Cognitive Reserve and Alzheimer Disease

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Cognitive Reserve and Alzheimer Disease

• Yaakov Stern, Alzheimer Dis. Asso.c Disord. 2006,
  20 S69S74.

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Who has a higher risk of developing Alzheimers
Disease?

• Higher IQ, education, occupational attainment, or
  participation in leisure activities

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Brain Reserve

• There does not seem to be a direct relationship
  between the degree of brain pathology or damage
  and the clinical symptoms of that damage.
• Is there a reserve against brain damage?

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Passive Model Brain Reserve Capacity

• Passive Models - Brain Reserve Capacity (BRC)
  derives from brain size or neuronal count.
• There may be individual differences in BRC.
• There is a critical threshold of BRC an amount
  of brain damage sustained before reaching a
  threshold for clinical expression.

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Cognitive Reserve (CR) Model

• The cognitive reserve (CR) model suggests that
  the brain actively attempts to cope with brain
  damage by using preexisting cognitive processing
  approaches or by enlisting compensatory
  approaches.
• Individuals with more CR would be more successful
  at coping with the same amount of brain damage.

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CR Neural Reserve

• CR may be implemented in 2 forms neural reserve
  and neural compensation.
• Neural reserve - brain networks or cognitive
  paradigms that are less susceptible to
  disruption, perhaps because they are more
  efficient or have greater capacity.
• In healthy people it is used when coping with
  increased task demands.
• In brain pathology it could help too

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CR- Neural compensation

• Neural compensation - people suffering from brain
  pathology use brain structures or networks (and
  thus cognitive strategies) not normally used by
  healthy people to compensate for brain damage.

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Models - Summary

• The fact that one patient can maintain more AD
  pathology than another but appear similar
  clinically can be explained by the CR models and
  not by the passive models.
• However, it is likely that both CR concepts are
  involved in providing reserve against brain
  damage.

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Measures of Reserve

• Anatomic measures such as brain volume, head
  circumference, synaptic count, or dendritic
  branching are effective measures of brain
  reserve.
• Many of these measures are influenced by life
  experience and may change over the lifetime.

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Measures of Reserve

• CR (cognitive reserve) is also influenced by
  lifetime experience
• Measures of socioeconomic status, such as income
  or occupational attainment.
• Educational attainment including - number of
  years of formal education, and degree of
  literacy.
• Measures of various cognitive functions, such as
  IQ.

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Measures of Reserve

• Genetics Exposure ? innate intelligence ?
  Education
• Still, education, or other life experiences,
  probably impart reserve over and above that
  obtained from innate intelligence.
• CR is not fixed at any point in ones lifetime
  it results from a combination of exposures.

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How does CR affect AD?

• Experiences associated with more CR do not
  directly affect brain reserve or the development
  of AD pathology.
• Rather, CR allows some people to better cope with
  the pathology and remain clinically more intact
  for longer periods of time.

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How does CR affect AD?

• Many of the factors associated with CR may also
  have direct impact on the brain itself. (ex.-IQ
  and brain volume).
• Environmental enrichment might prevent or slow
  accumulation of AD pathology.
• Estimating CR integrating the interactions
  between genetics, environmental influences on
  brain reserve and pathology, and the ability to
  actively compensate for the effects of pathology.

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Epidemiologic Evidence for CR

• Many studies have examined the relation between
  CR variables and incident dementia.
• Parallel studies have often examined the relation
  between these variables and cognitive decline in
  normal aging.

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Education and CR

• Several studies in India, England, and the United
  States reported no association between education
  and incident dementia.
• However, lower incidence of dementia in subjects
  with higher education has been reported by at
  least 8 cohorts, in France, Sweden, Finland,
  China, and the United States.

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Education and CR

• Education has a role in age-related cognitive
  decline.
• Several studies of normal aging reporting slower
  cognitive and functional decline in individuals
  with higher educational attainment.
• The same education related factors that delay the
  onset of dementia also allow individuals to cope
  more effectively with brain changes encountered
  in normal aging.

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Occupation and CR

• No or vague association between occupation and
  incident AD was found.
• Nevertheless, several studies have noted a
  relationship between occupational attainment and
  incident dementia.
• As mentioned above, occupational attainment was
  often noted to interact with educational
  attainment.

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Social Status and CR

• Germany - only poor quality living accommodations
  were associated with increased risk of incident
  dementia.
• Indicators of social isolation such as low
  frequency of social contacts within and outside
  the family circle, low standard of social support
  and living in single person household did not
  prove to be significant.

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Leisure Activities and CR

• Activities associated with lower risk of incident
  dementia
• Traveling, doing odd jobs, knitting
• Community activities, gardening
• Having an extensive social network, participating
  in mental, social, and productive activities
• Intellectual activities (reading, playing games,
  going to classes)
• Leisure activities (reading, playing board games
  or musical instruments, and dancing)

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Life Expectancy and CR

• In a prospective study of AD patients matched for
  clinical severity at baseline,54 patients with
  greater education or occupational attainment died
  sooner than those with less attainment.
• Does this contradict the CR hypothesis?

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Life Expectancy and CR

• At any level of clinical severity, the pathology
  of AD is more advanced in patients with CR.
• At some point, the greater degree of pathology in
  the high reserve patients would result in more
  rapid death.

