Clinical Aspects of Dementia:Emphasis on Alzheimer Disease

Summer School of Neuroscience and Aging Venice, Italy 10-14 June, 2013

Richard W. Besdine, MD,FACPProfessor of Medicine

Professor of Health Services Policy and PracticeGreer Professor of Geriatric Medicine

Director, Division of Geriatrics and Palliative MedicineDirector, Center for Gerontology and Healthcare Research

A L P E R T

M E D I C A L

S C H O O L

Population Aging

Average life expectancy (ALE) at birth in ancient Rome for a citizen was ~25 years; 35 years in Padova when Morgagni was dissecting

In 1900 America, 48: 50 for, 47 for; in 2013, 81 and 76, respectively – 1900 years for 1st 25-year gain in ALE, <100 years for the next

For Italians reaching adulthood in 2013, ALE is nearly 90 for women and >80 for men

Maximum life span increase, though slower than increase in ALE, has not slowed since 1950s

Nine Themes of Aging1

These themes are the conceptual basis for understanding the interactions of aging changes with diseases and risk factors

Themes explain relationships of symptoms, signs and diagnostic tests to disease and changes in organ function in older persons - special knowledge base of geriatric medicine

The themes facilitate analysis and understanding of the most complex and challenging clinical problems of older patients

Nine Themes of Aging2

1. Pure Aging – Changes in organ function due only to aging – presbyopia

2. Reduced capacity to maintain homeostasis if stressed – delirium, falls in hospitalized elders

3. Geriatrics Syndromes – Disease-age interactions produce specific common function losses – falls, delirium, syncope, dizziness, UI, weight loss

4. Interaction of disease with pure aging produces changes in disease behavior beyond syndromes – SDH more frequent

Nine Themes of Aging3

5. Pure aging misinterpreted as disease – slow information retrieval called dementia

6. Disease misinterpreted as pure aging effect – obvious dementia symptoms called “old age”

7. Medication Hazards – pure aging & disease ↑↑ risks of adverse drug effects – CNS, CV toxicity

8. Multimorbidity – Interactions of multiple diseases accelerate potential for harm

9. Diseases Special in Aging – Common only in elders; geriatricians must know – DCHF, AD

What is Human Aging?

●Not nearly as important as we thought?

●A set of predictable, gradual and inevitable changes in biological and psychological function, usually decremental, that occur in healthy persons with the passage of time

Age-related Structural Brain Changes

Enlarged Subdural space predisposes to SDH

Narrower gyri

Wider sulci

Enlarged ventricles

Neurologic Exam Changes of Aging

arm swing, tone - Dopamine neurons DTRs in feet Gag reflex Ability to prevent postural sway Ability to prevent orthostatic hypotension Baroreflex sensitivity Reemergence of primitive reflexes Hand- and foot-tapping speed Restricted upward gaze

Pure Aging Changes in Memory1

● Most memory functions change little with pure aging – mild in attention; elders more easily distracted, so avoid competing tasks

● Processing speed (reaction, retrieval, timed tasks, perceptual), free recall, multi-tasking all decline with age

● Retrieval of names, persons especially, and objects often transiently lost

Pure Aging Changes in Memory2

● Sensory memory - earliest stage (visual, auditory, tactile) - unstable, rapid decay; no age-related change

● Primary, or working (short-term) memory - rehearsal transfers sensory to short term memory - no loss with age

● Long term (secondary) - hours, days, years + Declarative (explicit) memory: either semantic

(facts, meanings; no Δ), or episodic (events, time, place; autobiography), aging decline

+ Procedural (implicit) – biking, music, knots - no Δ

Quality of Scientific Evidence Concerning Risk Factors for AD

Declines in Special Senses

● Vision - accommodation (presbyopia), low-contrast acuity, glare tolerance, adaptation, color discrimination, attentional visual field all decline, due to changes in the eye peripherally and in central processing

● Hearing - Neural, conductive and sensory losses (presbycusis); primarily high tones (consonants) – 50% clinically significant

Strength and Balance● Major confounders are disuse and disease● Muscle mass, strength ; modifiable by training –

at best ~15% by 80; fast twitch type 2 ● Sarcopenia (>50% ) common, NOT pure aging● Strength, cerebellar integrity, hearing and vision

all play a role in balance● Vestibular portion of 8th CN – degeneration of

otoconia (otolith granules) – multiple diseases, 8th N sensitivity to drugs are confounders

● Single stance, eyes closed a powerful discriminator

“Soon she developed a rapid loss of memory...”

