic obstructive pulmonary disease. Health Psychol. 1998;17(3):232-240. 46. Kozora E, Tran ZV, Make B. Neurobehavioral improvement after brief rehabilitation in patients with chronic obstructive pulmonary disease. J Cardiopulm Rehabil. 2002;22(6):426-430. 47. Pereira ED, Viana CS, Taunay TC, Sales PU, Lima JW, Holanda MA. Improvement of cognitive function after a three-month pulmonary rehabilitation program for COPD patients. Lung. 2011;189(4):279-285. 48. Kelly ME, Loughrey D, Lawlor BA, Robertson IH, Walsh C, Brennan S. The impact of cognitive training and mental stimulation on cognitive and everyday functioning of healthy older adults: a systematic review and meta-analysis. Ageing Res Rev. 2014;15:28-43. 49. Martin M, Clare L, Altgassen AM, Cameron MH, Zehnder F. Cognition-based interventions for healthy older people and people with mild cognitive impairment. Cochrane Database Syst Rev. 2011(1):CD006220. 50. Cambach W, Wagenaar RC, Koelman TW, van Keimpema AR, Kemper HC. The long-term effects of pulmonary rehabilitation in patients with asthma and chronic obstructive pulmonary disease: a research synthesis. Arch Phys Med Rehabil. 1999;80(1):103-111. 51. Griffiths TL, Burr ML, Campbell IA, Lewis-Jenkins V, Mullins J, Shiels K, Turner-Lawlor PJ, Payne N, Newcombe RG, Ionescu AA, Thomas J, Tunbridge J. Results at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trial. Lancet. 2000;355(9201):362-368. 52. Ries AL, Kaplan RM, Limberg TM, Prewitt LM. Effects of pulmonary rehabilitation on physiologic and psychosocial outcomes in patients with chronic obstructive pulmonary disease. Ann Intern Med. 1995;122(11):823-832. 53. Troosters T, Gosselink R, Decramer M. Short- and long-term effects of outpatient rehabilitation in patients with chronic obstructive pulmonary disease: a randomized trial. Am J Med. 2000;109(3):207-212.

192

Chapter 10

General discussion

195

ChapterÂ 10Â Cognitive impairment is being increasingly recognized as a significant comorbidity of chronic obstructive pulmonary disease (COPD).1-4 This thesis aimed to increase our current knowledge on cognitive impairment in COPD by assessing the prevalence of general and domain-specific cognitive impairment, and its association with clinical characteristics, brain abnormalities, and the efficacy of pulmonary rehabilitation (PR).

COPD: COgnitive-Pulmonary Disease? The incidence of cognitive impairment in COPD varies in different studies from 12% to 88%.5 In this thesis we showed that 4 out of 10 patients with COPD from the COgnitive-PD Study with mostly moderate to severe airflow limitation, who are referred for a PR program, have general cognitive impairment. In line with other studies,6,7 we demonstrated that general cognitive impairment is four times more common in COPD than in controls. Next to insight in the presence of global cognitive impairment and general cognitive impairment (e.g. MiniMental State Examination or compound scores of neurocognitive test scores respectively), it is useful to gain more information about domain-specific cognitive functions. Indeed, thereupon it can be verified whether the patient has an isolated problem or whether several domains are involved, which could enhance our understanding of problems experienced by the patient. For example, executive functioning problems may lead to an inadequate inhaler self-administration technique,8 and memory problems may lead to poor recall of inhaler technique and not remembering to use their inhaler.9 In chapter 6 we showed that impairments in specific cognitive domains were two to sixteen times more likely in patients with COPD compared to controls. Psychomotor speed, planning, and cognitive flexibility were the most affected, while memory performances did not differ between both groups. In contrast, analyses on data from the United Kingdom (UK) Biobank showed different memory performances (prospective memory, visuospatial memory, and numeric short-term memory) between persons with and without OLD (Chapter 2). This may be explained by the fact that the UK Biobank included a large sample size of more than 40,000 participants. It is possible that in our study the influence of outliers or performances of extreme high or low cognitively performing patients have a greater influence on the results because of our smaller sample size. Moreover, the distribution of comorbidities might have been different between the UK Biobank study sample and our COPD study population, whereupon a specific pattern of comorbidities in the UK Biobank study sample leads to deficits in memory performances, which not meet the criteria of memory impairment. Indeed, when we compared COPD patients and controls without comorbidities, the prevalence of impairments in psychomotor speed and memory did not differ between both groups (Chapter 6).

196

General discussion

COPD and cognition in relation to other diseases and comorbidities Impairments in cognitive functioning are increasingly recognized as an effect of many chronic diseases such as cardiovascular disease, Human Immunodeficiency Virus, chronic kidney disease, rheumatoid arthritis, stroke, diabetes, and COPD. Common risk factors, such as aging, smoking, low physical activity, and genetic predisposition may explain that cognitive impairment can be listed as one of the many complications of chronic diseases.10 There is, however, a lack of studies comparing cognitive functioning between COPD patients and other chronic diseases. Yet, an MRI study in patients with non-hypoxic severe COPD showed that cerebral metabolism was significantly altered and that the pattern of derangement differed from that seen in heart failure and diabetes.11 Moreover, in the current literature there is a suggestion that patients with COPD may have a specific pattern of cognitive impairment. It seems that patients with COPD are positioned between healthy controls and patients with Alzheimer's disease regarding their cognitive functioning.12,13 In addition, comorbidities are highly prevalent in patients with COPD, and this thesis demonstrated a higher prevalence of myocardial infarction, peripheral vascular disease, hemiplegia, and symptoms of anxiety and depression in COPD patients with general cognitive impairment to those without (Chapter 7). Comorbidities may explain part of the cognitive impairment in COPD. To explore whether the observed neuropsychological findings are related to the coexisting diseases, we compared patients with COPD without comorbidities and controls without comorbidities and found that cognitive flexibility, planning, and psychomotor speed were more often affected in patients with COPD (Chapter 6). Indeed, increased confusion and memory loss is more often described in patients who reported a stroke than among those with COPD.14

This thesis showed that patients with COPD and general cognitive impairment did not differ in baseline demographics, functional status, disease-specific health status, psychological wellbeing, and clinical characteristics, including smoking behavior, lung function, and results of arterial blood gases from patients without cognitive impairment (Chapters 7 and 8). The equal distribution of cognitive impairment across GOLD stages demonstrated that cognitive impairment is prevalent in patients with COPD, independent of severity of airflow limitation. Additionally, the prevalence of cognitive impairment did not differ across GOLD groups, which shows that cognitive impairment is prevalent in all symptom groups and risk groups of COPD (Chapter 7). Moreover, cognitive functioning was not related to sleep quality disturbances in an elderly ambulatory COPD population (Chapter 4). Using brain autopsies, we showed that COPD 197

Chapter 10

Pathogenesis of cognitive impairment in COPD

ChapterÂ 10Â seems not to be associated with an increase in specific neuropathologies, since there was no difference in the prevalence of degenerative and neoplastic brain changes between donors with and without COPD (Chapter 3). Also Borson and colleagues demonstrated that brain atrophy, number and estimated volume of white matter hyperintensities, and frontal and hippocampal neuro-chemical indices, did not differ between COPD and control groups.15 Moreover, Esser and colleagues demonstrated that patients with COPD showed no generalized cortical degeneration, however, gray matter decreases were present.16 Since we showed that Alzheimer-like and gross vascular pathology are not increased in donors with COPD, one would expect that the impact of COPD on the brain likely results from widely distributed changes in oxygenation, blood flow, and other respiratory, metabolic, or systemic inflammatory effects. Using MRI, previous research showed that right and left hippocampal volumes are significantly smaller in mild-to-moderate and severe COPD patients compared to controls.17 However, there was no significant difference between the mild-to-moderate COPD group and severe COPD group. The impact of these findings on cognitive functioning remains unknown. Actually, our study showed that there is no difference in hippocampal volume between cognitively high- and low-performing patients with COPD. Although cerebral small vessel disease (SVD) has been shown in patients with COPD,18,19 our study demonstrated comparable cerebral SVD in cognitively high- and low-performing patients (Chapter 8). Yet, pathologic changes might exist in COPD that are not detectable at MRI. The pathogenesis of cognitive impairment in COPD thus remains unknown. While comorbidities might partly explain cognitive impairment in COPD, they are not able to fully explain the pathogenesis of this phenomenon and, thus, other etiological contributors should be involved. First, there may be a genetic susceptibility for cognitive impairment in COPD. For example, respiratory and neurological diseases might share genetic variations that lead to an altered histone deacetylase (HDAC) expression20 or increased levels of metalloproteinase 9 (MMP9).21 Moreover, sirtuin 1 (SIRT1) is downregulated in COPD and its posttranslational modification is modified by smoking and oxidative stress. Downregulation of SIRT1 is involved in proinflammatory pathways, impairs mechanisms of neuronal repair and limits cognitive function processes.22 Second, we have shown that COPD patients in our sample in general have a lower IQ compared to controls matched for age, gender, and smoking status (Chapter 6), which may partially explain impairments in complex, higher-order cognitive functions (e.g. executive functioning).23 Third, medications, such as glucocorticoid drug medication, can affect cognition.24 Patients with Cushingâ&#x20AC;&#x2122;s disease, who have chronically elevated glucocorticoids levels, have been shown to be at risk for psychopathological disorders, reduced quality of life, as well as impairments in cognitive functioning.25 Since patients with COPD are often treated with glucocorticoids (e.g. prednisone), it might have a harmful effect on the

