Dementia
Lilly makes medicines that help people live longer, healthier and more active lives
Roy Yaari, MD Sr. Medical Advisor, Eli Lilly & Co.
Outline
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Definitions Diagnosis Treatment Future
Dementia: Definition and Key Types Dementia: A syndrome (group of symptoms) with multiple causes. Not a specific disease. A decline in mental ability (eg. memory) severe enough to interfere with daily activities. Subtype
Early, Characteristic Symptoms
AD dementia
• Impaired recent memory, apathy, depression • Commonly combined with vascular dementia
Vascular dementia
• Memory less affected; Impaired judgement & decisionmaking more prominent. Mood fluctuations • Impaired motor function; ‘post-stroke’ dementia
% Cause 60-80% Most Common
10%
Mixed dementia
Frontotemporal dementia
Dementia with Lewy Bodies
• Personality and mood disinhibition, • changes, Causes >50% of language all dementias10% difficulties; Memory typically spared
• Has >1 neuropathological cause • Sleep disturbances, cognitive fluctuations, visual • Postmortem studies: underdiagnosed hallucinations • Gait imbalance/slowness, parkinsonism features
https://www.alz.org/documents_custom/2017-facts-and-figures.pdf.
5%
Defining Features of AD Neuropathology in the Brain
Amyloid plaques1,2 • Composed of insoluble amyloidbeta protein (A), extracellular • Local neurodegenerative and inflammatory changes
Neurofibrillary tangles1,2 • Composed of abnormal forms of tau protein • Filamentous inclusions within nerve cells
Plaques and tangles images reproduced with permission of Dr. Dennis Dickson, Mayo Clinic, Jacksonville, FL 1. Querfurth HW, LaFerla FM. N Engl J Med 2010;362(4):329-44. (updated 364:588).
AD Continuum: Clinical ‘Staging’ by Symptoms Clinical Changes over Decades
Cognitive/Functional Worsening
Normal Normal Aging
Preclinical AD (Asymptomatic) • No or subtle change in cognition or function
AD Timecourse
MCI due to AD/ Prodromal AD
• Cognitive: Recent memory, naming, word-finding, visuo-spatial problems • Function: Subtle changes in complex tasks
AD Dementia (Mild to Severe Stages) • Cognition: Increasing severity of deficits • Function: Mild impairment to total dependence
0
Years of Disease
30
Note: Dotted lines around clinical ‘stages’ illustrate lack of discrete timing and symptoms 1. Sperling RA et al. Alzheimers Dement 2011;7:280-92. ; 2. www.alz.org/documents_custom/2017-facts-and-figures.pdf. ; 2. Dubois B, et al. Lancet Neurol 2010;9:1118-27.
Increased Understanding of Disease Pathophysiology Due to Advanced Diagnostic Tools1 Typical mid sagittal and transverse 11C-PiB PET images2
Pike KE et al. Brain. 2007;130:2837-2844, by permission of Oxford University Press
HA=healthy aging; 11C-PiB PET= 11C-Pittsburgh positron emission tomography; SUVR=standardized uptake value ratio 1. 2.
Sperling RA et al. Alzheimers Dement. 2011;7(3):280-292 Pike KE et al. Brain. 2007;130:2837-2844
Pathophysiological Changes that May Lead to AD Begin Before Symptoms Emerge1-3 ♌ Abnormal accumulation of two proteins, amyloid and tau, are believed to initiate a complex cycle of synaptic loss and neuronal death that lead to the clinical signs of AD1-3 Hypothetical model integrating AD immunohistology and biomarkers3
1. 2. 3.
Jack CR Jr et al. Lancet Neurol. 2010;9(1):119-128 Jack CR Jr et al. Lancet Neurol. 2013;12:207-216 Villemagne VL et al. Lancet Neurol. 2013;12:357-367
Alzheimer’s Disease Dementia: Global Impact
1 in 10 people aged 65+ have AD dementia Older population (65+) increasing1 Incidence of AD dementia increases with age – estimating1,2
1
1 in 3 people 85+ 75-84 yrs 44%
85+ yrs 38%
• >37 Million in 2017
• >100 Million in 2050 ♦ AD dementia cannot be prevented, slowed or cured1 Estimates based on 1. https://www.alz.org/documents_custom/2017-facts-and-figures.pdf. 2. http://www.who.int/features/factfiles/dementia/en/. Accessed January 5 2018.