“…only a tangle of fibrils indicates the place where a neuron was previously located.”

Alois Alzheimer - 1906

Auguste D

Immunocytochemical staining (anti-amyloid antibody) of neuritic plaques in the hippocampus of an AD patient

-amyloid Plaques

Neurofibrillary Tangles

Immunocyto-chemical staining (anti-tau antibody) of neurofibrillary tangles in hippocampus of an AD patient

Epidemiology of AD1

10% > age 65, ~40% > age 85 No clear ethnic or racial patterns – China data: 2.6%

65-67, 60% 95-99 (Chan KY et al. Lancet 2013; 381: 2016–23)

Is it getting more common? – probably not AD is a women’s problem

+ Majority of AD patients women; lifetime risk 32%, 18% men; prevalence > in 11 studies, up to 2:1

+ Women live longer once they have the disease+ Women are caregivers for AD victims

Epidemiology of AD2

60-80% of dementia >65 is AD (US studies)

>5 million now, 3-fold increase as baby boomers turn 70 and 80 beyond 2025

Costs of care in US $157-215 billion/yr (Hurd MD et al.

NEJM. 2013;368:1326-34).

5th leading cause of death

Survival after diagnosis <4 years (length bias), like aggressive cancer or severe CHF; should be on everyone’s hospice list

Wolfson C, et al. NEJM 2001;344:1111-6

Prevalence of Dementia by Age

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60–64 65–69 70–74 75–79 80–84 85–89 > 90

All types of dementia

Alzheimer's disease

Vascular dementia

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Worldwide dementia: the numbers will double every twenty years!!

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2001 2020 2040

Ferri et al., 2005, Lancet 366:2112-17

Million

If We Live Long Enough, Will We All be Demented?

Dementia prevalence doubles ~ every 5 years between age 65-85

Prevalence levels off in later years, as censoring by death from other causes outstrips rising incidence; does risk diminish? ~ 47% at 85 years (Evans,1989) ~ 58% at >95 years (Ebly,1994)

Universal cognitive aging - WAIS-R IQ “normal” at age 85 is 50% of correct answers at age 21

Median survival of women in the longest-lived countries has increased 3 months/year since 1840

We And Many Of Our Patients Will Live Long Enough To Develop AD

Oeppen J et al. Science. 2002;296:1029-1031

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Year

What is Dementia?

An acquired disorder producing decline in memory and other cognitive functions sufficient to affect daily life in an alert patient

Progressive and disabling

NOT a part of pure aging

Very different from normal cognitive lapses

AD by far the most common cause

When to be Concerned Sometimes it is the psychomotor slowing of aging

+ Recall of words or names temporarily lost+ Misplacing the car keys+ Worrying about memory+ Why are you in front of the refrigerator?

Never retrieving names or words Losing the car, major financial mistakes Forgetting entire conversations or events Not recognizing that there is a memory problem Repetition not just for emphasis

AD Is Often Underdiagnosed

Early AD is subtle - the initial signs and symptoms are easily missed

Fewer than half of AD patients (autopsy) are accurately diagnosed

Undiagnosed AD patients face unnecessary added social, financial and medical problems

Early diagnosis and appropriate intervention may lessen disease burden

Sano M et al. N Engl J Med. 1997:336:1216-1222

AD Often Misdiagnosed

Patient initially diagnosed with AD

Patient’s first diagnosis other than AD

Yes 28%

No 72%

21%

7%

9%

14%

14%

35%

Normal aging

Depression No diagnosis

Dementia (not AD) Stroke

Other

Clinical Picture

Insidious, progressive, global decline in cognitive abilities – peak onset ~75, but as young as 30s

Prominent specific cortical deficits, personality changes, executive troubles, catastrophic reactions

Behavioral disturbances very common Depression occurs in > 50% More than 1/3 of incident cases do not fit classic

picture; thus less likely diagnosed

The Impact of Dementia 75% of AD victims go to NH, stay >3 years Economic

~$200 billion annually for care and lost productivity – most expensive of all

In the US, Medicare, Medicaid, private insurance provide only partial coverage

Families bear greatest burden of expense Emotional

Direct toll on patients Nearly half of caregivers suffer depression

Mortality of

Dementia

Noale M et al. Dement Geriatr Cogn Disord 2003

Evaluation of Dementia1

Screening At annual physical >70 or earlier if red flags

Ask patient about any new problems with memory, mood, behavior and driving

Baseline MMSE and clock drawing or 3-word recall and clock (mini-cog)

Evaluation for positive screen Add reliable informant to interview Structured criteria – DSM or NINCDS-AD Search for causes Identify and manage co-morbidities Genetic testing not recommended in 2012

Chemistries (BUN/Creatinine, electrolytes, BS, calcium), CBC, Liver function tests

Thyroid, pituitary-adrenal axis Vitamin levels – B12, folic acid (?)

