Glymphatic MRI (gMRI), utilizing intrathecal Gd as CSF tracer, may demonstrate the capacity for brain clearance of toxic interstitial waste products, such as amyloid-β and tau, which are aggregated in Alzheimer`s disease. There seem to exist important differences between human subjects and previous observations in animal studies. Both glymphatic and brain lymphatic clearance is much slower in man. In iNPH dementia, glymphatic clearance was demonstrated to be reduced.
The glymphatic system is a brain-wide pathway for clearance of brain interstitial waste products along the perivascular route, and was first described in rodents (1,2). Amyloid-β, which is accumulated in the brain in Alzheimer`s disease (AD), is cleared by the glymphatic system, and is dependent on the brain water channel Aquaporin 4, as well as sleep. Impaired glymphatic function has been demonstrated associated with ageing, head trauma and stroke, to mention some.
There is also evidence of a glymphatic system in human beings at gMRI, where an MRI contrast agent (gadobutrol) is utilized as CSF tracer by intrathecal injection at the lumbar level, and consecutive T1 volume scans are performed at multiple time points through at least 24 hours. MRI contrast agents are not approved for intrathecal use in the clinic, but was used off-label in a study setting by permission of the National Medicine Agency. At 24 hours, we found tracer enhancement at all assessed brain locations. As in previous animal studies, enhancement was most pronounced in brain tissue adjacent to large artery trunks in the subarachnoid space, indicating an important role of pulsations for driving glymphatic flow. In a dementia cohort of patients with idiopathic normal pressure hydrocephalus (iNPH), there was delayed propagation of CSF tracer along arteries at the brain surface, as well as delayed clearance from the CSF at 24 hours (3).
In another study of iNPH (4), clearance of gadobutrol was found delayed from the entorhinal cortex, which also was thinner than in control subjects. Entorhinal cortex volume loss is typically an early finding in AD dementia. Reduced entorhinal clearance of neurotoxic molecules such as amyloid-β may therefore also be an important factor in iNPH dementia.
In animal studies, glymphatic clearance function has been found dependent of CSF/brain lymphatic clearance to neck lymph nodes, where amyloid-β can be detected. In human subjects, we found no proof of early tracer enhancement in these lymph nodes, which could be expected if lymphatic clearance along cranial nerves would be important, as consistently reported in animals. However, peak enhancement in human neck lymph nodes occurred at 24 hours and in parallel with peak glymphatic enhancement, suggesting that lymphatic clearance from the intracranial compartment may not be directly from CSF, but rather via glymphatic pathways (5).
Prof. Per Kristian Eide, MD, PhD, Dept. of Neurosurgery, OUS
Kyrre Eeg Emblem, PhD, Dept. of Physics, OUS
Prof. Kent-Andre Mardal, PhD, Dept. of Mathematics, UiO
Lars M. Valnes, MSc, Dept. of Mathematics, UiO
Svein-Are S. Vatnehol, MSc, The Interventional Centre, OUS
Ruth Sletteberg, MD, Dept. of Radiology, OUS
Bård Nedregaard, MD, Dept. of Radiology, OUS
Øivind Gjertsen, MD, Dept. of Radiology, OUS
1. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Science translational medicine 2012; 4(147): 147ra11.
2.Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. The Journal of clinical investigation 2013a; 123(3): 1299-309
3. Ringstad G, Vatnehol SAS, Eide PK. Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain 2017; 140(10):2691-2705.
4. 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 2018; 271678X18760974.
5. Eide PK, Vatnehol SAS, Emblem KE, Ringstad G. Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes. Sci Rep. 2018; 8(1):7194.