Dementia, Neuropathology

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Dementia, Neuropathology Neuropsychology

• Bruce Reed, PhD
• UC Davis

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disclosures

• We gratefully acknowledge support for this
  conference from the National Institute on Aging,
  grant R13AG030995-01A1.
• The views expressed in written conference
  materials or publications and by speakers and
  moderators do not necessarily reflect the
  official policies of the Department of Health and
  Human Services nor does mention by trade
  names,commercial practices, or organizations
  imply endorsement by the U.S.Government.

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The high costs of dementia

• Disability
• Institutionalization
• Annual costs gt150 Billion now
• Mortality
• Complicates all medical management

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Cognitive syndromes of aging

• Dementia Multiple acquired persistent cognitive
  impairments that cause disability
• Mild Cognitive Impairment (MCI) either a) a
  circumscribed cognitive impairment or b) multiple
  cognitive impairments not associated with
  significant functional impairment
• Delirium a transient confusional state
• Normal Cognitive Aging

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Dementia

• Multiple acquired persistent cognitive
  impairments that limit important daily functions
• A syndrome a defined set of symptoms without a
  particular etiology
• Disease a pathological process that produces a
  characteristic set of symptoms. Many different
  diseases cause dementia
• Dementia has biological causes and biological
  correlates, but it is defined behaviorally

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MCI

• A new name for a long-recognized state that is
  intermediate to normal and dementia
• Subject of intense research now as a prodromal
  state to AD
• converts to AD at 10-15 per year
• Some do not worsen, some get better
• Etiologically heterogeneous

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Individual paths of change over 6 years in
persons cognitively normal at baseline
Wilson et. al. Psychol Aging 2002
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Many different pathologies cause dementia

• Degenerative Brain Diseases
• Vascular
• Intoxications
• Infections
• Metabolic Disorders
• Nutritional Disorders
• Space-Occupying Lesions
• Normal Pressure Hydrocephalus
• Psychiatric Disorders

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Degenerative brain diseases

• Alzheimers disease
• Parkinsons disease
• Dementia with Lewy Bodies
• Frontotemporal dementia (Picks, FTLD)
• Huntingtons disease
• Progressive supranuclear palsy
• Corticobasalgangionic degeneration
• Etc.

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How important is it to distinguish between
dementia and the illnesses that cause dementia ?

• Depends on the question
• Very important for diagnosis and disease-specific
  prognosis
• Tends to be important in treatment trials
• May not be important for brain-behavior
  relationships
• May not be important for health services studies
• Depends on the sample
• How prevalent a particular pathology is likely to
  be
• What the mix is likely to include

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AD and CVD are the 1 and 2 major causes of
dementia in the elderly
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Dr. Alois Alzheimer
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1 Prevalence

• Prevalence is very low prior to age 60 and
  doubles every 5 years thereafter reaching 30-50
  above age 85

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The prevalence of AD is strongly linked to age
From Nessbaum Ellis (2003). NEJM, 348 1356.
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2 Symptoms

• Severe episodic memory impairment is hallmark
• Language, spatial, and other reasoning
  impairments follow
• Personality generally preserved
• Behavior disturbance common but highly variable

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3 Course

• Insidious onset, gradual progression
• Eventually leads to total disability (total care)
• averages about 9 years from diagnosis to death
  with wide variability.

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Clock House Copy
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Progressive decline of multiple abilities over 4
years
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Late Self portraits of William Utermohlen
1996
1998
2000
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Brain Basics
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4 Pathology Neurofibrillary tangles (tau) and
neuritic plaques (?-amyloid) are the defining
pathological markers of Alzheimers disease
plaque
tangles
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Amyloid in the brain
Courtesy of ADEAR (NIA)
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Two enzymes cut normal amyloid into fragments
Courtesy of ADEAR (NIA)
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Fragments join and form plaques
Courtesy of ADEAR (NIA)
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AD and the Brain
Neurofibrillary Tangles
Slide 18
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Progression of tangles in AD has a
characteristic spatial distribution
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Figure 1. Evolution of amyloid deposits in AD..
Progression of amyloid in AD is diffuse
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Atrophy of the brain caused by Alzheimers disease
Brain affected by AD Normal elderly brain
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Markers of Alzheimers Disease Hippocampal
Atrophy
Normal
Atrophy
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Atrophy of the hippocampus
normal size
Moderate atrophy
Severe atrophy
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5 Causes

• Etiologically complex
• Genetic factors are strong, but complex and not
  yet defined for most cases
• environmental factors remain largely undefined

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Genes and AD

• 3 known mutations and 1 chromosomal abnormality
  cause AD
• All cause young onset AD
• All affect amyloid production or processing
• Together they account for under 5 of all cases
• There is one known major genetic risk factor for
  AD--apolipoprotein e

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6 treatment

• many symptomatic treatments
• Drugs for cognitive symptoms have weak effects
• no disease modifying treatments

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Galantamine efficacy at 6 months
Raskin et al., Neurology 2000
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Ischemic Vascular dementia

• Dementia that is due to cerebral vascular disease

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1) Vascular lesions

• Infarcts death of brain tissue secondary to
  loss of blood supply
• White matter changes (WMH, WML) loss of
  integrity secondary to partial ischemia and
  micro-infarction
• (?) Cortical Atrophy
• (?) Hippocampal sclerosis

