Novel diffusion-weighted MRI assessment of cortical microstructural changes and their relationship to amyloid, tau and cognition in aging and Alzheimer's disease.

摘要 阿尔茨海默病(AD)具有较长的症状前时期，其特征是多种疾病共存 导致明显神经元损伤的病理生理过程。尽管大脑的研究结果已经得到了证实 AD后期(有症状)的萎缩，这些结构变化沿AD的轨迹 连续体仍然存在争议。重要的是，最近的研究表明，有证据表明， 临床前期脑皮质套内脑组织的微结构特征 这种疾病，以及这些变化被认为在早期的病理生理中起着重要的作用。 广告。然而，这些早期微结构变化对疾病进展的影响仍未得到充分研究。 主要是由于在人脑中研究它们的方法有限。最近出现了一种 使用扩散加权成像(DWI)技术的新的方法学神经成像方法已经成功 可以通过灰质中的皮质平均弥散系数来量化显微结构的变化。 以前使用这项技术的研究已经证明了临床前AD的微结构变化以及 常染色体显性AD的症状前突变携带者支持微结构改变的观点 都发生在疾病过程的早期。然而，早期区域Aβ在该地区的沉积机制 大脑与微结构变化有关，以及它们之间的相互作用如何导致疾病的进一步发展 仍然不为人知。在此R21计划中，我们将验证并进一步开发先进的DWI MRI方法 检测伴随阿尔茨海默病的微结构变化。通过使用多模式、最先进的方法 这项建议的总体目标是可视化早期微结构改变和 阿尔茨海默病临床前早期的病理改变(细胞外A、β和Tau)及其与 认知力。具体地说，使用来自现有NIA资助的丰富多模式数据集(哈佛老龄化)的数据 脑部研究)认知正常的老年人这项拟议的工作将确定横截面 显微结构变化与淀粉样蛋白Aβ负荷的区域关系，如用聚乙二醇单光子发射体层摄影测量(目标1)。 此外，我们将使用纵向数据来确定在基线时微观结构的变化是否预示着 T807(目标2)测量的tau沉积增加，随访时认知功能降低(目标3)，以及 β是否修改这些关系。拟议的工作可能会提供关键信息，以改进我们的 理解微结构变化如何与AD病理联系的机制基础，如 以及它们对大脑功能的影响。因此，这些发现可以极大地改善我们的 了解阿尔茨海默病的病因学演变，有助于疾病的临床诊断。

ABSTRACT Alzheimer’s disease (AD) has a long presymptomatic period characterized by the co-existence of several pathophysiological processes leading to overt neuronal damage. Despite the well-established findings of brain atrophy in the later (symptomatic) stages of AD, the trajectory of these structural changes along the AD continuum remains controversial. Importantly, recent studies have demonstrated evidence for changes in the microstructural properties of the brain tissue in the cortical mantle occurring already in the preclinical stage of the disease, and these changes have been suggested to play an important role in the early pathophysiology of AD. However, the impact of these early microstructural changes on disease progression remains understudied, mainly due to the limited methodological approaches to study them in the human brain. The recent advent of a novel methodological neuroimaging approach using diffusion-weighted imaging (DWI) technique, has made it possible to quantifying microstructural changes by means of cortical mean diffusivity in the grey matter. Previous studies using this technique have demonstrated microstructural changes in preclinical AD as well as presymtomatic mutation carriers of autosomal dominant AD, support the notion that microstructural changes are occurring early in the disease process. However, the mechanism by which early regional Aβ deposits in the brain are related to microstructural changes, and how their interactions may lead to further disease progression remains unknown. In this R21 proposal we will validate and further develop advanced DWI MRI methods for detecting the microstructural changes that accompany AD. By using multimodal, state-of the-art methods the overall objective of this proposal is to visualize the interplay between early microstructural alterations and pathological changes (extracellular Aβ and tau) across early preclinical stages of AD as well as its relation to cognition. Specifically, using data from an existing NIA-funded, rich multi-modality dataset (Harvard Aging Brain Study) of cognitively normal older individuals the proposed work will determine the cross-sectional regional relationship of microstructural changes with amyloid Aβ burden, as measured with PiB-PET (Aim 1). Furthermore, we will use longitudinal data to determine whether microstructural changes at baseline portends increased tau deposition, as measured with T807 (Aim 2), and lower cognition (Aim 3) at follow up, and whether Aβ modifies these relationships. The proposed work may provide critical information to improve our understanding of the mechanistic underpinnings of how microstructural changes are linked to AD pathology, as well as their effect on brain function. As a consequence, the findings could substantially improve our understanding of the evolution of AD etiology and may contribute to the clinical diagnosis of the disease.