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

痴呆表型中 FTLD-tau 的临床、神经解剖学和病理学特征

• 批准号: 10755406
• 负责人: Tamar D Gefen
• 金额: $ 1.07万
• 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/10755406
• 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; Disease; Environment; Failure; Frontotemporal Lobar Degenerations; Functional disorder; Future; Goals; Histologic; Human; Image; Impaired cognition; Impairment; Individual; Inferior frontal gyrus; International; Left; MRI Scans; Magnetic Resonance Imaging; Methods; Microglia; Modeling; Nerve Degeneration; Neuroanatomy; 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; Symptoms; Synapses; Syndrome; Tauopathies; Therapeutic; Tissues; Variant; Work; base; behavioral variant frontotemporal dementia; cerebral atrophy; clinical heterogeneity; clinical phenotype; cohort; corticobasal degeneration; diagnostic tool; granule cell; in vivo; language impairment; multidisciplinary; neuropathology; public health relevance; regional atrophy; specific biomarkers; tau Proteins

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.

额颞叶 种类 脑叶变性 (FTLD) 是一种在尸检中发现的神经退行性疾病，其基础是 是临床痴呆综合征的常见症状，是 65 岁以下痴呆症的第二大常见原因[1]。 FTLD 相关痴呆患者得不到充分的服务，部分原因是两者之间的复杂关系 痴呆症和潜在的病理学尚不清楚。大部分复杂性在于以下事实： 相同的病理 能 之间 可引起不同的痴呆综合症，反之，痴呆综合症 由多种病理引起。该提案的目标是建立关系 痴呆综合征、解剖性萎缩、细胞死亡和 FTLD 的一种特殊形式，称为 FTLD-tau。 那 一个 单身的 来解开复杂的局面 在此过程中，这项工作将有助于确定 FTLD-tau 神经变性的假定底物。 这项研究的重点是一组强大的死后人类标本，这些标本显示出最常见的形式 FTLD-tau 蛋白：皮克氏病、皮质基底节变性 (CBD) 和进行性核上性麻痹 (PSP)。 这些 tau蛋白病可能是原发性进行性失语症 (PPA) 的基础，这是一种临床痴呆综合征 特征化的 临床 单一 tau 蛋白病（皮克氏病）的特定靶点和细胞特征 和 分别） 临床 负责任的 病理学 (PPA-G 之间 还 分布 萎缩 PPA 和 bvFTD， 具体来说，为探索解剖学的组织和病理目标提供令人兴奋的机会 神经退行性疾病网络。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) 痴呆综合征，其特征是行为进行性改变。目标 1 将确定 生前确诊病例 不同的痴呆症综合征：PPA 的语义和语法变体（PPA-S 和 PPA-G， 和 bvFTD。这些痴呆综合征均与不同的萎缩模式相关 配置文件，探索解剖区域脆弱性的模型 用于认知或行为。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体视学方法来确定关系 FTLD-tau 病理学，不仅包括详细的临床特征和定量 MRI 萎缩模式，而且 神经元、神经胶质和突触异常。这项工作的一个中心假设是区域 FTLD-tau 的结构以及相关的细胞特征将与以下结构的解剖模式一致： 和独特的临床特征。 这是旨在建立临床、解剖学和病理学一致性的首批此类作品之一 临床痴呆综合征与引起这些综合征的 tau 蛋白病之间具有高度特异性。 提供理想的选择 d 这 病理性的 痴呆症临床异质性的基础，加深我们对选择性原则的理解 脆弱性，并且与 tau 病特异性诊断工具和治疗方法的开发高度相关。