198

199

Chapter 10

General discussion patient’s cognitive functioning. Fourth, hypoxemia and hypoxia may be contributors to the deterioration of cognitive functioning. Hypoxemia is defined as a condition where arterial oxygen tension (PaO2) is below normal (normal PaO2 = 10.6–12.6 kPa). Hypoxia is defined as the failure of oxygenation at the tissue level. Yet, hypoxia may not be present in patients with hypoxemia if the patient compensates for a low PaO2 by increasing oxygen delivery, which is typically achieved by increasing cardiac output or decreasing tissue oxygen consumption.26 Hypoxemia thus triggers different responses, and consequently leads to an increased brain blood flow and cerebral lactate concentration.27 There seems to be some disagreement about the consequences for cognitive functioning. Some studies have demonstrated diffuse mental deterioration in COPD patients with hypoxemia, with particular impairment of higher cognitive functions and deficits in abstract reasoning, memory, speed of test performance, motor skills and perceptual motor abilities,28,29 while other studies indicate a more specific pattern of cognitive dysfunction in memory and attention.12,30,31 The memory dysfunction may be related to the hippocampus or limbic memory regions sensitive to hypoxia, while the attentional deficits may be an effect of diffuse brain involvement secondary to hypoxia. Moreover, COPD patients with hypoxemia are often prescribed supplemental oxygen, which is able to prevent the patient from hypoxia and cognitive decline. There even may be improvement of cerebral functioning after starting with long-term oxygen therapy (LTOT). A minor positive effect of LTOT on speed of human information processing for hypoxaemic COPD patients has been demonstrated,31 and patients who received supplemental oxygen therapy had a decreased risk of cognitive impairment compared to hypoxaemic nonusers.32 Yet, it is possible that patients with COPD might be protected against the ischemic brain changes. Increased cerebral blood flow and vasodilatation of the bilateral internal carotid artery and vertebral artery, which are the main arteries supplying the brain, have been shown in COPD.33 When we take into account the possibility of a compensatory mechanism, other explanations for cognitive impairment in (hypoxemic) COPD patients should also be considered. Indeed, Grant and colleagues showed only a very weak correlation between hypoxia and cognitive impairment.34 As a consequence of hypoxia, oxidative stress, and thus the role of free radical damage, may be involved in cognitive impairment. Yet, senile plaques and neurofibrillary tangles, markers of oxidative damage, did not differ between deceased donors with and without COPD (Chapter 3). Despite the potential importance of hypoxia and hypoxemia in the pathogenesis of cognitive impairment in COPD, its understanding remains incomplete. Fifth, systemic inflammation might be associated with cognitive impairment in COPD through vascular mechanisms (as seen in comorbid cardiovascular and cerebrovascular disease) or independent of vascular-related conditions. Cytokines, for example, mediate cellular mechanisms involved in cognition such as cholinergic and dopaminergic pathways and can facilitate neurodegeneration or regeneration.36

ChapterÂ 10Â Sixth, hormonal influences may affect cognition. For example, estrogen plays an important role in the pathogenesis of cognitive decline and risk for Alzheimer disease. Yet, the relationship between hormones and cognition in COPD has not been investigated. Finally, acute COPD exacerbations requiring hospitalization are associated with significant declines in cognitive function.37 However, contradictive findings occur in the literate and the cognitive alteration may be temporarily due to systemic inflammation or change in medication.38 Moreover, CO2 retention due to abnormalities in the gas exchange or mechanical properties of the lung, leading to elevated arterial carbon dioxide levels, decreased arterial oxygen levels, or decreased arterial bicarbonate levels, can result in cerebral vasodilation and consequent neurologic dysfunction and cognitive impairment.

Clinical consequences of cognitive impairment Cognitive impairment often remains undetected and untreated in daily clinical practice. This might be due to the fact that on one hand the screening tools are not employed nowadays and that on the other hand patients often tend to deny that they are suffering from cognitive problems due to the stigma attached to them.3 Since we showed that cognitive impairment 1) is more prevalent in patients with COPD compared to non-COPD controls, 2) affects multiple cognitive domains (Chapter 5), and 3) is related to a higher drop-out rate during PR (Chapter 9), disease-management and PR should include active screening of cognitive impairment. The potential benefit of the application of active routine screening for cognitive impairment may be found in the early detection and management of potential complications of cognitive impairment, such as poor self-care behaviors, poor disease control, and drop-out during PR. The need for active screening is supported by our finding that cognitive impairment cannot be predicted based on demographical and clinical characteristics (Chapter 7). Moreover, collaborative models of care among providers such as physicians, hospitals, allied healthcare professionals and pharmacies in order to improve self-management, exacerbation management, medication adherence, and decrease PR dropout, are needed. Also involving family caregivers in the care plan of patients with COPD and cognitive impairment might be recommended.

Education and self-management Education aims to equip patients with information that will help them to manage the chronic condition. Next to the acquisition of health behavior knowledge, self-management aims to enable patients to take the information that they learn about their illness and foster disease-related skills that emphasize disease control through behavior change. The goal is for patients to develop a greater sense of confidence and self-efficacy with respect to their chronic

200

201

Chapter 10

General discussion condition in order to increase adherence to treatment, increase support and understanding from others, as well as to increase clinical outcomes.39 Despite the fact that the educational content of a PR program is not adapted to the level of cognitive functioning of patients with COPD, this thesis showed that PR is as effective in patients with and without cognitive impairment in increasing disease knowledge and reducing information needs after PR (Chapter 9). Although improvements in disease knowledge and information needs reached the minimal clinically important difference, mean changes were not significantly different between patients with and without controls. Moreover, 30.0% of patients with COPD showed working memory and/or verbal impairments. Yet, they did not significantly differ on the memory domain compared to controls after correcting for comorbidities. Since we found a comparable improvement in disease knowledge and information needs between patients with and without general cognitive impairment, the observed memory impairments may not be clinically relevant in terms of maintaining given educational information, guidelines, requests, or instructions. Our results, thus, do not support a need for tailoring education to the patient’s cognitive functioning. Yet, executive functioning impairments may lead to a ‘knowing-doing discrepancy’ in which patients can report specific instructions from the training but cannot translate these into specific behavioural and motor plans and activity in their daily life. Indeed, in community dwelling adults, cognitive impairment has been shown to be associated with complex activities of daily living disability, such as using the telephone, managing money and medications, grocery shopping and meal preparation.40 Consequently, this may influence self-management skills such as medication adherence. Indeed, COPD patients with cognitive impairment show a worse inhaler technique compared to those without cognitive impairment.41 In addition, it is possible that cognitive impairment leads to impaired health literacy, which is defined as the cognitive and social skills which determine the motivation and ability of individuals to gain access to, understand and use information in ways which promote and maintain good health. Health illiteracy has been shown to be associated with treatment failure in patients with tuberculosis.42 Moreover, cognitive impairment in executive functions among elderly has been associated with decreased levels of smoking cessation.43 Whether and to what extent this is true for patients with COPD remains unknown. Until now, there is only few data on the possible importance of impairments in various cognitive domains on clinically relevant outcomes and the predictive ability of one-time assessment of cognitive function to long-term outcomes. Antonelli-Incalzi and colleagues44 showed an association between cognitive impairment and need for support in basic daily activities, such as medication, getting dressed, and managing money. Therefore, self-management might benefit from individualized educational and care interventions taking into account the cognitive function level of the patient. For example, patients with cognitive impairment can be taught how to adopt behaviors using

ChapterÂ 10Â coping strategies, and how to appraise the efficacy of these behaviors. Also improving negative disease and rehabilitation perceptions or self-efficacy beliefs (beliefs about the individualâ&#x20AC;&#x2122;s ability to perform a particular behavior or to change a specific cognitive state successfully regardless of circumstances or contexts) of patients is a key element of many self-management support interventions.45 However, Dulohery and colleagues38 showed no correlation between cognitive functioning and exacerbations, emergency room visits, hospitalization, self-management skills or quality of life. The discrepancy between impairments in test performance and patient-related outcomes may be linked to methodological difficulties or different definitions of cognitive impairment. Moreover, it is possible that self-care behaviors do not require the level of performance called for during neuropsychological testing.46

Pulmonary rehabilitation PR is defined as a comprehensive intervention based on a thorough patient assessment followed by patient-tailored therapies that include, but are not limited to, exercise training, education, and behavior change. It aims to improve the physical and psychological condition of patients with chronic respiratory disease as well as to promote the long-term adherence to health-enhancing behaviors.47 This thesis showed that, in addition to disease knowledge and need for information, mean changes in the following PR outcomes did not differ between patients with and without cognitive impairment: functional exercise capacity, disease-specific health status, and psychological wellbeing. (Chapter 9). This suggests that cognitive impairment in COPD does not modify the effectiveness of PR and that PR is an effective treatment for patients with COPD and cognitive impairment. Moreover, in completers of a structured PR program it shows that impaired performances on neuropsychological tests may not be clinically relevant and matter in functional terms. However, patients with cognitive impairment at baseline are more susceptible to dropping out before completing PR compared to those without cognitive impairment at baseline. In addition, cognitive functioning was worse in dropouts compared to completers of PR. Also in non-depressed cocaine-dependent patients, cognitive domains that could be distinguished between cognitive-behavioral therapy completers and dropouts were attention, mental reasoning and spatial processing.48 Also in patients with chronic fatigue syndrome following cognitive behavioral therapy, lower neuropsychological test performance was associated with an increased risk of dropout.49 Therefore strategies are needed to decrease dropout and make completion of PR more feasible for patients with COPD and cognitive impairment. There are several interventions that might be beneficial in improving treatment adherence and possible sustained effects. Namely, it can be hypothesize that patients with cognitive impairments have more problems with transferring

202

203

Chapter 10

General discussion the knowledge gained during PR to daily activities or initiating health behavior change in a non-structured home environment.50 Although we did not assess the effect of domain-specific cognitive impairment on long term effects of PR, a screening approach which is able to verify which cognitive domains need specific and more attention should be more important than labelling the patient as having impairments in cognitive functioning.51 Accordingly, treatment plans can build on information about impairments in particular cognitive domains to guide the caregiver and patient in selecting or adapting environments, maximizing interpersonal communication strategies, and selecting assistive technologies to foster independence and an active life style after PR completion. The following interventions should be considered in the overall care of patients with COPD to improve treatment adherence and sustained effects of PR. First, role induction techniques in order to prepare patients for what would happen during PR could reduce early dropout. Education about the nature and process of treatment offers patients an expectation of rehabilitation success, dispels misconceptions about a treatment program, and has been shown to decrease drop out.52 Second, motivational interviewing has demonstrated nearly 50% reductions in dropout rates in substance abusers.53 It aims to elicit behavior change by helping patients to explore and resolve their ambivalent feelings toward treatment. The six key elements of motivational interviewing through which the major goals of motivational interviewing can be achieved are: feedback on personal risk or impairment, an emphasis on personal responsibility for change, clear advice to change, development of a menu of alternative change options, encouragement of therapist empathy, and facilitation of patient selfefficacy or optimism.54 Third, therapist feedback about patient progress on a regular basis tended to keep patients in treatment longer.55 A multidimensional approach to treatment that focuses on active involvement of the patient, encourages autonomy, highlights strengths rather than deficits, and normalizes patient problems should be encouraged. A strong therapeutic relationship, or alliance has been shown to predict treatment outcome56 and empathy, positive regard, caring, empathic listening, and reassessing motivation for change are techniques that can be learned by therapists and have been shown to improve the therapeutic relationship.57 Moreover, cognitive training for patients with COPD might be promising since simultaneous training of cognitive and physical abilities have been shown to improve cognitive and motor-cognitive dual task performance in elderly, offering greater potential on sustained effect of PR in daily life functioning, which usually involves the recruitment of multiple abilities and resources rather than a single one.54 López-Torres55 and colleagues demonstrated that cognitive functioning is modifiable and able to improve, since changes in clinical status produced a change in cognitive status in COPD patients. From exacerbation to discharge after an exacerbation, cognitive areas with more potential to change were visuoconstructional skills, attention, language, abstraction, delayed recall

ChapterÂ 10Â and orientation. From discharge to stable COPD, cognitive areas with more potential to change were visuoconstructional and naming. From exacerbation to stable COPD, cognitive areas with more potential to change were naming, attention, language, abstraction, and delayed recall. Moreover, internal monitoring or routine assessment of cognitive impairment and a good communication and decision-making across disciplines within a multidisciplinary team might optimize the PR process.56 Although improvements in cognitive performance have been shown after cognitive training programs, they often do not exceed those seen in control conditions.57 In patients with COPD with at rest or effort induced hypoxemia, cognitive training did not show significant changes in cognitive functioning after six months.58 Yet, it remains interesting to investigate whether cognitive training in COPD is able to slow down or prevent cognitive decline, to minimize dropout and increase benefits and maintenance of behavior change after PR. Remarkably, previous studies suggested that 50% of the subjects with mild cognitive impairment may exhibit progression to dementia within a three to five year period.59,60 Since mild cognitive impairment may indicate an increased risk of impending dementia, its identification could lead to implementation of secondary prevention strategies by controlling risk factors.41,42 In this regard, early detection of cognitive impairment in patients with COPD also has clinical importance.