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Vascular lesions on MRI
Lacunar Infarction
White Matter Hyperintensities
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2) There is a wide spectrum of cerebral vascular
disease
Stroke Silent Brain Infarction White Matter
Hyperintensities Accelerated Brain Atrophy
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3) Differential diagnosis of AD from vascular
dementia is difficult

• AD clinics tend to obtain unrepresentative
  samples that are disproportionately pure AD.
• Community based studies find that mixed pathology
  is very common

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Effect of sample source on prevalence estimates

• NACC database in 2003
• 1054 cases from 30 academic Alzheimers disease
  research programs
• AD was the primary neuropathological diagnosis in
  921
• Community based, large unselective sample (CFAS)
• 100 of 209 cases demented
• 64 with pathologically defined AD
• 78 with pathologically defined CVD
• most patients had mixed disease

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4) AD and vascular dementia appear to be
complexly related

• Share multiple risk factors
• May share pathogenic mechanisms, e.g. vascular
  disease may (?) promote AD pathology
• When they co-occur, are effects
• synergistic ?
• Additive ?
• Diminishingly additive ?

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Measuring dementia data types

• Laboratory (blood, csf, etc.)
• Medical (neurological) exams
• Brain imaging
• Measures of daily function
• Neuropsychological tests
• Psychiatric measures

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Neuropsychological tests

• Standardized tests of cognitive ability. Used in
  defining cognitive ability (and change), and in
  differential diagnosis of dementia.
• Psychometric dynamic range, should vary in
  relation to differences in ability
• Performance of individuals can be characterized
  in raw score, percentile or other scaled metrics
  relative to a normative sample.
• Tests are defined by items, and what they do, not
  what they are named.

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Global measures

• Used to quantitate overall premorbid ability
  and present ability
• Tests of native (premorbid) ability
• IQ (WAIS)
• NART
• Tests of current ability (dementia screens,
  dementia severity measures
• DRS ADAS MMSE
• All tap a variety of specific domains how many,
  which, and how they are weighted varies

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Cognitive Domains

• Attention
• Memory
• Language
• Spatial Reasoning
• Executive Function

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Domain-specific tests

• Measure more or less single functions or sets of
  closely related functions
• Characterize the nature of impairment rather than
  its simple presence.
• Useful
• when specific impairments may be obscured on
  omnibus measures
• in differential diagnosis
• For brain behavior correlations
• As building blocks for global measures
• Anatomic substrate of particular functions is
  generally both focal and distributed
• usually correlate moderately, sometimes highly

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Memory

• Long term, short term, working memory, remote
  memory, recent memory, semantic memory,
• Episodic memory refers to the learning, storage,
  and deliberate recall of context-specific
  (experiential) information
• Memory is to some degree modality specific, esp.
  verbal vs. nonverbal
• Hippocampus is a key structure supporting the
  process of forming new memories

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Neuropsychological tests of memory

• Are legion
• Most commonly used are paragraph recall and list
  learning
• Both require learning of novel material, and free
  recall after a delay of 10-30 minutes
• Recognition testing often added
• Yield multiple measures composite or delayed
  recall measures used most often.

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Executive function

• Not a single function but a set of functions
• Key functions
• generation of thought and behavior (response
  options, problem solving strategies)
• Regulation of behavior (initiation, monitoring,
  modifying in response to feedback) of behavior
• especially under circumstances where habitual
  responses are unavailable or inappropriate
• Active online manipulation of information
  critical
• Associated with frontal lobes, frontal systems

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Neuropsychological tests of executive function

• Newer, less uniformity in use than in other
  domains.
• Trail Making Test, Wisconsin Card Sorting test
• Fluency Controlled Oral Word Association Tests,
  Design Fluency
• Tests of working memory
• Digit span
• Sequence reversal, sequence alternation

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A chronic disease model of dementia
latent phase preclinical phase
clinical phase
symptoms
diagnosis
Initiation Factors genetics
environment life style

• Promoting Factors
• Age related change
• vascular risk factors?
• head trauma?
• hypoxia?
• stress, depression?

death
After R. Katzman, 1993
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Risk of Alzheimers disease goes down as amount
of education goes up
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Higher initial capacity or cognitive reservemay
delay clinical onset of dementia
functional impairment

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Thinking activities during adulthood correlates
with lowered risk of dementia
A 1 point increase in cognitive activity reduced
the risk of dementia 7
Verghese, et al. (2003). NEJM, 3482508
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APOE4 increases the risk of Alzheimers disease
and lowers the age of onset

84
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no e4's
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Relative risk of AD
82
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80
age at onset
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one e4
78
12
76
10
8
two e4's
74
6
72
4
70
2
68
0
e3/e3
e2/e2
e2/e3
e2/e4
e3/e4
e4/e4
data from Tsai, et. al., 1994
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Volume of Cortical Gray Matter by Group
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Seeing the pathology of Alzheimers disease in
the brain during life
C
A
B
Images courtesy of Dr. William Jagust, UC
Berkeley and Lawrence Berkeley National Laboratory
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Current Drug Therapies for AD

• Treatments for symptoms
• Drugs that increase acetylcholine levels
• Cognex (Tacrine)
• Aricept (Donepezil)
• Exelon (Rivastigmine)
• Razadyne (Reminyl) (Galantamine)
• NMDA Receptor Blocker
• Memantine (Namenda)