Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI

Absinta, Martina; Ha, Seung Kwon; Nair, Govind; Sati, Pascal; Luciano, Nicholas J.; Palisoc, Maryknoll; Louveau, Antoine; Zaghloul, Kareem A.; Pittaluga, Stefania; Kipnis, Jonathan; Reich, Daniel S.

doi:10.7554/elife.29738

Cited by 467 publications

(550 citation statements)

References 31 publications

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“…Given our pre- and post-contrast technique, we are able to include for the first time vessel wall and dural foci subtypes, which persist most frequently and their appearance very closely matches recent descriptions of meningeal lymphatics or the glial lymphatics system. 19–22 Longitudinal persistence of meningeal enhancement is not significantly different between those on or off immunomodulatory treatment; nor is there a significant difference in rates of longitudinal persistence between those with progressive clinical phenotypes (primary progressive MS and secondary progressive MS) and those without a progressive clinical phenotype (relapsing remitting MS). However, there is a significantly increased number of persistent foci in subjects that have worsening Expanded Disability Status Scale scores at 1 year compared to those that do not, suggesting that persistently enhancing meningeal foci may be an in-vivo imaging marker for ongoing meningeal inflammation causative of clinical progression.…”

Section: Resultsmentioning

confidence: 99%

“…Which anatomic/pathologic substrates are represented by vessel wall and dural foci is unknown, but interestingly, both closely match what was recently described for visualization of meningeal lymphatics by FLAIR MRI. 20–22 Thus, it is possible that these findings may represent gadolinium absorption by lymphatic structures after leakage into the cerebrospinal fluid. The accumulation of gadolinium signal alongside the outer wall of vessels in the vessel wall pattern is also very reminiscent of the expected location and direction of drainage of solutes from brain parenchyma along the recently described glymphatic system.…”

Section: Discussionmentioning

confidence: 99%

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Longitudinal Persistence of Meningeal Enhancement on Postcontrast 7T 3D-FLAIR MRI in Multiple Sclerosis

Jonas

Izbudak

Frazier

et al. 2018

AJNR Am J Neuroradiol

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Background and Purpose: Preliminary research has demonstrated that post-gadolinium 3D FLAIR MRI at 7T may be a valuable tool for detecting abnormal meningeal enhancement and inflammation in MS; however, researchers have not systematically investigated its longitudinal persistence. We hypothesize that persistence of meningeal enhancement in MS varies based on pattern of enhancement as well as demographic and clinical factors such as treatment status, disease phenotype, and disability score. Materials and Methods: Thirty-one subjects with MS were prospectively scanned before and after intravenous contrast administration at 2 time points, approximately 1 year apart. Fifteen subjects in the cohort were scanned another time approximately 1 year later. Foci of enhancement were categorized into four subtypes: subarachnoid spread/fill, subarachnoid nodular, vessel wall, and dural foci. We reviewed follow-up scans to determine whether foci changed between time points and then compared persistence to demographic and clinical variables. Results: Persistence ranged from 71–100% at 1 year, and 73–100% at 2 years depending on enhancement pattern. Subarachnoid spread/fill and subarachnoid nodular subtypes persisted less often than vessel wall and dural foci. Persistence was not significantly different between those on/off treatment and those with progressive/non-progressive diseases phenotypes. Number of persisting foci was significantly different in subjects with/without increasing Expanded Disability Status Scale scores (median 12 v 7.5, p=0.04). Conclusion: Longitudinal persistence of meningeal enhancement on 3D FLAIR at 7T in MS varies by pattern of enhancement and correlates with worsening disability; however, it is not significantly different in those on/off treatment or those with progressive/non-progressive disease phenotypes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Longitudinal Persistence of Meningeal Enhancement on Postcontrast 7T 3D-FLAIR MRI in Multiple Sclerosis

