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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG026276-09
Application #
8732596
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
9
Fiscal Year
2014
Total Cost
$400,389
Indirect Cost
$136,975
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Schindler, Suzanne E; Sutphen, Courtney L; Teunissen, Charlotte et al. (2018) Upward drift in cerebrospinal fluid amyloid ? 42 assay values for more than 10 years. Alzheimers Dement 14:62-70
Sato, Chihiro; Barthélemy, Nicolas R; Mawuenyega, Kwasi G et al. (2018) Tau Kinetics in Neurons and the Human Central Nervous System. Neuron 98:861-864
Babulal, Ganesh M; Chen, Suzie; Williams, Monique M et al. (2018) Depression and Alzheimer's Disease Biomarkers Predict Driving Decline. J Alzheimers Dis 66:1213-1221
Millar, Peter R; Balota, David A; Bishara, Anthony J et al. (2018) Multinomial models reveal deficits of two distinct controlled retrieval processes in aging and very mild Alzheimer disease. Mem Cognit 46:1058-1075
Gangishetti, Umesh; Christina Howell, J; Perrin, Richard J et al. (2018) Non-beta-amyloid/tau cerebrospinal fluid markers inform staging and progression in Alzheimer's disease. Alzheimers Res Ther 10:98
Vlassenko, Andrei G; Gordon, Brian A; Goyal, Manu S et al. (2018) Aerobic glycolysis and tau deposition in preclinical Alzheimer's disease. Neurobiol Aging 67:95-98
Roe, Catherine M; Babulal, Ganesh M; Stout, Sarah H et al. (2018) Using the A/T/N Framework to Examine Driving in Preclinical AD. Geriatrics (Basel) 3:
Stout, Sarah H; Babulal, Ganesh M; Ma, Chunyu et al. (2018) Driving cessation over a 24-year period: Dementia severity and cerebrospinal fluid biomarkers. Alzheimers Dement 14:610-616
Chen, Jason A; Fears, Scott C; Jasinska, Anna J et al. (2018) Neurodegenerative disease biomarkers A?1-40, A?1-42, tau, and p-tau181 in the vervet monkey cerebrospinal fluid: Relation to normal aging, genetic influences, and cerebral amyloid angiopathy. Brain Behav 8:e00903
Day, Gregory S; Musiek, Erik S; Morris, John C (2018) Rapidly Progressive Dementia in the Outpatient Clinic: More Than Prions. Alzheimer Dis Assoc Disord 32:291-297

Showing the most recent 10 out of 352 publications