Current Concepts in Intracranial Interstitial Fluid Transport and the Glymphatic System: Part II—Imaging Techniques and Clinical Applications

Abstract

A s reviewed in part I (1), the glymphatic system is a network unique to the central nervous system that allows for the dynamic exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) and has an essential role in normal homeostasis and clearance of interstitial solutes. The different compartments include the intracranial interstitial extracellular space (iECS), the paravascular space (PVS), defined here as between the endothelial basement membranes and the glial limitans of parenchymal perforating vessels that are continuous with the basal lamina of capillaries, and the CSF spaces with their transdural and transvenous efflux pathways. The anatomy and physiology of these multiple components present several challenges when designing techniques to clinically image glymphatic function, including length scales of the interstitium being orders of magnitude smaller than the spatial resolution of CT or MRI, the inability of conventional CT or MRI contrast agents to cross an intact blood-brain barrier (BBB) to access the PVS, and the slow transport velocities involved. In the following review, our attention turns to evaluation of the glymphatic system with imaging techniques, many of which are in the development phase but likely to advance to clinical use soon (Table). We also discuss the role of glymphatic function in the pathology of several common neurologic diseases, which supports the

Gut–Brain Axis as a Pathological and Therapeutic Target for Neurodegenerative Disorders

“…Many paradigms implicate the association of neurodegenerative diseases with infectious diseases and the putative biological function of some of the primary proteins implicated in these disorders. The aberrant accumulation of specific proteins, such as TDP-43 [16] and SOD1 [17] in ALS, amyloid β [18] and Tau [19] in AD, and α-synuclein [20] in PD, with similar proteinopathies seen in the chronic stage of ischemic stroke [21] can initiate a cascade of deleterious innate immunity processes that may contribute to the dysbiotic and dysfunctional GBA pathophysiological manifestations of NDDs. Recent review papers highlight the interaction between GBA and NDDs, with emphasis on diet, exercise, prebiotics and probiotics as treatments towards maintaining healthy microbiota in GBA [22][23][24][25][26][27].…”

Perivascular Spaces, Glymphatic System and MR

“…DCE-MRI for the human glymphatic system has its own drawbacks ( 90 ): (1) the potential adverse effects of GBCA accumulation in the brain, and (2) the long time required for the GBCA to reach and transit through the PVS after injection, which may limit its clinical utility. Furthermore, GBCA-free imaging of the glymphatic system is becoming increasingly popular.…”

Metabolic Contribution and Cerebral Blood Flow Regulation by Astrocytes in the Neurovascular Unit

“…Cerebral capillaries, the site of metabolism, along with the supply of oxygen and glucose, is also the site of metabolic product disposal [ 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. Specifically, it is easy to conceive that astrocytes in contact with the capillaries utilize the Virchow–Robin space, their outer lumen, for disposal.…”

“…Specifically, it is easy to conceive that astrocytes in contact with the capillaries utilize the Virchow–Robin space, their outer lumen, for disposal. Of particular interest is the glymphatic system (GS) as an excretory system for amyloid-β and phosphorylated tau proteins; it is well known that impaired activity of the GS leads to increased amyloid-β production and extracellular accumulation in the brain, and it is well known that, eventually, intracellular phosphorylated tau accumulation leads to neuronal death and Alzheimer’s disease [ 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. It is not yet clearly understood if a distinction can be made between substances specifically excreted via the GS and those supplied and excreted by the normal arteriovenous system.…”