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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Snitz, Beth E; Wang, Tianxiu; Cloonan, Yona Keich et al. (2018) Risk of progression from subjective cognitive decline to mild cognitive impairment: The role of study setting. Alzheimers Dement 14:734-742
Edelman, Kathryn; Tudorascu, Dana; Agudelo, Christian et al. (2017) Amyloid-Beta Deposition is Associated with Increased Medial Temporal Lobe Activation during Memory Encoding in the Cognitively Normal Elderly. Am J Geriatr Psychiatry 25:551-560
Molinuevo, José L; Rabin, Laura A; Amariglio, Rebecca et al. (2017) Implementation of subjective cognitive decline criteria in research studies. Alzheimers Dement 13:296-311
McDade, Eric; Sun, Zhaowen; Lee, Ching-Wen et al. (2016) The association between pulse pressure change and cognition in late life: Age and where you start matters. Alzheimers Dement (Amst) 4:56-66
Graziane, Julie A; Beer, Joanne C; Snitz, Beth E et al. (2016) Dual Trajectories of Depression and Cognition: A Longitudinal Population-Based Study. Am J Geriatr Psychiatry 24:364-73
Ganguli, Mary; Lee, Ching-Wen; Hughes, Tiffany et al. (2015) Who wants a free brain scan? Assessing and correcting for recruitment biases in a population-based sMRI pilot study. Brain Imaging Behav 9:204-12
Snitz, Beth E; Small, Brent J; Wang, Tianxiu et al. (2015) Do Subjective Memory Complaints Lead or Follow Objective Cognitive Change? A Five-Year Population Study of Temporal Influence. J Int Neuropsychol Soc 21:732-42
Snitz, Beth E; Lopez, Oscar L; McDade, Eric et al. (2015) Amyloid-? Imaging in Older Adults Presenting to a Memory Clinic with Subjective Cognitive Decline: A Pilot Study. J Alzheimers Dis 48 Suppl 1:S151-9
Rabin, Laura A; Smart, Colette M; Crane, Paul K et al. (2015) Subjective Cognitive Decline in Older Adults: An Overview of Self-Report Measures Used Across 19 International Research Studies. J Alzheimers Dis 48 Suppl 1:S63-86
Snitz, Beth E; Weissfeld, Lisa A; Cohen, Ann D et al. (2015) Subjective Cognitive Complaints, Personality and Brain Amyloid-beta in Cognitively Normal Older Adults. Am J Geriatr Psychiatry 23:985-93

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