ALZHEIMERS AND DEMENTIA UPDATE TOMA 2006

1
ALZHEIMERS AND DEMENTIA UPDATETOMA 2006

• G. BARRY ROBBINS, D.O., FACN
• Associate Professor and Chair
• Department of Neurobehavioral Sciences
• KCOM a college of ATSU

2
(No Transcript)
3
Goals

• Epidemiology
• Memory in typical aging
• Mild cognitive impairment
• Dementia syndromes
• Anterograde Amnesic Syndrome of AD
• Dementia due to Cerebrovascular disease
• Dementia Associated with Parkinsonism Dementia
  with Lewy Bodies
• Cognitive-Behavioral Syndrome of FTD
• Rapidly Progressive Dementias - Creutzfeldt-Jakob
  Disease
• Mental Status and functional Assessments
• Laboratory Evaluations
• Hierarchical Approach to Diagnosing Dementia
• Progress and Future Direction in the Diagnosis of
  Dementia

4
Number of People Age 65 and Over, by Age Group,
Selected Years 1990-2000 and Projected 2010-2050
Federal Interagency Forum on Aging-Related
Statistics 2004, Older Americans
5
Future Demographics

• On January 1, 2011, as the baby boomers begin to
  celebrate their 65th birthdays, 10,000 people
  will turn 65 every daythis will continue for 20
  years.
• Alliance for Aging Research
• By 2030, the number of older Americans is
  projected to have more than doubled to over 70
  millionrepresenting nearly 20 of the
  population.
• Federal Interagency Forum on Aging-Related
  Statistics 2004, Older Americans

6
Epidemiology of Dementia

• 18 million worldwide
• 4.5 million USA
• 14 million Americans are likely to be stricken by
  2050.
• Incidence - increases steadily
• 0.5 / year _at_ 65yrs
• 8 / year _at_ 85yrs
• Prevalence
• 3 _at_ 65yrs
• 47 after 85yrs

7
(No Transcript)
8
Prevalence of Dementia in USA

• Ages 40-65 1 in 1000
• Ages 65-70 1 in 50
• Ages 70-80 1 in 20
• Age 80 1 in 5

9
Alzheimers DiseasePrevalence and Incidence

• 4.5 million Americans suffer from Alzheimers
  disease. That number has more than doubled since
  1980.
• Hebert et al. 2003, Alzheimer Disease in the US
  Population
• 360,000 new cases of Alzheimers disease are
  diagnosed every year980 every day, 40 every
  hour.
• Cummings and Cole 2002, Alzheimer Disease

10
DementiaWorld Prevalence

• The total number of people with dementia in the
  world
• 11 million in 1980
• 18 million in 2000
• 40 million in 2025.
• By 2025
• there will be four times as many people with
  dementia in the developing world as there were in
  1980
• 71 of people with dementia will live in
  developing countries.

11
Memory in typical aging

• Myth Forgetfulness is an inevitable
  consequence of aging.
• Typical aging per se does not degrade memory - -
  - disease does.
• Everyday forgetfulness occurs in most
• Easy to overlook genuine memory lapses in
  dementia
• Misleads people with normal brain function who
  fear development of AD

12
Pseudo-Dementia

• Younger patient become preoccupied with memory
  loss anxiety is the enemy of recall.
• Some sharp or compulsive persons notice a normal
  slipping with age with ready recall or
  word-finding. (May require psychometrics to
  distinguish)
• Psychomotor retardation associated with severe
  depression - more abrupt onset
• (Some older patients have combined organic
  dementia and severe depression)

13
Clinical Definition of Dementia

• Key principles
• Patient has experienced a decline from some
  previous higher level of functioning
• The dementia significantly interferes with work
  or usual social activities
• Transparent vs blurred for families and
  physicians
• Comorbid conditions
• Marital and child-parent relationships

14
Psychometric Definition of Dementia

• Deficits apparent in gt 1 Cognitive Domain
• Recent memory ability to learn, retain, and
  retrieve newly acquired information
• Language ability to comprehend and express
  verbal information
• Visuospatial function ability to manipulate and
  synthesize nonverbal, geographic, or graphic
  information
• Executive function ability to perform abstract
  reasoning, solve problems, plan for future
  events, mentally manipulate more than one idea at
  a time, maintain mental focus in the face of
  distraction, or shift mental effort easily

