White matter degeneration: biomarkers in preclinical Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）以及由于轻度认知障碍（MCI）、基因型（APOE 4）和AD家族史而导致AD风险增加的人群的脑白色物质（WM）发生了实质性改变。新的数据表明，WM改变可以测量临床前与扩散张量成像（DTI），在没有灰质改变测量T1加权MRI。WM主要由髓鞘和轴突组成;然而，临床前受影响的WM组分仍然未知，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。拟议项目的目的是确定，在体内，WM改变的性质在临床前AD，早期大脑变化的时间模式，以及在何种程度上已知的AD机制影响临床前WM健康。中心假设是WM改变与tau病理学、β-淀粉样蛋白积累和神经炎症相关，并且先于灰质变性。中心假设将通过追求两个具体目标进行测试：目标1：确定AD病理学发展中白色物质改变和灰质改变的时间过程。这将通过在父母有AD家族史的人和匹配的对照中进行纵向MRI和脑脊液（CSF）收集来完成，以获得WM测量值（各向异性分数、DTI的径向扩散和轴向扩散、mcDESPOT MRI的髓鞘水分数图和CSF的髓鞘碱性蛋白、抗髓鞘抗体和神经丝轻蛋白）。这些指标将用于解释灰质指标（体积和皮质厚度）从基线至2年和4年随访的变化。目标二：确定AD中涉及的病理机制与AD易感脑区的临床前白色物质改变相关的程度。这将通过收集具有AD父母家族史的人和对照组中的纵向MRI和CSF来实现，其中AD的CSF生物标志物将用于预测由MRI和CSF索引的WM完整性的纵向变化。我们期望该项目的结果提供有关AD早期WM改变的新知识，提供导致AD早期诊断的信息，并有助于开发新的预防和治疗策略，从而降低这种毁灭性疾病的患病率。白色物质标志物在临床前AD的研究中受到的关注较少，并且临床前AD中的WM标志物仍然相对未探索。该项目将解决这一知识差距，除了提供新的数据，链接WM的改变，以假设的退化机制。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。 公共卫生相关性：如果不进行干预，阿尔茨海默病（AD）将造成毁灭性的人类死亡。阐明AD最早的大脑变化有望导致早期诊断，并积极促进预防策略和治疗的发展，从而降低AD的发病率。

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. PUBLIC HEALTH RELEVANCE: Without intervention, Alzheimer's disease (AD) will exert a devastating human toll. Clarifying the earliest brain changes in AD is expected to lead to earlier diagnosis, and contribute positively to the development of prevention strategies and treatments that in turn would decrease the incidence of AD.