Impact of Diabetes on Cognitive and Perfusion Inefficiencies in Preclinical AD

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Diabetes affects more than 30 million Americans over the age of 18, including nearly one quarter of Veterans. The estimated yearly cost of diabetes in the United States is $245 billion, and the medical expenditures of people with diabetes is 2.3 times higher than they would be in the absence of diabetes. In addition to the many medical complications and co-existing conditions associated with diabetes, diabetes also confers a greater risk for developing Alzheimer’s disease (AD) and dementia. AD pathogenesis is thought to begin many years prior to the clinical diagnosis, so there has been significant focus on the use of biological methods to detect AD prior to the frank cognitive impairment that is observed in the mild cognitive impairment (MCI) and dementia phases. While PET neuroimaging with radioactive tracers and lumbar puncture (LP) to obtain cerebrospinal fluid levels of AD markers (Ab, p-tau, total tau) have drawn significant attention and are important for our understanding of the pathogenesis of AD, these methods are not without limitations. Specifically, these approaches are expensive, still in experimental phases in regard to understanding implications of “positive” findings, invasive (require injection of radioactive tracers or LP), and often inaccessible due to location (e.g., rural setting), cost, or medical contraindications (e.g., on blood thinners). Therefore, there is a significant need to develop and implement sensitive neuropsychological markers that capture subtle, preclinical cognitive changes, before objective impairment associated with MCI and dementia. The proposed study aims to examine neuropsychological (NP) process scores as a method for detecting the earliest cognitive changes associated with diabetes and to use these scores to predict cognitive and functional decline. NP process scores are derived from standard NP tests, but provide information about how the Veteran obtained an overall total score (e.g., types of errors that were made, learning slope). Process scores have been shown to add value in predicting future cognitive decline and can be used to identify subtle cognitive decline in preclinical AD. This study will involve 1) a retrospective record review of 200 Veterans (100 with diabetes) without a neurocognitive disorder who previously completed a neuropsychological assessment as part of their VA clinical care, 2) recruitment of a subset of these 200 Veterans (n=46; [23 with diabetes]) to be followed longitudinally, and 3) prospective recruitment of 66 new Veterans (33 with diabetes) who will have baseline arterial spin labeling magnetic resonance imaging to examine cerebral blood flow as a potential marker of cognitive inefficiency in diabetes; they will also be followed longitudinally [(total longitudinal n=112)]. This study is highly innovative in that it is the first to use NP process scores to identify subtle cognitive changes and predict future decline in diabetic Veterans that do not yet have a neurocognitive disorder. The goal of this Career Development Award (CDA-2) is for the candidate to develop the necessary skills to become an independent scientist investigating the earliest cognitive changes and inefficiencies in Veterans with diabetes. This CDA-2 application includes a comprehensive training program that builds upon the applicant’s background and existing skills in NP assessment/diagnosis, cognitive aging, and longitudinal analyses. The training plan is focused on building additional competencies in understanding diabetes mechanisms and standards of care, neuroimaging of cerebral perfusion, and developing further expertise in application of NP process scores. The multidisciplinary mentoring team includes an endocrinologist, a magnetic resonance physicist, and neuropsychologists with expertise spanning both vascular risk factors and process scores. The proposed project and the exceptional training opportunities available at the VA San Diego Healthcare System and the University of California, San Diego will assist the applicant in accomplishing her long-term career objective of transitioning into an independent VA clinical scientist conducting patient-oriented research in the field of neuropsychology and dementia risk in diabetes.