Serology for Lyme, HIV, Syphillis Brain image (CT without contrast) if <65, symptoms

recent (<2yrs), focal neurologic signs, suspicion of NPH, or recent trauma

Neuropsychological testing if diagnosis unclear

Evaluation of Dementia2

Small GW, et al. JAMA. 1997;278:1363-1371

Criteria for Diagnosis of Dementia

Global cognitive impairment with clear sensorium Development of multiple cognitive deficits, with memory

impairment, and one or more of:

+ Aphasia+ Apraxia+ Agnosia+ Disturbance in executive functioning

Cognitive deficits are a significant decline from baseline and cause significant functional impairment

Deficits are not caused by delirium (R/O by work up)

In academic referral centers, accuracy of probable AD diagnosis is 81-100% (Galasko et al, 1994; Morris et al, 1988; Tierney, 1988)

In one post-mortem series, 77% of cases of “possible” AD had AD (Galasko et al, 1994)

In a community-based post-mortem series, accuracy of probable AD diagnosis was 75% (Lim et al, 1999)

Accuracy of NINCDS Criteria for AD

Risk Factors for AD Definite Possible/Probable Age Family History Head Injury Diabetes Atherosclerosis (stroke) History of depression Hypertension (stroke)HSV Apolipoprotein E4 Education (-) Down’s Syndrome Mediterranean diet (-)

Female Gender Exercise (-) Multiple mutations Intellectual work (-) Smoking Apolipoprotein E2 (-)

Proteolytic Cleavages of Amyloid Precursor Protein (APP) That Produce A42 Peptide

Selkoe DJ et al. JAMA. 2000;283:1615-1617.

-amyloid precursor protein

-secretase

A peptide

-secretase

Extracellular space

TM Cytoplasm

COOHNH2

alpha-secretase

Figure 4. Appearance of plaques and DAT

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46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85 86-90

Amyloid Plaques (Braak & Braak)

DAT - Average of Three Studies

Age (years)

Pro

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)

Courtesy of Dr. Mark Mintun

~10 years

Jack et al. Lancet Neurology, 2010

Cascade Model of Neurodegeneration in AD

Petersen RC et al. Current concepts in Mild Cognitive Impairment. Arch Neurol 2001;58:1985-1992.

Over time, persons with amnestic MCI are at risk of developing AD dementia

6-Year Change of Mild Cognitive Impairment

“The Prevention Paradigm”

Years

Cognitivefunction

MCI

Preclinical

Dementia

An intervention heremight “prevent” peoplefrom developing MCI or dementia

The Genetics of AD Mutations on chromosomes 1, 14, 21 (APP

regions) are associated with: Rare early-onset (<60) familial forms of AD Down syndrome

Apolipoprotein E alleles on chromosome 19 APOE4 allele a powerful risk for AD (1 allele

3X, 2 alleles 10X), and earlier by ~10 years APOE2 allele probably has protective effect

APOE in -amyloid plaques and neurofibrillary tangles; affect protein–protein interactions?

Presenilins and Their Role in AD

Presenilin 1 (PS1) and presenilin 2 (PS2) on chromosome 14 – mutations in the proteins coded by these genes are most common genetic cause of familial Alzheimer’s Disease

PS1 and PS2 cause increased secretion of the more amyloidogenic form of -amyloid (A42)

>100 subjects each of clinically characterized (research criteria) elders as AD, MCI or normal

Low amyloid 1-42 (Aβ42) level, high total tau protein (T-tau), and elevated phosphorylated tau protein 181 (P-tau 181) in >90% of AD patients, 73% MCI, 39% controls (↑↑ AD pattern, Apo E4)

Sensitivity 90% for AD, specificity 64% in 3 distinct data sets, by post-mortem

AD CSF pattern (low Aβ42, high P-tau 181) identified all MCI cases progressing to AD in 5 yrs

Diagnosis of AD - CSF Aβ42,Tau

Meyer GD et al. Arch Neurol. 2010;67(8):949-956

Vascular Dementia

2nd or 3rd (DLB) most common dementia

Affects ~5-10% of the population >90

Associated with stroke, cerebrovascular disease (white matter hyperintensities)

