Good plumbing for a healthy brain: new insights into the relationship between cerebral blood flow and tissue microstructural integrity

Abstract

AbstractAlzheimer’s disease (AD) has historically been regarded as a gray matter disease, with cortical atrophy on the macroscopic scale and development of amyloid‐β plaques and neurofibrillary tau tangles on the microscopic scale. However, this paradigm has been challenged mainly due to the continuous failure of anti‐amyloid interventions to stop cognitive decline. Researchers are now wondering whether these proteins aggregations are simply byproducts of other primary drivers of neurodegeneration. Based on these observations, a new paradigm put the myelination at the center of the pathophysiology of AD suggesting that alterations in myelin may lead to progressive disconnections of neural networks that could underlie age‐related cognitive decline and AD. Recent advances in quantitative MRI methodology have enabled probing tissue microstructure with exquisite sensitivity, particularly using diffusion tensor imaging and relaxation times, and has revealed nonlinear age‐related trajectories of cerebral tissues during aging. However, although sensitive to myelin, these MRI metrics are not specific precluding specific interpretation of the underlying mechanisms involved in these microstructural changes. To address this challenge, we have developed an advanced method, called BMC‐mcDESPOT, to measure myelin water fraction (MWF), a specific surrogate of myelin content, and provided the first in‐vivo evidence of myelin breakdown in mild cognitive impairment and dementias. Further, this method has opened the way to provide novel insights into the impact of vascular, genetic, and metabolic risk factors on myelination, as well as on the role of myelin in cognition and physical functioning. In this talk, we will present an overview of some of our recent improvements to further accelerate MWF imaging. We will also present results relating reversible risk factors, including cerebral blood flow, obesity and hypertension, to myelin integrity. Finally, we will discuss new results of the implication of cerebral myelination in longitudinal changes in cognition, including memory, executive function, attention, verbal fluency and processing speed, as well as in changes in gait speeds. Understanding the role of myelination in cognitive and physical functioning has the potential to provide a window into the underlying biology of age‐related brain diseases, and to nominate new MR imaging biomarkers for longitudinal assessment and targets for intervention.