Concordance between cortical atrophy and histopathology in PPA with AD pathology

项目总结摘要 神经退行性疾病中体内皮质萎缩的病理决定因素不是很好 被理解的部分原因是濒临死亡时缺乏磁共振(MR)成像。解决这个问题 为了解决定量脑成像作为体内疾病标志物的效用，这种关系是必要的 严重程度和进展。原发性进行性失语(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之间的关系提供了一个理想的模型，因为 它与集中在左半球语言中的不对称萎缩的特征模式有关 网络。这种相对集中的峰值萎缩模式允许在受试者内部比较受损的 以及相对较少的区域(例如，左半球与右半球；语言与记忆相关的区域)。 PPA可由阿尔茨海默病(AD)病理或额颞叶变性引起 左半球占优势分布的病理学。淀粉样蛋白斑块(AP)和神经纤维缠结 (NFTS)是AD的标志性病理特征，已知与神经元和突触丢失相一致 和激活的小胶质细胞堆积。这些标记之间的关系还没有被表征 在PPA中伴有AD病理(PPA-AD)，但将在本项目中进行检查。具体来说，目标1将决定 五种语言和两种非语言区域皮质萎缩的程度和严重程度(次级记忆和 在死亡2.5年内接受结构性磁共振扫描的PPA-AD参与者的视觉感觉)。目标2将 定量测定双侧全脑切片中NFT、AP、激活的小胶质细胞、神经元和突触密度 在目标1中调查的相同区域和PPA-AD参与者以确定组织学之间的关系 标记物及其与体内皮质萎缩测量的关联。我们的初步调查结果是一致的 与我们的假设一致，并显示PPA-AD在颞叶和大脑皮质萎缩表现为向左不对称。 顶叶语言区，对应着NFT密度最高和神经元密度较低的区域。 该项目的综合结果将确定神经退行性特征之间的关系，以便 明确PPA-AD认知功能减退背后的皮质变性的组织病理学基础。

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.