Jonas

Izbudak

Frazier

et al. 2018

AJNR Am J Neuroradiol

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“…After intrathecal gadobutrol, via methodology previously proposed by Iliff et al, the signal increase on brain MRI was shown to have a faster distribution than predicted by diffusion alone . More recently, meningeal lymphatic vessels were identified with large similarities in rodents and human subjects . Absinta and colleagues described a system of lymphatic vessels along dural venous sinuses on FLAIR and T1‐weighted black‐blood imaging after intravenous gadobutrol injection, exploiting the lack of blood–meningeal barrier in dural vessels.…”

Section: Discussionmentioning

confidence: 99%

Glymphatics Visualization after Focused Ultrasound‐Induced Blood–Brain Barrier Opening in Humans

Meng

Abrahão

Heyn

et al. 2019

Annals of Neurology

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It is currently unclear whether the glymphatic system, a brain‐wide interstitial fluid–cerebrospinal fluid exchange described in rodents, exists in humans. Focal blood–brain barrier disruption using magnetic resonance–guided focused ultrasound allows parenchymal penetration of gadobutrol contrast, creating an opportunity to study glymphatics in vivo noninvasively. We describe patterns of contrast distribution in the perivascular space, subarachnoid space, and space surrounding large veins draining toward the dural sinuses on fluid‐attenuated inversion recovery in subjects with Alzheimer disease and amyotrophic lateral sclerosis. This is the first evidence suggesting glymphatic efflux persists in humans. It's relevance to proteinopathies and drug delivery is discussed. ANN NEUROL 2019;86:975–980

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“…In 2012, the glymphatic pathway was first described in rodents by 2 photon‐microscopy studies, and then measured in the human brain with magnetic resonance imaging (MRI) before and multiple time points after intrathecal injection of a contrast agent (gadolinium) in 2015 . In the same year, a network of true lymphatic vessels within the mammalian dura mater that runs alongside blood vessels was confirmed by 2 independent teams, whereas the existence of MLVs in humans was reported with the visualization of high‐resolution T2–fluid attenuated inversion recovery (FLAIR), T1‐weighted black‐blood imaging in 2017, and confocal microscopy in 2018 …”

mentioning

confidence: 99%

Impairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human

Zhou

Cai

Zhang

et al. 2020

Annals of Neurology

196

185

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Objective Aging is a major risk factor for numerous neurological disorders, and the mechanisms underlying brain aging remain elusive. Recent animal studies demonstrated a tight relationship between impairment of the glymphatic pathway, meningeal lymphatic vessels, and aging. However, the relationship in the human brain remains uncertain. Methods In this observational cohort study, patients underwent magnetic resonance imaging before and at multiple time points after intrathecal administration of a contrast agent. Head T1‐weighted imaging was performed to assess the function of the glymphatic pathway and head high‐resolution T2–fluid attenuated inversion recovery imaging to visualize putative meningeal lymphatic vessels (pMLVs). We measured the signal unit ratio (SUR) of 6 locations in the glymphatic pathway and pMLVs, defined the percentage change in SUR from baseline to 39 hours as the clearance of the glymphatic pathway and pMLVs, and then analyzed their relationships with aging. Results In all patients (N = 35), the SUR of the glymphatic pathway and pMLVs changed significantly after intrathecal injection of the contrast agent. The clearance of both the glymphatic pathway and pMLVs was related to aging (all p < 0.05). The clearance of pMLVs was significantly related to the clearance of the glymphatic pathway (all p < 0.05), and the clearance of the glymphatic pathway was significantly faster in patients with early filling of pMLVs than those with late filling (all p < 0.05). Interpretation We revealed that both the glymphatic pathway and pMLVs might be impaired in the aging human brain through the novel, clinically available method to simultaneously visualize their clearance. Our findings also support that in humans, pMLVs are the downstream of the glymphatic pathway. Ann Neurol 2020;87:357–369

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Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI

Cited by 467 publications

References 31 publications

Longitudinal Persistence of Meningeal Enhancement on Postcontrast 7T 3D-FLAIR MRI in Multiple Sclerosis

Longitudinal Persistence of Meningeal Enhancement on Postcontrast 7T 3D-FLAIR MRI in Multiple Sclerosis

Glymphatics Visualization after Focused Ultrasound‐Induced Blood–Brain Barrier Opening in Humans

Impairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human

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