White matter degeneration: biomarkers in preclinical Alzheimer's Disease

摘要 有髓轴突缺失是症状性阿尔茨海默病(AD)的一个特征。我们的课题组还 临床前期检测到有髓轴突变性。我们正在进行的工作的一个主要主题是 一直在利用从髓鞘和轴突变性的测量中获得的信息来改善 对AD的理解。这是“白质变性：临床前生物标记物”的续展应用 阿尔茨海默病“。参与者包括来自威斯康星州阿尔茨海默氏症的认知正常的成年人 疾病研究中心和威斯康星州阿尔茨海默氏症预防登记处 纵向采用神经成像和脑脊液采集。在这份续期申请中，我们建议继续遵循 注册参与者以及招募更多参与者以丰富AD，包括认知正常的参与者 生物标记物阳性参与者、轻度认知障碍(MCI)患者和痴呆症参与者 由于AD的原因。参与者将每两年接受一次全面的神经成像。假设是这样的 有髓轴突的退化是AD过程中的一个关键方面，这是衡量白质的指标 在斑块情况下，变性(髓鞘和轴突)可作为神经变性的敏感标志。 和缠结堆积。我们将检查轴突的测量，包括主要测量神经丝 脑脊液和血液中的轻蛋白，以及多层扩散磁共振成像得出的轴突密度。我们还将评估 通过脑脊液生物标记物和mcDESPOT MRI进行髓鞘定量成像。我们的三个目标是1) 确定白质成熟/变性的标准，并确定AD病理的时间顺序 和神经变性，使用分位数回归和模式混合建模方法，2)确定 有髓轴突变性在多大程度上预测阿尔茨海默病的认知能力下降，以及3) 确定髓鞘和轴突变性的原因(S)。这项研究计划预计将提供信息 阿尔茨海默病发展的时间进程，疾病的严重性，以及新治疗策略的发展。

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.