<65 yrs 4%
65-74 yrs 16%
Incidence of AD Dementia by Age Group (years)
Economic Burden Through the Eyes of Caregivers
In 2016, caregivers of people with Alzheimerâ&#x20AC;&#x2122;s and other dementias provided an estimated 18 billion hours of informal (ie, unpaid) assistance, a contribution to the nation valued at $230 billion
Alzheimerâ&#x20AC;&#x2122;s Association. Alzheimers Dement. 2017:13(4):325-373
Timely Diagnosis Can Lead to Improved Management of Comorbid Conditions Managing comorbidities Underlying dementia is a risk factor for poor compliance with treatment goals (eg, diabetes, congestive heart failure)1 • Poor performance on the Mini-Cog™ was associated with higher 30-day readmission rates in one study in patients with heart failure2
Timely diagnosis can also reduce ineffective, expensive, crisis-driven use of healthcare resources1,3
1. 2. 3.
Hill JW et al. Neurology. 2002;58:62-70 Patel A et al. J Am Coll Cardiol. 2015;8:8-16 Relkin N. Am J Manag Care. 2000;6(22 suppl):S1111-S1118
A special thanks to ACT on Alzheimer’s® for their contributions to the educational content of this presentation
Timely Diagnosis Can Lead to Improved Patient Outcomes1 Decisions regarding medical care • Timely diagnosis can allow patients to be actively involved in decision making and may result in higher quality of care1,2
Patients participate in decisions that can affect their quality of life • Timely diagnosis could allow patients to create advanced directives1-3 • Diagnosis of dementia may reduce safety risks for patients and families4 Intervene to promote an environment that supports independence • Connecting caregivers with resources resulted in reduced rate of nursing home placement of the patient5
1. 2. 3. 4. 5.
A special thanks to ACT on Alzheimer’s® for their contributions to
Relkin N. Am J Manag Care. 2000;6(22 suppl):S1111-S1124 the educational content of this presentation Dubois B et al. J Alzheimers Dis. 2016;49(3):617-631 https://www.alz.org/documents_custom/public-health/2013-Value-of-Knowing.pdf. Published February 2013 Amjad H et al. J Am Geriatr Soc. 2016;64(6):1223-1232 Mittelman M, et al. Neurology. 2006;67(9):1592-1599
Modern Diagnosis of AD ♦ Medical and family history • Including psychiatric, cognitive, and behavioral history – with family/partner input ♦ Cognitive tests, physical and neurological examination ♦ Laboratory tests, brain imaging (MRI) • Rule out other causes of symptoms ♦ Biomarker tests
• Presence of amyloid burden, as indicated by PET and/or CSF levels 1. https://www.alz.org/documents_custom/2017-facts-and-figures.pdf.
Which Objective Assessment Tools Best Fit Your Patient Type and Practice? Testa
MMSE (Mini-Mental State Exam)
MoCA (Montreal Cognitive Assessment)
SLUMS (St Louis University Mental Status) aTests
Description A 30 point test that assesses orientation, memory, attention, naming, following verbal and written commands, sentence writing and complex figure drawing3
A 30-point test that assesses shortterm memory, recall, visuospatial abilities, multiple aspects of executive functioning, attention, concentration, working memory, language, and orientation4 A 30-point, 11-item scale that assesses attention, numeric calculation, immediate and delayed recall, animal naming, digit span, clock drawing, and figure recognition2
Timeb
Considerations
7-10 min
Most widely used; studied worldwide; education/age/language/culture bias; ceiling effect; purchase required1
10-15 min
Designed to test for MCI; available in multiple languages; education bias (<=12 years); limited data available in general practice settings1
7 min
No educational bias; tests many separate domains; does not test executive function; studied in a VA geriatric clinic1,2
are representative only; alternative tools are available and can be used at the discretion of the clinician times reported; times may vary
bAverage
1. 2.
Cordell CB et al. Alzheimers Dement. 2013;9(2):141-150 http://www.hsrd.research.va.gov/publications/esp/dementia.pdf
3. 4.
