White matter degeneration: biomarkers in preclinical Alzheimer's Disease

描述(申请人提供)：在阿尔茨海默病(AD)以及由于轻度认知障碍(MCI)、基因(APOE4)和父母AD家族史而增加AD风险的人中，脑白质(WM)显著改变。新的数据表明，在没有T1加权MRI测量的灰质变化的情况下，可以使用扩散张量成像(DTI)在临床前测量WM的变化。WM主要由髓鞘和轴突组成；然而，临床前影响的WM的成分仍然不清楚，这一现象背后的机制也是未知的。同样未知的是，早期的WM改变在多大程度上预示着未来大脑的进一步退化。该项目的目标是在体内确定临床前AD患者WM改变的性质，早期脑改变的时间模式，以及已知的AD机制对临床前AD患者WM健康的影响程度。中心假设是WM改变与tau病理、β-淀粉样蛋白积聚和神经炎症有关，并且先于灰质退化。中心假说将通过追求两个特定的目标来验证：目的1：确定AD病理发展过程中白质和灰质变化的时间进程。这将通过对有AD父母家族史的人和匹配的对照组进行纵向MRI和脑脊液(CSF)收集来获得WM测量(来自DTI的分数各向异性、径向和轴向扩散，来自mcDESPOT MRI的髓鞘水分图，以及来自脑脊液的髓鞘碱性蛋白、抗髓鞘抗体和神经丝轻蛋白)。这些测量将用于说明灰质测量(体积和皮质厚度)从基线到2年和4年随访的变化。目的2：建立阿尔茨海默病的病理机制在多大程度上与阿尔茨海默病易感脑区的临床前白质改变有关。这将通过收集有AD父母家族史的人和对照组的纵向MRI和CSF来完成，其中AD的CSF生物标记物将用于预测MRI和CSF所指示的WM完整性的纵向变化。我们期望这个项目的结果能提供有关AD早期WM改变的新知识，提供有助于AD早期诊断的信息，并有助于开发新的预防和治疗策略，从而有望降低这种毁灭性疾病的患病率。白质标记物在临床前AD的研究中受到的关注较少，而WM标记物在临床前AD中的研究相对较少。除了提供将WM改变与假想的退化机制联系起来的新数据外，该项目还将解决这一知识差距。该项目成功的可能性很高，因为PI的基础和临床科学研究人员团队精通基础和临床研究方法，擅长分析和解释MRI和CSF数据，专注于面临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.