Neurovascular coupling and waste clearance in aging brain

The National Institute on Aging awarded Case Western Reserve University $3,153,437 on August 1, 2026, under the Aging Research program (CFDA 93.866) to develop and validate novel MRI methods for quantitative assessment of glymphatic function in the aging brain.

The project will develop a three-dimensional magnetic resonance fingerprinting technique for dynamic, simultaneous tracking of oxygen-17 enriched water as a cerebrospinal fluid tracer and gadolinium-based contrast agents to measure glymphatic system efficiency in waste clearance from the central nervous system. The work addresses gaps in current neuroimaging tools: while dynamic contrast-enhanced MRI using gadolinium-based contrast agents has advanced understanding of cerebrospinal fluid transport at the whole-brain level, their large molecular size limits penetration into brain parenchyma and direct assessment of solute removal from brain interstitium. This project will enable comprehensive characterization of cerebrospinal fluid–interstitial fluid exchange and solute clearance dynamics. The underlying research objective targets age-related decline in glymphatic function and its contribution to neurodegenerative diseases, with investigation of how neurovascular coupling—the relationship between neural activity-induced hemodynamic changes and cerebrospinal fluid flow dynamics—changes with age and whether lifestyle interventions such as aerobic exercise training enhance waste clearance efficiency in aging brains.

The award runs from August 1, 2026, through July 31, 2030. Work is performed at Case Western Reserve University in Cleveland, Ohio, operating through the Office of Research Administration in affiliation with University Hospitals of Cleveland.

Abstract

Efficient clearance of metabolic waste from the central nervous system is essential for maintaining brain health across the lifespan. The glymphatic system plays a critical role in this process by facilitating the transport of cerebrospinal fluid (CSF) along periarterial spaces and its exchange with interstitial fluid (ISF). Emerging evidence suggests that age-related decline in glymphatic function contributes to the pathogenesis of neurodegenerative diseases. Lifestyle changes, such as improving aerobic capacity through exercise training, can enhance waste clearance efficiency in the aging brain; yet the underlying mechanisms remain poorly understood. Recent studies have identified a phenomenon known as bold- CSF coupling, in which neural activity-induced hemodynamic changes are temporally correlated with CSF flow dynamics, suggesting that neurovascular coupling may facilitate glymphatic transport during periods of heightened neural activity and metabolic demands. However, how bold-CSF coupling changes with age remains unclear. Progress in this aera has been hindered by limited tools for comprehensive assessment of glymphatic function. While dynamic contrast-enhanced MRI (DCE-MRI) using gadolinium-based contrast agents (GBCAS) has advanced our understanding of CSF transport at the whole-brain level, the large molecular size of GBCAS limits their penetration into brain parenchyma, thereby hampering direct assessment of solute removal from the interstitium. As a result, the dynamics of CSF-ISF exchange and solute clearance from brain parenchyma remain insufficiently characterized. The objective of this project is to develop and apply novel MRI methods for quantitative assessment of glymphatic function in vivo. Specifically, we will develop and validate a 3D magnetic resonance fingerprinting (MRF) technique for dynamic, simultaneous tracking of oxygen-17 enriched water (H217O) as a CSF tracer and GD-dota as a solute tracer, enabling comprehensive evaluation of CSF transport, CSF-ISF exchange, and solute clearance from a single MRF scan (aim 1). This method will be employed in pet-MRI studies to investigate how aging alters the interaction between neurovascular physiology and glymphatic function, and how these changes impact cerebral metabolism and cognitive performance (aim 2). Additionally, we will examine the role of exercise in modulating glymphatic function using novel preclinical models with high and low aerobic exercise capacity (aim 3). Successful completion of this project will yield novel imaging methodologies for comprehensive evaluation of glymphatic function and solute clearance. Moreover, IT will provide mechanistic insight into how neurovascular health and aerobic fitness influence brain aging, with broad implications for developing lifestyle-based strategies to mitigate cognitive decline and neurodegeneration.