15
Diagnostic Criteria for Dementia

• Presence of at least 2 of the following
  impairments.
• Impaired learning and impaired retention of new
  or recently acquired information (short-term
  memory)
• Impaired handling of complex tasks
• Impaired reasoning ability (Abstract thinking)
• Impaired spatial ability and orientation
• (constructional difficulty and agnosia)
• The impairments interfere with work or usual
  social activities or relationships with others
• The impairments represent a notable decline from
  a previous level of functioning
• The impairments do not occur exclusively during
  the course of delirium
• The impairments are not better explained by a
  major psychiatric diagnosis

16
Mild cognitive impairment

• Easy to recognize MCI ( a large intermediate zone
  between the cognitively normal elderly and those
  with dementia
• Impairment in at least 1 cognitive domain
  (usually recent memory) but who function
  independently in daily affairs.

17
Pathogenesis of Mild Cognitive Impairment
18
Mild cognitive impairment (MCI)

• 2 Variants Recognized
• Amnesic type
• Most common
• Preclinical manifestation of AD
• Most common - Impaired performance on delayed
  recall
• Multiple cognitive domains - localized impairment
  of other cognitive domains
• Less common
• Signal non-AD clinical syndromes

19
MCI (Amnesic type)

• Presence of a new memory complaint, preferably
  corroborated by an informant
• Objective evidence of impairment of short-term
  memory (for age)
• Normal general cognitive functions
• No substantial interference with work, usual
  social activities, or other activities of daily
  living
• No dementia, according to criteria
• Need Psychometric and laboratory evaluation to
  distinguish

20
Pittsburg Compound-B (PiB)

• PiB Identifies
• Alzheimers disease in vivo
• Those with high IQs who test normal on MMSE
• FTLD from Alzheimers disease
• PiB binds in the cortex or posterior cingulate
  gyrus
• 50-60 MCI patients progress to Alzheimers
  disease within 5 years
• Earlier identification of patients who have
  amyloid plaques will lead to earlier treatment

J. NeuroSci, Aug 24, 2005
21
Dementia Syndromes
Not All Dementing Illnesses Are Alike Syndrome
overlap is common

• Anterograde Amnesic Syndrome of AD
• Dementia due to Cerebrovascular disease
• Dementia Associated with Parkinsonism Dementia
  with Lewy Bodies
• Cognitive-Behavioral Syndrome of FTD

22
Differential Diagnosis of Dementia
Other dementias Frontal lobe dementia
Creutzfeldt-Jakob disease Corticobasal
degenerationProgressive supranuclear palsy
Many others
Vascular dementiasMulti-infarct
dementiaBinswangers disease
Dementia with Lewy bodies Parkinsons disease
Diffuse Lewy body disease Lewy body variant
of AD
Vascular dementias and AD
AD and dementia with Lewy bodies
AD
5
10
65
5
7
8
Small et al, 1997 APA, 1997 Morris, 1994.
23
Genetics of Alzheimers Disease
24
AD Risk Factors

• AGE
• Head injury
• Family history
• Low education
• Most individuals with dementia are not recognized
  early in clinical practice
• Now is the time to begin improving the detection
  rate of symptomatic dementia

25
Neurological Disease Alzheimers DiseaseThe
Burden of Neurological Disease The Human Burden

• Almost half of all people with Alzheimers
  disease have four or more chronic conditions.
• Partnership for Solutions 2002, Alzheimers
  Disease The impact of multiple chronic
  conditions
• Approximately three quarters of Alzheimers
  patients are admitted to a nursing home within
  five years of diagnosis.
• PhRMA 2004, Medicines Reduce the Burden of
  Alzheimers Disease
• State and federal Medicaid spending on nursing
  home care for beneficiaries with Alzheimers
  disease was 19 billion in 2000.
• The Lewin Group 2004, Saving Lives, Saving Money

26
Neurological Disease Alzheimers DiseaseThe
Burden of Neurological Disease The Economic
Burden

• Alzheimers disease is draining more than 100
  billion annually from the nations economy,
  costing American businesses 61 billion a year.
• Alliance for Aging Research 2004, Task Force on
  Aging Research and funding
• The cost of care for a person with Alzheimers
  disease in a facility is approximately 64,000
  per year.
• Alliance for Aging Research 2004, Task Force on
  Aging Research and funding
• Medicare spends 91 billion each year on caring
  for those with Alzheimers disease.
• Alzheimers Association

