Frontotemporal variety lobar degeneration (FTLD) i s a neurodegenerative disease found at autopsy that underlies a of clinical dementia syndromes, and is the second most common cause of dementia under age 65 [1]. Patients with FTLD-related dementias are underserved in part because the complex relationship between dementias and underlying pathology is not well understood. Much of the complexity lies in the fact that the same pathology caused dementia can cause different dementia syndromes and, conversely, that a single dementia syndrome can be by multiple pathologies. T he goal of this proposal is to disentangle the complex relationship between syndromes, anatomic atrophy, cell death, and a specific form of FTLD, known as FTLD-tau.In doing so, this work will help identify the putative substrates of neurodegeneration in FTLD-tau. This study focuses on a robust cohort of postmortem human specimens that show the most common forms of FTLD-tau: Pick's disease, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). These tauopathies can underlie primary progressive syndrome cellular features of a single tauopathy (Pick's disease) in syndromes: dementia model will cases stereological clinical central show high PPA and bvFTD, specifically, offer exciting opportunities for exploring the organization and pathologic targets of anatomic networks in neurodegenerative diseases. Outcomes of this multidisciplinary study will clarify progressive aphasia (PPA), a clinical dementia syndrome characterized by language impairment, and behaviora l variant frontotemporal dementia (bvFTD), a clinical dementia characterized by progressive changes in comportment. Aim 1 will determine the cases diagnosed antemortem with different dementia the semantic and agrammatic variants of PPA (PPA-S and PPA-G, respectively) and bvFTD. These syndromes are each associated with distinct patterns of atrophy and clinical profiles, providing an ideal to explore the selective vulnerabilities of anatomic regions responsible for cognition or behavior. Aim 2 study the converse relationship by investigating multiple pathologies Pick's disease, CBD, and PSP) in diagnosed antemortem with a single dementia syndrome (PPA-G or bvFTD). Histological and unbiased methods will be used to determine relationships between FTLD-tau pathology, not only to detailed profiles and quantitative MRI atrophy patterns, but also to neuronal, glial, and synaptic abnormalities. A hypothesis of t his work is that regional distributions of FTLD-tau — and related cellular features — will concordance with anatomic patterns of atrophy and distinct clinical profiles. This is one of the first works of its kind that aims to establish clinical, anatomic, and pathologic concordance of specificity between clinical dementia syndromes and the tauopathies that cause them. specific targets and ( the pathologic underpinningsof clinical heterogeneity in dementias,sharpen our understanding of the principles of s...