The overall goal of the proposed study is to identify the neurobiologic mechanisms underlying the association of psychological distress with dementia in aged humans. Recent research has shown that measures of psychological distress are related to risk of dementia and rate of cognitive decline but not with common age-related neuropathology associated with cognitive impairment (e.g., tau positive tangles, cerebral infarction). Based on a long history of mainly animal research, we hypothesize that psychological distress leads to neurodegenerative, stress hormone receptor, and neurotrophic changes in limbic structures that mediate the stress response and memory function, making the brain more vulnerable to common age-related pathology and increasing the likelihood that such pathology will be clinically expressed as dementia. The proposed study will take advantage of clinical and post-mortem data, and brain tissue, from older persons participating in the Religious Orders Study, all of whom agreed to annual detailed clinical evaluation and brain donation at the time of death. On post-mortem examination, we propose to quantify in three limbic regions neurons and dendrites, mineralocorticoid and glucocorticoid receptors, and the expression of brain-derived neurotrophic factor and its receptor and to examine their association with measures of psychological distress, dementia and cognitive function measured proximate to death. We then propose to examine the association of these post-mortem limbic indices with post-mortem indices of common age-related pathology (i.e., amyloid deposition, tangle formulation, cerebral infarction, Lewy bodies) and test the hypotheses that the post-mortem indices of limbic structure (i) mediate the association of psychological distress with incidence of dementia and level of cognition measured proximate to death and (ii) increase the likelihood that common age-related pathology is expressed clinically as dementia or cognitive impairment proximate to death. ? ? ?
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