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

项目总结 我们的R01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” 我们非常成功，发表了50多篇同行评议的出版物和许多新发现。在第二个周期中，我们 主要集中在TDP-43，tau和β-淀粉样蛋白如何导致神经退行性变 阿尔茨海默病神经病理改变(ADNC)。我们的研究是在756名ADNC的队列中进行的 案子。我们发现TDP-43在ADNC中的沉积是不均匀的，并首次表明 在ADNC中有两种不同类型的TdP-43沉积，我们称之为TdP型-α和-β。是什么 这一发现最有趣的是，TDP型-α与一种病理类型具有惊人的相似特征 FTLD-TDP(FTLD-TDP A型)的发生，而TDP型-β与神经纤维的存在密切相关 Tangles，因此也是tau。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)FTLD-TDP的TDP-43分子组成不同 金币。例如，虽然大多数包裹体由TDP-43的C-末端片段组成，但前包裹体和 血管周围包涵体由全长TDP-43组成，而不是C-末端片段。 因此，第三个周期的主要目标之一是进一步评估ADNC TDP类型(类型-α和类型-β) 与FTLD-TDP类型(类型-A、类型-B、类型-C)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，以便更好地理解TDP类型(类型-α 和类型-β)改变了TDP-43和神经退行性变之间的联系。我们会调查的， 具体地说，TDP如何包括TDP类型、tau和β-淀粉样蛋白等病理和遗传因素 随着时间的推移，与海马体和新皮质体积丢失的轨迹有关。我们的队伍将包括 死亡前有多次头部MRI扫描的病例(范围：每年2-13次；总扫描=2316次)。最后的, 但同样重要的是，我们将解决该领域最大的知识差距之一，即缺乏能够 帮助预测生前ADNC中TDP-43的存在。我们将使用[18F]氟脱氧葡萄糖PET，我们 结果表明，在预测TDP-43方面，MRI优于MRI。我们将首先开发生物标记物，然后在 独立队列。为了实现第三个周期的所有目标，我们将把队列规模扩大到1303人 经病理确诊的ADNC和FTLD病例。第三个周期的结果将显著改善 了解TDP-43和TDP-43类型，并帮助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是一种潜在的治疗靶点 治疗FTLD和现在的阿尔茨海默病，第三个周期可能也会对 菲尔德。

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.