Glymphatic Pathway of Gadolinium-Based Contrast Agents through the Brain: Overlooked and Misinterpreted

Deike-Hofmann, Katerina; Reuter, J.H.; Haase, Robert; Paech, Daniel; Gnirs, Regula; Bickelhaupt, Sebastian; Forsting, Michael; Schlemmer, Heinz Peter; Radbruch, Alexander

doi:10.1055/s-0037-1682165

Cited by 28 publications

(65 citation statements)

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“…[2][3][4][5]14,20,25,27 It has been reported that the CSF signal intensity in the lateral ventricles and the prepontine cistern was decreased at 24 h compared to 3 h post-administration of GBCA. 1 Decreased enhancement in the CSF at 24 h is consistent with the results of the present study. Leakage of IV-GBCA into the CSF might be affected by various conditions.…”

Section: Csf Enhancementsupporting

confidence: 92%

“…A recent report indicated that the cochlear perilymph signal intensity was increased at 24 h in healthy subjects compared to 3 h. 1 In the present study, the cochlear perilymph signal intensity was decreased slightly at 24 h compared to 4 h. Also in the previous study, the cochlear perilymph signal intensity tended to be higher in patients with white matter degeneration. 1 In the present study, no evaluation for white matter lesions in the brain was performed, and all patients had a suspicion of endolymphatic hydrops. The reason for the difference in the results between the present study and the previous study 1 is not known, but may be due to differences in the patient groups as well as the scan timing (i.e.…”

Section: Cochlear Perilymph Signal Intensitysupporting

confidence: 65%

“…3 In addition, an association of white matter degeneration and the degree of GBCA distribution in the CSF has also been documented. 1 A correlation of IV-GBCA leakage into the CSF with aging, white matter degeneration, BBB disruption and other pathophysiological conditions would be interesting for future research. The drainage of GBCA from CSF is also important issue in the research of the glymphatic system.…”

Section: Csf Enhancementmentioning

confidence: 99%

“…Various studies have shown that GBCAs distribute in various fluid spaces such as the CSF, the perilymph of the inner ear, the perivascular spaces of the basal ganglia, the meningeal lymphatics and the brain parenchyma after IV administration. [1][2][3][4][5]9,[14][15][16][17][18][19][20] The pattern for the intracranial distribution of intravenously administered GBCA might be associated with aging, blood-brain barrier (BBB) integrity, function of glymphatic system, and renal function. 2,3,21,22 The glymphatic system is the waste clearance system of the brain and has attracted much attention from a wide range of investigators.…”

Section: Introductionmentioning

confidence: 99%

“…26 Currently, the distribution patterns of intravenously administered GBCA in various fluid spaces of humans are under intense investigation as the first step of the glymphatic system and as a measure of BBB integrity. 1,25,27 For the evaluation of the glymphatic system in brain parenchyma, an intrathecal administration of a small dose of GBCA (IT-GBCA) is used by some investigators. 23,28 However, intrathecal administration of GBCA is usually contraindicated in a clinical setting.…”

Section: Introductionmentioning

confidence: 99%

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Intracranial Distribution of Intravenously Administered Gadolinium-based Contrast Agent over a Period of 24 Hours: Evaluation with 3D-real IR Imaging and MR Fingerprinting

et al. 2021

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Purpose: To evaluate the feasibility for the detection of slight contrast effects after intravenous administration of single dose gadolinium-based contrast agent (IV-SD-GBCA), the time course of the GBCA distribution up to 24 h was examined in various fluid spaces and brain parenchyma using 3D-real IR imaging and MR fingerprinting (MRF). Methods:Twenty-four patients with a suspicion of endolymphatic hydrops were scanned at pre-administration and at 10 min, 4 and 24 h post-IV-SD-GBCA. 3D-real IR images and MRF at the level of the internal auditory canal were obtained. The signal intensity on the 3D-real IR image of the cerebrospinal fluid (CSF) in the cerebellopontine angle cistern (CPA), Sylvian fissure (Syl), lateral ventricle (LV), and cochlear perilymph (CPL) was measured. The T 1 and T 2 values of cerebellar gray (GM) and white matter (WM) were measured using MRF. Each averaged value at the various time points was compared using an analysis of variance.

