The pathogenesis of idiopathic normal pressure hydrocephalus based on the understanding of AQP1 and AQP4

Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.

Background The glial-lymphatic or glymphatic pathway is a fluid clearance pathway recently identified in the rodent brain. This pathway subserves the flow of cerebrospinal fluid (CSF) into the brain along arterial perivascular spaces and thence into the brain interstitium facilitated by aquaporin-4 (AQP4) water channels. The pathway then directs flows 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 primarily active during sleep, when the clearance of harmful metabolites such as amyloid β (Aβ) increases two-fold relative to the waking state. Glymphatic dysfunction has been demonstrated in animal models of traumatic brain injury (TBI), Alzheimer’s disease (AD) and micro-infarct disease, most likely in relation to perturbed expression of AQP4. The recent characterizations of the glymphatic and meningeal lymphatic systems calls for revaluation of the anatomical routes for CSF-ISF flow and the physiological role that these pathways play in CNS health. Recent developments Recent work has revealed that several features of the glymphatic and meningeal lymphatic systems are also present in humans. MRI imaging of intrathecally-administered contrast agent shows that CSF flows along pathways closely resembling the glymphatic system outlined in rodents. Furthermore, PET studies reveal that Aβ 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 Aβ and tau tracers is reduced in patients with AD compared to healthy controls. The observed reduction in CSF clearance was associated with increasing grey matter Aβ levels in human brain, which is consistent with findings in mice showing that decreased glymphatic function leads Aβ accumulation. Altered AQP4 expression is also evident in brain tissue from AD or normal pressure hydrocephalus (NPH) patients; glymphatic MRI of NPH patients shows reduced CSF tracer entry and clearance. Where next? Future research is needed to confirm if specific factors driving glymphatic flow in rodents also apply to humans. Conducting longitudinal imaging studies to evaluate human CSF dynamics will determine if there is indeed a causal link between reduced brain solute clearance and the development of neurodegenerative diseases. Assessment of glymphatic function after stroke or TBI could identify if it correlates with neurological recovery. Gaining new insights into how behavior and genetics modify glymphatic function, and how this decompensates in disease should lead to the development of new preventive and diagnostic tools, as well as novel therapeutic targets.

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.