Brain pathologies, reserve and cognition in aging and dementia

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 DESCRIPTION (provided by applicant): In the last decades of life multiple brain pathologies accumulate at an accelerating pace and cognitive function declines. Multiple major scientific breakthroughs will be needed to alter this basic fact of cognitive aging. However, rates of cognitive decline are highly heterogeneous and brain pathology, even when comprehensively assessed, leaves most variation unexplained. It is clear that the there are great individual differences in the level of cognitive impairment that is seen at any level of brain pathology. It i therefore important to also understand the factors that reduce the impact of pathology when it occurs. "Reserve" is a useful construct for studying protective factors and is the focus of this project. Prior efforts created and validated a novel approach to the measurement of reserve, termed the "Reserve Index". The Reserve Index has been shown to modify the risk of converting from MCI to dementia, modify rates of cognitive decline, and modify the effects of progressive brain atrophy on longitudinal cognitive decline. This project pursues two key questions about reserve, namely how does it change over time and what factors build reserve? Because reserve depends on the integrity of the brain, accumulating pathology must eventually diminish reserve. Thus, to the extent that reserve modifies rates of clinical change, measuring changes in reserve will improve prediction of clinical trajectories. It has not previously been possible to measure changes in reserve, but this can be done with the Reserve Index. This project collects longitudinal volumetric MRI as a measure of brain pathology, uses sensitive and reliable neuropsychological tests to measure cognitive function longitudinally, and gathers data on demographic, experiential, and behavioral factors potentially related to reserve. Aim 1 is to extend the cross sectional measurement of reserve to a longitudinal framework, to develop appropriate models, and to test basic hypotheses about change in reserve and the effect of longitudinal reserve on clinical progression. Aim 2 investigates factors that may be associated with higher reserve, and Aim 3 investigates the same factors in relation to stability of reserve over time. Candidate factors were selected based on review of the literature, which suggests that cognitive stimulation and challenge, social engagement and physical exercise are all associated with better cognitive outcomes in old age. It has also been argued that it is not what people do but rather how they do it; "investment traits"-the tendency to seek and engage in effortful cognitive activities- may broadly shape experience by increasing cognitive challenge and thus contribute to reserve. Each of these behavioral factors, including the personality traits, can be modified by interventions. Improved understanding of reserve has the potential to improve the prediction of cognitive decline in aging and disease and to guide new interventions that reduce the impact of pathology-thus delaying, or possibly avoiding clinical outcomes like mild cognitive impairment (MCI) and dementia.