Quantitative MRI to Investigate Central Nervous System Waste Clearance in Health and Neurodegenerative Disease

Abstract

The lymphatic system is responsible for clearing metabolic waste and fighting infection throughout most of the body, but in the central nervous system, however, there are no conventional lymphatic vessels. Recent evidence from animal studies suggests the presence of a waste clearance system in the central nervous system, termed the glymphatic system. In the glymphatic system, cerebrospinal fluid (CSF) produced from the choroid plexus travels through paravascular spaces along penetrating cerebral arteries and enters the brain interstitium through aquaporin-4 channels located on astrocytic end feet surrounding these vessels. The CSF then travels through the interstitium via convective bulk flow and clears metabolic waste products with it, ultimately entering paravenous spaces and exiting the central nervous system through the venous system or meningeal lymphatic vessels surrounding the brain. This system has become increasingly relevant in the context of neurodegenerative diseases that are associated with neurotoxic protein aggregation, such as Alzheimer’s disease (AD). While it has been thought traditionally that these proteins are cleared through the cerebrospinal fluid (CSF) in the brain, the precise mechanisms by which CSF are produced, transported, and cleared through the brain remain poorly understood in humans. This is due in part to a lack of methods to investigate this system noninvasively in humans in vivo, as most of the foundational work on this system was performed in nonhuman animals, ex vivo, or in vitro. In this work, I provide several noninvasive magnetic resonance imaging (MRI) methods to assess proximal and distal components of the central nervous system waste clearance system in humans in vivo, thereby strengthening the collective understanding of this system in health and neurodegenerative disease. Specifically, I developed a deep learning method for automatic segmentation of the choroid plexus, the primary producer of CSF in the brain, and I utilized this method to quantify choroid plexus structure and function with anatomical and perfusion-weighted MRI, respectively, across the adult lifespan and in Alzheimer disease and related dementia. I also coupled these metrics with measurements of CSF flow down the cerebral aqueduct in order to produce surrogate markers of initial CSF circulation. Finally, I proposed a novel noninvasive MRI lymphangiography method to both visualize and provide flow-sensitive signal of the lymphatic thoracic duct, thus providing a structural and quantitative tool to connect the body’s lymphatic system with the central nervous system’s waste clearance system. This work provides several tools to assess different aspects of the central nervous system’s glymphatic waste clearance system, normative ranges for quantifications of these aspects, and insight into how aging and neurodegenerative disease impact this system. The demonstrated methods have the potential to impact the diagnosis and treatment assessment for a wide range of clinical conditions, including cancer, neurodegeneration, and lymphedema.