ALZHEIMERS RESEARCH PROJECT: Cerebral Microstructure in Aging and Dementia using Advanced Quantitative MRI

National Institute On Aging

Investigators

Linked publications & trials

Abstract

The dominant theory of Alzheimer's disease (AD) focuses on amyloid-beta plaques and tau proteins causing cognitive impairment. However, this theory has been questioned due to failed treatments targeting amyloid. Recent research highlights significant changes in white matter (WM) microstructure and composition in AD, including decreased myelin proteins and cholesterol and axonal degeneration. A new model suggests WM demyelination and axonal loss are central to AD's pathophysiology, with myelin breakdown releasing iron, promoting amyloid plaques, and destroying more myelin and axons. Myelin is crucial for brain function, but vulnerable to accumulation of amyloid, tau, and iron. Loss of oligodendrocytes or impaired myelin synthesis may lead to connectivity deficits, contributing to decreased CNS function. Advanced MRI techniques have been developed to map myelin content and axonal density, demonstrating myelin and axonal loss in AD, MCI, and vascular dementia. Significant progress has been achieved during the last fiscal year. Using our advanced MRI techniques: 1. Developing and refining advanced MRI techniques to quantify CNS components and properties, such as myelin content, axonal density, and neuroinflammation, for early diagnosis and monitoring of mild cognitive impairment (MCI) and AD. Specifically, we have developed BMC-mcDESPOT for myelin water fraction (MWF) imaging allowing for accurate quantification of myelin content, and C-NODDI for axonal density imaging enabling precise measurement of axonal density. We are currently working on improving these techniques to further accelerate imaging protocols and ensure even greater accuracy and precision in derived parameters. While working on further improving BMC-mcDESPOT and C-NODDI, we have also developed mc-USA, a sister method to BMC-mcDESPOT, which is applicable to all MRI machines, and have received NIH funding for patent protection, with ongoing work with lawyers to secure intellectual property rights. mc-USA will help democratization of MWF imaging world-wide. 2. Investigating how changes in these imaging biomarkers affect functional and cognitive impairments, in conjunction with other biomarkers, to elucidate neurodegeneration mechanisms. Building on our previous discovery demonstrating the implication of myelination in cognitive and motor function in normative aging, we are now expanding our efforts to investigate the role of white matter (WM) degeneration in MCI and AD, exploring how changes in WM microstructure and composition contribute to functional and cognitive decline. Specifically, we are working with collaborators in Germany on a longitudinal study examining myelin changes and their relationship with amyloid and tau, as measured using PET, in MCI subjects. Additionally, we are collaborating on a study of myelination and axonal degeneration patterns in autosomal dominant AD, further elucidating the complex interplay between WM changes and neurodegeneration. 3. Studying the impact of modifiable and nonmodifiable risk factors on CNS microstructure, composition, and function, using data from various cohorts like BLSA, GESTALT, and UK Biobank. We have shown that various modifiable and nonmodifiable risk factors impact myelin and axonal density, offering new insights to understand the complex interplay between risk factors and CNS health. Specifically, we showed that obesity, hypertension, and cardiovascular fitness all impact brain white matter integrity and composition especially myelination. We are now expanding this research to further investigate the impact of these risk factors on CNS microstructure, composition, and function, using data from various cohorts like BLSA, GESTALT, and UK Biobank, and exploring potential windows of opportunity for intervention and prevention.