Methodological considerations Although there is no consistency in defining cognitive impairment and no standardized neuropsychological evaluation as a gold standard for the assessment of cognitive impairment, there is a plethora of tools in the literature. However, until now, most studies on COPD used brief informant screening tools, such as the Mini Mental State Examination (MMSE), that might fail to detect more subtle forms of cognitive impairment. The MMSE is probably the most widely utilized screening tool, while it has limitations including relative insensitivity to change, confounding biases with respect to education, culture and language, and lack of emphasis on frontal/executive cognitive functions.61 Since there is no golden standard to assess cognitive impairment, we used Z scores cut-off points used in an earlier study to assess cognition in patients with COPD.62 However, it is possible that the cut-off scores used in this thesis lead to the inclusion of patients with mild cognitive impairments, compared to higher cut-off score which would detect merely more severe cognitively impaired patients. Consequently the cognitive functioning performances of patients with and without cognitive impairment in this study may not differ greatly, which might explain comparable findings between both groups. Yet, advantages of our comprised neuropsychological testing battery are the ability to assess general and domain-specific cognitive impairment and to compare the cognitive scores against appropriate

204

General discussion norms and consequently interpret in light of additional assistance during PR or in the patients home situation. Our results are of interest for several countries and healthcare systems where the studies were conducted predominantly. For example, the UK Biobank study recruited participants from the UK general population without a objectified diagnosis of COPD; the Dutch Brain Bank recruited brain donors from the Netherlands without information about lung function in their medical record; the SaRA study included elderly ambulatory COPD patients from geriatric institutions across Italy; and the COgnitive-PD study recruited participants from a tertiary referral center in the Netherlands. However, selection bias may reduce the generalizability of our results. Also confounding factors influence the comparison between studies and study groups. Finally, no causal conclusion can be drawn from our results. None of our studies assessed cognitive functioning at several time points and the development of cognitive impairment and its effects and consequences therefore remains unknown.

Although a growing body of information on the neuropsychological functioning of patients with COPD, some gaps remain. First, in the future we should take an intensive look at the potential benefit of the application of active routine screening for cognitive impairment in patients with COPD. There are several suggestions for improvement. First, by implementing routine screening before the start of a PR program we will be able to identify those patients who are at risk for dropping-out during PR. Yet it remains unknown whether active routine screening improves decision making and leads to positive effects of consequent interventions. Since the administration of a comprehensive neuropsychological test battery is time consuming, a second point for improvement would be to reduce the amount of neurocognitive tests from the COgnitive-PD Study test battery. Future research is needed to assess how many neuropsychological tests are needed to do a first cognitive screening in clinical practice with a comparable sensitivity in order to detect both general and domain-specific cognitive impairment. Moreover, it should be verified whether the (shortened) COgnitivePD testing battery 1) has a better sensitivity and specificity in COPD instead of one screening test (e.g. the MMSE); 2) has good validity; and 3) is effective in distinguishing between cognitive impairment in COPD and other chronic diseases such as heart failure. A third suggestion for improvement is to refine and adapt cut-off points to define cognitive impairment. Moreover, our knowledge on factors responsible for the pathogenesis and underlying etiology of cognitive impairment in patients with COPD should be further explored. For example, studies can focus on microstructural brain abnormalities by assessing diffusion tensor imaging data or using stain and more

205

Chapter 10

How to proceed?

ChapterÂ 10Â molecular or biochemistry approach to detect more subtle changes and microstructural brain changes. Moreover, if future research would be able to detect a subgroup of patients who are more likely to have cognitive impairment (e.g. patients with frailty, socially isolated patient with less cognitive stimulation or patients with incorrect inhaler use) it would be helpful to intervene early. Finally, long-term follow-up studies are needed to assess the consequences of cognitive impairment on self-management, disease-management, sustained effects of a PR program, and ways to decrease dropout. Moreover, whether and to what extent cognitive training is able to slow down or prevent cognitive decline, to optimize drop out and increase benefits and maintenance of behavior change after PR needs to be explored in future research.

General conclusion Chronic obstructive pulmonary disease (COPD) is a usually progressive disease and frequently associated with co-morbidities such as cognitive impairment. Cognitive functioning may fluctuate with the variable components of COPD like coexisting comorbidities. Yet, cognitive impairment in COPD cannot be predicted based on demographic and clinical characteristics alone. Therefore, active screening of impairment in cognitive functioning is needed and daily care, disease management and self-management programs, educational programs, and PR should take account of cognitive impairments in patients with COPD. Cognitive impairment should not be a barrier for patients to be referred for PR; both patient groups with and without cognitive impairment profit to the same extent from PR. However, it is important to note that patients with cognitive impairment are more susceptible to dropping out before completing PR. Strategies are needed to reduce dropout, and research towards the sustained effects of PR in patients with and without cognitive impairment is needed. Moreover, whether and to what extent cognitive training is beneficial for patients with COPD needs to be examined in future research.

206

General discussion

1. 2. 3.

6. 7.

8. 9.

10.

11.

12. 13.

14.

15.

16.

17. 18.

Cleutjens FA, Janssen DJ, Ponds RW, Dijkstra JB, Wouters EF. COgnitive-pulmonary disease. Biomed Res Int. 2014;2014:697825. Dodd JW, Getov SV, Jones PW. Cognitive function in COPD. Eur Respir J. 2010;35(4):913-922. Schou L, Ostergaard B, Rasmussen LS, Rydahl-Hansen S, Phanareth K. Cognitive dysfunction in patients with chronic obstructive pulmonary disease--a systematic review. Respir Med. 2012;106(8):1071-1081. Torres-Sanchez I, Rodriguez-Alzueta E, Cabrera-Martos I, Lopez-Torres I, Moreno-Ramirez MP, Valenza MC. Cognitive impairment in COPD: a systematic review. J Bras Pneumol. 2015;41(2):182-190. Hynninen KM, Breitve MH, Wiborg AB, Pallesen S, Nordhus IH. Psychological characteristics of patients with chronic obstructive pulmonary disease: a review. J Psychosom Res. 2005;59(6):429-443. Antonelli-Incalzi R, Corsonello A, Pedone C, Trojano L, Acanfora D, Spada A, Izzo O, Rengo F. Drawing impairment predicts mortality in severe COPD. Chest. 2006;130(6):1687-1694. Villeneuve S, Pepin V, Rahayel S, Bertrand JA, de Lorimier M, Rizk A, Desjardins C, Parenteau S, Beaucage F, Joncas S, Monchi O, Gagnon JF. Mild cognitive impairment in moderate to severe COPD: a preliminary study. Chest. 2012;142(6):1516-1523. Allen SC, Jain M, Ragab S, Malik N. Acquisition and short-term retention of inhaler techniques require intact executive function in elderly subjects. Age Ageing. 2003;32(3):299-302. Sulaiman I, Cushen B, Greene G, Seheult J, Seow D, Rawat F, MacHale E, Mokoka M, Moran CN, Sartini Bhreathnach A, MacHale P, Tappuni S, Deering B, Jackson M, McCarthy H, Mellon L, Doyle F, Boland F, Reilly RB, Costello RW. Objective Assessment of Adherence to Inhalers by COPD Patients. Am J Respir Crit Care Med. 2016. Poels MM, Vernooij MW, Ikram MA, Hofman A, Krestin GP, van der Lugt A, Breteler MM. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke. 2010;41(10 Suppl):S103-106. Shim TS, Lee JH, Kim SY, Lim TH, Kim SJ, Kim DS, Kim WD. Cerebral metabolic abnormalities in COPD patients detected by localized proton magnetic resonance spectroscopy. Chest. 2001;120(5):1506-1513. Incalzi RA, Gemma A, Marra C, Muzzolon R, Capparella O, Carbonin P. Chronic obstructive pulmonary disease. An original model of cognitive decline. Am Rev Respir Dis. 1993;148(2):418-424. Kozora E, Filley CM, Julian LJ, Cullum CM. Cognitive functioning in patients with chronic obstructive pulmonary disease and mild hypoxemia compared with patients with mild Alzheimer disease and normal controls. Neuropsychiatry Neuropsychol Behav Neurol. 1999;12(3):178-183. Greenlund KJ, Liu Y, Deokar AJ, Wheaton AG, Croft JB. Association of Chronic Obstructive Pulmonary Disease With Increased Confusion or Memory Loss and Functional Limitations Among Adults in 21 States, 2011 Behavioral Risk Factor Surveillance System. Prev Chronic Dis. 2016;13:E02. Borson S, Scanlan J, Friedman S, Zuhr E, Fields J, Aylward E, Mahurin R, Richards T, Anzai Y, Yukawa M, Yeh S. Modeling the impact of COPD on the brain. Int J Chron Obstruct Pulmon Dis. 2008;3(3):429-434. Esser RW, Stoeckel MC, Kirsten A, Watz H, Taube K, Lehmann K, Petersen S, Magnussen H, von Leupoldt A. Structural Brain Changes in Patients with Chronic Obstructive Pulmonary Disease. Chest. 2015. Li J, Fei GH. The unique alterations of hippocampus and cognitive impairment in chronic obstructive pulmonary disease. Respir Res. 2013;14:140. Lahousse L, Vernooij MW, Darweesh SK, Akoudad S, Loth DW, Joos GF, Hofman A, Stricker BH, Ikram MA, Brusselle GG. Chronic obstructive pulmonary disease and cerebral microbleeds. The Rotterdam Study. Am J Respir Crit Care Med. 2013;188(7):783-788.

