White matter degeneration: biomarkers in preclinical Alzheimer's Disease

描述（由申请人提供）：在阿尔茨海默病（AD）中，以及由于轻度认知障碍（MCI）、基因型（APOE4）和父母AD家族史而导致AD风险增加的人群中，脑白质（WM）发生了实质性改变。新的数据表明，在没有t1加权MRI测量灰质改变的情况下，临床前可以用弥散张量成像（DTI）测量WM改变。WM主要由髓磷脂和轴突组成；然而，临床前WM的影响成分仍然未知，这一现象的机制也是未知的。同样未知的是早期WM改变在多大程度上预示着未来额外的脑退化。该项目的目标是确定临床前AD患者体内WM改变的性质，早期大脑变化的时间模式，以及已知AD机制对临床前WM健康的影响程度。核心假设是WM的改变与tau病理学、β -淀粉样蛋白的积累和神经炎症有关，并在灰质变性之前发生。中心假设将通过追求两个具体目标来验证：目标1：确定AD病理发展中白质改变和灰质改变的时间进程。这将通过对父母有AD家族史的人群和匹配的对照组进行纵向MRI和脑脊液（CSF）收集来完成，以获得WM测量（分数各向异性，DTI的径向扩散和轴向扩散，mcDESPOT MRI的髓鞘水分数图，以及髓鞘碱性蛋白，抗髓鞘抗体和脑脊液的神经丝轻蛋白）。这些测量将用于解释从基线到2年和4年随访期间灰质测量（体积和皮质厚度）的变化。目的2：确定阿尔茨海默病的病理机制与阿尔茨海默病易感脑区临床前白质改变的关系程度。这将通过收集父母有AD家族史的人和对照组的纵向MRI和CSF来完成，其中AD的CSF生物标志物将用于预测MRI和CSF索引的WM完整性的纵向变化。我们期望这个项目的结果能够提供关于阿尔茨海默病早期WM改变的新知识，提供导致阿尔茨海默病早期诊断的信息，并有助于开发新的预防和治疗策略，从而有望减少这种毁灭性疾病的患病率。白质标志物在临床前AD的研究中较少受到关注，WM标志物在临床前AD的研究相对较少。该项目将填补这一知识空白，并提供将WM变化与假设的退化机制联系起来的新数据。该项目具有很高的成功可能性，因为PI的基础和临床科学研究团队精通基础和临床研究方法，是分析和解释MRI和CSF数据的专家，专注于AD风险的独特临床前人群，并配备了威斯康星州ADRC提供的特殊资源。

DESCRIPTION (provided by applicant): Brain white matter (WM) is substantially altered in Alzheimer's disease (AD), and in people who are at increased risk for AD due to mild cognitive impairment (MCI), genotype (APOE4), and parental family history of AD. New data suggest that WM alterations can be measured preclinically with diffusion tensor imaging (DTI), in the absence of gray matter alterations measured with T1-weighted MRI. WM is primarily composed of myelin and axons; however, the component of WM affected preclinically is still unknown, as are the mechanisms underlying this phenomenon. Also unknown is the extent to which early WM alterations signal additional future brain degeneration. The objective of the proposed project is to determine, in vivo, the nature of WM alterations in preclinical AD, the temporal pattern of early brain change, and the extent to which known AD mechanisms impact preclinical WM health. The central hypothesis is that WM alterations are related to tau pathology, accumulation of beta-amyloid, and neuroinflammation, and precede degeneration of gray matter. The central hypothesis will be tested by pursuing two specific aims: Aim 1: Determine the temporal time course of white matter alteration and gray matter alteration in the development of AD pathology. This will be accomplished by performing longitudinal MRI and cerebrospinal fluid (CSF) collection in people with parental family history of AD and matched controls to obtain WM measures (fractional anisotropy, radial diffusion and axial diffusion from DTI, myelin water fraction maps from mcDESPOT MRI, and myelin basic protein, anti- myelin antibody, and neurofilament light protein from CSF). These measures will be used to account for change in gray matter measures (volume and cortical thickness) from baseline to 2-year and 4-year follow-up. Aim 2: Establish the extent to which pathological mechanisms implicated in AD are related to preclinical white matter alterations in AD-vulnerable brain regions. This will be accomplished by collecting longitudinal MRI and CSF in people with parental family history of AD and controls where CSF biomarkers of AD will be used to predict longitudinal changes in WM integrity indexed by MRI & CSF. We expect the results of this project to provide new knowledge concerning early WM alterations in AD, provide information leading to earlier diagnosis of AD, and contribute to the development of new prevention and treatment strategies, which in turn is expected to reduce the prevalence of this devastating disease. White matter markers have received less attention in the study of preclinical AD, and WM markers in preclinical AD remain relatively unexplored. This project will address this gap in knowledge, in addition to providing novel data that links WM alterations to hypothesized mechanisms of degeneration. The project has a high likelihood of success because the PI's team of basic and clinical science investigators is well-versed in both basic and clinical research methods, is expert in analyzing and interpreting MRI and CSF data, is focusing on a unique preclinical population at risk for AD, and is equipped with exceptional resources provided by the Wisconsin ADRC.