Folstein MF et al. J Psychiat Res. 1975;12:189-198 Nasreddine ZS et al. J Am Geriatr Soc. 2005;53(4):695-699
There Are Many Objective Cognitive Tools Available, Including the Mini-Cogâ&#x201E;˘ Exam
Scoring of the Mini-Cog
Subject asked to recall 3 words
Word Recall 3 points
Subject asked to draw clock and set hands to 10 past 11
Clock Draw 2 points Total Score: 0-5 points
http://www.alz.org/documents_custom/minicog.pdf
AD Biomarkers in Various Stages of Development ♦ Definition: Measurable indicator of a biological state or condition in the living human body1,2 ♦ May be used to diagnose, assess risk, stage, evaluate response to treatment, or provide more definitive patient selection in clinical trials3
Genetic testing
CSF • Aβ • Tau • P-tau
MRI4*
FDG-PET5**
Amyloid-PET3**
Tau-PET6**
Blood • Aβ • Tau • P-tau Images obtained: *ADNI database, **Eli Lilly and Co.
1. Jack CR, et al. Lancet Neurol 2010; 9:119-28.; 2. https://www.alz.org/documents_custom/2017-facts-and-figures.pdf. 3. Cummings J. Translational Neurodegeneration 2017;6:25-31.
Medical Treatment1 Acetylcholinesterase Inhibitors
Indication
Donepezil (Aricept™) Rivastigmine (Exelon™) Galantamine (Razadyne™)
Mild-Mod-Severe AD Mild-Mod AD Mild-Mod AD
NMDA Antagonist Memantine (Namenda™)
1.
https://www.nia.nih.gov/health/how-alzheimers-disease-treated (last accessed 5/4/2018)
Mod-Severe AD
Medications to Avoid
♦ Opiates1 ♦ Benzodiazepines2 ♦ Meds with anticholinergic side effects3 • Diphenhydramine • Tricyclic antidepressants • Oxybutynin
♦ Others 1. 2. 3.
Identification, assessment, and management of pain in patients with advanced dementia. Malotte and McPherson. Mental Health Clinician 2016 6:2, 89-94 Use of Benzodiazepines in Alzheimer’s Disease. Defrancesco, Michaela et al. International Journal of Neuropsychopharmacology 18.10 (2015): pyv055. PMC. Web. 4 May 2018. American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012;60(4):616–31.
Participation in Clinical Trials
♦ Potential access to novel therapies ♦ Randomization to study drug vs placebo ♦ Access to additional medical oversight
Medical Management of Psychiatric Conditions in Dementia No FDA approved drugs Anti-psychotic drugs
Agitation & Psychosis1
Black box warning (1.7 x increased death rate, metaanalysis) Use lower doses Atypical antipsychotics preferred Less likely to produce extrapyramidal syndromes
Avoid/limit benzos
Depression & Anxiety2,3
Insomnia4,5
1. 2. 3. 4. 5.
Consensus statements emphasize SSRIs Use low doses Titrate based on response and side effects Avoid Tricyclic Antidepressants due to anticholinergic properties (amitriptyline, nortriptyline) Sleep hygiene Trazodone ď&#x192; usually tried first Mirtazapine (also helps with weight loss and depression) Benzos and diphenhydramine are not recommended
http://www.psychiatrictimes.com/geriatric-psychiatry/managing-psychosis-patients-alzheimer-disease (last accessed 5/4/2018) Ferretti et al. Journal of Geriatric Psychiatry and Neurology. Vol 14, Issue 1, pp.52-58 Starkstein et al. International Review of Psychiatry, Volume 20, 2008 - Issue 4 Camargos et al. Arq Neuropsiquiatr. 2011 Feb;69(1):44-9. Segers and Surguin. Alzheimer Dis Assoc Disord. 2014 Jul-Sep;28(3):291-3.
Opportunities in AD Drug Development
GOAL:
Earlier Screening
Therapies in Development
Diagnostic Biomarkers
1. 2.
Cummings J, et al. Alzheimers Dement, 2017; 24;3:367-84. Cummings JL, et al. Alzheimers Res Ther 2016;8:39-51.