207

Chapter 10

References

ChapterÂ 10Â 19. van Dijk EJ, Vermeer SE, de Groot JC, van de Minkelis J, Prins ND, Oudkerk M, Hofman A, Koudstaal PJ, Breteler MM. Arterial oxygen saturation, COPD, and cerebral small vessel disease. J Neurol Neurosurg Psychiatry. 2004;75(5):733-736. 20. Traylor M, Farrall M, Holliday EG, Sudlow C, Hopewell JC, Cheng YC, Fornage M. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. Lancet Neurol. 2012;11(11):951-962. 21. Zhou H, Wu Y, Jin Y, Zhou J, Zhang C, Che L, Jing J, Chen Z, Li W, Shen H. Genetic polymorphism of matrix metalloproteinase family and chronic obstructive pulmonary disease susceptibility: a meta-analysis. Sci Rep. 2013;3:2818. 22. Decramer M, Janssens W. Chronic obstructive pulmonary disease and comorbidities. Lancet Respir Med. 2013;1(1):73-83. 23. Friedman NP, Miyake A, Corley RP, Young SE, Defries JC, Hewitt JK. Not all executive functions are related to intelligence. Psychol Sci. 2006;17(2):172-179. 24. Judd LL, Schettler PJ, Brown ES, Wolkowitz OM, Sternberg EM, Bender BG, Bulloch K, Cidlowski JA, de Kloet ER, Fardet L, Joels M, Leung DY, McEwen BS, Roozendaal B, Van Rossum EF, Ahn J, Brown DW, Plitt A, Singh G. Adverse consequences of glucocorticoid medication: psychological, cognitive, and behavioral effects. Am J Psychiatry. 2014;171(10):1045-1051. 25. Pereira AM, Tiemensma J, Romijn JA. Neuropsychiatric disorders in Cushing's syndrome. Neuroendocrinology. 2010;92 Suppl 1:65-70. 26. Samuel J, Franklin C. Hypoxemia en Hypoxia. Gemeenschappelijke Chirurgische Ziekten - een Algoritmische Benadering van het Oplossen van het Probleem. New York: Aanzetsteen; 2008:391-394. 27. Vestergaard MB, Lindberg U, Aachmann-Andersen NJ, Lisbjerg K, Christensen SJ, Law I, Rasmussen P, Olsen NV, Larsson HB. Acute hypoxia increases the cerebral metabolic rate - a magnetic resonance imaging study. J Cereb Blood Flow Metab. 2015. 28. Grant I, Heaton RK, McSweeny AJ, Adams KM, Timms RM. Neuropsychologic findings in hypoxemic chronic obstructive pulmonary disease. Arch Intern Med. 1982;142(8):1470-1476. 29. Prigatano GP, Parsons O, Wright E, Levin DC, Hawryluk G. Neuropsychological test performance in mildly hypoxemic patients with chronic obstructive pulmonary disease. J Consult Clin Psychol. 1983;51(1):108-116. 30. Fioravanti M, Nacca D, Amati S, Buckley AE, Bisetti A. Chronic obstructive pulmonary disease and associated patterns of memory decline. Dementia. 1995;6(1):39-48. 31. Hjalmarsen A, Waterloo K, Dahl A, Jorde R, Viitanen M. Effect of long-term oxygen therapy on cognitive and neurological dysfunction in chronic obstructive pulmonary disease. Eur Neurol. 1999;42(1):27-35. 32. Karamanli H, Ilik F, Kayhan F, Pazarli AC. Assessment of cognitive impairment in long-term oxygen therapy-dependent COPD patients. Int J Chron Obstruct Pulmon Dis. 2015;10:20872094. 33. Albayrak R, Fidan F, Unlu M, Sezer M, Degirmenci B, Acar M, Haktanir A, Yaman M. Extracranial carotid Doppler ultrasound evaluation of cerebral blood flow volume in COPD patients. Respir Med. 2006;100(10):1826-1833. 34. Grant I, Prigatano GP, Heaton RK, McSweeny AJ, Wright EC, Adams KM. Progressive neuropsychologic impairment and hypoxemia. Relationship in chronic obstructive pulmonary disease. Arch Gen Psychiatry. 1987;44(11):999-1006. 35. Peacock JM, Folsom AR, Knopman DS, Mosley TH, Goff DC, Jr., Szklo M. Dietary antioxidant intake and cognitive performance in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) Study investigators. Public Health Nutr. 2000;3(3):337-343 36. Wilson CJ, Finch CE, Cohen HJ. Cytokines and cognition--the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc. 2002;50(12):2041-2056. 37. Federman AD, Wolf MS, Sheng T, O'Conor R, Martynenko M, Wisnivesky J. Diminished Cognitive Function Among Chronic Obstructive Pulmonary Disease Patients During Periods of Acute Illness Exacerbation. J Gerontol A Biol Sci Med Sci. 2016;71(2):279-280.

208

General discussion

38. Dulohery MM, Schroeder DR, Benzo RP. Cognitive function and living situation in COPD: is there a relationship with self-management and quality of life? International Journal of Chronic Obstructive Pulmonary Disease. 2015(10):1883-1889. 39. Cameron J, Worrall-Carter L, Page K, Riegel B, Lo SK, Stewart S. Does cognitive impairment predict poor self-care in patients with heart failure? Eur J Heart Fail. 2010;12(5):508-515. 40. Hung WW, Ross JS, Boockvar KS, Siu AL. Association of chronic diseases and impairments with disability in older adults: a decade of change? Med Care. 2012;50(6):501-507. 41. Turan O, Turan PA, Mirici A. Parameters affecting inhalation therapy adherence in elderly patients with chronic obstructive lung disease and asthma. Geriatr Gerontol Int. 2016. 42. de Albuquerque Mde F, Ximenes RA, Lucena-Silva N, de Souza WV, Dantas AT, Dantas OM, Rodrigues LC. Factors associated with treatment failure, dropout, and death in a cohort of tuberculosis patients in Recife, Pernambuco State, Brazil. Cad Saude Publica. 2007;23(7):15731582. 43. Brega AG, Grigsby J, Kooken R, Hamman RF, Baxter J. The impact of executive cognitive functioning on rates of smoking cessation in the San Luis Valley Health and Aging Study. Age Ageing. 2008;37(5):521-525. 44. Antonelli-Incalzi R, Corsonello A, Trojano L, Acanfora D, Spada A, Izzo O, Rengo F. Correlation between cognitive impairment and dependence in hypoxemic COPD. J Clin Exp Neuropsychol. 2008;30(2):141-150. 45. Lorig KR, Sobel DS, Ritter PL, Laurent D, Hobbs M. Effect of a self-management program on patients with chronic disease. Eff Clin Pract. 2001;4(6):256-262. 46. van Dijk D, Keizer AM, Diephuis JC, Durand C, Vos LJ, Hijman R. Neurocognitive dysfunction after coronary artery bypass surgery: a systematic review. J Thorac Cardiovasc Surg. 2000;120(4):632-639. 47. Spruit MA, Singh SJ, Garvey C, ZuWallack R, Nici L, Rochester C, Hill K. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med. 2013;188(8):e13-64. 48. Aharonovich E, Nunes E, Hasin D. Cognitive impairment, retention and abstinence among cocaine abusers in cognitive-behavioral treatment. Drug Alcohol Depend. 2003;71(2):207-211. 49. Goedendorp MM, van der Werf SP, Bleijenberg G, Tummers M, Knoop H. Does neuropsychological test performance predict outcome of cognitive behavior therapy for Chronic Fatigue Syndrome and what is the role of underperformance? J Psychosom Res. 2013;75(3):242-248. 50. Wettstein M, Wahl HW, Shoval N, Auslander G, Oswald F, Heinik J. Cognitive status moderates the relationship between out-of-home behavior (OOHB), environmental mastery and affect. Arch Gerontol Geriatr. 2014;59(1):113-121. 51. Cullen B, O'Neill B, Evans JJ, Coen RF, Lawlor BA. A review of screening tests for cognitive impairment. J Neurol Neurosurg Psychiatry. 2007;78(8):790-799. 52. Fosshage JL. The explicit and implicit dance in psychoanalytic change. J Anal Psychol. 2004;49(1):49-65. 53. Chair SY, Chan SW, Thompson DR, Leung KP, Ng SK. Effect of motivational interviewing on the clinical and psychological outcomes and health-related quality of life of cardiac rehabilitation patients with poor motivation. Hong Kong Med J. 2014;20(3 Suppl 3):15-19. 54. Theill N, Schumacher V, Adelsberger R, Martin M, Jancke L. Effects of simultaneously performed cognitive and physical training in older adults. BMC Neurosci. 2013;14:103. 55. Lopez-Torres I, Valenza MC, Torres-Sanchez I, Cabrera-Martos I, Rodriguez-Torres J, MorenoRamirez MP. Changes in Cognitive Status in COPD Patients Across Clinical Stag-es. Copd. 2015:1-6. 56. Wills CE, Holmes-Rovner M. Integrating Decision Making and Mental Health Interven-tions Research: Research Directions. Clin Psychol (New York). 2006;13(1):9-25. 57. Martin M, Clare L, Altgassen AM, Cameron MH, Zehnder F. Cognition-based interven-tions for healthy older people and people with mild cognitive impairment. Cochrane Database Syst Rev. 2011(1):CD006220.

209

Chapter 10

ChapterÂ 10Â 58. Incalzi RA, Corsonello A, Trojano L, Pedone C, Acanfora D, Spada A, Izzo O, Rengo F. Cognitive training is ineffective in hypoxemic COPD: a six-month randomized controlled trial. Rejuvenation Res. 2008;11(1):239-250. 59. Fischer P, Jungwirth S, Zehetmayer S, Weissgram S, Hoenigschnabl S, Gelpi E, Krampla W, Tragl KH. Conversion from subtypes of mild cognitive impairment to Alzheimer dementia. Neurology. 2007;68(4):288-291. 60. Gauthier S, Reisberg B, Zaudig M, Petersen RC, Ritchie K, Broich K, Belleville S, Brodaty H, Bennett D, Chertkow H, Cummings JL, de Leon M, Feldman H, Ganguli M, Hampel H, Scheltens P, Tierney MC, Whitehouse P, Winblad B, International Psychogeriatric Association Expert Conference on mild cognitive i. Mild cognitive impairment. Lancet. 2006;367(9518):1262-1270. 61. Shulman KI, Herrmann N, Brodaty H, Chiu H, Lawlor B, Ritchie K, Scanlan JM. IPA survey of brief cognitive screening instruments. Int Psychogeriatr. 2006;18(2):281-294. 62. Singh B, Parsaik AK, Mielke MM, Roberts RO, Scanlon PD, Geda YE, Pankratz VS, Christianson T, Yawn BP, Petersen RC. Chronic obstructive pulmonary disease and association with mild cognitive impairment: the Mayo Clinic Study of Aging. Mayo Clin Proc. 2013;88(11):1222-1230.

