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

痴呆表型中 FTLD-tau 的临床、神经解剖学和病理学特征 - Diversity Supplement

• 批准号: 10357251
• 负责人: Tamar D Gefen
• 金额: $ 2.14万
• 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/10357251
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Anatomy; Aphasia; Atrophic; Autopsy; Behavior; Behavioral; Bilateral; Brain; Cell Death; Cellular Morphology; Clinical; Cognition; Complex; Comprehension; Dementia; Development; Diagnosis; Diagnostic; Disease; Environment; Failure; Frontotemporal Dementia; 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; Progressive Aphasias; Progressive Supranuclear Palsy; Regional Anatomy; Semantic Dementias; Semantics; Specificity; Specimen; Structure; Symptoms; Synapses; Syndrome; Tauopathies; Therapeutic; Tissues; Variant; Work; base; 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 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.

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 造成的 失智 可以引起不同的痴呆综合症，相反，单一的痴呆综合症可以引起 由多种病理引起。该提案的目标是理清之间的复杂关系 综合征、解剖性萎缩、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 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的基础 进步 综合症 单一 tau 蛋白病（皮克氏病）的细胞特征 综合症： 失智 模型 将要 案例 立体学的 临床 中央 展示 高 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 进行性失语症（PPA），一种临床痴呆综合征，其特征为 语言障碍和行为变异型额颞叶痴呆 (bvFTD)，一种临床痴呆 其特征是行为举止逐渐发生变化。目标 1 将确定 生前诊断出患有不同痴呆症的病例 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脆弱性。目标2 通过研究皮克氏病、CBD 和 PSP 等多种病理学来研究逆关系 生前诊断为单一痴呆综合征（PPA-G 或 bvFTD）。组织学且公正 方法将用于确定 FTLD-tau 病理学之间的关系，而不仅仅是详细的 轮廓和定量 MRI 萎缩模式，还包括神经元、神经胶质和突触异常。一个 这项工作的假设是 FTLD-tau 的区域分布以及相关的细胞特征将 与萎缩的解剖模式和不同的临床特征相一致。 这是同类中最早的作品之一，旨在建立临床、解剖和病理学上的一致性。 临床痴呆综合征和引起这些综合征的 tau 蛋白病之间的特异性。 具体目标和 ( 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。