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Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways.

ABSTRACT: Tracers injected into CSF pass into the brain alongside arteries and out again. This has been recently termed the "glymphatic system" that proposes tracers enter the brain along periarterial "spaces" and leave the brain along the walls of veins. The object of the present study is to test the hypothesis that: (1) tracers from the CSF enter the cerebral cortex along pial-glial basement membranes as there are no perivascular "spaces" around cortical arteries, (2) tracers leave the brain along smooth muscle cell basement membranes that form the Intramural Peri-Arterial Drainage (IPAD) pathways for the elimination of interstitial fluid and solutes from the brain. 2 ?L of 100 ?M soluble, fluorescent fixable amyloid ? (A?) were injected into the CSF of the cisterna magna of 6-10 and 24-30 month-old male mice and their brains were examined 5 and 30 min later. At 5 min, immunocytochemistry and confocal microscopy revealed A? on the outer aspects of cortical arteries colocalized with ?-2 laminin in the pial-glial basement membranes. At 30 min, A? was colocalised with collagen IV in smooth muscle cell basement membranes in the walls of cortical arteries corresponding to the IPAD pathways. No evidence for drainage along the walls of veins was found. Measurements of the depth of penetration of tracer were taken from 11 regions of the brain. Maximum depths of penetration of tracer into the brain were achieved in the pons and caudoputamen. Conclusions drawn from the present study are that tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. The exit route is along IPAD pathways in which A? accumulates in cerebral amyloid angiopathy (CAA) in Alzheimer's disease. Results from this study suggest that CSF may be a suitable route for delivery of therapies for neurological diseases, including CAA.

SUBMITTER: Albargothy NJ

PROVIDER: S-EPMC6015107 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways.

Albargothy Nazira J NJ Johnston David A DA MacGregor-Sharp Matthew M Weller Roy O RO Verma Ajay A Hawkes Cheryl A CA Carare Roxana O RO

Acta neuropathologica 20180512 1

Tracers injected into CSF pass into the brain alongside arteries and out again. This has been recently termed the "glymphatic system" that proposes tracers enter the brain along periarterial "spaces" and leave the brain along the walls of veins. The object of the present study is to test the hypothesis that: (1) tracers from the CSF enter the cerebral cortex along pial-glial basement membranes as there are no perivascular "spaces" around cortical arteries, (2) tracers leave the brain along smoot ...[more]

PMID: 29754206

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Project description:BACKGROUND:The glymphatic (glial-lymphatic) pathway is a fluid-clearance pathway identified in the rodent brain in 2012. This pathway subserves the flow of CSF into the brain along arterial perivascular spaces and subsequently into the brain interstitium, facilitated by aquaporin 4 (AQP4) water channels. The pathway then directs flow towards the venous perivascular and perineuronal spaces, ultimately clearing solutes from the neuropil into meningeal and cervical lymphatic drainage vessels. In rodents, the glymphatic pathway is predominantly active during sleep, when the clearance of harmful metabolites such as amyloid ? (A?) increases two-fold relative to the waking state. Glymphatic dysfunction, probably related to perturbed AQP4 expression, has been shown in animal models of traumatic brain injury, Alzheimer's disease, and stroke. The recent characterisations of the glymphatic and meningeal lymphatic systems in rodents and in humans call for revaluation of the anatomical routes for CSF-interstitial fluid flow and the physiological role that these pathways play in CNS health. RECENT DEVELOPMENTS:Several features of the glymphatic and meningeal lymphatic systems have been shown to be present in humans. MRI scans with intrathecally administered contrast agent show that CSF flows along pathways that closely resemble the glymphatic system outlined in rodents. Furthermore, PET studies have revealed that A? accumulates in the healthy brain after a single night of sleep deprivation, suggesting that the human glymphatic pathway might also be primarily active during sleep. Other PET studies have shown that CSF clearance of A? and tau tracers is reduced in patients with Alzheimer's disease compared with healthy controls. The observed reduction in CSF clearance was associated with increasing grey-matter concentrations of A? in the human brain, consistent with findings in mice showing that decreased glymphatic function leads to A? accumulation. Altered AQP4 expression is also evident in brain tissue from patients with Alzheimer's disease or normal pressure hydrocephalus; glymphatic MRI scans of patients with normal pressure hydrocephalus show reduced CSF tracer entry and clearance. WHERE NEXT?: Research is needed to confirm whether specific factors driving glymphatic flow in rodents also apply to humans. Longitudinal imaging studies evaluating human CSF dynamics will determine whether a causal link exists between reduced brain solute clearance and the development of neurodegenerative diseases. Assessment of glymphatic function after stroke or traumatic brain injury could identify whether this function correlates with neurological recovery. New insights into how behaviour and genetics modify glymphatic function, and how this function decompensates in disease, should lead to the development of new preventive and diagnostic tools and novel therapeutic targets.

Dataset Information

Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways.

Publications

Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways.

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