210

Chapter 11

Summary Samenvatting Valorization Dankwoord Curriculum Vitae Publications

213

Summary

215

SummaryÂ Chronic obstructive lung disease (COPD) has long been considered a disease of the lungs, often caused by smoking. Nowadays, COPD is regarded as a multisystem disease. Both physical effects and effects on brains, including impaired psychological and cognitive functioning, have been demonstrated. Patients with COPD may have cognitive impairment, either globally or in single cognitive domains, such as information processing, attention and concentration, memory, executive functioning, and self-control. Cognitive impairment can have a negative impact on health and daily life and may be associated with widespread consequences for disease management programs. It is important to increase our understanding of cognitive functioning in patients with COPD in order to optimize patient-oriented treatment and to reduce personal discomfort, hospital admissions, and mortality. Therefore, the aim of this thesis was to assess the prevalence of general and domain-specific cognitive impairments in patients with COPD and to study the clinical characteristics of patients with cognitive impairment. Further, this thesis investigated the relationship between cognitive impairment in patients with COPD and disease severity, structural brain abnormalities, and PR efficacy (chapter 1). To date, cognitive functioning in patients with COPD has mostly been studied with broad scale measurements that do not separate the specific cognitive functions. Using data from the United Kingdom Biobank Resource, Chapter 2 offers a first attempt to assess different cognitive functions in 5,764 persons with and 37,275 persons without obstructive lung disease (OLD), a category of respiratory diseases characterized by airflow limitation, including COPD, chronic bronchitis, emphysema, asthma, bronchiectasis, upper airway lesions, bronchiolar diseases, and some interstitial lung diseases. Persons with OLD showed signiď&#x192;&#x17E;cant lower scores on cognitive measures of prospective memory, visuospatial memory, numeric short-term memory, and cognitive processing speed. Moreover, cognitive functioning was partially related to airflow limitation. Health care professionals should be aware of the presence and the possible impact of these cognitive impairments in the self-management, clinical management, and PR of persons with chronic respiratory diseases. The etiology of cognitive impairment in COPD remains largely unknown. Yet, hypoxemia and consequent hypoxia in patients with COPD are suggested to result in hypoxic stress in the brain and neuropathological brain changes. Chapter 3 reviews brain autopsy reports of 89 deceased donors with COPD and 89 deceased donors without COPD, using data from The Netherlands Brain Bank. No difference was observed in the presence of degenerative or neoplastic brain changes between deceased donors with and without COPD, while vascular brain changes were described more often in control donors. Longitudinal prospective studies using structural and functional brain magnetic resonance imaging (MRI)

216

Summary scans, along with the investigation of cognitive functioning, are needed to establish whether a causal relationship exists between brain abnormalities and cognitive impairment in patients with COPD. Both sleep disturbances and cognitive impairment are frequently found in patients with COPD. However, knowledge concerning the relationship between sleep and cognition in COPD is scarce. Chapter 4 aims to investigate the association between copying function, assessed with The Mini-Mental State Examination, and self-reported sleep quality disturbances, assessed with The Established Populations for Epidemiologic Studies of the Elderly questionnaire, and disease severity in all 562 COPD patients from the Salute Respiratoria nell’Anziano Study. Sleep disturbances were frequently reported by patients with COPD, but seem to be a weak correlate of cognitive functioning, nor a marker of disease severity. Yet, a trend was found towards worse copying function in patients with sleep disturbances in the total group and in GOLD I, suggesting that COPD patients with sleep disturbances may be more prone to cognitive impairments in higher-level cognitive functions as reflected by the copying function compared to COPD patients without sleep disturbances.

Cognitive impairment may interfere with disease-management in patients with chronic obstructive pulmonary disease (COPD), depending on which cognitive domains are affected. Chapter 6 compared the prevalence of domain-specific cognitive impairment between 90 patients with COPD and 90 non-COPD controls matched for age, educational level and smoking history. We found that cognitive impairment is present in 56.7% of patients with COPD, is four times more common than in non-COPD controls, and affects the domains psychomotor speed, planning, working memory, verbal memory, and cognitive flexibility. Comorbid diseases in COPD are likely to affect cognitive performance in COPD. Yet, impairments in executive functions may be more prone related to COPD specific factors. The identification of domain-specific cognitive impairment is necessary for further optimizing therapies (e.g., smoking cessation, self-management programs, and PR) for patients with COPD. 217

Summary

A longitudinal observational comparative study of patients with COPD referred for a comprehensive interdisciplinary pulmonary rehabilitation (PR) program and healthy control participants was designed to increase our understanding of cognitive functioning in patients with COPD. Baseline cognitive functioning in 183 patients with COPD was assessed during home visits using a detailed neuropsychological testing battery and compared with 90 non-COPD controls. Moreover, demographics, clinical characteristics, and outcomes of PR were assessed to gain insight in the relation with cognitive impairment in COPD. Additionally, an MRI substudy aimed to compare brain abnormalities between patients with COPD with and without cognitive impairment. The protocol of the COgnitive-PD study is described in Chapter 5.

SummaryÂ Identifying factors associated with cognitive impairment in patients with COPD can help clinicians to detect patients with possible cognitive impairment in need for further cognitive assessment. However, Chapter 7, found that the clinical characteristics of 183 COPD patients, including functional status, disease-specific health status and psychological wellbeing, were comparable for COPD patients with and without cognitive impairment. Moreover, the prevalence of cognitive impairment did not differ across different severity stages of COPD. Assessment of cognitive impairment in COPD thus requires an active screening approach across all GOLD stages. Structural brain abnormalities could possibly be associated with the presence of cognitive impairment through cigarette smoke, inflammation, vascular disease, or hypoxemia in patients with COPD. A subgroup of 55 patients from the COgnitive-PD study population underwent a brain 3T Magnetic Resonance Imaging (MRI). Chapter 8 compared MRI features of small vessel disease (SVD) and hippocampal volume (HCV) between cognitively high and low-performing individuals. There was no evidence for a relationship between cerebral SCD and HCV and cognitive functioning in patients with COPD. Additional studies will be needed to determine other possible mechanisms of cognitive impairment in patients with COPD, including microstructural brain changes and inflammatory,hormonal,- metabolic,- and (epi)genetic factors. Generally, cognitive functioning is needed to understand the challenges associated with the disease, to follow guidelines, to uptake information properly, to integrate feedback, to keep scheduled appointments, and to monitor performance. As PR is a complex, multidisciplinary intervention, the presence of cognitive impairment may have a negative impact on PR efficacy. Chapter 9 aimed to compare PR outcomes between patients with and without cognitive impairment. After PR, COPD patients with or without baseline cognitive impairment generally showed an improvement in functional status, health status, psychological wellbeing, knowledge about the disease and a decrease in need for information. Though patients with a cognitive impairment at baseline are at risk for drop out during PR, those who complete the program do benefit from PR. Cognitive impairment therefore is not a contraindication for PR in patients with COPD. In conclusion, this thesis demonstrates that general cognitive impairment is prevalent in more than half of the patients with COPD and that several cognitive domains are affected. Moreover, this thesis demonstrated that cognitive impairment does not affect the efficacy of PR. Yet, patients with cognitive impairment are more prone to dropping out during PR. Since we showed that cog-

218

219

Summary

Summary nitive impairment in COPD cannot be predicted based on demographic and clinical characteristics, an active screening approach for cognitive impairment is needed. Moreover, strategies are needed to reduce PR drop out.

Samenvatting

221

Samenvatting Voorheen werd chronisch obstructieve longziekte (COPD) beschouwd als een ziekte aan de longen, vooral veroorzaakt door roken. Tegenwoordig wordt het gezien als een multisysteemziekte, waarbij gelijktijdig sprake is van fysieke en psychologische gezondheidsproblemen, waaronder een verminderd cognitief functioneren. Patiënten met COPD kunnen cognitieve beperkingen hebben, zowel globaal of in één of meerdere cognitieve domeinen, zoals informatieverwerking, aandacht en concentratie, geheugen, executieve functies, en zelfbeheersing. Cognitieve beperkingen kunnen een negatieve invloed op de gezondheid en het dagelijks leven hebben en gepaard gaan met wijdverspreide gevolgen voor disease management programma’s. Om de patiëntgerichte behandeling voor patiënten met COPD te kunnen optimaliseren en persoonlijk ongemak, ziekenhuisopnames en sterfte te kunnen verminderen, is het van belang om de huidige kennis en inzichten in het cognitief functioneren bij patiënten met COPD uit te breiden. Het doel van dit proefschrift was dan ook om de prevalentie van algehele en domein-specifieke cognitieve beperkingen en de klinische kenmerken van patiënten met COPD en cognitieve beperkingen te onderzoeken. Daarnaast richtte dit proefschrift zich op de relatie tussen cognitieve beperkingen bij patiënten met COPD en de ernst van de ziekte, structurele hersenafwijkingen, en de werkzaamheid van longrevalidatie. Tot op heden werd het cognitief functioneren bij patiënten met COPD voornamelijk onderzocht met beknopte screeningsinstrumenten die niet in staat zijn om specifieke cognitieve functies te onderscheiden en onderzoeken. Met behulp van data van de United Kingdom Biobank Resource zijn verschillende cognitieve functies bij 5764 personen met en 37.275 personen zonder obstructieve longziekte (OLD) vergeleken (Hoofdstuk 2). OLD is een groep van respiratoire ziekten gekenmerkt door obstructie van de luchtwegen, waaronder COPD, chronische bronchitis, emfyseem, astma, bronchiëctasie, bovenste luchtwegen laesies, bronchiolaire ziekten en interstitiële longziekten. Personen met OLD hadden significant lagere scores op cognitieve maten van prospectief geheugen, visueel-ruimtelijk geheugen, numeriek korte-termijn geheugen en cognitieve verwerkingssnelheid. Bovendien was het cognitief functioneren deels gerelateerd aan de mate van obstructie van de luchtwegen. De effecten van cognitieve beperkingen in geheugen en informatieverwerking, zoals een verminderd medicatie management, verminderde slaap efficiëntie en een verminderd vermogen tot informatieverwerking, alsook het reageren op gegeven informatie, zijn reeds onderzocht in andere populaties. Professionals in de gezondheidszorg moeten alert zijn op de aanwezigheid van cognitieve beperkingen, alsook de mogelijke impact van cognitieve beperkingen op zelfmanagement, klinische behandeling en longrevalidatie voor personen met chronische luchtweg-aandoeningen.

