Clinical, Neuroanatomic, and Pathologic Signatures of FTLD-tau in Dementia Phenotypes

额颞 各种 脑叶变性（FTLD）是一种在尸检中发现的神经退行性疾病， 是临床痴呆综合征的第二大常见病因，是65岁以下痴呆的第二大常见病因[1]。 FTLD相关痴呆患者得不到充分的治疗，部分原因是 痴呆症和潜在的病理学还没有很好的理解。大部分的复杂性在于， 相同病理 可以 之间 会导致不同的痴呆综合症，反过来，痴呆综合症 由多种病理引起。本提案的目标是建立关系 痴呆综合征、解剖萎缩、细胞死亡和一种特定形式的FTLD，称为FTLD-tau。 的 一 单个 解开复杂的 在这样做的过程中，这项工作将有助于确定FTLD-tau中神经变性的假定底物。 这项研究的重点是一个强大的队列死后人类标本，显示最常见的形式 FTLD-tau蛋白：皮克病，皮质基底节变性（CBD）和进行性核上性麻痹（PSP）。 这些tau蛋白病可导致原发性进行性失语症（PPA），一种临床痴呆综合征 特征 临床 单个tau蛋白病（皮克病）的特异性靶点和细胞特征 与 ） 临床 负责 病理 （PPA-G 之间 也 分布 萎缩 PPA和bvFTD， 特别是，为探索组织和病理解剖目标提供了令人兴奋的机会， 神经退行性疾病的网络。这项多学科研究的结果将澄清 进行性语言障碍和行为变异性额颞叶痴呆（bvFTD）， 行为举止逐渐改变的痴呆综合征。目标1将决定 死亡前诊断的病例 不同的痴呆综合征：PPA的语义和语法变体（PPA-S和PPA-G， 和bvFTD。这些痴呆综合征各自与不同的萎缩模式相关， 轮廓，一种探索解剖区域脆弱性的模型 for cognition认知or behavior行为.目标2将通过调查多重性来研究匡威关系 （皮克病，CBD和PSP）在死前诊断为单一痴呆综合征的病例中 或bvFTD）。组织学和无偏体视学方法将用于确定关系 FTLD-tau病理学，不仅详细的临床特征和定量MRI萎缩模式， 神经元神经胶质和突触异常这项工作的一个中心假设是， FTLD-tau -和相关细胞特征-将显示与 和独特的临床特征。 这是第一个作品的同类，旨在建立临床，解剖和病理一致性 临床痴呆综合征和导致它们的tau蛋白病之间的高度特异性。 提供理想的选择性 D 的 病理 痴呆临床异质性的基础，加深我们对选择性治疗原则的理解。 脆弱性，并且与tau蛋白病特异性诊断工具和治疗的开发高度相关。

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.