Clinical Trial Design
Clinical Trial Recruitment
Make AD Dementia Preventable
Clinically Predictive Biomarkers
AD Drug Development: Key Therapeutic Targets BACE1 BACE inhibitors
APP
Soluble
Insoluble Plaques
Oligomers Monomers
Tau therapies Prevent: • Intracellular aggregation • Extracellular spread
Tau Pathology
A Production g-secretase modulators
Gamma (g)secretase
Symptomatic therapies
A antibodies
A antibodies
- Deposited A
- Soluble A
A Clearance mechanisms
Neuronal Dysfunction & Clinical Symptoms • Inflammation • Excitotoxicity • Neuroplasticity
Future combinations of therapies that target multiple points in cascade may enhance efficacy vs monotherapy Adapted from Citron M. Nat Rev Drug Discov.2010;9:387-98.
Lilly Neurodegeneration Portfolio: Therapeutics and Diagnostics (25APR2018) 0 Discovery 1 Phase I 2 Phase II 3 Phase III 4 Sub/Launch5
Therapeutics Solanezumab: Abeta mAb (LY2062430) Lanabecestat: BACE Inh (LY3314814)* N3pG mAb: Plaque (LY3002813) BACE Inh (LY3202626)/N3pG mAb combo Selective BACE1 Inhibitor Abeta42 mAb* Tau mAb
Amyloid - AD Tau - AD Symptomatic – PD Dementia
Anti-Tau small molecule D1 PAM Potentiator (LY3154207) Diagnostics Florbetapir: Amyloid PET Tracer Flortaucipir: Tau PET Tracer *Partnership with AstraZeneca; Abbreviations: combo=combination; Inh=inhibitor; mAb=monoclonal antibody; PET=positron emission tomography 1. https://www.lilly.com. Accessed 25 Apr 2018. 2. https://clinicaltrials.gov. Accessed 25 Apr 2018; 3. Data on File, Eli Lilly and Company.
Support of the PERSON with Dementia in Senior Care Communities Jan Dougherty, MS, RN, FAAN Special Projects Consultant Banner Alzheimerâ&#x20AC;&#x2122;s Institute
Objectives • Inspire all senior communities to become “dementia friendly” and “dementia friends” • Connect to the PERSON with dementia utilizing person centered care as the best practice in dementia care • Promote ongoing education of all staff – empowering them to know and support residents • Prepare to (re)create comfortable and supportive environments for people living with dementia • Recognize (ongoing) ambiguous loss in family caregivers
Letâ&#x20AC;&#x2122;s Do the Math 60% of people with dementia (PWD) live at home in the community â&#x20AC;˘ 25% of PWD live alone 42% of PWD live in assisted living communities 61% of nursing home residents have moderate to severe dementia By the age of 80, 75% of PWD are moved to residential care settings (compared to 4% of general population)
Fazio et al, 2018
Good dementia care is all of our business!
Dementia Friendly Communities â&#x20AC;˘ Communities where all people can live, age, and thrive â&#x20AC;˘ Communities are informed, safe and respectful to foster quality of life for those living with dementia and their care partners www.dfamerica.org
Residential and Specialty Care Sector Guide • Outlines a 3-step process to becoming “Dementia Friendly” with: • • • •
Organizational best practices General person-centered care practices Specific person-centered care practices Environmental design considerations
http://www.dfamerica.org/sector-guides-1/
Dementia Friends in Senior Communities Dementia Friends is a global movement changing the way people think, act and talk about dementia. By helping everyone in a community understand what dementia is and how it affects people, each of us can make a difference for people touched by dementia.
www.dementiafriendsusa.org
5 Key Messages of Dementia Friends 5 Key Messages: • Dementia is not a normal part of aging • Dementia is caused by diseases of the brain • Dementia is not just about having memory problems • It is possible to have a good quality of life with dementia • There’s more to the person than the dementia
“The single most important determinant of quality dementia care across all care settings is direct care staff.” Alzheimer’s Association, 2017
alz.org/qualitycare The Gerontologist, 2018, Vol. 58, S. 1
The essence of good dementia care is PERSON centered care • Know the person • Recognize and accept the person’s reality • Identify and support ongoing opportunities for meaningful engagement • Build and nurture authentic, caring relationships • Create and maintain a supportive community for individuals, families, and staff • Evaluate care practices regularly and make appropriate changes Fazio et al (2018). The Gerontologist, S10-S19.
