In Vivo Measurement of Human Brain Tissue, Blood, and CSF Dynamics Supporting Glymphatic Function - ABSTRACT Waste clearance in the central nervous system is impaired in many neurological diseases; its dysfunction likely accelerates the pathological accumulation of misfolded proteins that causes many dementias and hinders the efficacy of therapeutics designed to remove these proteins. There is a need for therapies that fortify and promote the brain’s own clearance mechanisms, but many of these mechanisms are still unknown due in part to the lack of noninvasive tools such as magnetic resonance imaging (MRI) to measure clearance dynamics in individual patients. Waste clearance in the brain relies on CSF flow, which has been demonstrated in response to arousal changes, cardiac-driven arterial pulsations, respiration, and neural activity, with hemodynamics often considered as a driving force. However, it is unknown to what extent the viscoelastic brain tissue motion may also influence CSF flow, in part because measuring tissue motion requires in vivo measurements and an intact cranium for unaltered intracranial pressure to observe brain motion in its natural state. Now, there is an opportunity to use sensitive MRI “motion-encoding” tools to quantify tissue and CSF motion and measure blood dynamics regionally at the level of a cortical gyrus to investigate how blood and tissue dynamics impact CSF flow. We propose to develop a novel MRI method to capture hemodynamics, brain tissue displacement, and CSF flow concurrently and at high spatial resolution, facilitating hypothesis testing of CSF flow mechanisms in vivo. To capture tissue displacements on the order of tens of microns, we propose to adapt the Displacement ENcoding with Stimulated Echoes (DENSE) method to our ultra-high magnetic field strength MRI scanner and extend it to measure hemodynamics concurrently. Our method is novel because blood, tissue, and CSF dynamics have not yet been measured concurrently in vivo, or at the targeted spatial scale of a cortical gyrus. We will measure these dynamics during the cardiac cycle and respiration, and in response to neuronal stimulation driven by a visual stimulation task, as each of these physiological processes are hypothesized to influence CSF dynamics. Given the concurrent measurement of all compartments, this method may be used in future studies of spontaneous neural dynamics, such as during sleep. Understanding flow mechanisms of CSF may reveal opportunities for therapeutic intervention to promote waste clearance in the aging brain. The applicant’s long-term goal is to lead an academic research team that is focused on applying novel neuroimaging techniques to critical questions in neurodegenerative disease. The proposed training plan centers on MRI physics and acquisition, advanced spatiotemporal analysis of neuroimaging data, research design and experimental methods, the pathophysiology of neurodegenerative disease, and professional development in science dissemination and leadership. The proposed research plan will take place at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, which is renowned for neuroimaging methods development and clinical translation and will further support the applicant’s training and career development.
