Impaired Glymphatic Drainage of Cerebrospinal Fluid in Early Stages of Synucleinopathy
Age-related impairment of drainage of cerebrospinal fluid from the brain is a topic of increasing interest. This was pioneered by the work of Leucadia Therapeutics, specifically focused on the drainage path for the olfactory bulb leading through the cribriform plate, but most present work is focused instead on the glymphatic system drainage that parallels the vasculature supplying the brain. The two pathways decline in capacity with age, but for very different reasons, and will need different forms of therapy. Thin channels for fluid flow through the cribriform plate ossify shut with age. The glymphatic system suffers from a failure of regulation of peristaltic flow through vessels, however.
Cerebrospinal fluid drainage is a way to remove metabolic waste from the brain. Declining flow means that this waste will build up. This includes the protein aggregates associated with neurodegenerative conditions, and probably a great many other forms of metabolic waste that individually have more subtle effects, but collectively act to provoke cell dysfunction when present at high levels. One of the more important consequences is thought to be a maladaptive inflammatory reaction in glial cells in the brain, which in turn drives the onset and progression of neurodegenerative conditions.
In today's open access paper, researchers assess measures indicative of loss of cerebrospinal fluid drainage in patients with isolated rapid eye movement (REM) sleep behaviour disorder (iRBD), which is a failure of the normal suppression of muscle activity during REM sleep. iRBD is now recognized as a very early symptom of synucleinopathies such as Parkinson's disease. Synucleinopathies are characterized by the aggregation and spread of misfolded α-synuclein through the central nervous system, and associated neuroinflammation. A failure of cerebrospinal fluid drainage can only make this worse, closing off one way to remove aggregated proteins, and increasing inflammation as a consequence.
CSF turnover dysfunction: a hidden early biomarker in iRBD?
Evidence in Alzheimer's disease and other dementias shows that changes in cerebrospinal fluid (CSF) turnover and perivascular spaces (PVS) volume are associated with disease progression through impairment of waste-clearance glymphatic pathways. Volume of CSF, PVS, and drainage structures such as venous sinus are mostly excluded in current MRI studies of premanifest synucleinopathy.
Here, we used MRI to investigate whether modifications in CSF, PVS, and venous sinus volumes occur in 18 prodromal synucleinopathy patients (namely isolated rapid-eye-movement sleep behavior disorder, iRBD) compared to 20 healthy young and 18 elderly controls. Our results demonstrated increased CSF and PVS volumes in iRBD without a matching increase in drainage venous structures, as observed in elderly controls. This suggests increased CSF and PVS fluid stasis, possibly due to impaired CSF filtration, a mechanism that could reduce glymphatic function and exacerbate the neurodegenerative process in iRBD.