White matter degeneration: biomarkers in preclinical Alzheimer's Disease

摘要 有髓鞘轴突的丧失是症状性阿尔茨海默病（AD）的特征。我们的研究小组还 在临床前阶段检测到有髓鞘轴突的变性。我们目前工作的一个主要主题是 一直在利用来自髓鞘和轴突变性测量的信息来改善 对AD的理解这是“白色变性：临床前生物标志物”的更新申请 老年痴呆症参与者包括来自威斯康星州阿尔茨海默氏症的认知未受损的成年人 疾病研究中心和威斯康星州老年痴呆症预防登记处对这些患者进行了随访 纵向与神经成像和CSF收集。在这次更新申请中，我们建议继续遵循 招募参与者，并招募额外的参与者以丰富AD，包括认知未受损的参与者 生物标志物阳性参与者、轻度认知障碍（MCI）个体和痴呆参与者 由于AD。参与者将每两年接受一次全面的神经成像。假设是， 有髓轴突的变性是AD过程的关键方面，并且测量白色物质 在斑块背景下，神经变性（髓鞘和轴突）可作为神经变性的敏感标志物 和缠结的积累。我们将检查轴突的测量，包括神经丝的主要测量 CSF和血液中的轻蛋白，以及来自多壳层扩散MRI的神经突密度。我们还将评估 通过CSF生物标志物和使用mcDESPOT MRI的定量髓磷脂成像测定髓磷脂。我们的三个目标是：（1） 定义白色物质成熟/变性的标准，并确定AD病理学的时间顺序 和神经变性，使用分位数回归和模式混合建模方法，2）确定 有髓鞘轴突变性的程度预测AD背景下的认知下降，以及3） 确定髓鞘和轴突变性的原因。这项研究计划预计将告知 AD发展的时间进程、疾病严重程度和新治疗策略的发展。

ABSTRACT Loss of myelinated axons is a feature of symptomatic Alzheimer's disease (AD). Our research group has also detected degeneration of myelinated axons in the preclinical phase. A major theme of our ongoing work has been to leverage the information derived from measures of myelin and axonal degeneration to improve the understanding of AD. This is a renewal application for “White matter degeneration: biomarkers in preclinical Alzheimer's Disease”. Participants comprise cognitively unimpaired adults from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Prevention who have been followed longitudinally with neuroimaging and CSF collection. In this renewal application, we propose to continue to follow enrolled participants as well as recruit additional participants to enrich for AD, including cognitively unimpaired biomarker positive participants, individuals with mild cognitive impairment (MCI), and participants with dementia due to AD. Participants will undergo comprehensive neuroimaging every two years. The hypothesis is that that degeneration of myelinated axons is a critical facet of the AD process, and that measures of white matter degeneration (myelin and axonal) can serve as sensitive markers of neurodegeneration in the context of plaque and tangle accumulation. We will examine measures of axons, including the primary measures neurofilament light protein in CSF and blood, and neurite density derived from multi-shell diffusion MRI. We will also evaluate myelin via CSF biomarkers and quantitative myelin imaging with mcDESPOT MRI. Our three aims are to 1) Define norms for white matter maturation/degeneration and determine the temporal ordering of AD pathology and neurodegeneration, using quantile regression and pattern mixture modeling approaches, 2) Determine the extent to which degeneration of myelinated axons predicts cognitive decline in the context of AD, and 3) Determine the cause(s) of myelin and axonal degeneration. This program of research is expected to inform upon the temporal course of AD development, disease severity, and the development of new treatment strategies.