Periarteriolar spaces modulate cerebrospinal fluid transport into brain and demonstrate altered morphology in aging and Alzheimer’s disease

Abstract

Perivascular spaces (PVS) drain brain waste metabolites, but their specific flow paths are debated. Meningeal pia mater reportedly forms the outermost boundary that confines flow around blood vessels. Yet, we show that pia is perforated and permissive to PVS fluid flow. Furthermore, we demonstrate that pia is comprised of vascular and cerebral layers that coalesce in variable patterns along leptomeningeal arteries, often merging around penetrating arterioles. Heterogeneous pial architectures form variable sieve-like structures that differentially influence cerebrospinal fluid (CSF) transport along PVS. The degree of pial coverage correlates with macrophage density and phagocytosis of CSF tracer. In vivo imaging confirms transpial influx of CSF tracer, suggesting a role of pia in CSF filtration, but not flow restriction. Additionally, pial layers atrophy with age. Old mice also exhibit areas of pial denudation that are not observed in young animals, but pia is unexpectedly hypertrophied in a mouse model of Alzheimer’s disease. Moreover, pial thickness correlates with improved CSF flow and reduced β-amyloid deposits in PVS of old mice. We show that PVS morphology in mice is variable and that the structure and function of pia suggests a previously unrecognized role in regulating CSF transport and amyloid clearance in aging and disease.

Gold nanoparticle-enhanced X-ray microtomography of the rodent reveals region-specific cerebrospinal fluid circulation in the brain

“…Unlike prior studies in adult rodents in which CSF tracers were observed in dorsal and cortical structures with emphasis on localization around the perivascular spaces of major and penetrating arteries 13 , 38 , 39 , 1.9 nm AuNP-XRM and corresponding histology revealed a robust pattern of CSF pathways entering the brain parenchyma from the interpeduncular and pontine cisterns as early as 10 minutes after intraventricular 1.9 nm AuNP injection (Fig. 1d–j ).…”

Sleep cycle-dependent vascular dynamics in male mice and the predicted effects on perivascular cerebrospinal fluid flow and solute transport

“…We defined PVS as the void between the lumen and endfoot sleeve to encompass all the potential pathways of CSF and solute flow in two-photon image recordings 11 . However, defining PVS in this way will over-estimate the actual PVS volume, as there are cellular and non-cellular constituents within this compartment, such as smooth muscle cells, macrophages, fibroblasts, and extracellular matrix proteins 25 , 26 , that likely hinder fluid flow. For example, the wall of penetrating arterioles consists of smooth muscle cells that would contract upon vasoconstriction.…”

“…The PVS is not an empty space and contains different cell types and extracellular components 11 , 25 , 26 . The precise neuroanatomical pathways where CSF and solutes flow, for instance if it is only the fluid filled PVS that allows for fluid and solute movement, or whether there are pathways in between the vascular smooth muscle cells, is still a matter of debate 11 .…”

“…First, whether sleep cycle-dependent vascular dynamics are global throughout the brain and whether they are synchronous along the vascular tree, or propagate in a proximal-to-distal direction or vice versa. This could depend on the type of arteriole PVS 25 . Second, how sleep cycle-dependent vascular dynamics are regulated.…”

The Glymphatic System: a Potential Key Player in Bacterial Meningitis

“…It would therefore be exciting to see whether the course of pneumococcal meningitis can be positively influenced by permanent anesthesia. Besides wakefulness, the activity of the glymphatic system decreases sharply during aging ( 14 , 15 ). It is worth investigating whether age-related glymphatic dysfunction contributes to the poorer prognosis of pneumococcal meningitis in the elderly ( 16 ).…”