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.

项目摘要 R 01的前两个周期题为“了解TDP-43在阿尔茨海默病和FTLD中的作用” 非常成功，发表了50多篇同行评议的论文，并有许多新发现。在第二个周期中，我们 主要集中在TDP-43，tau蛋白和β淀粉样蛋白如何导致那些患有神经退行性疾病的人的神经退行性变。 阿尔茨海默病神经病理学改变（ADNC）。我们的研究在756例ADNC的队列中进行 例我们发现TDP-43在ADNC中的沉积是不均匀的，并首次表明， 在ADNC中存在两种不同类型的TDP-43沉积，我们称之为TDP-α型和TDP-β型。是什么 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型与神经系统的存在密切相关。 tangles缠结，and therefore因此tau τ.第二个发现是，不同的包裹体与不同的 病理类型（A型、B型和C型）的TDP-43分子组成不同 物种。例如，虽然大多数内含物由TDP-43的C-末端片段组成，但预内含物和 血管周围包涵体由比C-末端片段更大的全长TDP-43负荷组成。 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） 与FTLD-TDP类型（A型，B型，C型）相关，通过调查与不同类型的 TDP-43的分子种类，包括C-末端片段、全长和磷酸化TDP-43。第二 R 01的目标是进一步研究第二周期的结果，以便更好地了解TDP类型（α型） 和β型）改变TDP-43与神经变性之间的关联。我们会调查的， 具体而言，TDP，包括TDP类型、tau和β-淀粉样蛋白以及其他病理和遗传因素， 与海马体和新皮层的体积随时间损失的轨迹相关。我们的队伍将包括 死亡前多次头部MRI扫描的病例（范围：每年2-13次MRI扫描;总扫描=2316）。最后， 但同样重要的是，我们将解决该领域最大的知识缺口之一，缺乏一种生物标志物， 有助于预测生活中ADNC中TDP-43的存在。我们将使用[18F]氟脱氧葡萄糖PET， 已显示在预测TDP-43方面优于MRI，上级。我们将首先开发生物标志物，然后在 独立队列。为了实现第三周期的所有目标，我们将把队列规模提高到1 303人。 病理证实的ADNC和FTLD病例。第三个周期的结果将大大改善 了解TDP-43和TDP-43类型，并帮助解决边界在哪里的恼人问题 位于ADNC中的TDP-43和FTLD-TDP之间。考虑到TDP-43是一种潜在的治疗靶点， 治疗FTLD和现在的阿尔茨海默病，第3个周期可能也会有显着的影响， 领域