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Section: Csf Enhancementsupporting

confidence: 92%

Section: Cochlear Perilymph Signal Intensitysupporting

confidence: 65%

Section: Csf Enhancementmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Intracranial Distribution of Intravenously Administered Gadolinium-based Contrast Agent over a Period of 24 Hours: Evaluation with 3D-real IR Imaging and MR Fingerprinting

et al. 2021

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Noninvasive Characterization of Human Glymphatics and Meningeal Lymphatics in an in vivo Model of Blood–Brain Barrier Leakage

Lirng

Ling

et al. 2020

Annals of Neurology

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Objective To evaluate human glymphatics and meningeal lymphatics noninvasively. Methods This prospective study implemented 3‐dimensional (3D) isotropic contrast‐enhanced T2 fluid‐attenuated inversion recovery (CE‐T2‐FLAIR) imaging with a 3T magnetic resonance machine to study cerebral glymphatics and meningeal lymphatics in patients with reversible cerebral vasoconstriction syndrome (RCVS) with (n = 92) or without (n = 90) blood–brain barrier (BBB) disruption and a diseased control group with cluster headache (n = 35). The contrast agent gadobutrol (0.2mmol/kg [0.2ml/kg]) was administered intravenously in all study subjects. Results In total, 217 patients (182 RCVS, 35 cluster headache) were analyzed and separated into 2 groups based on the presence or absence of visible gadolinium (Gd) leakage. Para‐arterial tracer enrichment was clearly depicted in those with overt BBB disruption, while paravenous and parasinus meningeal contrast enrichment was evident in both groups. Paravenous and parasinus contrast enrichment remained in RCVS patients in the remission stage and in cluster headache patients, suggesting that these meningeal lymphatic channels were universal anatomical structures rather than being phase‐ or condition‐specific. Additionally, we demonstrated nodular leptomeningeal enhancement in 32.3% of participants, which might represent potential lymphatic reservoirs. Four selected RCVS patients who received consecutive contrasted 3D isotropic FLAIR imaging after gadobutrol administration showed that the Gd persisted for at least 54 minutes and was completely cleared within 18 hours. Interpretation This large‐scale in vivo study successfully demonstrated the putative human para‐arterial glymphatic transports and meningeal lymphatics by clear depiction of para‐arterial, parasinus, and paravenous meningeal contrast enrichment using high‐resolution 3D isotropic CE‐T2‐FLAIR imaging noninvasively; this technique may serve as a basis for further studies to delineate clinical relevance of glymphatic clearance. ANN NEUROL 2021;89:111–124

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Retention of Gadolinium in Brain Parenchyma: Pathways for Speciation, Access, and Distribution. A Critical Review

Rasschaert

Weller

Schroeder

et al. 2020

Magnetic Resonance Imaging

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The unexpected appearance of T1 hyperintensities, mostly in the dentate nucleus and the globus pallidus, during nonenhanced MRI was reported in 2014. This effect is associated with prior repeated administrations of gadolinium (Gd)‐based contrast agents (GBCAs) in patients with a functional blood–brain barrier (BBB). It is widely assumed that GBCAs do not cross the intact BBB, but the observation of these hypersignals raises questions regarding this assumption. This review critically discusses the mechanisms of Gd accumulation in the brain with regard to access pathways, Gd species, tissue distribution, and subcellular location. We propose the hypothesis that there is early access of Gd species to cerebrospinal fluid, followed by passive diffusion into the brain parenchyma close to the cerebral ventricles. When accessing areas rich in endogenous metals or phosphorus, the less kinetically stable GBCAs would dissociate, and Gd would bind to endogenous macromolecules, and/or precipitate within the brain tissue. It is also proposed that Gd species enter the brain parenchyma along penetrating cortical arteries in periarterial pial‐glial basement membranes and leave the brain along intramural peri‐arterial drainage (IPAD) pathways. Lastly, Gd/GBCAs may access the brain parenchyma directly from the blood through the BBB in the walls of capillaries. It is crucial to distinguish between the physiological distribution and drainage pathways for GBCAs and the possible dissociation of less thermodynamically/kinetically stable GBCAs that lead to long‐term Gd deposition in the brain. Level of Evidence 5. Technical Efficacy Stage 3.

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Glymphatic Pathway of Gadolinium-Based Contrast Agents through the Brain: Overlooked and Misinterpreted

Cited by 28 publications

References 0 publications

Intracranial Distribution of Intravenously Administered Gadolinium-based Contrast Agent over a Period of 24 Hours: Evaluation with 3D-real IR Imaging and MR Fingerprinting

Intracranial Distribution of Intravenously Administered Gadolinium-based Contrast Agent over a Period of 24 Hours: Evaluation with 3D-real IR Imaging and MR Fingerprinting

Noninvasive Characterization of Human Glymphatics and Meningeal Lymphatics in an in vivo Model of Blood–Brain Barrier Leakage

Retention of Gadolinium in Brain Parenchyma: Pathways for Speciation, Access, and Distribution. A Critical Review

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