Glymphatic Pathway of Gadolinium-Based Contrast Agents Through the Brain

Abstract

Background: The "glymphatic system" (GS), a brain-wide network of cerebrospinal fluid microcirculation, supplies a pathway through and out of the central nervous system (CNS); malfunction of the system is implicated in a variety of neurological disorders. In this exploratory study, we analyzed the potential of a new imaging approach that we coined delayed T2-weighted gadolinium-enhanced imaging to visualize the GS in vivo. Methods: Heavily T2-weighted fluid-attenuated inversion recovery (hT2w-FLAIR) magnetic resonance imaging was obtained before, and 3 hours and 24 hours after intravenous gadolinium-based contrast agent (GBCA) application in 33 neurologically healthy patients and 7 patients with an impaired blood-brain barrier (BBB) due to cerebral metastases. Signal intensity (SI) was determined in various cerebral fluid spaces, and white matter hyperintensities were quantified by applying the Fazekas scoring system. Findings: Delayed hT2w-FLAIR showed GBCA entry into the CNS via the choroid plexus and the ciliary body, with GBCA drainage along perineural sheaths of cranial nerves and along perivascular spaces of penetrating cortical arteries. In all patients and all sites, a significant SI increase was found for the 3 hours and 24 hours time points compared with baseline. Although no significant difference in SI was found between neurologically healthy patients and patients with an impaired BBB, a significant positive correlation between Fazekas scoring system and SI increase in the perivascular spaces 3 hours post injection was shown. Interpretation: Delayed T2-weighted gadolinium-enhanced imaging can visualize the GBCA pathway into and through the GS. Presence of GBCAs within the GS might be regarded as part of the natural excretion process and should not be mixed up with gadolinium deposition. Rather, the correlation found between deep white matter hyperintensities, an imaging sign of vascular dementia, and GS functioning demonstrated feasibility to exploit the pathway of GBCAs through the GS for diagnostic purposes.

Hydraulic resistance of periarterial spaces in the brain

“…From the continuity equation (expressing conservation of mass), we know that this net flow must continue in some form through other parts of the system (e.g., along perivascular spaces around penetrating arteries, arterioles, capillaries, venules). This is supported by recent magnetic resonance imaging studies in humans that have demonstrated that CSF tracers are transported deeply into the brain via perivascular spaces [9–11].…”

Age-Dependent Signal Intensity Changes in the Structurally Normal Pediatric Brain on Unenhanced T1-Weighted MR Imaging

“…[2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Furthermore, various pathologic and nonpathologic states are now known to result in brain parenchymal signal intensity changes on unenhanced T1WI, including gadolinium deposition. [21][22][23][24][25][26][27][28][29][30] Chronologic signal intensity changes on T1WI and myelination patterns within the cortex and subcortical white matter, corpus collosum, and various white matter tracts within the supratentorial and infratentorial brain have been well-characterized in pediatric and adult populations. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]19,20 However, agedependent T1WI signal intensity alterations within the deep gray nuclei, cerebellar nuclei, and brain ...…”

Varying perivascular astroglial endfoot dimensions along the vascular tree maintain perivascular-interstitial flux through the cortical mantle

“…Contrast-based studies carried out in rodents 13 , non-human primates 23 , and human subjects 37–39 demonstrate CSF from cisternal compartments travels along perivascular spaces surrounding leptomeningeal vessels and enters the brain along perivascular spaces surrounding penetrating vessels (also termed Virchow-Robin spaces). From here, solutes such as fluorescent tracers or gadolinium-based MRI contrast agents that do not cross the blood brain barrier and are not taken up by astrocytes exchange into the brain interstitium via gaps between overlapping perivascular astroglial endfoot processes.…”