222

Samenvatting Het ontstaan van cognitieve beperkingen bij patiënten met COPD is vooralsnog grotendeels onbekend. Hypoxemie en hypoxie kunnen resulteren in hypoxische stress in de hersenen en leiden tot neuropathologische veranderingen in de hersenen. Met behulp van data van de Nederlandse Hersenbank werd in Hoofdstuk 3 hersenautopsieverslagen vergeleken van 89 overleden donoren met COPD en 89 overleden donoren zonder COPD. Er werd geen verschil gevonden in de aanwezigheid van degeneratieve of neoplastische veranderingen tussen de hersenen van overleden donors met en zonder COPD, terwijl vasculaire veranderingen vaker werden gevonden in de hersenen van controle donoren. Longitudinale prospectieve studies zullen nodig zijn om met behulp van structurele en functionele magnetic resonance imaging (MRI) hersenscans, in combinatie van data van het cognitief functioneren, vast te stellen of er een causaal verband bestaat tussen hersenafwijkingen en cognitieve beperkingen bij patiënten met COPD. Naast cognitieve stoornissen, worden ook slaapstoornissen vaak gerapporteerd bij patiënten met COPD. Echter, informatie over de relatie tussen slaap en cognitie bij COPD is schaars. Hoofdstuk 4 onderzoekt de associatie tussen het cognitieve copy function vermogen en zelf-gerapporteerde beperkingen in slaapkwaliteit en ernst van de ziekte in 562 COPD-patiënten van de Salute respiratoria nell'Anziano Study. Slaapbeperkingen werden vaak gerapporteerd door patiënten met COPD, maar vertonen een zwakke correlatie met cognitief functioneren. Daarnaast blijken slaapbeperkingen geen marker van de ernst van de ziekte te zijn. Wel werd een trend gevonden waarbij patiënten (in de totale groep en in GOLD I) met slaapstoornissen een slechtere prestatie hadden op het cognitieve copy function vermogen. Dit suggereert dat COPD patiënten met slaapstoornissen vatbaarder zijn voor cognitieve beperkingen in de hogere cognitieve functies zoals blijkt uit de copy function vergeleken met COPD patiënten zonder slaapstoornissen.

223

Samenvatting

Om meer inzicht te krijgen in het cognitief functioneren van patiënten met COPD, werd de COgnitive-PD study opgezet. Een longitudinale observationele vergelijkende studie van patiënten met COPD verwezen voor longrevalidatie en gezonde controle deelnemers. Het baseline cognitief functioneren van 183 patiënten met COPD werd beoordeeld tijdens huisbezoeken met behulp van een uitgebreide neuropsychologische testbatterij en vergeleken met het cognitief functioneren van 90 controles zonder COPD. Demografische gegevens, klinische kenmerken en uitkomstmaten van de longrevalidatie werden beoordeeld om inzicht te krijgen in de relatie met cognitieve beperkingen bij patiënten met COPD. Daarnaast werd een MRI substudie verricht om hersenafwijkingen te vergelijken tussen patiënten met COPD met en zonder cognitieve beperkingen. Het onderzoeksprotocol van de COgnitive-PD study wordt beschreven in Hoofdstuk 5.

Samenvatting Cognitieve beperkingen kunnen interfereren met disease management programma’s voor patiënten met COPD, afhankelijk van welke cognitieve domeinen zijn aangetast. Hoofdstuk 6 vergelijkt de prevalentie van domein-specifieke cognitieve beperkingen tussen de 90 patiënten met COPD en 90 controles zonder COPD, gematcht voor leeftijd, opleidingsniveau, en rookstatus. We vonden dat cognitieve beperkingen bij 56,7% van de patiënten met COPD aanwezig waren. Ook waren cognitieve beperkingen vier keer zo vaak aanwezig in patienten ten opzichten van controles, en waren de cognitieve domeinen psychomotorische snelheid, planning, werkgeheugen, verbaal geheugen en cognitieve flexibiliteit aangetast. Bijkomende aandoeningen spelen mogelijk een rol bij de aanwezigheid van cognitieve beperkingen bij patiënten met COPD, maar spelen COPD-specifieke factoren een grotere rol bij de beperkingen in de executieve functies. De identificatie van domein-specifieke cognitieve beperkingen is noodzakelijk voor verdere optimalisering van therapieën, zoals het stoppen met roken, zelfmanagement programma's, en longrevalidatie, voor patiënten met COPD. Het identificeren van factoren die samenhangen met cognitieve beperkingen bij patiënten met COPD kan artsen helpen om patiënten met een aanwezige cognitieve beperkingen op te sporen voor verdere cognitieve beoordeling. Hoofdstuk 7 toonde aan dat de klinische kenmerken van 183 patiënten met COPD, zoals functionele status, ziekte-specifieke gezondheidsstatus, en psychisch welbevinden, vergelijkbaar waren voor COPD patiënten met en zonder cognitieve beperkingen. Bovendien was de prevalentie van cognitieve beperkingen vergelijkbaar tussen de verschillende ernststadia van COPD. De beoordeling van cognitieve beperkingen bij COPD vereist dus een actieve screening in alle GOLD stadia. Structurele hersenafwijkingen worden in de literatuur geassocieerd met de aanwezigheid van cognitieve beperkingen, direct of indirect via sigarettenrook, ontstekingen, vasculaire ziektes, of hypoxemie bij patiënten met COPD. Een subgroep van 55 patiënten uit de COgnitive-PD study populatie ondergingen een 3T MRI scan van de hersenen. In Hoofdstuk 8 worden cerebral small vessel disease, een aandoening van de kleine bloedvaatjes in de hersenen en het hippocampus volume tussen cognitief hoog en cognitief laag presterende patiënten met COPD met elkaar vergeleken. Er werd geen bewijs gevonden voor een relatie tussen cerebral small vessel disease en hippocampus volume en het cognitief functioneren bij patiënten met COPD. Vervolg studies zijn nodig om andere mogelijke mechanismen van cognitieve beperkingen bij patiënten met COPD te onderzoeken, waaronder microstructurele veranderingen in de hersenen en inflammatoire-, hormonale-, metabolische- en (epi)genetische factoren.

224

Samenvatting Cognitieve beperkingen kunnen interfereren met het opnemen, begrijpen, en integreren van informatie, en het onthouden van afspraken. Cognitieve beperkingen kunnen daarom negatieve gevolgen hebben voor een longrevalidatie programma. Hoofdstuk 9 vergelijkt longrevalidatie uitkomsten tussen patiënten met en zonder cognitieve beperkingen. Na longrevalidatie vertonen zowel patiënten met COPD met, alsook zonder cognitieve beperkingen, verbetering van de functionele status, gezondheidsstatus, psychologisch welbevinden, kennis van de ziekte en een afname van behoefte aan informatie. Hoewel patiënten met cognitieve beperkingen een verhoogd risico op uitval tijdens de revalidatie hebben, hebben patiënten die de longrevalidatie afronden baat bij het longrevalidatie programma. Cognitieve beperkingen zijn dus geen contra-indicatie voor longrevalidatie bij patiënten met COPD .

225

Samenvatting

Samenvattend toont dit proefschrift aan dat cognitieve beperkingen aanwezig zijn bij meer dan de helft van de patiënten met COPD en dat verschillende cognitieve domeinen zijn aangedaan. Daarnaast is in dit proefschrift aangetoond dat cognitieve beperkingen geen effect hebben op uitkomstmaten van longrevalidatie. Daarentegen hebben patiënten met cognitieve beperkingen wel een verhoogd risico op uitval tijdens de revalidatie. Omdat cognitieve beperkingen niet te voorspellen zijn op basis van demografische en klinische kenmerken, is een actieve screening voor cognitieve beperkingen nodig.

Valorization

227

Valorization This thesis describes a series of studies that aimed to investigate neuropsychological functioning in patients with COPD in a number of areas. Various chapters throughout this thesis described the theoretical and practical implications of this research. In the present valorization section, these studies and their outcomes are further positioned in a broader societal framework in order to address how this scientific knowledge can be transferred to and utilized in practice. The societal value will be reflected on from four different perspectives: (1) relevance of the scientific findings for practice; (2) non-scientific target groups to whom the findings are relevant; (3) translation of the findings in concrete activities and products; and (4) innovativeness, planning, and feasibility of these activities and products.

1. Relevance Previous researchers already showed that cognitive impairment is prevalent in patients with COPD. However, cognitive functioning has mostly been studied with broad-scale measurements, which do not separate specic cognitive functions. Moreover, healthcare providers have been concerned about the possible effects of cognitive impairment on pulmonary rehabilitation (PR) and daily functioning in patients with COPD. This thesis highlighted the high prevalence of general and domain-specific cognitive impairment in patients with COPD compared to non-COPD controls, that cognitive impairment in COPD cannot be predicted by clinical characteristics, and that it affects the completion of a PR program. As PR aims to improve patients’ physical and psychological condition and to promote long-term adherence to health-enhancing behaviors, it is essential that patients complete the entire course of treatment. Therefore, we demonstrated the existence of a societal and economic relevance on the need for PR interventions to reduce dropout. Moreover, this thesis created an opportunity for societal value of new implementations and adaptations in the assessment and PR program for patients with COPD (e.g. an active screening for cognitive impairment).

2. Target groups Besides the patient, also healthcare providers and the environment of the patient (e.g. families and other members of their social network) are important target groups for providing positive support and encouragement, in order to optimize the patient’s disease perception, disease management, and long-term behavior changes.

228

Valorization

2.1 Patients with COPD Patients need to be aware of the possible presence of cognitive impairment and its possible consequences. Increased self-awareness and insight might trigger patients to change their behavior, which consequently may increase the patient’s motivation and disease management which can lead to completion of a PR program. In addition, to ease the early detection of cognitive impairment, patients have to be encouraged to express and be conscious of subjective cognitive failures. In this context self-awareness and self-evaluation are important aspects which may increase their self-control. Self-control consists of a subset of self-regulatory processes which aim to prevent yielding to unwanted impulses or urges. It is important for the patient’s independency, adaptability, flexibility, control, autonomy, and self-management. This thesis, therefore, demonstrated that it is important to include the patient as an important member of the interdisciplinary treatment team during the assessment phase and treatment program. Moreover, patients need to be open-minded for routine assessment of their neuropsychological functioning.

