Clinical application of intrathecal gadobutrol for assessment of cerebrospinal fluid tracer clearance to blood

Eide, Per Kristian; Mariussen, Espen; Uggerud, Hilde Thelle; Pripp, Are Hugo; Lashkarivand, Aslan; Hassel, Bjørnar; Christensen, Hege; Hovd, Markus Herberg; Ringstad, Geir

doi:10.1172/jci.insight.147063

Cited by 35 publications

(50 citation statements)

References 66 publications

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“…Additionally, in vivo measurements in humans demonstrating trans-arachnoid molecular passage in the PSD region were conducted by introducing gadolinium contrast into the subarachnoid space via intrathecal injection [ 2 ], with subsequent T 1 -weighted imaging detailing contrast progression to the PSD. Following this finding, a more recent study using intrathecal gadobutrol injection assessed the clearance of CSF in humans over an extended time period of 48 h in adults with CSF leakage disorders [ 29 ]. This study observed an increase of the CSF tracer in the blood after approximately 10 h, yet a delayed increase in the tracer in extracranial lymphatic structures, which peaked at approximately 24 h post-injection.…”

Section: Discussionmentioning

confidence: 99%

Parasagittal dural space and cerebrospinal fluid (CSF) flow across the lifespan in healthy adults

Hett

McKnight

Eisma

et al. 2022

Fluids Barriers CNS

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Background Recent studies have suggested alternative cerebrospinal fluid (CSF) clearance pathways for brain parenchymal metabolic waste products. One fundamental but relatively under-explored component of these pathways is the anatomic region surrounding the superior sagittal sinus, which has been shown to have relevance to trans-arachnoid molecular passage. This so-called parasagittal dural (PSD) space may play a physiologically significant role as a distal intracranial component of the human glymphatic circuit, yet fundamental gaps persist in our knowledge of how this space changes with normal aging and intracranial bulk fluid transport. Methods We re-parameterized MRI methods to assess CSF circulation in humans using high resolution imaging of the PSD space and phase contrast measures of flow through the cerebral aqueduct to test the hypotheses that volumetric measures of PSD space (1) are directly related to CSF flow (mL/s) through the cerebral aqueduct, and (2) increase with age. Multi-modal 3-Tesla MRI was applied in healthy participants (n = 62; age range = 20–83 years) across the adult lifespan whereby phase contrast assessments of CSF flow through the aqueduct were paired with non-contrasted T1-weighted and T2-weighted MRI for PSD volumetry. PSD volume was extracted using a recently validated neural networks algorithm. Non-parametric regression models were applied to evaluate how PSD volume related to tissue volume and age cross-sectionally, and separately how PSD volume related to CSF flow (significance criteria: two-sided p < 0.05). Results A significant PSD volume enlargement in relation to normal aging (p < 0.001, Spearman’s-$$\rho$$ ρ = 0.6), CSF volume (p < 0.001, Spearman’s-$$\rho$$ ρ = 0.6) and maximum CSF flow through the aqueduct of Sylvius (anterograde and retrograde, p < 0.001) were observed. The elevation in PSD volume was not significantly related to gray or white matter tissue volumes. Findings are consistent with PSD volume increasing with age and bulk CSF flow. Conclusions Findings highlight the feasibility of quantifying PSD volume non-invasively in vivo in humans using machine learning and non-contrast MRI. Additionally, findings demonstrate that PSD volume increases with age and relates to CSF volume and bi-directional flow. Values reported should provide useful normative ranges for how PSD volume adjusts with age, which will serve as a necessary pre-requisite for comparisons to persons with neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 99%

Parasagittal dural space and cerebrospinal fluid (CSF) flow across the lifespan in healthy adults

Hett

McKnight

Eisma

et al. 2022

Fluids Barriers CNS

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“…With regard to CSF clearance of neurotoxic solutes involved in neurodegeneration, human data suggest CSF resorption capacity at the upper brain convexities plays a minor role, as tracer clearance from CSF peaks in blood far earlier than peak levels are reached in CSF underneath the skull vertex. 37 The relative importance of meningeal lymphatic vessels for egress of neurotoxic metabolites in neurodegenerative disease needs to be further studied. Experimental data have shown that impaired meningeal lymphatic function caused reduced paravascular influx of macromolecules into the brain, and reduced efflux from the interstitial space.…”

