2. • Why the concept of cognitive reserve?
• Definition
• Theories for explanation
• Passive and active models
• Measures of reserve
• Epidemiological evidences
• Imaging in CR
• Implications of CR for diagnosis, early detection, and
treatment of AD
3. The Concept: 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?
• For example: Katzman described 10 cases of cognitively normal elderly
women who were discovered to have advanced Alzheimer disease (AD)
pathology in their brains at death.
Katzman R, Aronson M, Fuld P, et al. Development of dementing illnesses in an 80-year-old
volunteer cohort. Ann Neurol. 1989;25:317–324.
4. Passive Model – Brain Reserve Capacity
• Old concept
• Passive Models - Brain Reserve Capacity (BRC) derives
from brain size or neuronal count.
• There may be individual differences in BRC.
• It is fix and does not change with time, experience or
training
• There is a critical threshold of BRC: an amount of brain
damage sustained before reaching a threshold for clinical
expression.
5. 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.
• provides a ready explanation for why many studies have demonstrated that higher
levels of intelligence and of educational and occupational attainment are good
predictors of which individuals can sustain greater brain damage before
demonstrating functional deficit.
6. 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…
7. 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.
• These concepts are particularly important when attempting to
formulate and interpret functional imaging studies that
investigate CR.
8. 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.
9. Measures of reserve
Reserve may be
1. Structural: ‘extra’ neurons and synapses, brain volume, head
circumference or dendritic branching
2. Functional: a degree of excess capacity or compensatory mechanisms
such that the brain could continue to perform well despite damage
Many of these measures are influenced by life experience and may change
over the lifetime.
Question is how to quantify this abstract construct?
• common approach is to use other variables as markers of, or proxies for,
reserve; the most common such variable being years of education.
• There are many such variables
10. Measures of Reserve
• As we discussed, CR (cognitive reserve) is
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.
11. Measures of Reserve
• Genetics + Exposure innate intelligence
Education (marker of innate intelligence)
• 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 one’s lifetime it results
from a combination of exposures.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
• Occupational attainment was often
noted to interact with educational
attainment.
18. 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.
19. 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)
20. 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?
21. 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.
22. 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).
23. Imaging Studies – resting CBF
Alexander GE, Furey ML, Grady CL, et al. Association of premorbid function
with cerebral metabolism in Alzheimer’s disease: implications for the
reserve hypothesis. Am J Psychiatr. 1997;154:
165–172.
24. Imaging Studies – resting CBF
Stern Y, Alexander GE, Prohovnik I, et al. Relationship between lifetime occupation and parietal flow:
implications for a reserve against Alzheimer’s disease pathology. Neurology. 1995;45:55–60.
25. 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.
2003;60:1909–1915.
26. 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.
27. PET and verbal recognition
• H2
15O PET was used to measure regional CBF in
patients and healthy elders during a verbal
recognition task.
• Task difficulty was adjusted so that each subject’s
recognition accuracy was 75%.
• In addition, CBF was measured for different study list
size.
28. 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 -> 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
29. PET and verbal recognition
• The remaining 11 AD patients recruited a
different network:
– Temporal cortex
– Calcarine cortex
– Posterior cingulate
– Vermis. calcarine
Posterior
cingulate
vermis
temporal
Stern Y, Moeller JR, Anderson KE, et al. Different brain networks mediate task performance in normal aging and AD: defining
compensation. Neurology. 2000;55:1291–1297.
30. PET and verbal recognition
• Higher study list size -> 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.
31. 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.
32. 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 (example) of CR.
33. 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. 2004;61: 73–78.
34. 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 -> higher adaptive activation:
Compensation for the effects of AD pathology
in the AD patients
• This is consistent with our definition of neural
compensation.
35. 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.
36. 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.
37. Conclusions
• Clinical evaluation alone is an insufficient
measure of a patient’s 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.
38. Conclusions
• There is a need for measuring individual’s 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 patient’s status.
• Important for: early diagnosis, determine prognoses
and progression over time.
39. 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
individual’s 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.
40. How to improve the cognitive reserve?
• Enriched environment(EE)
• Cognitively stimulating activities
• Cognitive training
• Physical training
• likely to increase our CR, thus making us more
resilient to cognitive decline and damage
41. Enriched environment(EE)
• This term has been given to environmental conditions that
facilitate enhanced sensory, cognitive, and motor stimulation.
• EE has been seen to improve experience-dependent
microdevelopment.
• EE has been found to promote neurogenesis, synaptogenesis,
and transgenerational transmission.
• EEs are meaningful social engagement and activities that
provide a sense of mastery.
• These are complex, highly structured enjoyable activity that
provide opportunity for self-expression, e.g., charity, clubs,
group games, voluntary work, and caring for sick.
42. Cognitively stimulating task
• Sharing knowledge and experiences
• Gardening and other community activities
• Learning magic
• Crossword puzzles
• Juggling
• Formal education, reading books and magazines
• Musical instruments, dancing, and leisure activity
• La Rue recommendation (2008) suggests following for better
memory: to carve out time for cognitively stimulating
activities that one enjoys, to add some new challenging
pursuits as time and energy allow, to engage in these pursuits
several times a week, and to participate in social interaction.
43. Cognitive training
• Advanced cognitive training for independent and vital elderly (ACTIVE)
study undertook training of older adults in areas of reasoning, memory,
and processing speed.
• Improvement in cognition lasted at least 5 years with booster training.
• In Experience Corps (EC) project, elders were taught literacy, mathematics,
and conflict resolution in elementary school. Training showed
improvement in executive function and memory.
• There are many cognitive training websites available, few of these include
• www.fitbrains.com
• www.gamesforthebrain.com
• www.mybraintrainer.com
• www.luminosity.com
• www.sharpbrains.com
44. Physical training
• Aerobic fitness training in older adult promoted
significant increase in gray (cortical neurons) and
white matter (connecting pathways)
• Physical and cognitive training combined had
multiplier effect.
47. References
• Stern Y. Review article: Cognitive Reserve and Alzheimer Disease:
Alzheimer Dis Assoc Disord, Volume 20, Number 2, April–June 2006
• Stern Y. CRITICAL REVIEW: What is cognitive reserve? Theory and research
application of the reserve concept. Journal of the International
Neuropsychological Society (2002), 8, 448–460
• Prakash J, Ryali V, Srivastava K, Bhat PS, Shashikumar R. Cognitive reserve:
The warehouse within. Ind Psychiatry J. 2011 Jul;20(2):79-82.
• Stern Y. Reviews and perspectives: Cognitive reserve. Neuropsychologia 47
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