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

额颞部 品种 脑叶变性I S，尸检中发现的一种神经退行性疾病 在临床痴呆综合征中，是65岁以下痴呆症的第二大常见原因[1]。 患有FTLD相关痴呆的患者得不到足够的服务，部分原因是 痴呆症和潜在的病理还没有被很好地理解。大部分复杂性在于这样一个事实，即 相同的病理 能 在两者之间 会导致不同的痴呆症，反之亦然，痴呆症 是由多种病理因素引起的。这项提议的目标是建立关系 痴呆症、解剖萎缩、细胞死亡，以及一种特殊形式的FTLD，称为FTLD-tau。 那 一个 单人 为了解开这个情结 通过这样做，这项工作将有助于确定FTLD-tau中可能的神经退行性变的底物。 这项研究集中在显示最常见形式的死后人类样本的强大队列中 FTLD-tau：Pick病、皮质基底膜变性(CBD)和进行性核上性瘫痪(PSP)。 这些神经官能症可能是一种临床痴呆综合征--原发性进行性失语(PPA)的基础 特征化 临床 单纯性肌萎缩侧索硬化症(皮克氏病)的特定靶点和细胞特征 使用 分别) 临床 负责任的 病理学 (PPA-G 在两者之间 也是 分配 萎缩 PPA和bvFTD， 具体地说，为探索解剖学的组织和病理靶点提供令人兴奋的机会 神经退行性疾病中的网络。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型额颞叶痴呆(BvFTD)，a 以行为渐进性改变为特征的痴呆症。目标1将决定 6例死前确诊病例 痴呆的不同证型：PPA的语义和语法变体(PPA-S和PPA-G， 和bvFTD。这些痴呆症候群都与不同类型的萎缩和 Profile，一种探索解剖区域脆弱性的模型 对于认知或行为而言。目标2将通过调查多个 (匹克氏病、CBD和PSP)在生前诊断为单一痴呆综合征的病例中 或bvFTD)。将使用组织学和无偏见的体视学方法来确定关系 FTLD-tau病理，不仅有详细的临床表现和量化的MRI萎缩模式，而且 神经元、神经胶质细胞和突触的异常。这项工作的一个中心假设是地区性的 FTLD-tau-以及相关的细胞特征-将显示与 和清晰的临床特征。 这是第一批旨在建立临床、解剖学和病理学一致性的同类著作之一。 临床痴呆症和引起痴呆的神经官能症之间的高度特异性。 提供理想的选择性 D 这个 病理性 支持痴呆的临床异质性，加深我们对选择性治疗原则的理解 易损害性，与开发专门针对脊椎病的诊断工具和治疗方法高度相关。

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.