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

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， 病理 造成 痴呆 可以引起不同的痴呆综合症，相反，单一的痴呆综合症可以是 由多种病理学引起。这一建议的目的是理清 综合征，解剖萎缩，细胞死亡和一种特定形式的FTLD，称为FTLD-tau。 因此，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 进步 综合征 一个单一的tau蛋白病（皮克病）的细胞特征， 综合征： 痴呆 模型 将 例 立体学 临床 中央 显示 高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 进行性失语症（PPA），一种临床痴呆综合征，其特征在于 语言障碍和行为变异性额颞叶痴呆（bvFTD），一种临床痴呆 以行为举止的逐渐变化为特点。目标1将决定 2000年6月至2001年12月， PPA的语义和语法变体（分别为PPA-S和PPA-G）和bvFTD。这些 每种综合征都与不同的萎缩模式和临床特征相关，提供了理想的 探索负责认知或行为的解剖区域的选择性弱点。目的2 通过研究多种病理学（皮克病、CBD和PSP）， 生前诊断为单一痴呆综合征（PPA-G或bvFTD）。组织学和无偏倚 方法将用于确定FTLD-tau病理之间的关系，不仅详细 轮廓和定量MRI萎缩模式，而且神经元，神经胶质和突触异常。一 他工作假设是FTLD-tau的区域分布-和相关的细胞特征-将 与萎缩的解剖模式和不同的临床特征一致。 这是其第一个作品，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蛋白病之间的特异性。 具体目标和 ( 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 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 selective vulnerability, and are highly relevant for the development of tauopathy-specific diagnostic tools and treatments.