Brain-wide pathway for waste clearance captured by contrast-enhanced MRI

Abstract

The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer's disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast-enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para-arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimer's disease susceptibility and progression in the live human brain. IntroductionIn the classical model, cerebrospinal fluid (CSF) is actively secreted by the choroid plexus of the cerebral ventricles and travels by bulk or pulsatile flow through the ventricular system, flowing from the fourth ventricle into the subarachnoid space through the foramina of Luschka and the foramen of Magendie. From the subarachnoid space, CSF is thought to be reabsorbed into the blood stream either via arachnoid granulations of the dural sinuses or by passing out of the cranial cavity along cranial nerve sheathes to be eliminated through the cervical lymphatics (1, 2). Fluid movement along this CSF column is commonly measured by MRI. Phase-contrast MRI allows the visualization of CSF flow dynamics and is used clinically in the evaluation of communicating versus noncommunicating hydrocephalus, normal pressure hydrocephalus, and arachnoid cysts (3). Contrast-enhanced magnetic resonance cisternography can also be used to identify CSF leaks in the treatment of spontaneous intracranial hypotension or CSF rhinorrhea (4,5).In a recent study (6), we reported that, contrary to the textbook model of CSF secretion and reabsorption, a large proportion of subarachnoid CSF recirculates through the brain parenchyma along paravascular spaces and exchanges with the interstitial fluid (ISF) (a process referred to herein as CSF-ISF exchange). The flow of fluid along these paravascular routes and through the interstitium is supported by transglial water movement through astrocytic aquaporin-4 (AQP4) water channels and facilitates the efficient clearance of interstitial solutes, including soluble amyloid...

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

“…Interestingly, this new work [162] emphasized that tracer movement in the brain parenchyma (outside of the perivascular spaces) was size dependent and consistent with diffusion as the mechanism of transport, using a cisternal infusion paradigm in mice that was very similar to that employed by Iliff et al [91]. A separate recent experimental study in rats [137] has also confirmed the role of tracer size-dependent diffusive transport at the pial brain surface using a similar cisternal infusion paradigm to the Nedergaard group [89]. Finally and perhaps most importantly, the Verkman group replicated many of the original Iliff et al cisternal infusion experiments in AQP4-null animals and found no qualitative or quantitative differences in ovalbumin distribution between wild type and AQP4 null mice (or between wild type and AQP4 null rats) [162].…”

“…The perivascular spaces (PVS) 1 of cerebral blood vessels have in recent years been the subject of increasing research focus as pathways for CSF/ISF exchange [1,74,89,91,95,112,137,138,162], but controversy exists over their precise role [58,77,96,161,162]. Indeed, the glial components (astrocyte foot processes) that provide the outer boundary of the PVS within the parenchyma have been proposed to serve a special function for CNS clearance and waste turnover, forming the basis for a so-called 'glymphatic' circulation [91,124] that may potentially allow a more complete exchange of CSF and ISF at both superficial and deep sites spanning the entire neural axis.…”

Antigen Presentation After Stroke

“…These routes allow the drainage of interstitial fluid and solutes out of the brain parenchyma through the glymphatic system [24][25][26][27][28]. Brain fluid and macromolecules can eventually reach the cervical lymph nodes along extracranial nerves through the cribiform plate [29][30][31], and through the recently described lymphatic vessels in the dura matter of the mice [32,33].…”

Cerebral Vascular Leak in a Mouse Model of Amyloid Neuropathology

“…Following such leak, particles will presumably be transported by the glymphatic pathway. [39][40][41] It is unclear how efficient such transport is, but constitutes one possible mechanism for particle transport to far corners of the brain. Extrapolating our results to the human condition would suggest that older patients with greater amyloid burden could be expected to allow larger amounts of nanoparticles to enter the brain from the vasculature.…”