27
Alzheimers DiseaseThe Future Cost of
Neurological Disease

• Medicare spending for those with Alzheimers
  disease will triple by 2015to 189 billion from
  62 billion in 2000. By 2050, Medicare will be
  spending more than 1 trillion on beneficiaries
  with Alzheimers and related dementias.
• The Lewin Group 2004, Saving Lives, Saving Money

28
Diagnostic Criteria for the Anterograde Amnesic
Syndrome of Alzheimers Disease

• Presence of major impairments in learning and
  retaining new information (memory) and at least 1
  of the following impairments
• Handling complex tasks
• Reasoning ability
• Spatial ability and orientation
• Language
• Impairments notably interfere with work or usual
  social activities or relationships with others
• Impairments represent a notable decline from a
  previous level of functioning

29
Diagnostic Criteria (cont)

• Impairments are insidious in onset and
  progressive
• Impairments do not occur exclusively during the
  course of delirium
• Impairments are not better explained by a major
  psychiatric diagnosis
• Impairments are not better explained by a
  systemic disease or another brain disease

30
Amnesic Syndrome of AD

• Most common observations noticed by Informants
• Pervasive forgetfulness
• Failure to pay bills
• Taking medications incorrectly
• Problems with time orientation
• Personality changes
• Apathy
• Loss of interest in previous past-times and
  activities
• Loss of initiative
• Insight is lost early (anosognosia)

31
Alzheimers Disease
Spect Scan
32
Diagnostic Criteria for Dementia with
Cerebrovascular Disease

• Similar Criteria as AD
• Important Characteristics
• Onset or dramatic worsening of existing
  impairments that occurred within 3 months of a
  stroke (focal neurological deficit)
• Presence of bilateral brain infarctions
  (involving cortical or subcortical gray matter
  structures

33
Dementia Due to Cerebrovascular Disease (VaD)

• Infarctions may be silent
• Non dominant hemisphere
• Micro infarctions (lacunar infarctions)
• Severe white matter disease
• 5 of dementia patients have pure VaD
• 15 have Vad and AD
• 1 in 10 to 1 in 5 patients with dementia have a
  VaD component
• Initial cognitive symptoms depend on location of
  infarction

34
VaD

• Prognosis worse that that of AD
• Mean survival of AD 6 years
• Mean survival of VaD 3 years
• VaD benefits from cholinesterase inhibitors
• Treat Risk factors
• Hypertension
• Diabetes mellitus
• Anti-platelet drugs ?

35
Vascular Dementia
36
Vascular Dementia
Spect Scan
37
Dementia Associated with Parkinsonism Dementia
with Lewy Bodies (DLB)

• Similar criteria as AD
• Must have at least 2 of the following
• Parkinsonism
• Prominent, fully formed visual hallucinations
• Substantial fluctuations in alertness or
  cognition
• REM sleep behavior disorder

38
DLB

• Common Cognitive Deficits that distinguish DLB
  from AD
• DLB
• Slightly better confrontational naming and verbal
  memory
• Worse executive function and visuospatial
  functions
• More apathetic

39
DBL Treatment

• Prognosis faster progression and shorter
  survival than AD
• Treatment involves several strategies
• Cognitive impairment
• Neuropsychiatric features
• Motor dysfunction
• Autonomic dysfunction
• Sleep disorders

40
Progressive Supranuclear Palsy (PSP)

• Cognitive deficits are milder
• Apathy
• Slowing of cognitive processing
• Memory deficits
• Distinguished from AD and DLB by
• Prominent parkinsonian signs
• Gait and balance disorder - falling
• Brainstem abnormalities

41
Progressive Supranuclear Palsy
Facial appearance Poker face
42
Progressive Supranuclear Palsy
Retrocollis (neck extension)
43
Paresis of vertical gaze (Downward paresis)
Progressive Supranuclear Palsy
44
Cognitive-Behavioral Syndrome of Frontotemporal
Dementia (FTD)

• Early manifestations of either of the following
  impairments
• Decline in regulation of personal or social
  interpersonal conduct
• Loss of empathy for the feelings of others
• Socially inappropriate behaviors that are rude,
  caustic, irresponsible, or sexually explicit
• Mental rigidity
• Inflexibility in interpersonal relationships or
  emotional blunting
• Decline in personal hygiene and grooming
• Altered dietary habits
• Impaired reasoning or impaired handling of
  complex tasks out of proportion to impairments of
  recent memory or to spatial abilities

