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.

项目摘要/摘要 原发性进行性失语症(PPA)是一种在保留的语言背景下出现的语言痴呆 记忆。它可由多种神经病理实体引起，包括阿尔茨海默病(AD)和 额颞叶退行性变(FTLD)。所有PPA变种的一个核心特征是选择性和 语言占优势的大脑半球(通常是左侧)的不对称性神经变性。在过去15年里， 西北PPA计划招募患者进行两年一次的认知评估、多模式成像和 基因特征。所有患者的生物液和尸检人员的脑组织 与国家阿尔茨海默氏症协调中心(NACC)和国家阿尔茨海默氏症协调中心(NACC)共享 阿尔茨海默病和相关痴呆症中央资料库(NCRAD)。这群人代表着什么 可以说是世界上最大的深度表型PPA患者登记。在这个项目的下一个周期中， PPA组将根据神经病理而不是临床变量进行分层。三个互动的具体目标 是通过多模式成像来表征神经病理的不对称性的特定指纹；识别 神经病理学与神经突触破坏、炎症标记物、基因表达和 他们大脑半球的不对称性；并探索选择性左半球易感性的分子特征 以及通过遗传分析获得的记忆韧性。我们将继续在现有和 新的项目和发展单一学科的研究方法，而不是集体研究，以便个人 大脑组织的差异也可以考虑在内。最主要的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 调查了独特的PPA队列，两个半球的尸检组织的可用性，因此不对称可以 被量化、图论方法的网络体系结构、不对称的遗传探索 大脑半球的脆弱性，以及疾病语言的个性化单一主题映射的开发 网络。西北PPA研究计划在以下方面做出了重要贡献 PPA的神经生物学和认知特征表明，相同的综合征(例如，PPA)可以 由多个神经病理实体引起的，一种疾病(例如，AD)可以导致多种综合征， 临床表现是由网络解剖而不是分子病理学决定的。穿过 这项工作已经成为建立病理生理异质性原则的典范 痴呆症患者。这项提案的目的将有助于进一步阐明 神经退行性疾病，神经退行性变中半球不对称的基础，内部 语言网络的结构，以及调节记忆功能弹性的机制 PPA伴AD神经病理。