PROJECT SUMMARY. The increasing prevalence of dementia worldwide is considered a looming public health crisis, and few effective treatments are available to alleviate patients’ cognitive decline and associated psychiatric symptoms. Primary progressive aphasia (PPA) is a clinical dementia syndrome defined as an initial, focal decline in language abilities and atrophy of the language-dominant hemisphere. While not a core diagnostic criterion, most persons with PPA also develop severe neuropsychiatric symptoms, such as apathy and disinhibition, which are distressing and burdensome to both patients and their caregivers. Determining the biological substrates of these symptoms is challenging because one dementia syndrome can result from several underlying pathologies. In PPA, for example, underlying neuropathologies include Alzheimer’s disease (AD) and frontotemporal lobar degeneration with tauopathy (FTLD-tau) or TAR DNA-binding protein 43 (FTLD-TDP). The exact biological substrates causing neuropsychiatric symptoms to emerge and worsen over time in dementia syndromes are unclear. Understanding how regional distributions of various pathologies lead to neuropsychiatric presentations may serve as a valuable antemortem biomarker and deepen our knowledge of brain-behavior relationships. A central hypothesis is that each pathology will be associated with distinct neuropsychiatric signatures that change predictably with disease progression. To investigate this, the proposed research will identify the neuropsychiatric symptoms unique to AD, FTLD-tau, and FTLD-TDP within one dementia syndrome (PPA). The focus of Aim 1 of this study is to characterize distinct neuropsychiatric phenotypes of multiple underlying pathologies as they lead to PPA. It is hypothesized that symptoms will initially diverge between neuropathologies and will converge in the final stages of disease. Unique and shared neuropsychiatric symptoms will be assessed longitudinally between AD, FTLD-tau, and FTLD-TDP in PPA relative to each other and to a cognitively healthy group. The goal of Aim 2 is to determine relationships between neuropsychiatric signatures and pathologic markers in frontal and limbic brain regions. It is expected that hemispheric and regional densities of different these markers will show strong associations with salient neuropsychiatric symptoms. Bilateral frontal and limbic regions will be analyzed for pathologic inclusions, neuronal and synaptic integrity, and neuroinflammatory (microglia) markers, which will be quantified in whole hemisphere sections using unbiased stereology and digital pathology methods. This project will occur within the Northwestern Alzheimer’s Disease Center, which is a multidisciplinary, international PPA referral center that will provide access to over 50 postmortem brains from persons with PPA and thus represents an ideal environment for the proposed research and training. The public health impact of this study is substantial as AD, FTLD-tau, a...