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

痴呆表型中 FTLD-tau 的临床、神经解剖学和病理特征

• 批准号: 9885738
• 负责人: Tamar D Gefen
• 金额: $ 39.5万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9885738
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Anatomy; Aphasia; Atrophic; Autopsy; Behavior; Behavioral; Bilateral; Brain; Cell Death; Cells; Cellular Morphology; Cessation of life; Clinical; Cognition; Complex; Comprehension; Dementia; Development; Diagnosis; Diagnostic; Disease; Environment; Failure; Frontotemporal Lobar Degenerations; Functional disorder; Future; Goals; Histologic; Human; Image; Impaired cognition; Impairment; Individual; Inferior frontal gyrus; International; Lead; Left; Lobar; MRI Scans; Magnetic Resonance Imaging; Methods; Microglia; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Neuropsychology; Outcome; Pathologic; Pathology; Patients; Pattern; Personality; Phenotype; Pick Disease of the Brain; Pick body; Primary Progressive Aphasia; Progressive Supranuclear Palsy; Regional Anatomy; Semantics; Specificity; Specimen; Structure; Symptoms; Synapses; Syndrome; Tauopathies; Therapeutic; Tissues; Variant; Work; base; behavioral variant frontotemporal dementia; cerebral atrophy; clinical heterogeneity; clinical phenotype; cohort; corticobasal degeneration; granule cell; in vivo; language impairment; multidisciplinary; neuropathology; public health relevance; specific biomarkers; tau Proteins; tau-1; tool

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.

额颞 种类 LOBAR变性（FTLD）是尸检时发现的一种神经退行性疾病 临床痴呆综合征的症状，是65岁以下痴呆症的第二大最常见原因[1]。 与FTLD相关的痴呆症患者的服务不足，部分原因是 痴呆症和基本病理学尚不清楚。复杂的大部分在于一个事实，即 相同的病理 能 之间 会引起不同的痴呆综合症，相反 是由多种病理引起的。该提议的目的是关系 痴呆综合征，解剖萎缩，细胞死亡和特定形式的FTLD，称为FTLD-TAU。 那 一个 单身的 解开综合体 在此过程中，这项工作将有助于确定FTLD-TAU中神经退行性的假定底物。 这项研究重点是强大的验尸人类标本，该标本显示了最常见的形式 FTLD-TAU：Pick的疾病，皮质型变性（CBD）和进行性超导剂麻痹（PSP）。 这些tauopathies可以是原发性进行性失语症（PPA），一种临床痴呆综合征 特征 临床 在 和 （分别） 临床 负责任的 病理 （PPA-G） 之间 还 分布 萎缩 PPA和BVFTD， 具体而言，为探索解剖学的组织和病理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 通过进行性语言障碍和行为变体额颞痴呆（BVFTD）， 痴呆综合征的特征是评论的渐进变化。 AIM 1将确定 病例诊断性股 不同的痴呆综合症：PPA的语义和分析变体（PPA-S和PPA-G，， 和bvftd。这些痴呆综合症各自与萎缩的不同模式有关 配置文件，一个探索解剖区域脆弱性的模型 用于认知或行为。 AIM 2将通过研究多个 （Pick's Disision，CBD和PSP）在单个痴呆综合征的诊断性驱动器中 或bvftd）。组织学和公正的立体方法将用于确定关系 FTLD-TAU病理学，不仅用于详细的临床特征和定量MRI萎缩模式，还 神经元，神经胶质和突触异常。这项工作的一个核心假设是区域 ftld-tau以及相关的蜂窝特征 - 将与解剖模式一致 和不可分割的临床特征。 这是旨在建立临床，解剖和病理一致性的同类作品之一 临床痴呆综合征与引起它们的tauopathies之间的高特异性。 提供理想的选择性 d 这 病理学 痴呆症中临床异质性的基础，增强了我们对选择性原则的理解 脆弱性，并且与开发特定于Tauopathy的诊断工具和治疗高度相关。