Roe CM, Mintun MA, D'Angelo G, Xiong C, Grant EA, Morris JC. Alzheimer disease and cognitive reserve: variation of education effect with carbon 11-labeled Pittsburgh Compound B uptake. Arch Neurol. 2008 Nov;65(11):1467-71. PubMed.
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This work adds yet another piece of evidence for the so-called cognitive reserve hypothesis, meaning that persons with greater cognitive reserve are able to withstand more Alzheimer-type pathology without becoming demented. The authors found that the uptake of [11C]PIB interacted with years of education in predicting scores in several measures of cognition. In other words, persons who were "[11C]PIB positive" and had the highest education were clinically rated as less impaired in cognitive performance than individuals with less education.
The findings are in accordance with earlier epidemiological, clinical, pathological, and functional imaging (cerebral metabolic rate and amyloid imaging) studies supporting the cognitive reserve hypothesis and delayed clinical expression of the disease in high-educated patients with marked Alzheimer pathology.
One strength of the study by Morris et al. is a large number (161 non-demented individuals and 37 patients with Alzheimer disease) of study participants allowing adequate statistical evaluation. Longitudinal follow-up studies in cohorts like the one in this study are important to verify whether the predictions derived from cross-sectional studies on the relationship between the degree of amyloid pathology and cognition and the possible modifying effect of education will hold true.
University of Southern California Keck School of Medicine
This report also indirectly illustrates the complexities of using individual putative biomarkers in clinical trials, either to characterize disease severity or as a surrogate outcome measure, without interpreting the marker within the context of the demographic and clinical characteristics of the patients.
For example, a drug may–hypothetically –markedly lower PIB uptake and may not have a perceptible clinical effect in, say, a group of higher-educated patients with high PIB uptake at baseline. Yet the same drug might be seen to not lower PIB uptake but improve cognitive function in a subgroup of lower-educated patients (who may or may not have lower PIB uptake and poorer cognitive function at baseline than the higher-educated group).
Under this hypothetical, an otherwise respectable effect drug might not be recognized. In brief, it may be time to model "cognitive reserve" into clinical trial designs.
Columbia University
I don't see much that is fundamentally new about these findings. My and other groups have demonstrated similar relationships in the past using cerebral blood flow as a proxy for pathology. In that instance, we were able to show that when controlling for clinical severity, people with higher education had lower CBF, suggesting that they had more advanced pathology. David Bennett did this with postmortem studies as well. In his study, too, at any level of cognition pre-death, those with higher education had more pathology. These new data reinforce that.
Also, previous analyses were done on patients with AD. Here the analyses focus on people who are PIB-positive, whether or not they have AD, although no information is provided about the overlap between those who are PIB-positive and those who have an AD diagnosis. A lot more work will have to be done to understand the implications of being PIB-positive and nondemented.
The major news here is the use of PIB as an indication of pathology in living people. This in theory is better than the CBF that we had used, because it is a direct measure of pathology, while CBF is an indirect measure. Unfortunately, for PIB the main thing that you get is absence or presence of pathology (rather than a continuous measure of pathology severity). Therefore, the analyses had to compare the relationship of education to cognition in people who were and were not PIB-positive.
Our group is actively investigating the neural implementation of cognitive reserve. The epidemiology suggests that some people can cope with or compensate for AD pathology better than others, but how does this work in the brain? We have two main ideas.
1. Neural reserve: there is inter-individual variability in the networks that subserve cognitive processes in healthy individuals such that these networks are more efficient or have higher capacity in some people than others. Those people with higher cognitive reserve might be able to tolerate pathology better because their existing networks are more efficient, have higher capacity, or are more resilient in some other way. We perform imaging studies that investigate this idea.
2. Neural compensation: when pathology damages the neural networks that normally serve cognition, people might "compensate" by recruiting other networks not normally used. Perhaps people who can recruit these networks more readily can compensate better. Alternately, some people might be able to continue to use the existing networks longer before they have to compensate. We are also pursuing this idea with imaging studies.
Finally, we have been pursuing the idea that there may be some generic cognitive reserve network or cognitive process that can aid performance across a wide range of tasks. The ability to invoke this process would allow people to cope better with pathology.
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