Understanding the role of TDP-43 in Alzheimer’s disease and FTLD

了解 TDP-43 在阿尔茨海默病和 FTLD 中的作用

• 批准号: 10446997
• 负责人: Keith A Josephs
• 金额: $ 66.92万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446997
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease therapy; Amyloid beta-Protein; Atrophic; Attention; Autopsy; Awareness; Biological Markers; Brain; C-terminal; Cessation of life; DNA-Binding Proteins; Data; Deposition; Development; Diagnosis; Diagnostic; Disease; Frontotemporal Lobar Degenerations; Genetic; Goals; Head; Heterogeneity; Hippocampus (Brain); International; Knowledge; Length; Life; Ligands; Light; MRI Scans; Magnetic Resonance Imaging; Manuscripts; Measures; Medial; Modeling; Molecular; Morphology; Neocortex; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Pathogenesis; Pathologic; Patients; Peer Review; Performance; Play; Positron-Emission Tomography; Process; Prognosis; Proteins; Publications; Role; Scanning; System; Temporal Lobe; Testing; Time; Variant; Work; base; cerebral atrophy; cohort; fluorodeoxyglucose positron emission tomography; hippocampal atrophy; improved; individual patient; link protein; neocortical; neuroimaging; novel; predictive modeling; risk variant; targeted treatment; tau Proteins; therapeutic target

PROJECT SUMMARY The first two cycles of our R01 entitled, “Understanding the role of TDP-43 in Alzheimer's disease and FTLD” were very successful with over 50 peer-reviewed publications and many novel discoveries. In the 2nd cycle we focused mainly on how TDP-43, tau and beta-amyloid contributed to neurodegeneration in those with Alzheimer's disease neuropathologic changes (ADNC). Our studies were conducted on a cohort of 756 ADNC cases. We discovered that TDP-43 deposition in ADNC was heterogeneous and for the first time showed that there are two distinct types of TDP-43 deposition in ADNC that we termed TDP type-α and type-β. What is most interesting about this discovery is that TDP type-α have strikingly similar features to one pathological type of FTLD-TDP (FTLD-TDP type A) while TDP type-β is strongly associated with the presence of neurofibrillary tangles, and hence tau. A second discovery was that different inclusions associated with the different pathological types of FTLD-TDP (type A, type B and type C) had different molecular compositions of TDP-43 specie. For example, while most inclusions consisted of C-terminal fragments of TDP-43, pre-inclusions and perivascular inclusions consisted of a greater burden of full-length TDP-43 than C-terminal fragments. Therefore, one of the main goals of the 3rd cycle is to further assess how ADNC TDP types (type-α and type-β) are related to FTLD-TDP types (type-A, type-B, type-C) by investigating associations with the different molecular specie of TDP-43 including C-terminal fragments, full-length and phosphorylated TDP-43. A second goal of the R01 is to further our findings from the 2nd cycle in order to better understand how TDP types (type-α and type-β) modifies the associations between TDP-43 and neurodegeneration. We will investigate, specifically, how TDP, including TDP types, tau and beta-amyloid and other pathological and genetic factors are associated with trajectories of volume loss of hippocampus and neocortex over time. Our cohort will consist of cases with multiple head MRI scans (range: 2-13 yearly MRI scans; total scans=2316) prior to death. Last, but not least, we will address one of the biggest knowledge gaps in the field, the lack of a biomarker that can help predict the presence of TDP-43 in ADNC during life. We will use [18F]fluorodeoxyglucose PET, which we have shown is superior to MRI, to predict TDP-43. We will first develop the biomarker and then test it in an independent cohort. In order to accomplish all the aims of the 3rd cycle we will upgrade our cohort size to 1303 pathologically confirmed cases of ADNC and FTLD. Findings from this 3rd cycle will significantly improve understanding of TDP-43, and TDP-43 types, and help to address the nagging issue of where the boundary lies between TDP-43 in ADNC and FTLD-TDP. Given that TDP-43 is a potential therapeutic target for the treatment of FTLD and now Alzheimer's disease, the 3rd cycle will likely also have a significant impact on the field.

项目概要 我们 R01 的前两个周期标题为“了解 TDP-43 在阿尔茨海默病和 FTLD 中的作用” 取得了巨大成功，发表了超过 50 篇经过同行评审的出版物和许多新颖的发现。在第二个周期中我们 主要关注 TDP-43、tau 和 β-淀粉样蛋白如何导致患有神经退行性疾病的患者 阿尔茨海默病神经病理改变（ADNC）。我们的研究是在 756 名 ADNC 患者的队列中进行的 案例。我们发现 ADNC 中的 TDP-43 沉积是不均匀的，并首次表明： ADNC 中有两种不同类型的 TDP-43 沉积，我们称为 TDP α 型和 β 型。什么是 这一发现最有趣的是 TDP α 型与一种病理类型具有惊人相似的特征 FTLD-TDP（FTLD-TDP A 型），而 TDP β 型与神经原纤维的存在密切相关 缠结，因此也有 tau 蛋白。第二个发现是不同的内含物与不同的 FTLD-TDP的病理类型（A型、B型和C型）具有不同的TDP-43分子组成 硬币。例如，虽然大多数内含物由 TDP-43 的 C 端片段组成，但预内含物和 血管周围包涵体含有比 C 端片段更大的全长 TDP-43。 因此，第3周期的主要目标之一是进一步评估ADNC TDP类型（α型和β型） 通过调查与不同类型的关联，与 FTLD-TDP 类型（A 型、B 型、C 型）相关 TDP-43 的分子种类，包括 C 末端片段、全长和磷酸化的 TDP-43。一秒钟 R01 的目标是进一步推进我们在第二个周期中的发现，以便更好地了解 TDP 类型（α 型 和β型）改变了TDP-43和神经退行性变之间的关联。我们将调查， 具体来说，TDP如何影响，包括TDP类型、tau蛋白和β-淀粉样蛋白以及其他病理和遗传因素 随着时间的推移，与海马体和新皮质体积损失的轨迹相关。我们的队列将包括 死亡前进行多次头部 MRI 扫描的病例（范围：每年 2-13 次 MRI 扫描；总扫描次数 = 2316）。最后的， 但并非最不重要的是，我们将解决该领域最大的知识差距之一，即缺乏可以 帮助预测 ADNC 一生中 TDP-43 的存在。我们将使用[18F]氟脱氧葡萄糖 PET，我们 已显示在预测 TDP-43 方面优于 MRI。我们将首先开发生物标记物，然后在 独立队列。为了实现第三周期的所有目标，我们将把队列规模升级到 1303 人 病理确诊的 ADNC 和 FTLD 病例。第三周期的结果将显着改善 了解 TDP-43 和 TDP-43 类型，有助于解决边界在哪里的棘手问题 位于 ADNC 中的 TDP-43 和 FTLD-TDP 之间。鉴于 TDP-43 是该病的潜在治疗靶点 FTLD 和现在的阿尔茨海默氏病的治疗，第三个周期也可能对 场地。