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Intrathecal Use of Gadobutrol for Glymphatic MR Imaging: Prospective Safety Study of 100 Patients - AJNR News Digest
May-June 2020
Patient Safety

Intrathecal Use of Gadobutrol for Glymphatic MR Imaging: Prospective Safety Study of 100 Patients

Eide picture

Per Kristian Eide

Ringstad picture

Geir Ringstad

Neurodegenerative diseases are typically characterized by toxic deposits of proteins from brain metabolism. As such, amyloid-beta plaques and tau neurofibrillary tangles are hallmark lesions of Alzheimer disease (AD).1 Several amyloid-beta isoforms and tau protein seem to be excreted from brain along paravascular routes in free communication with the subarachnoid compartment and CSF. Recent studies have demonstrated that brain molecular clearance is highly dependent on CSF clearance to meningeal lymphatic vessels.2 MRI contrast agents do not readily cross the intact BBB in either direction; therefore, when a contrast agent is administered in CSF (intrathecally), it can be assumed to be confined outside the BBB. The MRI contrast agent may therefore serve as a surrogate marker and resemble extravascular distribution and clearance of other hydrophilic molecules, including some amyloid-beta isoforms and tau.

We obtained permission from the National Medicine Agency of Norway and the regional ethical committee to study the distribution and clearance of intrathecally injected gadobutrol by long-term, multiphase MRI in patients undergoing neurosurgical work-up of different CSF circulation disorders. As we reported in the AJNR, the intrathecal safety profile of gadobutrol was comparable with iodixanol, and the frequency of adverse events depended on the diagnosis.3

In several studies, we assessed the utility of gadobutrol as a CSF tracer. In patients with idiopathic normal pressure hydrocephalus (iNPH) dementia, who typically have histologic overlap with AD in brain specimens, we found a significantly reduced CSF molecular clearance rate compared with a younger reference cohort of patients with suspicion of CSF leaks, idiopathic intracranial hypertension, and cysts.4 From brain tissue, we also detected reduced molecular clearance from the entorhinal cortex, an area where atrophy is known to precede hippocampal degeneration in AD.5 From the hypothesis that brain molecular clearance of neurotoxic metabolites is impaired in the early symptomatic or even preclinical phase, we have suggested that the method may have the potential to diagnose reduced molecular clearance capacity before irreversible neurodegeneration has occurred.6

The observation that a molecule such as gadobutrol may enter all brain regions from CSF4 may be important for our understanding of how the BBB can be bypassed by intrathecal treatment of neurologic diseases, and also sheds new light on mechanisms behind the deposition of linear gadolinium-based contrast agents outside the BBB, as MRI contrast agents are shown to leak into CSF after intravenous administration.7

Given the significance of meningeal lymphatic vessels for brain molecular clearance, we have lately also initiated a search for efflux pathways directly from CSF. In a recent study, we demonstrated enhancement along cranial nerve outlets at the skull base, as expected, but also found trans-arachnoid efflux of gadobutrol to the parasagittal dura.8 This area is in the immediate vicinity of previously reported dural meningeal vessels, where tight junctions are lacking.2 CSF may therefore serve as a carrier fluid between the immune system at the level of the meninges and the brain.9 Thus, the former concept of the brain’s “immune privilege” is challenged.

References

  1. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239–59
  2. Da Mesquita S, Louveau A, Vaccari A, et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature 2018;560:185–91
  3. Edeklev CS, Halvorsen M, Lovland G, et al. Intrathecal use of gadobutrol for glymphatic MR imaging: prospective safety study of 100 patients. AJNR Am J Neuroradiol 2019;40:1257–64
  4. Ringstad G, Valnes LM, Dale AM, et al. Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight 2018;3: e121537
  5. Eide PK, Ringstad G. Delayed clearance of cerebrospinal fluid tracer from entorhinal cortex in idiopathic normal pressure hydrocephalus: a glymphatic magnetic resonance imaging study. J Cereb Blood Flow Metab 2019;39:1355–68
  6. Eide PK, Ringstad G. In vivo imaging of molecular clearance from human entorhinal cortex: a possible method for preclinical testing of dementia. Gerontol Geriatr Med 2019;5:2333721419889739
  7. Nehra AK, McDonald RJ, Bluhm AM, et al. Accumulation of gadolinium in human cerebrospinal fluid after gadobutrol-enhanced MR imaging: a prospective observational cohort study. Radiology 2018;288:416–23
  8. Ringstad G, Eide PK. Cerebrospinal fluid tracer efflux to parasagittal dura in humans. Nat Commun 2020;11:354
  9. Rustenhoven J, Kipnis J. Bypassing the blood-brain barrier. Science 2019;366:1448–49

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