45
FTD

• Uncommon
• Dramatic presentation suggests a psychiatric
  disorder
• Principal manifestations are changes in
• Personality
• Comportment
• Judgment
• Diagnosis Neuroimaging

46
Neuropathology of FTD

• Involves 1 of 3 non-AD pathologies
• Pick Body-positive, tau-positive, frontotemporal
  predominate degenerative dementia
• Tau-positive CBD
• Degenerative disorder with frontotemporal
  predominance that is Tau-negative and lacks other
  distinctive histology

47
Fronto-Temporal Dementia
Spect scan
48
Rapidly Progressive Dementias

• Potentially reversible conditions
• Autoimmune encephalopathy
• Toxic
• Medication misuse, overuse, adverse effects
• Alcohol related
• Metabolic disturbances
• Thyroid, vitamin B12, electrolyte, hepatic, renal
  and calcium-based disturbances
• Depressive disorders
• Acute stroke
• Structural lesions neoplasm, CSDH, NPH
• Sub-acute/chronic encephalitis
• Fatal, irreversible conditions
• Creutzfeldt-Jakob Disease
• Paraneoplastic limbic encephalitis

49
Clinical CJD 80 occurrence between 50-70 yrs.

• Initial Symptoms

• Vague feelings of fatigue
• Disordered sleep
• Decreased appetite

1/3

• Memory loss
• Confusion
• Uncharacteristic behavior

1/3
1/3
50
Major Clinical Signs in Sporadic
Creutzfeldt-Jakob Disease
Sign
Frequency

• Cognitive deficits (dementia), including 100
• psychiatric and behavioral abnormalities
• Myoclonus gt80
• Pyramidal tract signs gt50
• Cerebellar signs gt50
• Extrapyramidal signs gt50
• Cortical visual deficits gt20
• Abnormal extraocular movements gt20
• Lower-motor-neuron signs lt20
• Vestibular dysfunction lt20
• Seizures lt20
• Sensory deficits lt20
• Autonomic abnormalities lt20

New England Journal of Medicine, vol. 339,
Nov.-Dec. 1998
51
Comparison of New-Variant and Sporadic
Creutzfeldt-Jakob Disease
Characteristic
New Variant
Sporadic

• Mean age at onset (yr) 29 60
• Mean duration of disease (mo) 14 5
• Most consistent and prominent Psychiatric,
  sensory Dementia,
• early signs symptoms
  Myoclonus
• Cerebellar signs ( of patients) 100 40
• Electroencephalographic periodic 0 94
• complexes ( of patients)
• Pathological changes Diffuse amyloid
  sparse plaques
• Plaques plaques in 10

New England Journal of Medicine, vol. 339,
Nov.-Dec. 1998
52
Mental Status and functional Assessments

• History taking and Assessment of Function
• Mental Status Examinations
• Neurological Examination
• Integration of MS testing and Informants
  Assessments

53
Assessment of Daily Activities

• Recalling recent events and conversations
• Keeping track of personal items (e.g., keys,
  wallet, purse, glasses)
• Writing checks, paying bills, balancing a
  checkbook
• Assembling tax records, business affairs, or
  papers
• Shopping alone for clothes, household
  necessities, or groceries
• Playing a game of skill, working on a hobby
• Heating water, making a cup of coffee, turning
  off stove
• Preparing a balanced meal
• Keeping track of current events
• Paying attention to, understanding, discussing a
  TV show, book or magazine
• Remembering appointments, family occasions,
  holidays, medications
• Traveling out of the neighborhood, driving,
  arranging to take buses

54
Mental Status Assessment

• Interview the spouse informant separately
• Down plays in front of patient
• Informant unaware, denies, or impaired
• Repeat assessment in 1 week
• Mild dementia
• MMSE is insensitive
• Short Test of Mental Status (STMS) Mayo
• Screen with the Mini-Cog (3-5 minutes)
• Clock drawing test
• Recall of 3 unrelated objects

55
Mini-Cog Assessment for Dementia

• Combines
• An un-cued 3 item recall test
• Clock-drawing test (CDT)
• Administered in appx. 3 minutes
• Instruct the patient to listen carefully to and
  remember 3 unrelated words and then to repeat the
  words
• Instruct the patient on CDT
• Ask the patient to repeat the 3 previously
  presented words

56
(No Transcript)
57
Scoring of the CDT

• Give 1 point for each recalled word after the CDT
  distracter. Score 1 3
• A score of 0 indicates a positive screen for
  dementia
• A score of 1 or 2 with an abnormal CDT indicates
  a positive screen for dementia
• A score of 1 or 2 with a normal CDT indicates a
  negative screen for dementia
• A score of 3 indicates a negative screen for
  dementia
• CDT is normal if all numbers are present in the
  correct sequence and position, and the hands
  readably display the requested time.

