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.

Project Narrative More than five million people in the United States living with Alzheimer’s disease, and this number grows substantially due to the population aging, resulting in burdens on the economy, families and caregivers of patients. While volumetric MRI biomarkers are useful to assess the risk of Alzheimer’s disease, their diagnostic value is still limited since the association between biomarkers and neuropathological changes remains unclear. With the help of advanced high-gradient MRI system, this project will establish an in vivo diffusion MRI microscopy technology targeting tissue microstructure in the brain gray matter, which will expand our understanding of underlying mechanisms of disease progression, and may provide prognostic and confirmatory biomarkers and aid in the assessment of treatment efficacy for Alzheimer’s disease and related dementias.