Dementia by Argentum

Dementia

Lilly makes medicines that help people live longer, healthier and more active lives

Roy Yaari, MD Sr. Medical Advisor, Eli Lilly & Co.

Outline

♦ ♦ ♦ ♦

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

Years of Disease

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 â&#x2122;Ś 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 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™)

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

- 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