Cognitive Reserve and Alzheimer Disease

Yaakov Stern, Alzheimer Dis. Asso.c Disord. 2006, 20: S69–

S74.

Who has a higher risk of developing Alzheimer’s Disease? Higher IQ, education, occupational

attainment, or participation in leisure activities

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?

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.

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.

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…

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.

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.

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.

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.

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 one’s lifetime it results from a combination of exposures.

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.

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.

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.

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.

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.

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.

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.

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)

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?

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.

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).

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.

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.

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.

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.

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.

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

PET and verbal recognition The remaining 11 AD patients recruited a

different network: Temporal cortex Calcarine cortex Posterior cingulate Vermis.

calcarinePosterior cingulatevermis

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.