Subjective declines in memory and thinking abilities are commonly reported in older adults. Recent studies indicate that complaints predict subsequent cognitive decline and incident Alzheimer's disease (AD), at least in some older adults. Furthermore, complaints have been associated with biological markers of AD, such as brain atrophy, reduced brain metabolism, and AD neuropathology on autopsy. These findings suggest that, for some, cognitive complaints likely represent a pre-symptomatic stage of AD which may provide an even earlier therapeutic opportunity than mild cognitive impairment (MCI). Amyloid-beta (A?) imaging studies indicate that brain A? plaques are present in 20-30% of cognitively normal older individuals, consistent with postmortem studies. Recent reports show A? deposition in normal older adults to be associated with longitudinal cognitive decline, brain volume loss, and altered glucose metabolism, supporting the idea of sub-clinical neuronal dysfunction. The proposed research will investigate whether cognitive complaints may represent a facet of early A? -associated, sub-clinical neuronal dysfunction, along with subtle cognitive deficits and gradual cognitive decline. It will also investigate the role of personality, mood and reporting bias in the measurement of subjective cognitive complaints and their relationship to A? deposition. This career development proposal will provide the foundation for a research program dedicated to investigating the early natural history of cognition associated with AD pathology in aging. To date, my training has afforded me a broad background in clinical neuropsychology and functional MRI. My short-term goals are to undertake in-depth training in A? imaging with PET, using Pittsburgh Compound B (PiB);to learn modern psychometric approaches to develop and refine cognitive outcome scales;and to learn advanced approaches to analyzing longitudinal cognitive data. The institutional environment is well-matched to these training goals, including Mentors Dr. William Klunk, a co-inventor of the amyloid tracer PiB, and Drs. Mary Ganguli and Judith Saxton, each a leader in AD and MCI research. Key elements of the career development plan include supervised research experiences with Mentors/Consultants, courses and workshops. The research plan includes implementation of a complete, original PiB-PET study of cognitively normal participants self-referred to a Memory Disorders Clinic, as well as the step-wise development, refinement and validation of a new scale for subjective cognitive complaints. Through these training and research activities, I will establish myself as an independent scientist with a unique set of skills, utilizing neuroimaging and advances in psychometric measurement to investigate early cognitive predictors of AD. This work will contribute significantly toward understanding the prognostic significance of cognitive complaints and amyloid deposition in non-demented individuals. Potentially, it will advance understanding of the extended preclinical phase of AD and how best to initially identify it.

Public Health Relevance

This research proposal will determine whether subjective complaints of impaired memory and thinking in older adults are related to the pathological brain changes of Alzheimer's disease (AD). It will investigate the role of personality, mood and reporting bias in the measurement of subjective complaints and their relationship to amyloid-beta plaques in the brain. The results could lead to the development of a new scale to initially screen for the presence of very early AD brain changes, potentially leading to improved future treatment outcomes.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZAG1-ZIJ-7 (02))
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Hsiao, John
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University of Pittsburgh
Schools of Medicine
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