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

新型弥散加权 MRI 评估皮质微结构变化及其与淀粉样蛋白、tau 蛋白和衰老和阿尔茨海默病认知的关系。

• 批准号: 9807571
• 负责人: Patrizia Vannini
• 金额: $ 26.85万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807571
• 关键词: Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animals; Biological; Brain; Brain region; Cell membrane; Clinical; Cognition; Cognitive; Data; Data Set; Dementia; Deposition; Diffuse; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Elderly; Etiology; Evolution; Functional disorder; Funding; Future; Human; Hypertrophy; Image; Imaging Techniques; Impaired cognition; In Vitro; Individual; Lead; Link; Magnetic Resonance Imaging; Measures; Methodology; Methods; Myelin; Nerve Degeneration; Neuroglia; Neurons; Parietal; Pathologic; Pathology; Play; Positron-Emission Tomography; Process; Property; Role; Sampling; Spatial Distribution; Structure; Techniques; Testing; Tracer; Up-Regulation; Water; Work; abeta accumulation; abeta deposition; aging brain; base; brain tissue; cerebral atrophy; clinical Diagnosis; disease diagnosis; extracellular; follow-up; gray matter; improved; multimodality; mutation carrier; neuroimaging; neuroinflammation; neuropathology; novel; pre-clinical; tau Proteins; tau aggregation

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.

摘要 阿尔茨海默氏病（AD）具有长的前驱期，其特征在于几种阿尔茨海默氏病（AD）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很好地证实了 AD后期（症状性）萎缩，这些结构变化的轨迹沿着AD 连续体仍然存在争议。重要的是，最近的研究表明， 已经在临床前阶段发生的皮质外套中的脑组织的显微结构特性 疾病，这些变化已被建议发挥重要作用，在早期的病理生理 AD.然而，这些早期微结构变化对疾病进展的影响仍然研究不足， 这主要是由于在人脑中研究它们的方法学途径有限。最近出现的一个 一种新的方法学神经影像学方法，使用扩散加权成像（DWI）技术，使它 可以通过灰质中的皮质平均扩散率来量化微结构变化。 以前使用这种技术的研究已经证明了临床前AD的微观结构变化以及 常染色体显性AD的前对称性突变携带者，支持微结构变化的概念， 都发生在疾病的早期然而，早期区域性Aβ沉积在大脑中的机制， 大脑与微结构变化有关，以及它们的相互作用如何导致疾病的进一步进展 仍然未知。在本R21提案中，我们将验证并进一步开发先进的DWI MRI方法， 检测伴随AD的微结构变化。通过使用多模态，最先进的方法 该提案的总体目标是可视化早期微观结构变化之间的相互作用， AD早期临床前阶段的病理变化（细胞外Aβ和tau）及其与 认知.具体而言，使用来自现有的由国家免疫局资助的丰富的多模态数据集（哈佛老龄化 脑研究）的认知正常的老年人，拟议的工作将确定横截面 微结构变化与淀粉样蛋白Aβ负荷的区域关系，如PiB-PET所测量（Aim 1）。 此外，我们将使用纵向数据来确定基线时的微观结构变化是否预示着 在随访时，如用T807测量的tau沉积增加（Aim 2）和认知降低（Aim 3），以及 Aβ是否改变了这些关系。拟议的工作可能会提供关键信息，以改善我们的 了解微观结构变化如何与AD病理学联系的机制基础， 以及它们对大脑功能的影响。因此，这些发现可以大大改善我们的 了解AD病因学的演变，可能有助于疾病的临床诊断。