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

额颞叶变性分子病理学的微观和大规模网络

基本信息

批准号：
10685403
负责人：
David John Irwin
金额：
$ 74.66万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685403
关键词：
Affect Age Anatomic Models Autopsy Behavioral Brain Brain region Cells Cerebral hemisphere Cerebrum Classification Clinical Clinical Trials Cognitive Data Dementia Diagnosis Diagnostic Diffusion Magnetic Resonance Imaging Disease Disease Progression Disparate Distant FDA approved Frontotemporal Dementia Frontotemporal Lobar Degenerations Gliosis Goals Graph Histology Histopathology Human Image Knowledge Language Length Life Magnetic Resonance Imaging Maps Microscopic Modeling Monitor Nerve Degeneration Neurocognitive Neurodegenerative Disorders Neuroglia Neurons Pathogenesis Pathogenicity Pathologic Pathology Patients Pattern Persons Population Predictive Value Primary Progressive Aphasia Process Prognosis Progressive Disease Proteins Sampling Science Social Network Staging Surgical incisions Syndrome Tauopathies Variant Work behavioral variant frontotemporal dementia biomarker validation brain cell cellular pathology clinical care cohort connectome density digital graph theory gray matter improved in vivo in vivo Model interdisciplinary approach molecular pathology multimodal neuroimaging neuroimaging neuroimaging marker neuron loss neuropathology novel prognostic protein TDP-43 protein aggregation structural imaging targeted treatment tau Proteins theories white matter

项目摘要

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.

摘要该提案的总体目标和目的是整合数字组织病理学和结构神经影像学数据，以模拟与额颞叶相关的分子病理学扩散模式痴呆（FTD）。FTD是一种无法治愈的进行性神经退行性疾病，老年痴呆症患者年龄在40-65岁之间。FTD临床综合征包括行为变异（bvFTD）和原发性进行性失语症（PPA）。与FTD临床相关的基础神经病理学综合征被分类为具有tau（FTLD-Tau）或TDP-43的额颞叶变性（FTLD （FTLD-TDP）脑细胞中的蛋白质细胞内切口，目前只能在尸检这些不同的蛋白质病可导致临床上难以区分的FTD临床bvFTD和PPA 生活中的症状这些蛋白质的致病形式在细胞间的传播会导致疾病因此，靶向该过程的疾病修饰疗法的主要障碍是能够检测并追踪这些特定的蛋白质聚集体神经成像的网络科学方法在存活患者中发现bvFTD和PPA患者在对应于神经认知的脑区域中存在疾病网络的社会/执行和语言功能，但疾病的进展模式，这些神经认知网络中的这些特定蛋白质病是未知的。最重要的假设是这一建议是FTLD-Tau和FTLD-TDP在细胞病理学中具有部分可分离的模式，选择性影响大规模区域认知网络的神经元和神经胶质的微观网络，以及这可用于区分和跟踪这些死亡前的病理。本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，大脑中的FTLD-Tau和FTLD-TDP病理学。接下来，将进行网络科学分析，在高密度采样中研究这些不同病理的传播的微观连接模式额颞部的不同区域最后，网络分析将应用于纵向生前结构成像，以确定进行性FTLD-Tau和FTLD-TDP的“特征” 临床bvFTD和PPA的神经病理学网络。这些发现将发现组织病理学验证的进行性疾病的标志物，其告知FTLD-tau患者中传播病理学的理论， FTLD-TDP，并提供体内疾病进展的病理学验证的临床和解剖学模型，将有助于诊断，分期和预后的FTD谱疾病。