Cerebral Waste Accumulation and Glymphatic Clearance as Mechanisms of Human Neurological Diseases

Abstract

The brain is a complex system that requires continual regulation of parenchymal pressure, osmolarity, and waste removal for optimal function; despite this, human brain lacks any obvious extension of lymphatic circulation for moderating fluid and waste regulation. We recapitulate herein a recent analysis of proteinaceous waste deposition in the human brain, its observed route of clearance, and the implications of abnormal accumulation along this clearance pathway as a potential mechanism of neurological diseases. This study uncovered an analogous staining pattern of cerebral phosphorylated tau in temporal lobe epilepsy (TLE) and chronic traumatic encephalopathy (CTE). Regardless of the underlying physiopathology, p-tau elimination occurred via circulation through the perivenous space, as predicted by a glymphatic route of clearance. Remarkably, we demonstrated that p-tau is associated with a neurological disease that can develop independent of head trauma, since in both CTE and TLE: 1) Extracellular p-tau followed unidirectional, fluid-driven pathways that led toward the space bordering large (>100 μm diameter) blood vessels; 2) Tau-positive staining occurred within astroglial cells adjacent to blood vessels, which signified transcellular transport of p-tau as a potential secondary efflux route; 3) P-tau frequently appeared clustered within the perivenous space. This waste aggregation bears significant implications in the disruption of interstitial fluid circulation, which may contribute to exacerbation of disease states. A better understanding of waste elimination in the human brain may prove significant as a therapeutic target to improve parenchymal fluid circulation, and consequently, mitigate the hydrostatic, osmotic and oncotic imbalances that often cause or exacerbate brain diseases.

Children with autism spectrum disorder present glymphatic system dysfunction evidenced by diffusion tensor imaging along the perivascular space

“…[1] The glymphatic system is a vital system for removing protein waste products from the brain. [2] CSF removes waste proteins from the tissue as it reaches the interstitial space. [3,4] The CSF-ISF fluid, mixed with interstitial waste solutes, is then carried to the large central veins’ perivenous compartment, where it exits into lymphatic vessels and the systemic circulatory system.…”

Variances of quantifying of Virchow–Robin spaces detecting the different functional status of glymphatic system in simple febrile seizures affected by seizures duration

“…[ 1 ] The disruption of CSF-ISF exchange can obstruct waste and secretory product clearance, exacerbating VRs dilation. [ 31 ] Furthermore, an accumulation of products within the VRs, such as albumin, and disordered ionic gradients obstruct waste removal and perivascular fluid flow, aggravating VRs dilation. [ 15 ] Moreover, tau protein has been linked to axonal damage in the recurrent seizures brain.…”

“…[ 15 ] Moreover, tau protein has been linked to axonal damage in the recurrent seizures brain. [ 31 , 32 ] The elimination of tau protein by the glymphatic system was similar to that of β amyloid. [ 33 ] However, animal models suggest that overexpressed tau protein will accumulate in the extracellular and perivascular regions due to inadequate clearance.…”

Automated Methods for Detecting and Quantitation of Enlarged Perivascular spaces on MRI

“… 66 This could be explained by the release of tau protein in response to axonal injury caused by the seizure. 68 , 69 Thus, an accumulation of tau in the brain could cause an enlargement of the PVS and poor drainage via the glymphatic system.…”