New approach to studying white matter aging: symmetric multimodal fusion of MRI techniques targeting different biophysical properties of white matter

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DESCRIPTION One of the missing pieces of the puzzle towards development of successful treatments against cognitive decline and Alzheimer’s Disease and Related Dementias (ADRD) may be understanding of the white matter (WM). For many years, WM aging has been studied almost solely using diffusion MRI (dMRI), and predominantly with diffusion tensor imaging. The limitations of dMRI have lead to inconsistent associations of WM integrity with cognition and brain function, and an underappreciation of the role of WM in adult neuroplasticity. The goal of this proposal is to provide a new multimodal approach for studying WM microstructure in living humans. Our approach combines several advanced quantitative MRI techniques sensitive to different biophysical properties of myelin and axons. As no single MRI technique – even the most advanced – can fully characterize WM tissue, we will use symmetric fusion analysis to capitalize on the strengths and overcome the limitations of each technique. Specifically, we will use the multiset Canonical Correlation Analysis with joint Independent Component Analysis (mCCA+jICA) to extract modality-shared and modality-unique independent components (IC) differentiating the WM of younger from older adults. Our sample will include cognitively and neurologically healthy younger (n=35, 20-30y) and older adults (n=50 60-80y). The 45min-long scan will include Neurite Orientation Density and DIspersion Imaging to quantify axonal density, fiber orientational dispersion, and extracellular volume, a T1-based myelin water imaging, sensitive to water trapped in myelin lipid bilayers, and quantitative magnetization transfer, sensitive to the exchange of magnetization with myelin macromolecules. Aim 1 will test whether the multimodal approach confirms the selective vulnerability to aging in late-developing WM regions. Aim 2 will test whether the multimodal measure of age-related myelin and axonal loss correlates with memory, processing speed, executive function and fluid abilities, measured with the Virginia Cognitive Aging Project battery and the NIH Toolbox®. Exploratory analyses will test sex differences in the above aims. Together, our novel multimodal approach will lead to a more robust and unbiased characterization of the aging WM microstructure and provide new evidence for hotly debated models of cognitive aging. Once established, our approach will be validated in animal models of cognitive decline, extended to more diverse samples, and combined with fMRI. Our ultimate aim is to identify new WM targets for treatments for ADRD, to improve diagnosis of pre-symptomatic dementia to allow early interventions, and to identify protective and risk factors for WM aging.