Microscopic and Large-Scale Networks of Molecular Pathology in Frontotemporal Lobar Degeneration

摘要 这项提案的总体目标和目标是将数字组织病理学和结构 用神经影像数据模拟与额颞部相关的分子病理扩散模式 痴呆症(FTD)。FTD是一种无法治愈的进行性神经退行性疾病，是一种常见的 痴呆症患者年龄在40-65岁之间。FTD的临床症状包括行为变异 (BvFTD)和原发性进行性失语(PPA)。与FTD临床相关的潜在神经病理学 综合征被归类为伴有tau(FTLD-Tau)或TDP-43的额颞叶变性(FTLD) (FTLD-TDP)脑细胞内蛋白质内切口处，目前只能在 验尸报告。这些不同的蛋白病变可导致临床上无法区分的FTD、临床bvFTD和PPA。 生活中的综合症。这些蛋白的致病形式在细胞间传播导致疾病 因此，针对这一过程的疾病修改疗法的一个主要障碍是能够 在生前检测和跟踪这些特定的蛋白质聚集体。神经成像的网络科学方法 在活着的患者中发现bvFTD和PPA患者的大脑区域与神经认知相对应的疾病 社会/执行和语言功能的网络，但疾病的发展模式 这些神经认知网络中的特定蛋白病变是未知的。最重要的假设是 这一建议是FTLD-Tau和FTLD-TDP具有部分可分离的细胞病理模式 神经元和胶质细胞的微观网络，选择性地影响大规模的区域认知网络，以及 这可以用来区分和追踪这些生前的病理。这项研究的目的是首先 进行详细的数字组织病理学研究，以量化和比较细胞和区域模式 FTLD-Tau和FTLD-TDP大脑病理。接下来，将执行网络科学分析以 在高密度采样中研究这些不同病变传播的微观连通性模式 分别来自每个半球的多个额颞区。最后，网络分析将应用于 纵向生前结构成像确定进行性FTLD-Tau和FTLD-TDP的“征象” 临床bvFTD和PPA的神经病理网络。这些发现将发现组织病理学验证 进展性疾病的标志物，为FTLD-tau和FTLD-tau在人类中传播病理的理论提供信息 FTLD-TDP，并提供经病理学验证的体内疾病进展的临床和解剖学模型 将有助于FTD谱系疾病的诊断、分期和预后。

ABSTRACT The overall goals and objectives of this proposal are to integrate digital histopathology and structural neuroimaging data to model patterns of spread of molecular pathology associated with frontotemporal dementia (FTD). FTD is an incurable progressive neurodegenerative disorder that is a common form of dementia in patients between the ages of 40-65. FTD clinical syndromes include the behavioral-variant (bvFTD) and primary progressive aphasia (PPA). The underlying neuropathology associated with FTD clinical syndromes is classified as frontotemporal lobar degeneration (FTLD) with either tau (FTLD-Tau) or TDP-43 (FTLD-TDP) proteinaceous intracellular incisions in brain cells, which currently can only be detected at autopsy. These disparate proteinopathies can result in clinically indistinguishable FTD clinical bvFTD and PPA syndromes during life. Cell-to-cell spread of pathogenic forms of these proteins contributes to disease pathogenesis and thus, a major obstacle for disease modifying therapies targeting this process is the ability to detect and track these specific protein aggregations antemortem. A network science approach to neuroimaging in living patients finds bvFTD and PPA patients have disease in brain regions corresponding to neurocognitive networks for social/executive and language functioning, respectively, but the patterns of disease progression of these specific proteinopathies within these neurocognitive networks is unknown. The overarching hypothesis of this proposal is that FTLD-Tau and FTLD-TDP have partially dissociable patterns of cellular pathology in microscopic networks of neurons and glia that selectively impact large-scale regional cognitive networks, and this can be used to differentiate and track these pathologies antemortem. The aims of this study are to first perform a detailed digital histopathological study to quantify and compare the cellular and regional pattern of FTLD-Tau and FTLD-TDP pathology in the cerebrum. Next, network-science analytics will be performed to study the microscopic connectivity patterns of spread of these disparate pathologies in high-density sampling from multiple frontotemporal regions in each hemisphere. Finally, network analytics will be applied to longitudinal antemortem structural imaging to define “signatures” of progressive FTLD-Tau and FTLD-TDP neuropathology networks in clinical bvFTD and PPA. These findings will discover histopathology-validated markers of progressive disease that inform theories of spreading pathology in humans with FTLD-tau and FTLD-TDP, and provide pathology-validated clinical and anatomical models of in vivo disease progression that will be useful for diagnosis, staging and prognosis in FTD-spectrum disorders.