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 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。大部分复杂性在于相同的事实 病理 引起 失智 会引起不同的痴呆综合症，相反，单个痴呆综合征可以是 通过多种病理。该提议的目标是解散 综合征，解剖萎缩，细胞死亡和特定形式的FTLD，称为ftld-tau.in 因此，这项工作将有助于识别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）和进行性超胸骨麻痹（PSP）。这些 tauopathies可以是主要的 进步 综合征 在 综合征： 失智 模型 将要 案例 立体论 临床 中央 展示 高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 进行性失语（PPA），一种以临床痴呆综合征为特征的 语言障碍和行为变体额颞痴呆（BVFTD），临床痴呆症 以评论的渐进变化为特征。 AIM 1将确定 病例被诊断出患有不同痴呆症的Anthertem PPA（分别为PPA-S和PPA-G）和BVFTD的语义和分析变体。 综合征各自与萎缩和临床特征的不同模式相关联，提供了理想 探索负责认知或行为的解剖区域的选择性漏洞。目标2 通过研究多种病理选择的疾病，CBD和PSP来研究相反关系 诊断出患有单个痴呆综合征（PPA-G或BVFTD）的股。组织学和公正 方法将用于确定FTLD-TAU病理学之间的关系，不仅用于细节 特征和定量MRI萎缩模式，但也针对神经元，神经胶质和突触异常。一个 他的工作的假设是FTLD-TAU的区域分布以及相关的蜂窝特征将 与萎缩的解剖学模式和独特的临床特征的一致性。 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陶氏病之间的特异性。 特定目标和 （（ 病理 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。