ASYMMETRIC NEURODEGENERATION AND LANGUAGE IN PRIMARY PROGRESSIVE APHASIA

原发性进行性失语症的不对称神经变性和语言

• 批准号: 10440152
• 负责人: MAREK-MARSEL M MESULAM
• 金额: $ 208.97万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440152
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease related dementia; Anatomy; Architecture; Autopsy; Brain; Cerebral hemisphere; Characteristics; Clinical; Cognitive; Dementia; Development; Disease; Enrollment; Evaluation; Fingerprint; Foundations; Frontotemporal Lobar Degenerations; Gene Expression; Genetic; Glia Maturation Factor; Heterogeneity; Individual Differences; Language; Left; Light; Mediating; Memory; Molecular; Molecular Profiling; Multimodal Imaging; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Participant; Patients; Phenotype; Predisposition; Primary Progressive Aphasia; Registries; Research; Research Methodology; Symptoms; Syndrome; Tissues; Tropism; Variant; Work; base; brain tissue; cohort; genetic analysis; graph theory; imaging genetics; inflammatory marker; innovation; molecular pathology; network architecture; neuropathology; personalized medicine; preservation; programs; prospective; repository; resilience

PROJECT SUMMARY / ABSTRACT Primary Progressive Aphasia (PPA) is a dementia of language that emerges on a background of preserved memory. It can be caused by multiple neuropathologic entities, including Alzheimer's disease (AD) and frontotemporal lobar degenerations (FTLD). The one core feature of all PPA variants is the selective and asymmetric neurodegeneration of the language-dominant (usually left) hemisphere. For the past 15 years, the Northwestern PPA Program has enrolled patients for biennial cognitive evaluation, multimodal imaging, and genetic characterization. Biofluids on all patients and brain tissue from those who have come to autopsy have been banked, curated, and shared with the National Alzheimer's Coordinating Center (NACC) and the National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD). This cohort represents what is arguably the world's largest registry of deeply phenotyped PPA patients. During the next cycle of this project, PPA groups will be stratified by neuropathology rather than clinical variant. The three interactive specific aims are to characterize neuropathology-specific fingerprints of asymmetry through multimodal imaging; to identify neuropathology-specific correlates of neurosynaptic disruption, inflammatory markers, gene expression, and their hemispheric asymmetry; and to explore molecular signatures of selective left hemisphere susceptibility and memory resilience through genetic analyses. We will continue prospective enrollment into existing and new projects and develop research methodology for single-subject rather than group studies so that individual differences in brain organization can be taken into account. An overarching theme will be the clinicopathology of asymmetry, which is the single universal core feature of PPA, and which offers a unique setting for investigating the mechanisms of selective vulnerability. The innovative aspects include access to a uniformly investigated unique PPA cohort, availability of autopsy tissue from both hemispheres so that asymmetry can be quantitated, graph theory approaches to network architecture, genetic explorations of asymmetric hemispheric vulnerability, and development of personalized single-subject mapping of the diseased language network. The Northwestern PPA Research Program has made key contributions to research on the neurobiology and cognitive characteristics of PPA by showing that the same syndrome (e.g., PPA) can be caused by multiple neuropathologic entities, that a single disease (e.g., AD) can cause multiple syndromes, and that clinical manifestations are determined by network anatomy rather than molecular pathology. Through this work PPA has become a paradigmatic entity for establishing principles of pathophysiologic heterogeneity in dementia. The aims in this proposal will help to shed additional light on the anatomical tropisms of neurodegenerative diseases, the foundations of hemispheric asymmetry in neurodegeneration, the internal architecture of the language network, and the mechanisms that mediate the resilience of memory function in PPA with AD neuropathology.

项目概要/摘要 原发性进行性失语症 (PPA) 是一种语言痴呆症，出现在保留语言能力的背景下。 记忆。它可能由多种神经病理学实体引起，包括阿尔茨海默病 (AD) 和 额颞叶变性（FTLD）。所有 PPA 变体的一个核心特征是选择性和 语言优势半球（通常是左半球）的不对称神经变性。在过去的 15 年里， 西北 PPA 计划已招募患者进行两年一次的认知评估、多模态成像和 遗传特征。所有患者身上的生物体液以及前来尸检的脑组织均已检测到 已存储、整理并与国家阿尔茨海默病协调中心 (NACC) 和国家阿尔茨海默病协调中心共享 阿尔茨海默病和相关痴呆症集中存储库 (NCRAD)。这个群体代表了什么 可以说是世界上最大的深度表型 PPA 患者登记处。在该项目的下一个周期中， PPA 组将根据神经病理学而不是临床变异进行分层。三个互动的具体目标 通过多模态成像来表征神经病理学特异性的不对称指纹；识别 神经突触破坏、炎症标记物、基因表达和神经病理学特异性相关性 他们的半球不对称；并探索选择性左半球易感性的分子特征 和通过遗传分析的记忆恢复能力。我们将继续对现有和 新项目并开发针对单一主题而不是小组研究的研究方法，以便个人 可以考虑大脑组织的差异。首要主题将是临床病理学 不对称性，这是 PPA 的单一通用核心特征，并为 研究选择性脆弱性的机制。创新方面包括获得统一的 研究了独特的 PPA 队列，来自两个半球的尸检组织的可用性，以便不对称性可以 量化、网络架构的图论方法、不对称的遗传探索 半球脆弱性，以及患病语言的个性化单受试者映射的开发 网络。西北 PPA 研究计划为以下方面的研究做出了重要贡献： 通过证明相同的综合征（例如，PPA）可以是 PPA 的神经生物学和认知特征 由多种神经病理学实体引起，单一疾病（例如 AD）可引起多种综合征， 临床表现是由网络解剖学而不是分子病理学决定的。通过 这项工作 PPA 已成为建立病理生理异质性原则的典范实体 在痴呆症中。该提案的目标将有助于进一步阐明 神经退行性疾病、神经退行性疾病中半球不对称的基础、内部 语言网络的架构，以及调节记忆功能弹性的机制 PPA 与 AD 神经病理学。