Concordance between cortical atrophy and histopathology in PPA with AD pathology

PPA 中皮质萎缩和组织病理学与 AD 病理学之间的一致性

• 批准号: 9768333
• 负责人: Daniel Timothy Ohm
• 金额: $ 1.99万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768333
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Amyloid beta-Protein; Area; Associative aphasia; Atrophic; Attention; Autopsy; Bilateral; Biological Markers; Brain; Brain imaging; Brain region; Cessation of life; Characteristics; Clinical; Cognitive; Data; Dementia; Deposition; Development; Disease; Disease Marker; Disease Progression; Esthesia; Evaluation; Event; Frontotemporal Lobar Degenerations; Histologic; Histopathology; Impaired cognition; Investigation; Language; Language Disorders; Left; Lesion; Logistics; MRI Scans; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Mediating; Memory; Microglia; Modeling; Motor; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neuropsychology; Parietal; Participant; Pathogenesis; Pathologic; Pathology; Patients; Pattern; Phenotype; Population; Primary Progressive Aphasia; Progressive Disease; Reporting; Role; Scanning; Severities; Severity of illness; Structure; Study Subject; Synapses; Syndrome; Time; Tissues; Visual; base; cerebral atrophy; cohort; demographics; density; experimental study; glial activation; gray matter; improved; in vivo; insight; interest; language impairment; multidisciplinary; neuroimaging; neuron loss; neuropathology; neurotoxic; spatial relationship

PROJECT SUMMARY ABSTRACT The pathologic determinants of in vivo cortical atrophy in neurodegenerative disease are not well understood due in part to the lack of magnetic resonance (MR) imaging close to death. Resolving this relationship is necessary for addressing the utility of quantitative brain imaging as an in vivo marker for disease severity and progression. Primary progressive aphasia (PPA) is a clinical language dementia syndrome that provides an ideal model for exploring the relationship between cortical atrophy and underlying pathology because it is associated with a signature pattern of asymmetric atrophy concentrated in the left hemisphere language network. This relatively focal pattern of peak atrophy allows for within-subject comparisons between damaged and relatively spared regions (e.g., left vs. right hemisphere; language vs. memory-related regions). PPA can be caused by either Alzheimer disease (AD) pathology or frontotemporal lobar degeneration pathology with a left-hemisphere dominant distribution. Amyloid-ß plaques (APs) and neurofibrillary tangles (NFTs) are the hallmark pathologic features of AD that are known to coincide with neuronal and synaptic loss and accumulation of activated microglia. The relationships among these markers have not been characterized in PPA with AD pathology (PPA-AD), but will be examined in this project. Specifically, Aim 1 will determine the extent and severity of cortical atrophy in five language and two non-language regions (subserving memory and visual sensation) of PPA-AD participants who had structural MR scans within 2.5 years of death. Aim 2 will quantify NFT, AP, activated microglia, neuron, and synapse densities in bilateral whole-hemisphere sections in the same regions and PPA-AD participants investigated in Aim 1 to determine the relationships among histologic markers, and their associations to in vivo measures of cortical atrophy. Our preliminary findings are consistent with our hypotheses and show that PPA-AD displays a leftward asymmetry of cortical atrophy in temporal and parietal language regions that corresponds to the highest densities of NFTs and lower densities of neurons. Combined results from this project will identify relationships among neurodegenerative features in order to discern the histopathologic basis of cortical degeneration underlying cognitive decline in PPA-AD.

项目摘要 在神经退行性疾病中，体内皮质萎缩的病理决定因素尚不清楚， 部分原因是由于缺乏接近死亡的磁共振成像。解决这一 定量脑成像作为疾病的体内标记物， 严重性和进展。原发性进行性失语症（PPA）是一种临床语言痴呆综合征， 为探索皮质萎缩和潜在病理学之间的关系提供了理想的模型， 它与集中在左半球语言的不对称萎缩的特征模式有关 网络这种相对局灶性的峰值萎缩模式允许在受试者内比较受损的 以及相对空闲的区域（例如，左半球与右半球;语言与记忆相关区域）。 PPA可以由阿尔茨海默病（AD）病理或额颞叶变性引起 左半球优势分布的病理学。淀粉样蛋白斑块（AP）和神经纤维缠结 NFT是AD的标志性病理特征，已知其与神经元和突触损失一致 和激活的小胶质细胞的积累。这些标记物之间的关系尚未得到表征 在PPA与AD病理（PPA-AD），但将在本项目中进行检查。具体而言，目标1将确定 五个语言和两个非语言区域的皮质萎缩的范围和严重程度（损害记忆和 视觉）的PPA-AD参与者谁有结构MR扫描死亡的2.5年内。目标2将 定量双侧全半球切片中的NFT、AP、活化的小胶质细胞、神经元和突触密度， 目的1中研究的相同区域和PPA-AD参与者，以确定组织学之间的关系。 标记物及其与皮质萎缩的体内测量的关联。我们的初步调查结果 与我们的假设，并表明PPA-AD显示颞叶皮质萎缩的不对称性， 顶叶语言区对应于NFT的最高密度和神经元的较低密度。 该项目的综合结果将确定神经退行性特征之间的关系， 辨别PPA-AD中认知下降的皮质变性的组织病理学基础。