In-vivo MRI-based prediction of TDP43 pathology in aging

摘要 反式反应DNA结合蛋白43（TDP 43）病理学，一种罕见的原发性蛋白质异常， 肌萎缩侧索硬化症和额颞叶变性，现在被认为是一种常见的疾病， 年龄相关的神经病理学，在尸检中发现约50%的老年人。根据最近的 有证据表明，衰老中的TDP 43病理与更快的认知能力下降和更高的 老年痴呆症，超越了阿尔茨海默氏症和其他与年龄相关的神经病理学的贡献。尽管 由于其高频率和有害作用，TDP 43只能在尸检中诊断，目前有 没有提供关于衰老中TDP 43病理学存在的体内准确信息的方法。 该项目的总体目标是开发和测试基于MRI的TDP 43体内分类器 通过将多模式MRI和病理学结合起来，在来自大型 社区cohorts具体来说，我们建议a）使用基于前-后-后-的机器学习来训练TDP 43分类器。 活体MRI测量老年人脑的宏观结构、微观结构和化学特征 人，B）在体内翻译这些分类器，以及c）使用纵向临床，体内MRI， 和病理学数据。我们已经产生了一种独特的体外和体内 拉什记忆和衰老项目（MAP）基础设施内的多模态MRI病理学数据库 （R 01 AG 17917）和宗教秩序研究（ROS）（P30 AG 010161），两个纵向的流行病学临床- 老年病理学队列研究招募非痴呆个体，随访率高， 尸检率利用我们的数据库，我们已经产生了令人信服的初步结果，以支持我们的目标。 首先，我们已经证明，离体脑MRI数据可以链接到体内MRI数据。第二，我们展示 TDP 43病理学与特定的脑MRI特征相关，而与其他年龄相关的特征无关。 病理学第三，基于离体MRI，我们显示出高TDP 43分类性能（AUC=0.81）。 在患有和不患有共病阿尔茨海默病病理（一种常见的共存病理）的人中的特征。 第四，我们证明了从离体MRI分类获得的置信度得分与 TDP 43病理学沉积的进展（即TDP 43分期）。最后，我们翻译了初步的离体 TDP 43分类器用于体内，并在小样本中证明其具有高体内分类 表现，并独立地与较低的认知相关。我们建议进一步开发和测试这一点， 有前途的体内MRI分类器的TDP 43病理老化。

ABSTRACT Transactive response DNA-binding protein 43 (TDP43) pathology, a primary protein abnormality in the rare diseases amyotrophic lateral sclerosis and frontotemporal lobar degeneration, is now recognized as a common age-related neuropathology, detected at autopsy in approximately 50% of older persons. According to recent evidence, TDP43 pathology in aging is associated with more rapid cognitive decline and higher odds of dementia, above and beyond contributions from Alzheimer’s and other age-related neuropathologies. In spite of its high frequency and deleterious effects, TDP43 can only be diagnosed at autopsy, and there is currently no approach that provides in-vivo accurate information about the presence of TDP43 pathology in aging. The overall goal of the proposed project is to develop and test an in-vivo MRI-based classifier of TDP43 pathology in aging by combining multimodal MRI and pathology in the same older persons from large community cohorts. Specifically, we propose to a) train TDP43 classifiers using machine learning based on ex- vivo MRI measurements of macro-structural, micro-structural and chemical brain characteristics of older persons, b) translate these classifiers in-vivo, and c) test them in-vivo using longitudinal clinical, in-vivo MRI, and pathology data on older adults enrolled without dementia. We have generated a unique ex-vivo and in-vivo multimodal MRI-pathology database within the infrastructure of the Rush Memory and Aging Project (MAP) (R01AG17917) and Religious Orders Study (ROS) (P30AG010161), two longitudinal, epidemiologic clinical- pathologic cohort studies of aging that recruit non-demented individuals and have high follow-up rates and high autopsy rates. Using our database, we have produced compelling preliminary results in support of our aims. First, we have demonstrated that ex-vivo brain MRI data can be linked to in-vivo MRI data. Second, we show that TDP43 pathology is related to specific brain MRI characteristics independent of other age-related pathologies. Third, we show high TDP43 classification performance (AUC=0.81) based on ex-vivo MRI features in persons with as well as without comorbid Alzheimer’s pathology (a common coexisting pathology). Fourth, we demonstrate that the confidence score obtained from ex-vivo MRI classification is linked to the progression of deposition of TDP43 pathology (i.e. TDP43 stages). Finally, we translated a preliminary ex-vivo TDP43 classifier for use in-vivo and demonstrated in a small sample that it has high in-vivo classification performance, and is independently associated with lower cognition. We propose to further develop and test this promising in-vivo MRI classifier of TDP43 pathology in aging.