The overall goal of this supplement is to determine the effects of Alzheimer's disease (AD) on brain tau, longitudinal change of tau, and the relationship of tau to the symptomatology of AD, measured with the tau- specific PET ligand [18F]-T807. Our major hypotheses will be that 1) the distribution of brain tau will correspond to the previously reported Braak & Braak staging, 2) tau in older subjects is associated with cognitive impairment and increased in the presence of brain amyloid (A) deposition (measured by [18F]-AV45 PET), 3) brain tau correlates with A, and cognition especially memory function, and 4) longitudinal change of tau correlates with A burden and clinical/cognitive status. Considerable evidence suggests that, while brain A might precipitate cognitive decline in aging, severity of the decline is more closely linked to deposition of brain tau. Pathological studies and early tau PET studies suggest that brain tau correlates with the symptoms of AD more strongly than do measures of Ab. The subjects in this project will be selected from the longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI), which has enrolled over 1400 subjects since 2004 and has the overall goal to validate biomarkers for AD clinical trials. ADNI examines relationships between clinical status/cognition and a variety of biomarkers including A PET, FDG PET, magnetic resonance imaging (MRI), cerebrospinal fluid A/tau/ptau/proteomics, GWAS and whole genome sequencing. We propose a tau PET add on to ADNI with T807 on 46 subjects in each of 5 subject groups, for a total of 230 subjects: cognitively normal controls, elders with subjective memory complaints, early mild cognitive impairment (MCI), late MCI, and dementia due to AD. We also propose a longitudinal study on 22 subjects/group, prior to the expiration of the present application. Avid Radiopharmaceuticals is developing synthesis/distribution sites for their Phase 2 study, and this project will be providd T807 from those sites without cost. Therefore, this application only requests funds for the delivery of the radiotracer to clinical sites, PET scanning, QC and analysis of the PET scans, informatics, and administrative costs. All data will be analyzed along with the data acquired, processed and analyzed by ADNI and will be made publicly available to all scientists in the world using the existing ADNI website supported by the Laboratory of Neuroimaging at University of Southern California. Measurement of brain tau including longitudinal change of tau, using PET, is a highly innovative approach to determining the causes of cognitive impairment. Furthermore, the role of tau in leading to cognitive decline appears to be crucial in late-life age related cognitive decline and dementia. To our knowledge this is the first large multisite application to perform tau PET scanning. This application takes advantage of a large number of well characterized subjects enrolled in ADNI. Therefore, this application is extremely cost effective, and the results are expected to have high impact on our knowledge concerning the relationships between tau, cognition, and other AD biomarkers. These studies will be crucial for clinical trials oriented towards molecular treatments of AD.
The overall goal of this competitive supplement to the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to determine the effects of Alzheimer's Disease (AD) pathology on cognitive deterioration by examining relationships between a number of factors associated with AD and brain tau. This project uses [18F]-T807 (provided by AVID without cost, ), a new tau PET ligand, to detect tau in a longitudinal study of 230 normal elders, subjects with MCI and patients with AD who are currently enrolled in ADNI. Because of the close correlation between brain tau and memory/ cognitive functioning, there is optimism that longitudinal brain tau measures could ultimately become a validated surrogate for AD trials, thus the results are expected to have high impact on our knowledge concerning the effects of AD on human brain function, leading to improved diagnosis, and successful treatment trials.
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