White matter degeneration: biomarkers in preclinical Alzheimer's Disease

白质变性：临床前阿尔茨海默病的生物标志物

• 批准号: 8461579
• 负责人: Barbara Brigitta Bendlin
• 金额: $ 29.16万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461579
• 关键词: Accounting; Address; Adult; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Anisotropy; Antibodies; Atrophic; Attention; Axon; Basic Science; Biological Markers; Brain; Brain imaging; Brain region; Cerebrospinal Fluid; Clinical; Clinical Research; Clinical Sciences; Collection; Data; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disease Marker; Early Diagnosis; Exhibits; Family; Family history of; Future; Genotype; Health; Human; Image; Image Analysis; Incidence; Individual; Interleukin-6; Intervention; Knowledge; Lead; Link; Literature; Magnetic Resonance; Maps; Measures; Myelin; Myelin Basic Proteins; Nature; Nerve Degeneration; Neurobiology; Outcome; Participant; Pathology; Pattern; Populations at Risk; Prevalence; Prevention strategy; Radial; Recording of previous events; Research; Research Methodology; Research Personnel; Resolution; Resources; Risk; Sampling; Sensitivity and Specificity; Signal Transduction; Specific qualifier value; Staging; TNF gene; Techniques; Testing; Thick; Time; Treatment Efficacy; Water; Weight; Wisconsin; Work; abeta accumulation; base; disease diagnosis; disorder control; follow-up; gray matter; high risk; imaging modality; in vivo; indexing; innovation; longitudinal design; middle age; mild cognitive impairment; myelin degeneration; neurofilament protein L; neuroinflammation; novel; pre-clinical; preclinical study; sex; success; tau Proteins; treatment strategy; white matter; white matter change

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.

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 (APOE4) 和父母家庭而导致 AD 风险增加的人群中，脑白质 (WM) 发生显着改变公元的历史。新数据表明，在没有 T1 加权 MRI 测量的灰质改变的情况下，可以通过弥散张量成像 (DTI) 来测量 WM 改变。 WM 主要由髓磷脂和轴突组成；然而，临床前受影响的 WM 成分以及这种现象背后的机制仍然未知。同样未知的是早期 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 中 WM 改变的性质、早期大脑变化的时间模式以及已知 AD 机制影响临床前 WM 健康的程度。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有关，并且发生在灰质变性之前。将通过追求两个具体目标来检验中心假设： 目标 1：确定 AD 病理学发展中白质改变和灰质改变的时间过程。这将通过对有 AD 父母家族史的人和匹配对照者进行纵向 MRI 和脑脊液 (CSF) 收集来实现，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、和髓磷脂碱性蛋白、抗髓磷脂抗体和来自 CSF 的神经丝轻蛋白）。这些测量将用于解释灰质测量（体积和皮质厚度）从基线到 2 年和 4 年随访的变化。目标 2：确定 AD 涉及的病理机制与 AD 易感脑区临床前白质改变的相关程度。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能够提供有关 AD 早期 WM 改变的新知识，提供导致 AD 早期诊断的信息，并有助于制定新的预防和治疗策略，从而有望减少这种疾病的患病率毁灭性的疾病。白质标记物在临床前 AD 研究中受到的关注较少，而临床前 AD 中的 WM 标记物仍然相对未经探索。该项目除了提供将 WM 改变与假设的退化机制联系起来的新数据之外，还将解决这一知识空白。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，是分析和解释 MRI 和 CSF 数据的专家，专注于独特的临床前危险人群AD，并配备了威斯康星州 ADRC 提供的特殊资源。