2.2 Healthcare providers A better understanding of the presence and possible consequences of cognitive impairment in COPD is not only important for the patients themselves, but also for healthcare providers, since we have shown that patients with cognitive impairment are more likely to dropout during PR. Therefore, it is important that healthcare providers are aware of the possibility of cognitive impairment in patients and its impact and consequences. Moreover, they need to recognize and respond to clear warning signals of cognitive impairment, such as forgetting appointments, a low concentration, or when patients seem unmotivated. Indeed, this thesis underlines the importance to identify cognitive impairment in COPD in its early stages. If patients create negative disease beliefs or expectations of PR, it is likely that they dropout more easily. Therefore it is important to create a supportive environment during PR and to respond to opportunities to improve a patient’s performance, by for example motivational interviewing. A proactive approach of problem recognition, anticipation and successful management by the healthcare providers within the multidisciplinary PR team is needed. Vertical and horizontal communication and decision-making across disciplines, and internal monitoring or routine assessments of early indicators of cognitive impairment might be a beneficial part of the current PR routine.

Although not assessed in this thesis, it is possible that COPD patients with cognitive impairment have more difficulties to adapt to their daily life after a PR

229

Valorization

2.3 The environment

Valorization program and are more dependent on organizations, family members, or informal caregivers for products, services, or maintaining behavior changes (e.g. physical activity). Again, this highlights the need for anticipation, recognition, and responding effectively to any cognitive impairments that may threaten long-term outcomes.

3. Activities and products A part of the valorization is dissemination which includes the process of broadcasting a message to the public. The current findings have been presented during the European Respiratory Society (ERS) congress in 2013 (Barcelona, Spain), 2014 (Munich, Germany), and 2016 (London, United Kingdom) as well as during the Neurological Disorder Summit Conference in 2015 (San Francisco, United States). During the ERS congress in 2013, the abstract entitled ‘Cognitive functioning in OLD: Results from the UK Biobank’ was selected for press release. Furthermore, the results have led to review and original articles in scientific national and international journals and have been presented during workshops and courses organized by CIRO and other institutions. However, to create societal value, one needs to go further than publishing and communicating findings at conferences. I am willing to use the full spectrum of presentation and communication skills, developed during the PhD track, in educational sessions for the patient, health-care providers, and the external environment of the patient in order to optimize knowledge on how to deal with the cognitive impairments. Then, the implementation of a practical neuropsychological testing battery to assess cognitive functioning should become a component of the multidimensional assessment of patients with COPD. Communication of our findings should lead to a greater emphasis on the involvement of informal care providers or caregivers (e.g. for practical help, motivational interviewing, and emotional support) during and after PR to reduce dropout and to maintain long-term behavior changes. Therefore, health-care providers across all disciplines need to be taught strategies to optimize patient’s disease perception and management. For example, understanding and anticipating the concerns of the patient and identifying the likely deficits in his or her disease perception will help target interventions to improve their self-perceived efficacy to manage symptoms. Moreover, overcoming these deficits will help the patient alleviate worries while going through the PR program. The health care professionals can enhance the patient’s disease perception and management by helping the patient interpret physical and psychological states relative to the disease trajectory. Moreover, a cognitive training program might be incorporated during PR.

230

ValorizationÂ Â

4. Innovation, implementation, and feasibility

231

Valorization

The COgnitive-PD neuropsychological testing battery is unique in that it is developed to assess the prevalence of all components of interest to obtain a complete overview of the cognitive functioning of the patient with COPD. It not only concentrates on general cognitive impairment, but also on impairments in specific cognitive domains. Nowadays, cognitive functioning is not being evaluated during the initial assessment of PR. Yet, it is beneficial in order to recognize patients with cognitive impairment and, if needed, provide them with additional care from informal and formal caregivers. Although we recommend the COgnitive-PD neuropsychological testing battery based on the differentiation between impairments in specific cognitive domains, it is a very time consuming testing battery. Therefore, our results may be the basis for additional research in order to invent a testing battery to screen for cognitive impairment during the PR assessment for patients with COPD which includes a minimum of sensitive tests which are able to differentiate between cognitive domains. Moreover, our results may motivate other researchers to stay active in the neuropsychological topic in patients with COPD. Furthermore, innovative is that the efficacy of PR was compared between patients with and without cognitive impairment. The complexity of care as reflected by a higher dropout rate in patients with COPD with cognitive impairment provides important insights for health policy makers and insurance companies. Finally, the current findings are basis and inspiration for future research questions. Still more research is necessary to increase our understanding of the etiology and prevention of cognitive impairment in patient with COPD. Moreover, the current findings may further provoke discussion about how to adapt the PR program to optimize PR completion and whether and to what extent cognitive impairment in patients with COPD affects long-term outcomes. Whether cognitive training during PR is able to 1) slow down or prevent cognitive decline, 2) to prevent dropout, or 3) to increase benefits and maintenance of behavior change after PR, needs to be further investigated.

Dankwoord

233

Dankwoord Finis coronat opus, het einde kroont het werk. Maar mijn thesis is niet compleet met deze Latijnse quote. Na lange tijd komt nu het perfecte moment om iedereen te bedanken, want vier jaar promoveren doe je immers niet alleen. Hoe hectisch een promotietraject ook kan zijn, des te belangrijker is een goede band en de juiste ontspanning met je begeleiders, collega’s, vrienden en familie. Daarom ben ik blij dat ik hier al deze mensen ‘officieel’ kan bedanken! Hooggeleerde promotor prof. dr. E.F.M. Wouters, beste Emiel ofwel Miel, bedankt voor de kans om bij u te mogen promoveren! Ik ben het medisch wetenschappelijk onderzoek enorm gaan waarderen. Zonder u geen manuscript, artikel en proefschrift. Bedankt! Weledelzeergeleerde copromotor dr. D.J.A. Janssen, beste Daisy, ik herinner me nog als de dag van gisteren dat ik na mijn sollicitatie het telefoontje met zowel goed als slecht nieuws kreeg. De vacature waar ik op had gesolliciteerd was vergeven, maar jullie hadden een ander project voor mij in petto dat door mij ingevuld kon worden. En daar startte mijn vierjarig avontuur. Ik wil jou van harte bedanken voor je begeleiding en het kritisch belichten van mijn onderzoek. De snelheid waarmee jij manuscripten reviseerde en mijn vele e-mails telkens beantwoordde blijft ongelofelijk. Uit het feit dat mijn teksten in de loop van de tijd minder rood gekleurd terugkwamen, blijkt dat ik veel van je geleerd heb! Ik kon me geen betere of intelligentere copromotor voorstellen. Hartelijk bedankt. Prof. dr. R.W.H.M. Ponds, beste Rudolf, en dr. J.B. Dijkstra, beste Jeanette, jullie wil ik ook graag bedanken voor de hulp en wetenschappelijke begeleiding tijdens mijn promotie periode als tweede promotor en copromotor. Besprekingen met jullie waren een bron van creatieve ideeën. Bedankt voor de inspiratie. Prof. dr. R. Antonelli-Incalzi, dear Raffaele, and Prof. dr. C. Pedone, dear Claudio, one of the chapters presented in this thesis originates from a close collaboration with you. I am very thankful for the opportunity to do a research project for three months at your institution. You warmly welcomed me at Policlinico Campus Bio-Medico in Rome. I would like to thank you for the supervision and support you provided during my fellowship in the beautiful city of Rome and beyond. And to my Italian colleagues and lunch mates I would like to say that I really miss our cappuccino breaks and the delicious Italian pastas, pizzas, tiramisu, and so on. Grazie Mille! Furthermore, I would like to thank all co-authors (Candy, Claudio, Daisy, Ed, Emiel, Frits, Heidi, Jan, Jeanette, Julie, Lowie, Martijn, Paul, Raffaele, Rudolf and Saartje) who contributed to the research presented in this thesis. Dank voor

234

Dankwoord jullie kritische blik op mijn werk. Van zowel de positieve als negatieve feedback heb ik veel opgestoken. Ook wil ik graag de medewerkers uit de kliniek, van de CIRO-afdelingen longfunctie en biometrie, bedanken. Tevens wil ik mijn stagiaires Liza en Kiki respectievelijk bedanken voor de hulp bij het maken van huisbezoeken en het beoordelen van de MRI-scans. Zonder jullie allemaal geen complete data! Members of the assessment committee, Prof. dr. Jos M.G.A. Schols (chairman), Prof. dr. Caroline M. van Heugten, Prof. dr. Frans R.J. Verhey, Prof. dr. Dorly J.H. Deeg, and Prof. dr. Andreas von Leupoldt, thank you for the time and effort you spend on the judgement and/or defense of my thesis. Wat zou promoveren zijn zonder leuke collegaatjes? Ik ben dankbaar dat ik met zulke fantastische mensen op een kamer (lees: het gezelligheidshok!) heb mogen zitten: Anouk, Carmen, Cindy, Coby, Dionne L-B, Dionne S, Jeannet, Nienke, Rafael, Sarah, Vasilis en Wai-Yan. Nogmaals, promoveren doe je niet alleen. Jullie gaven me een duwtje in de rug wanneer het nodig was. In vier jaar tijd hebben we letterlijk en figuurlijk samen vele kilometers afgelegd. De gezelligheid in de auto, de saamhorigheid tijdens de congressen, maar ook het medeleven wanneer een artikel voor de zoveelste keer werd afgewezen, heeft ons een superteam gemaakt. De leuke dinertjes, de calorierijke traktaties en ter compensatie onze dagelijkse wall-sit challenge, vaak pijnigend maar ó zo hilarisch, zal ik zeer zeker gaan missen. Met jullie heb ik van de sunny side of science kunnen genieten. Dank jullie wel hiervoor! Ook bijzonder veel dank aan alle patiënten en vrijwilligers (mijn controlegroep) die vol enthousiasme en soms onder moeilijke omstandigheden hun spaarzame tijd hebben opgeofferd voor deelname aan mijn onderzoek. Uw inzet en uw betrokkenheid waren bewonderenswaardig. Ook de gastvrijheid bij u thuis, na soms vele kilometers op de weg te hebben afgelegd, maakte de huisbezoeken heel aangenaam. Daarnaast zijn er buiten het werk om ook nog een aantal andere dierbare personen die ik heel graag wil bedanken.

235

Dankwoord

Lieve Susan, jij was bij uitstek de vriendin die ervoor zorgde dat ik ook aan ontspanning toe kwam. Van kleine afternoon meetings, samen koken, een filmpje pikken, samen dansen, ons hart luchten en daarna weer hardop lachen, tot mooie stedentrips. Je wist mij altijd over te halen om gezellige dingen te doen. Dankjewel hiervoor!

