Neuroimaging of Dedifferentiation and Memory Across the Lifespan

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DESCRIPTION (provided by applicant): This proposal is a response to NOT-OD-058, "NIH Announces the Availability of Recover Act Funds for Competitive Revision Applications." It utilizes new neuroimaging advances (including amyloid imaging) that were not even available to the project at the time of initial application. It will enable the hiring or maintenance of a total of 2.3 full time people: the effort of a full-time post-doc; a full-time research assistant, and a part-time laboratory technician, in addition to providing employment for personnel at an under-utilized PET scanner at the University of Texas Southwestern Medical School. It is quite common to find that entirely normal, healthy older adults show significant neuropathology at autopsy in the form of amyloid deposition. Although amyloid deposition is a characteristic feature of all patients with Alzheimer's Disease (AD), it is also present in many normal adults, is observed in individuals with Mild Cognitive Impairment (MCI) at a level higher than normals, and is a strong predictive factor in conversion from MCI to AD. In the past, it has been nearly impossible to study the relationship of amyloid deposition to cognitive and neural function in healthy adults, as amyloid deposition could only be measured at autopsy. Very recently, however, new radiotracer compounds have been developed that, when injected in an individual, bind to amyloid deposits in his or her brain. We propose to add an amyloid PET scan and genotyping of APOE-e4 (a known risk factor for cognitive decline and Alzheimer's disease) to the Dallas Lifespan Brain Study (DLBS), an NIA-funded study that fully characterizes 350 adults-50 participants at each decade from the 20's through the 80's-and includes extensive measurement of cognitive function, brain structure, and brain function. We hypothesize that amyloid is one critical, initiating event that plays a central role in neurocognitive decline in cognitively normal adults. Moreover, because the DLBS is a MERIT award to P.I. Denise Park, we have the ability to utilize the amyloid measures taken in the first five years to predict trajectories of neural structure, function and cognitive behavior at longitudinal follow-up. The DLBS, with the inclusion of the amyloid data, will provide what we believe to be the most complete characterization of normal cognitive aging in the literature, and allows for the testing of a broad range of hypotheses about how the pathology of amyloid deposition affects both brain and behavior in healthy, highly-selected adults. Avid Pharmaceuticals has agreed to provide the ligand (AV-45) to our study at no cost, so that only PET and personnel costs are requested, making the study of a large sample of healthy elderly financially feasible. At present, the largest published study of amyloid deposition in healthy older adults consists of 43 participants. This is largely due to the cost and scarcity of the ligands used to measure amyloid deposition. PUBLIC HEALTH RELEVANCE: Amyloid deposition occurs in the brains of a subset of healthy adults, and always occurs in the brains of individuals with Alzheimer's disease. We can at last measure amyloid deposition in vivo in humans with PET scanning. We propose to add measures of amyloid deposition to the Dallas Lifespan Brain Study which will provide the best estimate of amyloid deposition in healthy adults to date, and provide baseline information that will be critical in the early diagnosis and interventions for Alzheimer's disease.