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

FTLD-Tau 人类视网膜成像生物标志物与 FTLD-TDP 和非记忆性 AD 的关系

• 批准号: 10738848
• 负责人: Benjamin J. Kim
• 金额: $ 212.64万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738848
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Autopsy; Biological Markers; Brain; Cerebrospinal Fluid; Clinical; Clinical Trials; Cognition; Data; Dementia; Development; Disease; Disease Progression; Enrollment; Exclusion; Eye; FDA approved; Frontotemporal Lobar Degenerations; Health; Histology; Human; Image; Image Analysis; Immunohistochemistry; Life; Longitudinal Studies; MAPT gene; Magnetic Resonance Imaging; Measures; Methodology; Mission; Modality; Modeling; Molecular; Morphology; Nerve Degeneration; Nerve Fibers; Neurologist; Ophthalmologist; Optical Coherence Tomography; Pathology; Patient imaging; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Photoreceptors; Plasma; Probability; Prognosis; Progressive Supranuclear Palsy; Proteins; Public Health; Reporting; Research; Research Personnel; Retina; Severities; Severity of illness; Stains; Syndrome; Tauopathies; Testing; Thinness; Time; Tissues; United States National Institutes of Health; Work; brain tissue; clinically relevant; cohort; comparison control; cost; endophenotype; fiber cell; frontotemporal degeneration; ganglion cell; genetic testing; imaging Segmentation; imaging biomarker; improved; innovation; interdisciplinary approach; neural; neuropathology; participant enrollment; predict clinical outcome; protein TDP-43; retinal imaging; segmentation algorithm; tau Proteins; tau mutation; tau-1; therapy development

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.

项目摘要/摘要 额颞变性（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 这65岁及以下的疾病（AD）。没有FDA批准的FTD药物，开发 由于没有足够的生物标志物来使病理病理学受到严重限制。大多数情况 FTD是由与蛋白质TAU（FTLD-TAU）或蛋白质TAR DNA结合蛋白相关的异常引起的 - 43（FTLD-TDP）。但是，在尸检之前可能很难确定哪些患者有异常 来自tau与TDP-43异常的人相比。此外，可能很难区分 尸检来自非肺AD（NAAD）患者的FTD患者。临床试验测试疗法 临床区分的问题阻碍了针对FTD的基本分子原因 FTLD-TAU，FTLD-TDP和NAAD。由于这些原因，迫切需要为FTD开发生物标志物 频谱障碍作为基于机制的疗法出现。主要使用光学相干断层扫描 （OCT），本应用程序的目的是评估残留图像异常作为可以可以的生物标志物 区分这些蛋白质病并在跨学科，深的背景下预测预后 内聚型方法。基于FTD患者的初步横断面和纵向研究 AD和肌萎缩性侧性硬化症中视网膜内部稀疏的报道（TDP-43蛋白质病与 ftd），总体假设是特定的基础TAU，TDP-43或淀粉样蛋白β神经病理学 痴呆可能导致视网膜的特异性异常，这是神经组织的延伸。因此，OCT具有潜力 作为快速，低成本和非侵入性生物标志物。拟议的目的是：1a）确定是否再次 OCT检测到的异常是将FTLD-TAU与FTLD-TDP和NAAD区分开的生物标志物。 1b） 为了确定OCT检测到的视网膜异常是否可以预测临床结果； 2）确定痴呆症是否 由组织学和免疫组织化学检测到的相关神经病理学存在于 在我们的FTD和NAAD患者队列中，眼睛注视着尸检。使用严格的方法论，调查人员将 通过眼科医生和神经科医生进行深度的内向型，排除混杂疾病，执行 具有经过验证的OCT图像分割算法的横截面和纵向OCT图像分析， 直接比较患者群体，并跟随患者进行大脑和眼睛的尸检。发展视网膜 成像是将FTLD-TAU与FTLD-TDP区分开的生物标志物和NAAD将是重要的贡献 因为这将有助于解决当前的困难，以正确地将FTD患者纳入临床试验。这 研究具有创新性，因为它可以通过跨学科来与现状相去甚远 仔细表型的方法，以确定视网膜是否是基础蛋白质病的生物标志物。 该项目将为包括OCT在内的生物标志物模型打开新的视野，并将推动使用剩余 与FTLD-TDP和NAAD相关的FTLD-TAU的强大生物标志物成像。