Often coexists with AD neuropathology; undetected stroke makes dementia symptoms much worse (Snowdon DA. JAMA. 1997;277:813-817)

Decline in cognition, function, and behavior

Dementia With Lewy Bodies 15%–25% of all dementia in the elderly Onset ~75–80 years Survival ~3.5 years (<1–20) Slight male predominance Characterized by

Fluctuating cognitive impairment (~80%) Visual hallucinations, nightmares (>60%) Parkinsonism (65%–70%) Frequent severe neuroleptic side effects

DLB Biology Alpha-synuclein (α-syn), normally a soluble CNS protein of

unknown function, encoded by SNCA gene, can aggregate abnormally to form insoluble fibrils (primary Lewy body structure) in synucleinopathies (DLB, PD, multiple system atrophy)

An α-syn fragment, known as the non-Aβ component (NAC) of AD amyloid, originally found in an amyloid-enriched fraction, is fragment of its precursor, NACP (human α-syn)

Occasionally, Lewy bodies contain tau; α-syn and tau are two distinct filament subsets in same inclusion bodies

α-syn pathology is also found occasionally in both sporadic and familial cases of AD disease

Ranked by Frequency of Occurrence (% of Patients)

McKeith IG et al. Neurology. 2000;54:1050-58

Apathy/indifference 72.5 Appetite; eating disorder34.2Anxiety 70.0 Elation/euphoria18.3Depression/dysphoria 65.8 Disinhibition16.7Delusions 58.3Agitation/aggression 55.0Irritability/lability 55.0Aberrant motor 53.3

Symptoms >50% of Patients (%) Symptoms <50% of Patients (%)

Behavioral Symptoms in DLB

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Ballard C et al. Curr Psychiatry Rep. 1999;1:49-60

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Symptoms in DLB versus AD

*P<.05

*P<.01 vs placebo; **P<.001 vs placebo

Adapted from McKeith, et al, 2000.

BaselineIm

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Neuro-psychiatricInventory (NPI) 10-Item Score

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3–12 mg/d (n=59)Placebo (n=61)

NPI 10-Item Score—Percentage of Patients Improving by ³30% from Baseline

* *70

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Cholinesterase Inhibitor (AChEI) Effects on Behavioral Symptoms in DLB

Perry, et al, 1985; Korczyn, 2001

Parkinson’s Disease and Dementia

At least one-third of Parkinson’s Disease (PD) patients develop dementia

Patients with PD show degeneration of the nucleus basalis of Meynert and low brain choline acetyl transferase levels

The dementia of PD is not improved by dopaminergic drugs (e.g., L-DOPA, pergolide, bromocriptine, bupropion, dopamine)

Cholinesterase inhibitor therapy in PD appears to be beneficial

Fronto-temporal Dementia FTD is most common fronto-temporal neuro-

degeneration; rarer than AD, Vascular and DLB Characterized more by pattern of behavioral deficits

than by neuropsychological impairment Clinical features: 1) distractibility, impersistence, 2)

↓in personal hygiene, grooming; 2) inflexibility, mental rigidity; 3) hyper-orality, diet change; 4) utilization behavior; and 5) perseverative, stereotyped behavior

Current treatment only for symptoms; no evidence of benefit from any drug class, including AChEIs

Serotonin deficit may play a role in behavior

Perry RJ. Neurology. 2001;56:46-51. Neurology. 2000;54:2277-84. Morris JC. Neurology. 2001;57:173-174.

Physician Role in Dementia Care

Thorough evaluation to make the diagnosis Honest information - truth, but not bludgeon Continuing care - "patient" includes family unit, as well

as the victim with plaques and tangles Reality testing - timing and appropriateness of support

services and institutionalization Ethical and appropriate choices for EOL care - not at

first encounter, but not to wait for a crisis either+ Restricted Rx, advance directives beyond DNR+ Code status, tube feeding, hospitalization, Abx

Maximize General Medical Health

Decrease excess morbidity; i.e., evaluation and optimal care for co-morbidities - all worsen cognition Periodic examinations Routine lab screening, based on problem list Preventive interventions that make sense

+ Vaccines, mammograms, FOB/endoscopy, OP?+ Only if action consistent with advance directives

Comprehensive evaluation for sudden decline; delirium common, AD doesn’t worsen overnight

Non-pharmacologic Interventions Care management and psychosocial interventions Educate caregivers – understand the disease, caregiver

stress, avoid antipsychotics Performance and behavior

+ Scheduled toileting+ behavior modification, avoid triggers; distract, redirect+ Exercise+ Music, massage, pet therapy

Environmental modification+ Safe space to wander+ Remove toxins, weapons

Does AD Caregiver Support Effect Nursing Home Admission?

