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 can between can cause different dementia syndromes and, conversely, dementia syndrome be caused by multiple pathologies. The goal of this proposal is relationship dementia syndromes, anatomic atrophy, cell death, and a specific form of FTLD, known as FTLD-tau. that a single to disentangle the complex 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 aphasia (PPA), a clinical dementia syndrome characterized clinical specific targets and cellular features of a single tauopathy (Pick's disease) in with respectively) clinical responsible pathologies (PPA-G between also distributions atrophy of 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 by progressive language impairment, and behavioral variant frontotemporal dementia (bvFTD), a dementia syndrome characterized by progressive changes in comportment. Aim 1 will determine the cases diagnosed antemortem different dementia syndromes: the semantic and agrammatic variants of PPA (PPA-S and PPA-G, and bvFTD. These dementia syndromes are each associated with distinct patterns of atrophy and profiles, an model to explore the vulnerabilities of anatomic regions for cognition or behavior. Aim 2 will study the converse relationship by investigating multiple ( Pick's disease, CBD, and PSP ) in cases diagnosed antemortem with a single dementia syndrome or bvFTD). Histological and unbiased stereological methods will be used to determine relationships FTLD-tau pathology, not only to detailed clinical profiles and quantitative MRI atrophy patterns, but to neuronal, glial, and synaptic abnormalities. A central hypothesis of this work is that regional of FTLD-tau — and related cellular features — will show concordance with anatomic patterns of and istinct clinical profiles. This is one of the first works of its kind that aims to establish clinical, anatomic, and pathologic concordance high specificity between clinical dementia syndromes and the tauopathies that cause them. providing ideal selective d the pathologic underpinningsof clinical heterogeneity in dementias,sharpen our understanding of the principles of selective vulnerability, and are highly relevant for the development of tauopathy-specific diagnostic tools and treatments.

PUBLIC HEALTH RELEVANCE STATEMENT. The at age death, tau form o frontotemporal lobar degeneration (FTLD-tau) is a class of neurodegenerative diseases found autopsy that underlies a wide range of clinical dementia syndromes, commonly affecting individuals under 65. The proposed work aims to clarify the relationship between FTLD-tau, pathologic markers of cell in vivo MRI atrophy patterns, and distinct clinical features of FTLD-related dementia syndromes. f Findings will inform our understanding of the putative substrates of neurodegeneration in FTLD-tau, and are highly relevant to the future development of disease-specific biomarkers and therapeutic approaches.