Leaders are Central to Person Centered Care The Leader’s Role includes: • providing a clear vision of what this means, • developing practices that value employees, • creating systems to support staff development, • designing supportive and inclusive physical and social environments, • ensuring quality improvement mechanisms. Brooker, D. (2004). Reviews in Clinical Gerontology, 13, 215–222.
Initial and Ongoing Education is Crucial • Understanding the condition • Person-centered care practices & tools • Addressing behavioral expression and distress • “Help me”—“I will help you.” • “I’m scared”—“I will keep you safe.” • “I don’t know how/what to do”—“I will show you” or “You are doing everything right.” • “I’m sad/lonely/missing someone”—I’m sorry for your loss/upset/feeling; I would like to spend time with you.”
• Best practice strategies for bathing, continence and oral care** • Meaningful engagement **Direct Care Workers/CNAs
Person Centered Care
Staff Outcomes • Improvement in knowledge, attitudes, selfefficacy, burnout, job satisfaction • Individual/group reflection activities lead to improved personcenteredness; job satisfaction • Positive psychology improves teamwork and improved attitudes toward residents
Best Practice Approaches
Resident Outcomes • Reduction in (BPSD) behaviors • Improved interaction between staff and residents • Impact on how staff behave toward residents • **Staff training with managers demonstrated the best resident outcomes
Gilster, Boltz, and Dalessandro, The Gerontologist, 2018, Vol. 58, No. S103-113
Organizational Outcomes • Reduction in adverse events, pain, falls with injury, and depression • Strong association between hours of inservice and quality indicators
Meaningful Engagement
• The core of good dementia care • Every employee plays a role • Individually targeted activities provide: • Meaning • Affirmation of remaining abilities (self-esteem) • Support for who they ARE • Include self-care activities • Participate in “community life” • Group activities, festivities, celebrations • Serve on advisory groups to inform us of needs
Creating Comfortable & Supportive Environments
• Open the campus to others beyond families and guests of residents • Coffee house/café; meeting space; gardens, memory café, etc.
• Rethinking the use of space • Creating ADHC on campus, etc.
Creating Comfortable & Supportive Environments • Pay close attention to wayfinding • Signage with words & pictograms for most important areas (e.g. restrooms) • Directional symbols
• Uniform lighting • Maximize sunlight; use of circadian lighting
• Provide contrast between surfaces, walls and thresholds • Avoid high gloss, patterned/speckled surfaces • Color and contrast important in bathrooms
• Homelike space • • • • •
Dining room should have less than 10-12 people gathered Small clusters of chairs to promote conversation Kitchens that invite participation Colors, pictures, names, objects of interest to find person’s own space Toilet visible from person’s bed
• Maximize use of outdoor space • Free(er) access to the out of doors Calkins, M. The Gerontologist, 2018, Vol. 58, No. S114-126
Stirling Standards for Dementia Friendly Design As a person with dementia in this building and its associated outside space: • I feel calm and relaxed • I am safe as possible from falls and infection • I am able to find my way with ease • I have things to do • I will be able to go outside when I want to • I will be helped to eat well • I will be able to sleep well https://www.dementiaaction.org.uk/assets/0000/7618/dsdcthe_stirling_standards_for_dementia_120430_1.pdf
Support of Care Partners • Information & education • Overcoming stigma • Skill building • Understanding and intervening with behavioral expressions and upset • Learning to ask for and accept help • Building community • Finding others in a like situation – avoiding isolation • Building rapport with staff and becoming part of the team • Respite Care • Acknowledging “ambiguous loss”* • Person is physically present but psychologically changed/ absent *Boss, 2011. Loving Someone who has dementia
Thank you for being heroes to those living with dementiaâ&#x20AC;Ś.helping them to live well!
Questions? Jan Dougherty, MS, RN, FAAN Special Projects Consultant Banner Alzheimerâ&#x20AC;&#x2122;s Institute Phoenix, AZ jan.dougherty@bannerhealth.com