The goal of this R01 application is to investigate the relationships among late-life depression (LLD), cognitive impairment and progressive neurodegeneration with two imaging approaches: a novel PET ligand (Pittsburgh Compound-B;PiB) that binds to amyloid and volumetric MRI of white matter hyperintensities (WMH). The guiding hypothesis is that individuals who develop LLD have evolving cognitive impairments as a consequence of distinct underlying neuropathologic changes that frequently are expressed as Mild Cognitive Impairment (MCI). Amyloid and WMH are major neuropathologic features that lower brain reserve capacity, and in turn, increase risk of expressing clinical Alzheimer's disease. To pursue this goal, using the joint infrastructure of the University of Pittsburgh's Advanced Center for Intervention and Services Research for Late-Life Mood Disorders (MH071944) and the Alzheimer's Disease Research Center (AG05133), individuals with remitted depression will undergo PiB-PET imaging for amyloid pathology and MRI to determine WMH volume. We will study 100 remitted depressed subjects with a range of cognitive classifications (50 cognitively normal, 50 MCI) and follow them for 3 years with longitudinal clinical, cognitive and laboratory data collection through Dr. Butters'R01 (MH072947;"Pathways Linking Late-Life Depression to MCI &Dementia"). WMH and PiB-PET data from these subjects will be compared with similar data on 25 never-depressed non-amnestic MCI subjects gathered through the proposed research along with 75 never-depressed subjects with a range of cognitive classifications (50 cognitively normal, 25 amnestic MCI), collected under the auspices of two other funded awards (Program Project Grant AG025204 "In Vivo PiB-PET Amyloid Imaging: Normals, MCI &Dementia" and MERIT Award AG025516 "Brain Amyloid and Cognition in Normal Elderly"). We will test a series of linked hypotheses that postulate the neuropathologic substrates of some of the pathways by which elderly, depressed patients develop cognitive impairment and lead some to Alzheimer's disease.

Public Health Relevance

This research study will gather information that will improve understanding of why elderly depressed individuals have an increased risk of developing dementia. To meet this goal we will study participants from related studies, with new brain scanning methods that detect cerebrovascular disease and amyloid, one of the key substances that accumulates in the brains of individuals with Alzheimer's disease. If we can better identify individuals at risk for developing specific types of dementia, such as Alzheimer's disease, then they can be candidates for treatment at the earliest disease stages, as new dementia treatments become available.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Evans, Jovier D
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University of Pittsburgh
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Rodakowski, Juleen; Skidmore, Elizabeth R; Reynolds 3rd, Charles F et al. (2014) Can performance on daily activities discriminate between older adults with normal cognitive function and those with mild cognitive impairment? J Am Geriatr Soc 62:1347-52
Diniz, Breno Satler; Reynolds 3rd, Charles F; Begley, Amy et al. (2014) Brain-derived neurotrophic factor levels in late-life depression and comorbid mild cognitive impairment: a longitudinal study. J Psychiatr Res 49:96-101
Koenig, Aaron M; Butters, Meryl A; Begley, Amy et al. (2014) Response to antidepressant medications in late-life depression across the spectrum of cognitive functioning. J Clin Psychiatry 75:e100-7
Hall, Charles A; Reynolds 3rd, Charles F; Butters, Meryl et al. (2014) Cognitive functioning in complicated grief. J Psychiatr Res 58:20-5
Koenig, Aaron M; Butters, Meryl A (2014) Cognition in Late Life Depression: Treatment Considerations. Curr Treat Options Psychiatry 1:1-14
Koenig, Aaron M; Bhalla, Rishi K; Butters, Meryl A (2014) Cognitive functioning and late-life depression. J Int Neuropsychol Soc 20:461-7
Campbell, Grace B; Whyte, Ellen M; Sereika, Susan M et al. (2014) Reliability and validity of the Executive Interview (EXIT) and Quick EXIT among community dwelling older adults. Am J Geriatr Psychiatry 22:1444-51
Gildengers, A G; Chisholm, D; Butters, M A et al. (2013) Two-year course of cognitive function and instrumental activities of daily living in older adults with bipolar disorder: evidence for neuroprogression? Psychol Med 43:801-11
Diniz, Breno S; Butters, Meryl A; Albert, Steven M et al. (2013) Late-life depression and risk of vascular dementia and Alzheimer's disease: systematic review and meta-analysis of community-based cohort studies. Br J Psychiatry 202:329-35
Erickson, Kirk I; Gildengers, Ariel G; Butters, Meryl A (2013) Physical activity and brain plasticity in late adulthood. Dialogues Clin Neurosci 15:99-108

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