Due to an aging population and increased lifespan, dementia is an increasing clinical and public health issue. The most common and well-known cause is Alzheimer’s disease (AD), but other important disorders are involved in the development of AD-related dementias (ADRD). What is less appreciated is that Parkinson’s disease (PD), the second most common neurodegenerative disease, while often associated with motor dysfunction, contributes to ADRD with an incidence of dementia as high as 80% in late stages in which most have AD co-pathology. Therefore, this population exhibits a range of cognitive deficits that enables insight into mechanisms involved in ADRD. There seem to be two distinct cognitive profiles in these patients. One is a benign frontal profile characterized by executive and attention deficits, whereas the other is a posterior profile characterized by memory and visuospatial deficits that is associated with faster progression to dementia, often with AD co-pathology. The premise of this application is that identifying the neural circuitry underlying frontal and posterior function may provide insight into structural alterations occurring in ADRD. Dopaminergic therapies are known to improve frontal circuitry function, but not posterior circuitry, leading to the hypothesis that posterior circuit alterations are due to non-dopaminergic pathology, such as AD co-pathology. If true, the pattern of frontal-vs-posterior involvement may lead to differential responses to current treatments in ADRD. I plan to apply diffusion tensor tractography, a sensitive and widely available MRI technique, to measure microstructural integrity of white matter (WM) connections between brain regions. My central hypothesis is that WM alterations in frontal and posterior circuitry occurs in PD (Aim 1); that these alterations are associated with specific cognitive deficits and relate to differing rates of progression to dementia (Aim 2); and the ratio of frontal to posterior damage (F/P ratio) modulates the cognitive response to treatment (e.g., levodopa, deep brain stimulation, Aim 3). These aims will be implemented by leveraging existing datasets allowing a cost-effective and impactful investigation. This study immediately will impact knowledge of WM circuits related to dementia with insight into underlying mechanisms and therapeutic strategies, as well as provide the foundational line of research for future study of microstructural signatures of AD/ADRD. I have assembled a world-class mentoring team with expertise in areas related to my research and a history of highly-successful mentoring. The environment and institutional resources available to me for this project are excellent with a well-developed training plan and access to required equipment and research datasets. The proposed project and training plan will position me at the intersection of neuroscience and engineering, and enable me to tackle important clinical problems with the latest technological advanceme...