Section: Discussionmentioning

confidence: 99%

Molecular trans-dural efflux to skull bone marrow in humans with CSF disorders

Ringstad

Eide

2021

Brain

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Dural sinuses were recently identified as a hub for peripheral immune surveillance of brain-derived antigens cleared through cerebrospinal fluid. However, animal studies have also indicated that substances and cells may enter the intracranial compartment directly from bone marrow. We utilized magnetic resonance imaging and a cerebrospinal fluid tracer to investigate in vivo whether intracranial molecules can move via dura to skull bone marrow in patients with suspicion of cerebrospinal fluid disorders. Tracer enrichment in cerebrospinal fluid, dural regions and within skull bone marrow was assessed up to 48 hours after intrathecal administration of gadobutrol (0.5 ml, 1 mmol/ml) in 53 patients. In subjects diagnosed with disease, tracer enrichment within diploe of skull bone marrow was demonstrated nearby the parasagittal dura, nearby extensions of parasagittal dura into diploe, and in diploe of skull bone remote from the dura extensions. This crossing of meningeal and skull barriers suggests that bone marrow may contribute in brain immune surveillance also in humans.

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“… 7 Eide et al [ 215 ] have reported on concentrations of gadobutrol in brain and blood after injection into lumbar CSF. “The peak concentration in blood (at about 10 hrs) preceded by far peak tracer enhancement at MRI in extra-cranial lymphatic structures (at about 24 hrs) as shown in previous studies, indicating a major role of the spinal canal in CSF clearance capacity.“ This emphasizes yet again that distribution of markers for extracellular fluids by CSF is an important factor in their delivery to the brain parenchyma.…”

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confidence: 99%

The glymphatic hypothesis: the theory and the evidence

Hladky

Barrand

2022

Fluids Barriers CNS

130

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The glymphatic hypothesis proposes a mechanism for extravascular transport into and out of the brain of hydrophilic solutes unable to cross the blood–brain barrier. It suggests that there is a circulation of fluid carrying solutes inwards via periarterial routes, through the interstitium and outwards via perivenous routes. This review critically analyses the evidence surrounding the mechanisms involved in each of these stages. There is good evidence that both influx and efflux of solutes occur along periarterial routes but no evidence that the principal route of outflow is perivenous. Furthermore, periarterial inflow of fluid is unlikely to be adequate to provide the outflow that would be needed to account for solute efflux. A tenet of the hypothesis is that flow sweeps solutes through the parenchyma. However, the velocity of any possible circulatory flow within the interstitium is too small compared to diffusion to provide effective solute movement. By comparison the earlier classical hypothesis describing extravascular transport proposed fluid entry into the parenchyma across the blood–brain barrier, solute movements within the parenchyma by diffusion, and solute efflux partly by diffusion near brain surfaces and partly carried by flow along “preferred routes” including perivascular spaces, white matter tracts and subependymal spaces. It did not suggest fluid entry via periarterial routes. Evidence is still incomplete concerning the routes and fate of solutes leaving the brain. A large proportion of the solutes eliminated from the parenchyma go to lymph nodes before reaching blood but the proportions delivered directly to lymph or indirectly via CSF which then enters lymph are as yet unclear. In addition, still not understood is why and how the absence of AQP4 which is normally highly expressed on glial endfeet lining periarterial and perivenous routes reduces rates of solute elimination from the parenchyma and of solute delivery to it from remote sites of injection. Neither the glymphatic hypothesis nor the earlier classical hypothesis adequately explain how solutes and fluid move into, through and out of the brain parenchyma. Features of a more complete description are discussed. All aspects of extravascular transport require further study.

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Clinical application of intrathecal gadobutrol for assessment of cerebrospinal fluid tracer clearance to blood

Cited by 35 publications

References 66 publications

Parasagittal dural space and cerebrospinal fluid (CSF) flow across the lifespan in healthy adults

Parasagittal dural space and cerebrospinal fluid (CSF) flow across the lifespan in healthy adults

Molecular trans-dural efflux to skull bone marrow in humans with CSF disorders

The glymphatic hypothesis: the theory and the evidence

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