Pathology-guided 7T neuroimaging biomarker in FTLD-TDP

TDP-43蛋白质病是一种常见形式的神经退行性痴呆（即额颞叶痴呆，FTD）， 年龄小于65岁的患者（即额颞叶变性伴TDP-43蛋白病，FTLD-TDP）， 老年痴呆症和衰老的共同病理。目前没有生物标志物模式， 可以准确识别和追踪活体患者中的TDP-43介导的神经退行性变，这对神经退行性变的研究具有重大意义。 针对TDP-43相关疾病机制的临床试验的障碍。事实上，FTLD-TDP是 无法治愈的疾病，无法可靠地诊断和与临床相似的患者区分开来， Tau病（FTLD-Tau），使尸检成为诊断的金标准。这个项目的首要目标是 该项目是将人脑组织的数字组织学与高分辨率的离体7特斯拉（7T）磁 图1示出了使用核磁共振成像（MRI）对人脑连接体中的TDP-43疾病进行建模的方法。我们的目标是首先使用ex 对神经认知网络重要的灰质（GM）区域的体内7T MRI引导采样， FTD临床症状，并将TDP-43和临床上无法区分的FTLD-Tau的分布与 确定TDP-43蛋白质病的显微镜GM细胞模式。接下来，我们将检查TDP-43病理学 在独特的深白色物质（WM）束中，并对比TDP-43和tau病理学的分布 神经认知网络中的WM通路的研究。最后，我们将研究GM TDP-43病理在7T MRI离体成像中的层状特征。成功实现这些目标将 提供急需的尸检数据，以指导开发组织病理学验证的 FTD相关的宏观神经认知网络中的进行性微观TDP-43疾病。

TDP-43 proteinopathy is a common form of neurodegenerative dementia (i.e. frontotemporal dementia, FTD) in patients younger than 65 (i.e. frontotemporal lobar degeneration with TDP-43 proteinopathy, FTLD-TDP) and is a common co-pathology in Alzheimer’s disease and aging. There are currently no biomarker modalities that can accurately identify and track TDP-43 mediated neurodegeneration in living patients, which poses a major obstacle for clinical trials targeting TDP-43 associated mechanisms of disease. Indeed, FTLD-TDP is an incurable condition and cannot be reliably diagnosed and differentiated from clinically similar patients with tauopathy (FTLD-Tau) during life, making autopsy the gold-standard for diagnosis. The overarching goal of this project is to integrate digital histology of human brain tissue with high-resolution ex vivo 7 Tesla (7T) magnetic resonance imaging (MRI) to model TDP-43 disease in the human brain connectome. We aim to first use ex vivo 7T MRI guided sampling of grey matter (GM) regions important for neurocognitive networks that underly FTD clinical symptoms and contrast the distribution of TDP-43 and clinically indistinguishable FTLD-Tau to determine microscopic GM cellular patterns of TDP-43 protienopathy. Next, we will examine TDP-43 pathology in uniquely sampled deep white matter (WM) tracts and contrast the distribution of TDP-43 and tau pathology in WM pathways of neurocognitive networks using graph theoretic analysis. Finally, we will examine GM laminar features of TDP-43 pathology in 7T MRI ex vivo imaging. Successful completion of these aims will provide critically needed autopsy-data to guide development of histopathology-validated markers of progressive microscopic TDP-43 disease in macroscale neurocognitive networks implicated in FTD.