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

基本信息

批准号：
8667387
负责人：
Barbara Brigitta Bendlin
金额：
$ 30.52万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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/8667387
关键词：
Accounting Address Adult Affect Age Alzheimer&apos s Disease Alzheimer&apos 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-1 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

项目摘要

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）：阿尔茨海默氏病（AD）以及由于轻度认知障碍（MCI），基因型（APOE4）和AD的父母家族史而导致的AD风险增加的人在阿尔茨海默氏病（AD）中发生了重大改变。新数据表明，在没有用T1加权MRI测量的灰质变化的情况下，可以通过扩散张量成像（DTI）来临床上的WM改变。 WM主要由髓磷脂和轴突组成。然而，受WM影响的临床上的成分仍然未知，这一现象的基础机制也是如此。同样未知的是，早期WM改变在多大程度上向未来的脑退化表示额外的未来。拟议项目的目的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的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-淀粉样蛋白的积累和神经炎症的积累以及灰质变性有关。中心假设将通过追求两个具体目标来检验：目标1：确定AD病理发展中白质改变和灰质改变的时间时间过程。 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）。这些措施将用于说明从基线到2年和4年随访的灰质度量（体积和皮质厚度）的变化。目标2：确定与AD有关的病理机制与AD可构成的临床前白质改变有关的程度。这将通过收集纵向MRI和CSF来实现AD和对照家族历史的人，其中AD的CSF生物标志物将用于预测MRI＆CSF索引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，这反过来又有望降低这种毁灭性疾病的流行。白质标记在临床前AD的研究中受到了较少的关注，并且临床前AD中的WM标记仍然相对尚未探索。除了提供将WM改变与假设的变性机制联系起来的新数据外，该项目还将解决知识的这一差距。该项目的成功可能性很大，因为PI的基本和临床科学研究者团队在基本和临床研究方法方面都精通，专家是分析和解释MRI和CSF数据的专家，它专注于一个针对AD风险的独特临床前人群，并且配备了WISCONSIN ADRC提供的特殊资源。