Clinical Aspects of Dementia:
Emphasis on Alzheimer Disease
Summer School of Neuroscience and Aging
Venice, Italy 10-14 June, 2013
Richard W. Besdine, MD,FACP
Professor of Medicine
Professor of Health Services Policy and Practice
Greer Professor of Geriatric Medicine
Director, Division of Geriatrics and Palliative Medicine
Director, Center for Gerontology and Healthcare Research
ALPERT
MEDICAL
SCHOOL
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 25year 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
Alois Alzheimer - 1906
“…only a tangle of fibrils indicates
the place where a neuron was
previously located.”
“Soon she developed
a rapid loss of memory...”
-amyloid Plaques
Immunocytochemical staining (anti-amyloid antibody) of
neuritic plaques in the hippocampus of an AD patient
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
45
All types of dementia
40
Alzheimer's disease
35
Vascular dementia
30
25
20
15
10
5
0
60–64
65–69
70–74
75–79
80–84
Age (years)
85–89
> 90
Worldwide dementia: the numbers will
double every twenty years!!
Million
81.1
80
60
42.3
40
24.3
20
0
2001
2020
2040
Ferri et al., 2005, Lancet 366:2112-17
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
Oeppen J et al. Science. 2002;296:1029-1031
Life Expectancy in Years
We And Many Of Our Patients Will
Live Long Enough To Develop AD
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
35%
14%
No
72%
Yes
28%
14%
9%
7%
21%
Dementia (not AD)
Stroke
Depression
No diagnosis
Normal aging
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
Evaluation of Dementia2

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
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)

Accuracy of NINCDS Criteria for AD

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)
Risk Factors for AD
Definite
Possible/Probable
Age
Head Injury
Atherosclerosis (stroke)
Hypertension (stroke)
Apolipoprotein E4
Down’s Syndrome
Female Gender
Multiple mutations
Smoking
Family History
Diabetes
History of depression
HSV
Education (-)
Mediterranean diet (-)
Exercise (-)
Intellectual work (-)
Apolipoprotein E2 (-)
Proteolytic Cleavages of Amyloid Precursor
Protein (APP) That Produce A42 Peptide
-amyloid precursor protein
Extracellular
space
TM
Cytoplasm
A peptide
COOH
NH2
-secretase
alpha-secretase
-secretase
Selkoe DJ et al. JAMA. 2000;283:1615-1617.
Figure 4. Appearance of plaques and DAT
70.00
Amyloid Plaques (Braak & Braak)
Proportion (%)
60.00
50.00
DAT - Average of Three Studies
40.00
30.00
20.00
~10 years
10.00
0.00
46-50
51-55
56-60
61-65
66-70
71-75
76-80
81-85
Age (years)
Courtesy of Dr. Mark Mintun
86-90
Cascade Model of Neurodegeneration in AD
Jack et al. Lancet Neurology, 2010
6-Year Change of Mild Cognitive Impairment
Over time, persons with
amnestic MCI are at risk of
developing AD dementia
Petersen RC et al. Current concepts in Mild Cognitive Impairment. Arch Neurol 2001;58:1985-1992.
“The Prevention Paradigm”
Cognitive
function
Preclinical
An intervention here
might “prevent” people
from developing MCI
or dementia
MCI
Dementia
Years
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 (A42)
Diagnosis of AD - CSF Aβ42,Tau




>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 E4)
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
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
Behavioral Symptoms in DLB
Ranked by Frequency of Occurrence (% of Patients)
Symptoms >50% of Patients (%)
Apathy/indifference
Anxiety
Depression/dysphoria
Delusions
Agitation/aggression
Irritability/lability
Aberrant motor
72.5
70.0
65.8
58.3
55.0
55.0
53.3
Symptoms <50% of Patients (%)
Appetite; eating disorder
Elation/euphoria
Disinhibition
34.2
18.3
16.7
McKeith IG et al. Neurology. 2000;54:1050-58
Percentage of Patients
with Symptoms
Symptoms in DLB versus AD
*P<.05
80
DLB
AD
70
60
50
40
*
30
20
10
*
*
*
0
Ballard C et al. Curr Psychiatry Rep. 1999;1:49-60
–7
–6
–5
AChEI
–4
Placebo
–3
–2
–1
0
Baseline
70
*
Patients Improving (%)
–8
NPI 10-Item Score—Percentage of
Patients Improving by 30% from Baseline
Neuro-psychiatric
Inventory (NPI) 10-Item Score
Improvement
Mean Change from Baseline
Cholinesterase Inhibitor (AChEI) Effects on
Behavioral Symptoms in DLB
60
**
50
40
30
20
10
0
12
Weeks
*P<.01 vs placebo; **P<.001 vs placebo
Adapted from McKeith, et al, 2000.
20
Week 20
AChEI
3–12 mg/d (n=59)
Placebo (n=61)
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
Perry, et al, 1985; Korczyn, 2001
Fronto-temporal Dementia





FTD is most common fronto-temporal neurodegeneration; 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
Proportion of AD Patients Remaining at Home
Probability of NH Admission After Caregiver Intervention
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
Time in Years
Mittelman MS et al. JAMA. 1996;276:1725-1731
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 longlasting 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
Probability of Remaining at
Home
1
0.8
Placebo
High Dose
Higher Dose
0.6
0.4
0
100
200
300
400
500
Days
600
700
800
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, homehealth 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
 Stop
Rx without evaluation is dangerous
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