From cells to complex syndromes: using networks to understand heterogeneity in TDP-related frontotemporal degeneration and aging

额颞叶退行性变(FTD)是一种临床上研究较少的神经退行性疾病，是世界上最常见的 65岁以下人群中阿尔茨海默病(AD)后的常见痴呆症。最常见的病理 与FTD相关的是由~43的反式DNA/RNA结合蛋白引起的额颞叶变性 KD(TDP-43(FTLD-TDP))，这也是绝大多数患有 共同发生的肌萎缩侧索硬化症(FTD-ALS)谱系障碍以及年龄的关键力量- 相关疾病，如以边缘为主的年龄相关性TDP-43脑病(晚期)。自从发现了一个 TDP-43病理在人类疾病中的作用，在实验细胞和 疾病的动物模型。然而，人脑有许多独特的特性，与明显相关 在这些实验模型中不易复制的人类临床疾病。知识方面的主要差距 从而限制了疾病修正治疗试验的发展。其中之一是我们有限的知识 TDP-43异常积聚和进展的病理生理后果 水平。在微观层面上，一个主要的限制是大多数TDP-43积聚的患者都有零星的 只有在尸检时才能可靠地识别的疾病，尽管约20%的病例有家族性FTLD(FFTLD)和 已知的生前病理。我们在将这种知识转化为宏观层面上受到限制，在那里FTLD- TDP病理表现在人类身上，具有不同的临床特征，如情感上的不同 无论有无运动障碍，都会出现调节障碍和语言障碍。此外，有有限的 了解导致疾病进展速度差异很大的因素。在五部小说中， 独立但协同的项目和支持每个项目的五个核心，这是独特的， 多学科，计划项目赠款(PPG)采用了研究 与TDP-43相关的神经网络在分子、微观和宏观水平上的崩溃 人类。我们假设，我们新颖的、集成良好的网络视角将填补 通过阐明对TDP-43异常的病理生理学和TDP-43的病理生理学机制的认识 疾病进展的相关模式，并提供了识别的新视角 TDP-43病理在生命及其纵向过程中的积累。这项建议与 在2019年阿尔茨海默病及相关疾病(ADRD)峰会上，FTD的最高优先事项。通过 专注于在分子、微观和宏观层面对大脑功能的神经网络的破坏， 我们的多学科网络方法将阐明TDP-43异常的病理生理学和在 ，并检测TDP-43病理对痴呆和痴呆患者临床疾病的影响 使用新的方法来提高我们对人类TDP-43病理的机械理解的衰老 保持最高水平的科学严谨性，并为治疗试验等紧迫的临床需求做出贡献。

Frontotemporal degeneration (FTD) is an understudied clinical neurodegenerative condition that is the most common dementia after Alzheimer disease (AD) in people younger than 65. The most common pathology associated with FTD is frontotemporal lobar degeneration due to transactive DNA/RNA binding protein of ~43 kD (TDP-43 (FTLD-TDP), and this is also the underlying pathology in the vast majority of patients who have co-occurring amyotrophic lateral sclerosis (FTD-ALS) spectrum disorders as well as a critical force in age- related disorders such as limbic-predominant age-related TDP-43 encephalopathy (LATE). Since discovering a role for TDP-43 pathology in human disease, important progress has been made in experimental cellular and animal models of disease. However, the human brain has many unique properties associated with distinctly human clinical disorders that are not easily replicated in these experimental models. Major gaps in knowledge thus constrain the development of disease-modifying treatment trials. Among these is our limited knowledge of the pathophysiologic consequences of the accumulation and progression of abnormal TDP-43 at a molecular level. At a microscopic level, a major limitation is that most patients with accumulating TDP-43 have sporadic disease that can be identified reliably only at autopsy, although ~20% of cases have familial FTLD (fFTLD) with known pathology during life. We are limited at translating this knowledge to a macroscale level where FTLD- TDP pathology is manifested in humans with heterogeneous clinical features as diverse as emotional dysregulation and impaired language both with and without a motor disorder. Moreover, there is limited knowledge of the factors contributing to the highly varying rates of disease progression. In five novel, independent but synergistic Projects and five Cores that support each of the Projects, this unique, multidisciplinary, Program Project Grant (PPG) adopts the innovative perspective of investigating the TDP-43-associated breakdown of neural networks at molecular, microscopic and macroscale levels in humans. We hypothesize that our novel, well-integrated, network perspective will fill major gaps in knowledge by elucidating mechanistic insights into the pathophysiology of abnormal TDP-43 and the associated pattern of disease progression, and offer a fresh perspective on the identification of accumulating TDP-43 pathology during life and its longitudinal course. This proposal is consistent with the highest priorities for FTD at the 2019 Alzheimer’s Disease and Related Disorders (ADRD) summit. By focusing on disruption of neural networks at molecular, microscopic and macroscale levels of brain functioning, our multidisciplinary network approach will elucidate the pathophysiology and spread of abnormal TDP-43 in humans, and examine the consequences of TDP-43 pathology for clinical disease during life in dementia and aging using fresh approaches to improve our mechanistic understanding of TDP-43 pathology in humans while maintaining the highest level of scientific rigor and contributing to urgent clinical needs such as treatment trials.