Int J Geriatr Psychiatry 2000 15(11) 1021-1027
58
Diagnosing AD in primary carecognitive assessment
The Clock Draw Test
Time 5.00 Score 7 (normal) Time
'no real time' Score 2 (demented)
Time .10.30 Score 3 (demented) Time
1/4 past 25 Score 3 (demented)
Cognitive Assessment
Thalmann et al 1996.
59
Laboratory Evaluation of Dementia

• Psychometric testing
• CBC, electrolyte panel, calcium, Serum Urea
  Nitrogen, Creatinine, glucose
• Vitamin B12
• Thyrotropin
• MRI
• EEG for CJD
• CSF for CJD or rapidly progressive dementias

60
Hierarchical Approach to Diagnosing Dementia
61
Neurological Disease Alzheimers DiseaseThe
Human Value

• A recent study showed that memantine (Namenda), a
  NMDA receptor antagonist approved to treat
  moderate-to-severe Alzheimers, significantly
  slows cognitive decline and reduces the need for
  caregiving by 45.8 hours per month.
• Reisberg et al. 2003, Memantine in
  Moderate-to-Severe Alzheimers Disease
• Donepezil (Aricept), a cholinesterase inhibitor,
  has been found to slow progression of Alzheimers
  disease in its early stages, delaying the need
  for nursing home care by an average of 30 months
  .
• Provenzano et al. 2001, Delays in Nursing Home
  Placement for Patients with Alzheimers Disease
  Associated with Donepezil

62
Neurological Disease Alzheimers DiseaseThe
Economic Value

• Research shows that use of donepezil leads to a
  four-fold increase in drug costs however, it
  significantly lowers overall medical costs,
  reducing medical treatment and prescription drug
  costs by 3,891 per patient, per year.
• Hill et al. 2002, The Effect of Donepezil Therapy
  on Health Care Costs in a Managed Care Plan
• Galantamine (Razadyne), a cholinesterase
  inhibitor, delays Alzheimers patients need for
  full-time care, with overall cost savings
  estimated at 4,256 per patient.
• Caro et al. 2003, Rational Choice of
  Cholinesterase Inhibitor for the Treatment of
  Alzheimers

63
Functional Features of the Cholinergic System
64
Progress and Future Direction in the Diagnosis of
Dementia

• Our understanding of dementia has advanced
  remarkably in the past 20 years
• As primary care physicians see more patients with
  dementia and as more of these physicians are
  trained to perform mental status examinations,
  confidence and success in diagnosing dementia
  should increase
• In the next decade, the focus may shift to
  earlier diagnosis and identification of
  individuals without dementia who are at risk of
  AD or other specific forms of dementia
• The highly likely development of effective
  preventive or arrestive therapies in the next 20
  years will substantially increase the need for
  early, accurate clinical diagnosis

65
Alzheimers Disease
Senile Plaque
66
Plaques and Tangles In Alzheimers Disease
67
Neurotrophins

• A study led by researchers at the San Francisco
  VA Center and the University of North Carolina,
  Chapel Hill has identified several new compounds
  that could play a role in preventing or treating
  and other degenerative conditions of the nervous
  system.
• In culture, the compounds bind with a receptor
  found in the brain and called p75NTR. In the
  body, p75NTR is a binding site for molecules
  known as neurotrophins, which normally promote
  the growth and development of neurons and other
  cells but, according to other studies, can also
  kill them, depending on how and where they bind
  to a cell.

68
Reduction of A? burden in entorhinal cortex
In PDAPP mice following A? injection
69
Healthy Longevity Plan

• Memory exercises crossword, brainteasers
• Daily walks
• Balanced diet - 5 small meals a day
• Omega-3 fats
• Antioxidants
• Whole grains
• Relaxation exercises

70
Cardiovascular Disease Heart Disease and
StrokeThe Human Value
Death Rates for Coronary Heart Disease, 1950-1998
National Center for Chronic Disease Prevention
and Health Promotion 2003, The Burden of Chronic
Disease and the Future of Public Health