RCT of >200 early or middle-stage AD caregivers/spouses, follow up nearly 4 years

6 sessions of individual, family counseling within 4 months of enrollment and join support group

What happened to the Alzheimer patients after their caregivers attended the 6 sessions?

What about nursing home admission?

Mittelman MS et al. JAMA. 1996;276:1725-1731

Mittelman MS et al. JAMA. 1996;276:1725-1731

Probability of NH Admission After Caregiver Intervention

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Time in Years

2/3 RR,329 days more at

home

Caregivers in intervention 1/3 less likely to place spouses in NH; greatest benefit if mild or moderate dementia

Dementia Caregiver Interventions Alzheimer’s Association – a remarkable organization

providing education and support network FOR caregivers Education and support for caregivers Contact person identified, phone # for emergencies Advance directives, LTC + financial planning Caregivers’ physical, mental health; consider primary

care visits coincident with those for AD patient Use of respite and adult day care Simplify and structure home environment Driving and home safety

Treatment of AD Symptoms

Consider possibility of excess disability

Depression - >50% during disease course

Agitation, aggression, delusions

Wandering – behavioral, caregiver interventions

Incontinence – evaluate, treat

Malnutrition – treat, but weight loss common

Altered sleep – behavioral, modern hypnotics

Treatment of AD Pathology Proven effective therapies

+ Reduce stroke risk+ Cholinesterase inhibitors (“minimally effective”)+ Memantine – approved for severe dementia

Proven ineffective therapies+ Antioxidants+ Ginko biloba+ Estrogen+ Anti-inflammatory drugs (NSAIDs)+ Drugs to improve cerebral blood flow

Statins? Probably not

Cholinesterase Inhibitor Side Effects

Common, sometimes transient, but may be long-lasting and disabling - dose-related; titrate slowly, take with food+GI – NVD, anorexia, weight loss+Vivid dreams/nightmares+Headache

Less common

+Agitation

+Hypotension

Delay in NH Placement with Donepezil

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Drugs for Dementia Behavior Disorders

Antipsychotics have demonstrated superior results in most randomized trials, but off label use

Be sure symptoms justify these dangerous drugs: agitation, aggression or delusions that disrupt care and impair life quality for caregiver and patient

Data conflicting whether atypical agents are better, but easier to use – fewer daily side effects of sedation or movement disorders, but FDA black box for all antipsychotic agents (stroke, CV death)

Use should be short-term, low dose

Risks of Atypical Antipsychotics

FDA review of 15/17 placebo-controlled trials showed numerical increase in risk of death with atypical anti-psychotic drugs in dementia patients (olanzapine, aripiprazole, risperidone, quetiapine)

5,106 subjects, 1.6-1.7x increase in mortality - heart failure, sudden death, pneumonia

May also be true for other atypicals (clozapine and ziprasidone) and typical neuroleptic drugs, but data insufficiently persuasive for FDA

Conflicting reports of increased stroke risk with risperidone; no FDA warning

Resources for Managing Dementia

Attorney for will, conservatorship, estate planning; can be helpful with advance directives

Community: neighbors & friends, aging & mental health networks, adult day care, respite care, home-health agency

Organizations: Alzheimer’s Association (caregiver support groups), Area Agencies on Aging, Councils on Aging

Services: Meals-on-Wheels, senior citizen centers

Principles of Dementia Care

Complicating diseases often missed Hospitals are dangerous - avoid if at all possible

Dementia brain exquisitely sensitive to drugs - avoid

Useful Rx should not be withheld for age or dementia

Painful Rx should be very carefully considered

Symptomatic Rx without evaluation is dangerous

Stop Rx whose side effects are worse than symptoms

Assess response to Rx often and stop ineffective Rx

Summary

Dementia is common, but never normal aging

AD is most common, followed by vascular dementia and dementia with Lewy bodies

Thorough evaluation is mandatory, both for diagnosis and identification of coexisting conditions whose treatment can influence course of dementia

Treatment directed at function and quality of life, using drugs and behavioral interventions

Social and instrumental resources supplement care for patient, caregivers and family members