Consistent with the prediction of the CR hypothesis, we found that activities had a negative correlation with CBF in patients with AD when controlling for disease severity. This relationship was seen primarily in voxels located in the temporal but also in temporal-occipital-parietal association cortices, the areas in which CBF changes are typically noted in AD. This inverse association was still present when both education and IQ were included in the model. This indicates that there is a unique relationship between activities and CBF over and above the relationship of CBF to education and IQ.
A previous study noted an inverse association between educational attainment and CBF (controlling for disease severity) in parietal areas.11
In our study, we observed a similar negative correlation between education and CBF, localizing to parietal, frontal, and temporal regions.
Another study found an inverse association between premorbid IQ and CBF in prefrontal, premotor, orbitofrontal, superior parietal, thalamic, and anterior cingulate areas.13
In our study, similar results (in terms of directionality of the relationship between IQ and CBF) were obtained. Significant correlations included thalamic, temporal, parietal, frontal, and cingulate areas in our study.
The observed differences in localization between previous studies and the present one could derive from the different types of functional imaging modalities used (xenon and fluorodeoxyglucose in previous studies vs oxygen 15 here), different covariates reflecting disease severity used in the analysis, different denominators used for intensity normalization, or different measures of IQ. Most notable, however, is the different methods of analysis: both previous studies used a region-of-interest analysis when they examined the associations between education and CBF and IQ and CBF,11,13
while we elected to use a voxelwise analysis. Because we were able to replicate the directionality and, to a certain extent, the localization of these earlier findings with a voxelwise analysis, the validity of these previous observations is strengthened.
We detected significant associations in different areas of the brain depending on whether education or IQ or activities were used in the analyses. At first approximation, this may suggest that different aspects of CR mediate clinical protection in an anatomically specific way: ie, patients with high educational attainment can be maintained at similar clinical severity status when the pathologic changes AD affect certain areas of the brain, while patients with high IQ or leisure activity scores can be maintained when other brain regions are affected. Nevertheless, it is also possible that different aspects of CR are not region-specific and that the locations reported in our analyses generally co-localize to the same extended association areas usually affected by AD. The combination of the limited number of subjects included in our analyses and our conservative approach for controlling for type I error might have limited our power to detect significant associations in the whole spectrum of affected areas of the brain. In addition, the locations reported in our analyses represent only local maxima of more extended areas of the brain (). Maintaining intellectual and social engagement through participation in everyday activities seems to buffer healthy individuals against cognitive decline in later life.43-45
We recently reported the results of a longitudinal epidemiologic study in northern Manhattan, NY.18
Thirteen leisure activities (intellectual, social, and physical in character) were assessed in 1772 healthy elderly subjects who were prospectively followed for up to 7 years. Even when multiple potentially confounding factors were controlled for, subjects with high leisure activity scores had 38% less risk of developing dementia. There are at least 2 other large prospective cohorts that have reported a protective effect for leisure16
and cognitive activities17
in relationship to incident dementia.
A limitation of the present study is that activities were assessed in patients with mild dementia and that the extent to which they participated in these activities might have been affected by the disease. Optimally, activities should have been recorded during presymptomatic periods. However, as described in the “Results” section, our patients were at early stages of AD and the reported changes in their activities over the last 10 years were ostensibly negligible. We therefore used the recorded activity score as an estimate of lifestyle during the 10 years before study enrollment.
To further explore this potential bias, we repeated the analyses using reconstructed scores for the subjects who reported decreased time devoted to activities, adding in points for the activities they reported to exercise less over the last 10 years. The results for all models were essentially unchanged. We elected to use the contemporaneous activity score for the analyses because it is less prone to recollection bias. The fact that the activities information was corroborated by the informant also added to the face validity of the scores.
The activity scale items collected in this study reflected not only intellectual and social activities but also physical ones. Epidemiologic evidence that physical exercise may delay cognitive impairment is equivocal. While high levels of physical activity were associated with reduced risk of dementia in at least 4 prospective studies,18,46-48
no effect of exercise on dementia and cognitive impairment risk was reported from other cohorts.17,49
Additionally, there is basic research evidence that environmental enrichment in the form of voluntary wheel running is associated with enhanced neurogenesis in the adult mouse dentate gyrus.50
It has also been shown that physical activity sustains cerebral blood flow51
and may improve aerobic capacity and cerebral nutrient supply.52,53
Therefore, although it is conceivable that physical activity may merely be a nonspecific marker of good health indirectly related to dementia (or not related to dementia at all), it is also possible that it has a direct physiologic association with brain disease.
Recent evidence indicates that certain areas of the brain retain the capability to generate new neurons into adulthood, not only in rodents54
but also in humans.56,57
Thus, it is possible that the stimulation provided by everyday intellectual and social activities facilitates the maintenance of general cognitive skills in a manner that is analogous to physical exercise for musculoskeletal and cardiovascular functions.43
This reserve could be the result of a physiologic process involving increased synaptic density in the neocortical association cortex acquired by stimulation.58
This study does not indicate that more engagement in activities affords some kind of immunity to the neuropathologic aspect of the AD process. On the contrary, we assume that the pathologic changes in AD progress independently of life activities. The concept of CR was developed in an attempt to explain interindividual differences in the degree of pathologic changes in the brain necessary for the clinical expression of disease.59
This has been confirmed in multiple studies, which have found that a significant proportion of clinically nondemented individuals manifest neuropathologic changes consistent with AD at autopsy60,61
More engagement in activities may supply a reserve that allows an individual to cope longer before AD is clinically expressed. Aspects of life experience, such as social, intellectual, and physical activities, could modify the paradigms used by the brain to mediate a task by making individuals more efficient or resilient in the face of pathologic changes in the brain or by recruitment of alternate networks.
The activity score may simply represent innate rather than acquired abilities. However, activities, education, and IQ seem to have a unique association to CBF, which supports the concept that aspects of life experience may modulate reserve. The hypothesized contribution of life experiences, styles, and activities to the ability to cope with the pathologic changes in AD suggests the possibility of interventions that might delay the onset of the clinical symptoms of the disease.