Dankwoord Ditzelfde geldt ook voor jou, Natascha! We hadden onze reis naar Thailand al geboekt toen ik mijn PhD-baan kreeg aangeboden. Gelukkig was het geen probleem om een maandje later te starten. Gedurende mijn promotietraject heb ik nog vaak aan onze geweldige tijd terug kunnen denken met jou. En ook na een drukke werkweek kon ik me vaak verheugen op samen Thais eten of samen sushi maken. Khob khun ka! Simon, jij gaf stabiliteit en perspectief aan de waan van de dag. Heel erg bedankt voor jouw grote hulp bij het maken van formules en allerlei berekeningen waar ik zelf niets van begreep, maar waardoor mijn dataverwerking een heel stuk makkelijker werd. En wat was ik blij dat ik in jou een uitlaatklep heb gevonden. Jouw mentale steun op de momenten dat ik het hard nodig had waardeer ik enorm. Ook hiervoor dankjewel! Gary, you are a dear friend who could recognize scientific struggles and put them into perspective. It is a bless to have met you in your own museum in New York. Despite your very busy life, you were always interested in my research progress. We always had a great time with a lot of laughter, whether in Amsterdam, Rome, or through the phone. Our conversations were always a great way to look at the bright sight of life. Thank you so much, my bodyguard. Lieve Chantal, Daisy, Esmee, Sifra, en Veerle, jullie hebben mijn reis al vanaf de bachelor studie meegemaakt. Van jullie heb ik veel gezelligheid en steun gekregen. Als enige van ons zessen sloeg ik de weg van het onderzoek in. Maar dankzij jullie bleef ik gelukkig op de hoogte van het reilen en zeilen in de GGZ. Ook nog altijd een groot interessegebied voor mij. Onze psychologenuitjes moeten we er zeker in houden! Moniek en Yvanca, jullie hebben ervoor gezorgd dat ik de maandagen en dinsdagen niet achter m’n bureau bleef zitten. Onze sportieve uurtjes wilde ik voor geen goud missen. Er moest al heel wat tussen komen om een keertje te moeten overslaan. Na een full body work-out of een uurtje zumba was mijn hoofd weer helemaal leeg en kon ik weer met heldere geest verder met mijn onderzoek. Queridos salseros y salseras, mijn avondjes op de dansvloer in het weekend waren één grote energiebron om er op maandagochtend weer tegenaan te gaan. Op de dansvloer vergat ik even mijn drukke PhD-leven. Samen met jullie danste ik op salsa- en bachatafeestjes in heel Nederland en zelfs ver daarbuiten. Bedankt voor de dansjes en gezellige avondjes Gino, Inge, Kuma, Rob en de rest! Andrea, grazie mille! Muchísimas gracias a ustedes Carmen, Darío, Diego, Helmer y Karel!

236

Dankwoord Chantal en Dionne L-B, lieve paranimfen, altijd waren jullie geïnteresseerd in mij, mijn onderzoek, en de voortgang ervan. Omdat jullie altijd achter mij hebben gestaan, ben ik blij om jullie ook bij de laatste loodjes letterlijk ‘achter mij’ te hebben staan! Mijn dank hiervoor is groot.

237

Dankwoord

Natuurlijk gaat mijn grootste dank uit naar mijn papa, mama, en mijn lieve broertje Toine. Ugge bijdrage is natuurlijk neet in woorden oet te drukke. Pap, ich treed noe in de voetsporen van mien grote voorbeeld. 28 joar geleje stongse zelf dien proefschrift hie in Mestreech te verdedigen. Dus doe wits precies wat vuur een traject ich moosj doerlopen. Bedankt vuur ut kritisch doerlezen van mien iesjte manuscript en ut geven van tips and tricks woadoer ich doanoa de kneepjes al snel zelf doer hej. Elke kier als ich weer een artikel gepubliceerd hej, woar ich stiekem dubbel blie omdat ich wis wie trots se dan woars op dien kleine meid. En noe, op de vooravond van mien verdediging, krieg ich oog nog enkele letste adviezen van dich. Geweldig! En mam, dich wis van elke kleine of grotere overwinning - van de inclusie van een nuuje patiënt in mien ongerzeuk tot aan de acceptatie van een nuuj artikel - een feestje te maken zo wie alleen een échte lieve mam dat zou kinne. Of alse merktes dat ich weer toe woar aan ontspanning, hej vur een stedentrip, of geweun een terrasje pikken of een wandeling in de natuur zo gepland. Toine, dien nuchterheid en humor hub ich altijd gewaardeerd. In combinatie mit dien relativeringsvermogen woare er neet ummer zo veul beren op de weg gedurende de afgelopen veer joar. Nogmaals, ontiegelijk bedankt vuur ugge onophoudelijke steun, vertrouwen, en motivatie. Zonger uch hulp en goei zurg hej ich dit alles neet vuur elkaar gekrege. Mien eeuwige dank vuur alles!

Curriculum Vitae

239

C.V.

Curriculum vitae Fiona Cleutjens was born on the 29th of November, 1989 in Oirsbeek, the Netherlands, as the oldest of two. After attending primary school, she graduated in 2008 from high school (Gymnasium, Sint-Janscollege, Hoensbroek). Since an early age, Fiona demonstrated a strong preference towards psychology and human biology. This typical combination of interests urged her to initiate a study ‘Health sciences’ (Maastricht University, Maastricht). After earning her Bachelor in 2011, she became progressively convinced that getting to know people on a personal level, to learn their stories and what is meaningful to them, did matter the most. She earned her Master degree in ‘Mental Health’ (Maastricht University, Maastricht) with honors (cum laude). During her clinical internships she noticed that she was very interested in neuropsychological diagnostics, what makes people unique and how different factors shape our personality. She gained her Certificate in Psychodiagnostics during her Master year at the Neurosis and Psychosis care programs (The Public Centre for Mental Health, Rekem, Belgium). At The Personality Problem Program (PsyQ, Heerlen) she performed research and further developed her understanding of personality disorders and its complex behavioral and emotional patterns while doing clinical interviews, psychological testing, and taking part in Schema-Focused Therapy and Systems Training for Emotional Predictability and Problem Solving (STEPPS) for Borderline Personality Disorder. After graduating in Mental Health in September 2012, she was offered a position as PhD student at CIRO (Prof. Dr. E.F.M. Wouters and Dr. D.J.A. Janssen, CIRO, Horn). Her research focused on neuropsychological functioning in patients with chronic obstructive pulmonary disease (COPD) and the effects on functional exercise capacity, disease-specific health status, psychological wellbeing, COPD-related knowledge, and the need for information. During her PhD she was granted for a European Respiratory Society (ERS) threemonth fellowship which she performed at the Department of Geriatrics (Prof. Dr. R Antonelli-Incalzi, Policlinico Universitario Campus Biomedico, Rome, Italy). The results of this thesis have been presented at ERS conferences (Barcelona 2013, Munich 2014, and London 2016) and at the Neurological Disorder Summit (San Francisco 2015). As of May 1st 2017, she will start a postdoctoral research project at the Department of Rheumatology (Maastricht University, Maastricht).

241

Publications

243

List of publications

Cleutjens FAHM, Spruit MA, Ponds RWHM, Vanfleteren LEGW, Franssen FME, Gijsen C, Dijkstra JB, Wouters EFM, Janssen DJA (in press). Cognitive impairment and clinical characteristics in patients with COPD. Chron Respir Dis. Cleutjens FAHM, Ponds RWHM, Spruit MA, Burgmans S, Jacobs HIL, Gronenschild EHBM, Staals J, Franssen FME, Dijkstra JB, Vanfleteren LEGW, Hofman PA, Wouters EFM, Janssen DJA. The Relationship between Cerebral Small Vessel Disease, Hippocampal Volume and Cognitive Functioning in Patients with COPD: An MRI Study. Frontiers in Aging Neuroscience. 2017;9(88). Cleutjens FAHM, Spruit MA, Ponds RWHM, Vanfleteren LEGW, Franssen FME, Dijkstra JB, Gijsen C, Wouters EFM, Janssen DJA. The Impact of Cognitive Impairment on Efficacy of Pulmonary Rehabilitation in Patients With COPD. J Am Med Dir Assoc. 2017; ;18(5):420-426. Cleutjens FAHM, Franssen FME, Spruit MA, Vanfleteren LEGW, Gijsen C, Dijkstra JB, Ponds RWHM, Wouters EFM, Janssen DJA. Domain-specific cognitive impairment in patients with COPD and control subjects. Int J Chron Obstruct Pulmon Dis. 2017;12:1-11. Cleutjens FAHM, Pedone C, Janssen DJA, Wouters EFM, Incalzi RA. Sleep quality disturbances and cognitive functioning in elderly patients with COPD. ERJ Open Research. 2016;2(3). Cleutjens FAHM, Triest FJJ, Wilke S, Vanfleteren LEGW, Franssen FME, Janssen DJA, Rutten EPA, Spruit MA, Wouters EFM. New insights in chronic obstructive pulmonary disease and comorbidity. Am J Respir Crit Care Med. 2015;191(9):1081-1082. Cleutjens FAHM, Spruit MA, Beckervordersandforth J, Franssen FME, Dijkstra JB, Ponds RWHM, Wouters EFM, Janssen DJA. Presence of brain pathology in deceased subjects with and without chronic obstructive pulmonary disease. Chron Respir Dis. 2015;12(4):284-290. Cleutjens FAHM, Spruit MA, Ponds RWHM, Dijkstra JB, Franssen FME, Wouters EFM, Janssen DJA. Cognitive functioning in obstructive lung disease: results from the United Kingdom biobank. J Am Med Dir Assoc. 2014;15(3):214-219. Cleutjens FAHM, Janssen DJA, Ponds RWHM, Dijkstra JB, Wouters EFM. COgnitive-pulmonary disease. Biomed Res Int. 2014;2014:697825.

Cleutjens FAHM, Wouters EFM, Dijkstra JB, Spruit MA, Franssen FME, Vanfleteren LEGW, Ponds RWHM, Janssen DJA. The COgnitive-Pulmonary Disease (COgnitive-PD) study: protocol of a longitudinal observational comparative study on neuropsychological functioning of patients with COPD. BMJ Open. 2014;4(3):e004495.

245

Publications

Cleutjens FAHM, Janssen DJA, Gijsen C, Dijkstra JB, Ponds RWHM, Wouters EFM. Cognitieve beperkingen bij patiënten met COPD: een overzicht. [Cognitive impairment in patients with COPD: a review]. Tijdschr Gerontol Geriatr. 2014;45(1):1-9.