Human Retinal Imaging Biomarkers for FTLD-Tau in Relation to FTLD-TDP and Nonamnestic AD

项目摘要/摘要 额颞退行性变(FTD)是一种与阿尔茨海默氏症一样常见的进行性神经退行性疾病 65岁及以下的人患有疾病(AD)。目前还没有FDA批准的治疗FTD的药物，而且开发 由于缺乏足够的致病病理生物标志物，治疗受到严重限制。大多数情况下 FTD是由与tau蛋白(FTLD-Tau)或TAR DNA结合蛋白相关的异常引起的 -43(FTLD-TDP)。然而，在尸检前很难确定哪些患者有异常。 与来自TDP-43异常的对照。此外，在此之前可能很难区分 尸检FTD患者与非遗忘型AD(NAAD)患者。测试疗法的临床试验 针对临床辨证分型问题阻碍FTD发生的分子机制 FTLD-Tau、FTLD-TDP和NAAD。出于这些原因，迫切需要开发FTD的生物标记物 随着基于机制的治疗的出现，谱系障碍应运而生。主要使用光学相干层析成像 (OCT)，本应用程序的目标是评估视网膜图像异常作为可以 在跨学科、深层次的背景下，区分这些蛋白病变并预测预后 内表型方法。基于对FTD患者的初步横断面和纵向研究 AD和肌萎缩侧索硬化症(一种与TDP-43相关的蛋白质病)中视网膜内层变薄的报道 Ftd)，总体假设是潜在的tau，tdp-43，或淀粉样蛋白β的神经病理。 痴呆症可能会导致视网膜的特定异常，视网膜是神经组织的延伸。因此，OCT具有潜力 作为一种快速、低成本和非侵入性的生物标志物。建议的目标是：1)确定视网膜是否 OCT检测到的异常是FTLD-TAU与FTLD-TDP和NAAD的生物标记物；1B) 确定OCT检测到的视网膜异常是否可以预测临床结果；2)确定痴呆症 组织学和免疫组织化学检测到的相关神经病理在视网膜中存在。 在我们的FTD和NAAD患者队列中进行尸检。在严谨的方法下，调查人员将 由眼科医生和神经科医生进行深入的内表型分析，排除混杂疾病，执行 用经过验证的OCT图像分割算法对横截面和纵向OCT图像进行分析， 直接比较患者组，并跟随患者进行脑部和眼睛的尸检。发育中的视网膜 作为区分FTLD-TAU和FTLD-TDP和NAAD的生物标志物，成像将是一个重要的贡献 因为这将有助于解决目前在正确招募FTD患者参加临床试验方面的困难。这 研究是创新的，因为它代表了对现状的重大偏离，采取了跨学科的 通过仔细的表型分析来确定视网膜是否是潜在蛋白质病的生物标志物。 该项目将为包括OCT在内的生物标记物模型开辟新的天地，并将推动视网膜的使用 与FTLD-TDP和NAAD相比，成像是FTLD-Tau的一个强大的生物标志物。

Project Summary/Abstract Frontotemporal degeneration (FTD) is a progressive neurodegenerative condition as common as Alzheimer’s Disease (AD) in those 65 and younger. There are no FDA approved medications for FTD, and development of therapies is severely limited by the absence of adequate biomarkers for the causative pathology. Most cases of FTD are caused by abnormalities related to the protein tau (FTLD-Tau) or the protein TAR DNA binding protein – 43 (FTLD-TDP). However, it can be difficult to determine prior to autopsy which patients have abnormalities from tau versus those with abnormalities from TDP-43. Furthermore, it can be difficult to distinguish prior to autopsy those patients with FTD from those with nonamnestic AD (naAD). Clinical trials testing therapies aimed at the underlying molecular causes of FTD are hindered by the problem of clinically distinguishing FTLD-Tau, FTLD-TDP, and naAD. For these reasons, there is an urgent need to develop biomarkers for FTD spectrum disorders as mechanism-based therapies emerge. Primarily using optical coherence tomography (OCT), the objective in this application is to evaluate retinal image abnormalities as biomarkers that can distinguish these proteinopathies and predict prognosis in the context of an interdisciplinary, deep endophenotyping approach. Based on preliminary cross-sectional and longitudinal studies in FTD patients and reports of inner retina thinning in AD and amyotrophic lateral sclerosis (a TDP-43 proteinopathy related to FTD), the overall hypothesis is that the underlying tau, TDP-43, or amyloid β neuropathology of a particular dementia may lead to specific abnormalities of the retina, an extension of neural tissue. OCT thus has potential as a rapid, low-cost, and non-invasive biomarker. The proposed aims are: 1A) To determine if retinal abnormalities, detected by OCT, are biomarkers distinguishing FTLD-Tau from both FTLD-TDP and naAD; 1B) To determine if retinal abnormalities, detected by OCT, predict clinical outcomes; 2) To determine if dementia relevant neuropathologies, as detected by histology and immunohistochemistry, are present in the retina of eyes at autopsy in our cohort of FTD and naAD patients. With rigorous methodology, the investigators will perform deep endophenotyping by ophthalmologists and neurologists, exclude confounding diseases, perform cross-sectional and longitudinal OCT image analyses with a validated OCT image segmentation algorithm, directly compare patient groups, and follow patients to autopsy of the brain and eyes. Developing retinal imaging as a biomarker distinguishing FTLD-Tau from FTLD-TDP and naAD would be a significant contribution because it would help resolve the current difficulty in properly enrolling FTD patients into clinical trials. This research is innovative as it represents a significant departure from the status quo by taking an interdisciplinary approach with careful phenotyping to determine if the retina is a biomarker for the underlying proteinopathy. This project will open new horizons for biomarker models including OCT, and it will advance the use of retinal imaging as a powerful biomarker for FTLD-Tau in relation to FTLD-TDP and naAD.