This is a revised competing renewal application for a program project grant (PPG) that focuses on subcortical ischemia vascular dementia (SIVD) in comparison to Alzheimer disease (AD). Based upon new findings during the initial funding period, we propose that dementia in both AD and SIVD is associated with changes in cerebral cortex, including atrophy, glucose hypometabolism, and loss of N-acetylaspartate [NAA]. The mechanisms leading to these cortical changes, however, are likely to differ and during the renewal we will further explore the mechanisms operant in SIVD. Using a longitudinal study design, we will also determine whether the regional pattern or rate of structural, metabolic, biochemical and perfusion changes are helpful for differential diagnosis and prognosis. The Central Coordinating Core (CC) will continue to recruit and follow to autopsy 500 subjects representing a spectrum of cognitive impairment, as well as ischemic vascular- and AD- type pathology. The Imaging Core will localize lacunes and measure volumes of lacunes (L), white matter lesions (WML), cortical gray matter (cGM)), and hippocampus (HV). The Pathology Core will determine the nature and rate the severity of neurodegenerative, ischemic, and cerebrovascular lesions. Four research projects are proposed (Note: Project 4 was discontinued): Project 1 (Reed et al.) Will used fluoro deoxyglucose positron emission tomography (FDG-PET) to study the utility of the regional and longitudinal pattern of cerebral metabolic rate for glucose (CMRgic) for differential diagnosis and prognosis. Project 2 (Weiner et al.) will use 1H MRSI and perfusion MR to study the utility of [NAA], myoinositol, and blood flow for diagnosis and prognosis. Project 3 (Chui et al) will co-register the clinical MRI to post-mortem brain to determine the pathological correlates of hippocampal and cortical atrophy, WML, and lacunes. Project 5 (Mungas et al) will use multi- variate random effect analyses to model, over time, the neuropsychological and MRI measures correlates of dementia in SIVD and AD. By integration of multi-dimensional data obtained using state of the art methods, we propose to advance understanding of the pathogenesis of SIVD, and to provide practical tools for diagnosis and prognosis.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-DAG-4 (J1))
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Buckholtz, Neil
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University of Southern California
Schools of Medicine
Los Angeles
United States
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Haaksma, Miriam L; Calderón-Larrañaga, Amaia; Olde Rikkert, Marcel G M et al. (2018) Cognitive and functional progression in Alzheimer disease: A prediction model of latent classes. Int J Geriatr Psychiatry 33:1057-1064
La Joie, Renaud; Ayakta, Nagehan; Seeley, William W et al. (2018) Multisite study of the relationships between antemortem [11C]PIB-PET Centiloid values and postmortem measures of Alzheimer's disease neuropathology. Alzheimers Dement :
Lao, Yi; Nguyen, Binh; Tsao, Sinchai et al. (2017) A T1 and DTI fused 3D corpus callosum analysis in MCI subjects with high and low cardiovascular risk profile. Neuroimage Clin 14:298-307
Ramirez-Gomez, Liliana; Zheng, Ling; Reed, Bruce et al. (2017) Neuropsychological Profiles Differentiate Alzheimer Disease from Subcortical Ischemic Vascular Dementia in an Autopsy-Defined Cohort. Dement Geriatr Cogn Disord 44:1-11
Seo, Sang Won; Ayakta, Nagehan; Grinberg, Lea T et al. (2017) Regional correlations between [11C]PIB PET and post-mortem burden of amyloid-beta pathology in a diverse neuropathological cohort. Neuroimage Clin 13:130-137
Zheng, Ling; Vinters, Harry V; Mack, Wendy J et al. (2016) Differential effects of ischemic vascular disease and Alzheimer's disease on brain atrophy and cognition. J Cereb Blood Flow Metab 36:204-15
Durazzo, Timothy C; Korecka, Magdalena; Trojanowski, John Q et al. (2016) Active Cigarette Smoking in Cognitively-Normal Elders and Probable Alzheimer's Disease is Associated with Elevated Cerebrospinal Fluid Oxidative Stress Biomarkers. J Alzheimers Dis 54:99-107
Villeneuve, Sylvia; Rabinovici, Gil D; Cohn-Sheehy, Brendan I et al. (2015) Existing Pittsburgh Compound-B positron emission tomography thresholds are too high: statistical and pathological evaluation. Brain 138:2020-33
Bron, Esther E; Smits, Marion; van der Flier, Wiesje M et al. (2015) Standardized evaluation of algorithms for computer-aided diagnosis of dementia based on structural MRI: the CADDementia challenge. Neuroimage 111:562-79
Vinters, Harry V (2015) Emerging concepts in Alzheimer's disease. Annu Rev Pathol 10:291-319

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