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Imaging Studies resting CBF

• Several imaging studies of CR in AD used resting
  cerebral blood flow (CBF).
• These studies have found negative correlations
  between resting CBF and years of education,
  premorbid IQ, occupation and leisure.
• The negative correlations are consistent with the
  CR hypothesis prediction that at any given level
  of disease clinical severity a subject with a
  higher level of CR should have greater AD
  pathology (ie, lower CBF).

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Imaging Studies resting CBF
Alexander GE, Furey ML, Grady CL, et al.
Association of premorbid function with cerebral
metabolism in Alzheimers disease implications
for the reserve hypothesis. Am J Psychiatr.
1997154 165172.
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Imaging Studies resting CBF
Stern Y, Alexander GE, Prohovnik I, et al.
Relationship between lifetime occupation and
parietal flow implications for a reserve against
Alzheimers disease pathology. Neurology.
1995455560.
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Imaging Studies Neuropathologic

• A neuropathologic analysis showed that for the
  same degree of brain pathology there was better
  cognitive function with each year of education.

Bennett DA, Wilson RS, Schneider JA, et al.
Education modifies the relation of AD pathology
to level of cognitive function in older persons.
Neurology. 20036019091915.
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Functional Imaging of CR

• Functional imaging studies should be able to
  capture the differences in how tasks are
  processed due to CR.
• One approach - to identify patterns of
  task-related activation that differ between AD
  patients and controls, and to determine whether
  they are compensatory.

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PET and verbal recognition

• H215O PET was used to measure regional CBF in
  patients and healthy elders during a verbal
  recognition task.
• Task difficulty was adjusted so that each
  subjects recognition accuracy was 75.
• In addition, CBF was measured for different study
  list size.

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PET and verbal recognition

• In healthy elders and 3 AD patients, a network of
  brain areas was activated during performance
• Left anterior cingulate
• Anterior insula
• Left basal ganglia
• Higher study list size -gt increased recruitment
  of the network
• Individuals who are able to activate this network
  to a greater degree may have more reserve against
  brain damage.

Left anterior cingulate
anterior insula
Basal ganglia
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PET and verbal recognition

• The remaining 11 AD patients recruited a
  different network
• Temporal cortex
• Calcarine cortex
• Posterior cingulate
• Vermis.

temporal
Posterior cingulate
calcarine
vermis
Stern Y, Moeller JR, Anderson KE, et al.
Different brain networks mediate task performance
in normal aging and AD defining compensation.
Neurology. 20005512911297.
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PET and verbal recognition

• Higher study list size -gt increased activation of
  this network.
• Neural compensation - This alternate network may
  be used by the AD patients to compensate for the
  effects of AD pathology.

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Neural Compensation

• Is this alternate network associated with better
  performance?
• In several studies, some elders showed additional
  activation in areas contralateral to those
  activated by younger subjects.
• The elders who showed this additional activation
  performed better than those who did not,
  indicating that it was compensatory.

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PET and Nonverbal Tasks

• A PET study identified brain areas whose
  activation during performance of a nonverbal
  memory task correlated with an index of CR
  calculated from measures of education and
  literacy.
• Such areas were identified in both healthy
  controls and patients with AD, suggesting that
  these areas may reflect the neural instantiation
  of CR.

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PET and Nonverbal Tasks
Scarmeas N, Zarahn E, Anderson KE, et al.
Cognitive reserve mediated modulation of positron
emission tomographic activations during memory
tasks in Alzheimer disease. Arch Neurol. 200461
7378.
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PET and Nonverbal Tasks

• Some brain areas showed
• Increased activation as a function of increased
  CR in the elderly controls
• Decreased activation in the AD patients.
• Higher CR -gt higher adaptive activation
• Compensation for the effects of AD pathology in
  the AD patients
• This is consistent with our definition of neural
  compensation.

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Summary

• In summary, the imaging evidence is beginning to
  provide support for the 2 hypothesized neural
  mechanisms underlying CR
• Neural reserve which emphasizes preexisting
  differences in neural efficiency or capacity.
• Neural compensation, which reflects individual
  differences in the ability to develop new,
  compensatory responses to the disabling effects
  of pathology.

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Conclusions

• Clinical observation of mild cognitive impairment
  may be accompanied by very minimal pathology or
  more than enough to meet pathologic criteria for
  AD.
• A proportion of this variability may be explained
  by CR.
• Measuring CR therefore becomes an important
  component of the diagnostic process.

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Conclusions

• Clinical evaluation alone is an insufficient
  measure of a patients true status.
• Indexes of pathology
• Biomarkers
• Imaging AD pathology itself
• Imaging the effect of pathology on resting
  metabolism in entire brain
• Imaging the effect of pathology on particularly
  vulnerable brain area.

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Conclusions

• There is a need for measuring individuals CR -
  the ability to cope with pathology.
• CR may be evaluated using educational and
  occupational attainment and quantified using
  functional imaging.
• The combination of clinical characterization,
  measures of underlying pathology and indices of
  CR would provide a more complete picture of a
  patients status.
• Important for early diagnosis, determine
  prognoses and progression over time.

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Conclusions

• Finally, the fact that different life exposures
  including education, occupation and leisure,
  impart reserve against AD in epidemiologic
  studies raises the possibility that an
  individuals CR could be increased through some
  set of systematic exposures or interventions.
• This would result in a nonpharmacologic approach
  for reducing risk of developing AD.

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