Early structural and functional changes in the brains of individuals at risk for developing dementia of the Alzheimer type (DAT) are not well understood. Typically a diagnosis of DAT is made using neuropsychological performance testing and clinical evaluation. Previous work by our group and others has identified a preclinical phase of DAT that is associated with a constellation of changes in biomarkers including decreased cerebral spinal fluid (CSF) Abeta42 (AP42) levels, increased fibrillar amyloid deposits in the brain as detected by PET (using Pittsburgh B compound (PIB)), and increased atrophy, particularly within the hippocampus. An interaction exists between these biomarkers and risk factors for DAT such as family history and genotype (ie., apolipoprotein E (APOE). The exact sequence of preclinical events, and their effects on neuronal dysfunction that leads to DAT, remain unclear. Recent advancements in MR imaging could provide unique information in this regard. Specifically three techniques- resting state functional connectivity MRI (fcMRI), diffusion tensor imaging (DTI), and arterial spin labeling (ASL) perfusion imaging, could provide sensitive measures of neuronal function (fcMRI), cerebral blood flow (ASL) and white matter integrity (DTI). Repeated longitudinal measures using these neuroimaging techniques could add new information concerning the temporal course associated with the very earliest changes in brain function associated with DAT. This project has 3 aims:
Aim 1 : Changes in neuronal structure using fcMRI, ASL and DTI in a cross-sectional analysis will be correlated with age, APOE genotype, and biochemical and behavioral biomarkers.
Aim 2. Subjects followed longitudinally with repeat fcMRI, ASL, and DTI will provide a temporal profile of the sequence of changes in neuroimaging biomarkers.
Aim 3 : Associate the rates of change over time in fcMRI, resting cerebral blood flow, and radial diffusivity in DTI measures with cognitive decline (Clinical Core), changes in cortical amyloid load as assessed by PIB (Project 1), changes in CSF biomarkers (Project 2), and neuropsychological measures (Project 3).

Public Health Relevance

Successful completion of the proposed research will allow for the unique correlation between structural and functional brain imaging measures with multiple biochemical (CSF and PET PIB) and behavioral markers. These should provide a more complete understanding of the sequence of pathological changes that culminate in DAT. In addition, the identification of early biomarkers could be used to test the efficacy of novel treatment alternatives.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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National Institute on Aging Initial Review Group (NIA)
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Washington University
Saint Louis
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Chen, Ling; Sun, Jianguo; Xiong, Chengjie (2016) A multiple imputation approach to the analysis of clustered interval-censored failure time data with the additive hazards model. Comput Stat Data Anal 103:242-249
Staley, Lyndsay A; Ebbert, Mark T W; Parker, Sheradyn et al. (2016) Genome-wide association study of prolactin levels in blood plasma and cerebrospinal fluid. BMC Genomics 17 Suppl 3:436
Staley, Lyndsay A; Ebbert, Mark T W; Bunker, Daniel et al. (2016) Variants in ACPP are associated with cerebrospinal fluid Prostatic Acid Phosphatase levels. BMC Genomics 17 Suppl 3:439
Ingber, Adam P; Hassenstab, Jason; Fagan, Anne M et al. (2016) Cerebrospinal Fluid Biomarkers and Reserve Variables as Predictors of Future ""Non-Cognitive"" Outcomes of Alzheimer's Disease. J Alzheimers Dis 52:1055-64
Gordon, Brian A; Blazey, Tyler; Su, Yi et al. (2016) Longitudinal β-Amyloid Deposition and Hippocampal Volume in Preclinical Alzheimer Disease and Suspected Non-Alzheimer Disease Pathophysiology. JAMA Neurol 73:1192-1200
Babulal, Ganesh M; Ghoshal, Nupur; Head, Denise et al. (2016) Mood Changes in Cognitively Normal Older Adults are Linked to Alzheimer Disease Biomarker Levels. Am J Geriatr Psychiatry 24:1095-1104
Jack Jr, Clifford R; Knopman, David S; Chételat, Gaël et al. (2016) Suspected non-Alzheimer disease pathophysiology--concept and controversy. Nat Rev Neurol 12:117-24
Ebbert, Mark T W; Staley, Lyndsay A; Parker, Joshua et al. (2016) Variants in CCL16 are associated with blood plasma and cerebrospinal fluid CCL16 protein levels. BMC Genomics 17 Suppl 3:437
Lucey, Brendan P; Mcleland, Jennifer S; Toedebusch, Cristina D et al. (2016) Comparison of a single-channel EEG sleep study to polysomnography. J Sleep Res 25:625-635
Cummings, Jeffrey; Aisen, Paul S; DuBois, Bruno et al. (2016) Drug development in Alzheimer's disease: the path to 2025. Alzheimers Res Ther 8:39

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