Revealing tissue microstructure in the brain gray matter in Alzheimer's disease using in vivo high-gradient diffusion MRI

使用体内高梯度扩散 MRI 揭示阿尔茨海默病大脑灰质的组织微观结构

• 批准号: 10488630
• 负责人: Hong Hsi Lee
• 金额: $ 42万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-14 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10488630
• 关键词: 3-Dimensional; Address; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Applications Grants; Award; Axon; Biological Markers; Blood; Brain; Cell Size; Cells; Cerebrospinal Fluid Proteins; Clinic; Clinical; Computer software; Data; Dementia; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Doctor of Philosophy; Early Diagnosis; Early Onset Alzheimer Disease; Early identification; Electron Microscopy; Ensure; Evaluation; Faculty; Family Caregiver; Future; General Hospitals; Geometry; Goals; High Performance Computing; Histologic; Histology; Histopathology; Human; Imaging Techniques; Impaired cognition; Interdisciplinary Study; Intervention; Joints; Knowledge; Laboratories; Leadership; Magnetic Resonance Imaging; Massachusetts; Measurement; Measures; Medicine; Mentorship; Microscopic; Microscopy; Monitor; Monte Carlo Method; Mus; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurons; Onset of illness; Paper; Pathologic; Patients; Peer Review; Persons; Physics; Positioning Attribute; Positron-Emission Tomography; Postdoctoral Fellow; Radiology Specialty; Research; Resolution; Resource Sharing; Risk; Running; Scientist; Structure; Symptoms; System; Techniques; Technology; Testing; Three-dimensional analysis; Time; Tissues; Training; Translating; Treatment Efficacy; United States; Validation; Varicosity; Work; aging population; base; biomedical imaging; biophysical model; brain tissue; career; career development; clinical translation; cluster computing; connectome; density; diagnostic value; experience; experimental study; graduate student; gray matter; high dimensionality; high risk; imaging biomarker; imaging facilities; in vivo; innovative technologies; instructor; light microscopy; magnetic resonance imaging biomarker; medical schools; meetings; microCT; mild cognitive impairment; neuronal cell body; next generation; non-invasive imaging; novel; novel therapeutics; prognostic; protein biomarkers; research study; senior faculty; simulation; skills; success; tau Proteins; tau-1; theories; tool; treatment response; white matter; white matter change

Project Summary/Abstract Alzheimer’s disease (AD) accounts for about 70% of dementia cases, and the number of AD patients continues to grow substantially due to the worldwide phenomenon of population aging, prompting the call for innovative technologies that will enable the early identification of patients at risk and monitoring of disease progression and therapeutic response. There is a known sequence of pathological alterations that develop in Alzheimer’s disease (AD) long before frank cognitive decline, offering potential targets for early detection of disease onset with subsequent interventions. While volumetric MRI changes are useful to assess the presence of neurodegeneration, regional cortical volume loss is a relatively late structural marker of neurodegeneration in AD. On the other hand, diffusion MRI (dMRI) is a non-invasive imaging technique sensitive to pathological changes on the cellular level, at least three orders of magnitude below the nominal spatial resolution of conventional MRI. So far, most AD studies using dMRI have largely focused on white matter changes. However, on histopathology, AD is primarily a cortical disease. The ability to probe early microstructural changes in GM in vivo would open the door to assessing disease onset and progression, facilitating the development of disease- modifying therapy. This project will bridge the gap in understanding changes in GM tissue microstructure in AD and mild cognitive impairment (MCI) using a combination of tools in multiple domains, such as biophysical modeling, ex vivo and in vivo dMRI, and histological validation. We will address this multi-faceted research challenge through the following aims: Aim 1: Establish time-dependent dMRI measurements to evaluate the density of axonal varicosities, size of cell body (soma), and soma/neurite density using a high-gradient MRI system. By leveraging the very strong diffusion gradients on the current and next-generation Connectome MRI scanner, we will develop a novel technique for evaluating the tissue microstructure in healthy subjects, AD and MCI patients. Aim 2: Validate in vivo and ex vivo dMRI measures of axonal and soma structure via Monte Carlo simulations of diffusion and histological analysis in three-dimensional realistic substrates based on light and electron microscopy, and micro-CT data. Aim 3: Assess the correlation of GM microstructural parameters with cognitive dysfunction, amyloid and tau PET scans, and blood and cerebrospinal fluid protein biomarkers, such as amyloid beta, total and phosphorylated tau (P-tau 181 and P-tau 217). In summary, building on our previous success in assessing white matter microstructure using dMRI, our study in GM promises to provide reliable noninvasive imaging markers of neurodegeneration, facilitating our understanding of the mechanisms underlying the progression of AD. Ultimately, the quantification of GM microstructure will offer prognostic and confirmatory biomarkers for neurodegenerative diseases, facilitating the assessment of treatment efficacy with the emergence of new therapies for AD and related dementias.

项目总结/文摘