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.

/pdf/a-paravascular-pathway-facilitates-csf-flow-through-the-1hqfwoq6nv.pdf

A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.

The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting the BBB are presented

/pdf/blood-brain-barrier-breakdown-in-alzheimer-disease-and-other-5ci9wdqp56.pdf

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

Diffusion in the extracellular space (ECS) of the brain is constrained by the volume fraction and the tortuosity and a modified diffusion equation represents the transport behavior of many molecule...

/pdf/diffusion-in-brain-extracellular-space-4beypnugcc.pdf

Diffusion in brain extracellular space.

Intrathecal antibody production is a hallmark of multiple sclerosis and humoral immunity is thought to play an important role in the inflammatory response and development of demyelinated lesions. The presence of lymphoid follicle-like structures in the cerebral meninges of some multiple sclerosis patients indicates that B-cell maturation can be sustained locally within the CNS and contribute to the establishment of a compartmentalized humoral immune response. In this study we examined the distribution of ectopic B-cell follicles in multiple sclerosis cases with primary and secondary progressive clinical courses to determine their association with clinical and neuropathological features. A detailed immunohistochemical and morphometric analysis was performed on post-mortem brain tissue samples from 29 secondary progressive (SP) and 7 primary progressive (PP) multiple sclerosis cases. B-cell follicles were detected in the meninges entering the cerebral sulci of 41.4% of the SPMS cases, but not in PPMS cases. The SPMS cases with follicles significantly differed from those without with respect to a younger age at multiple sclerosis onset, irreversible disability and death and more pronounced demyelination, microglia activation and loss of neurites in the cerebral cortex. Cortical demyelination in these SPMS cases was also more severe than in PPMS cases. Notably, all meningeal B-cell follicles were found adjacent to large subpial cortical lesions, suggesting that soluble factors diffusing from these structures have a pathogenic role. These data support an immunopathogenetic mechanism whereby B-cell follicles developing in the multiple sclerosis meninges exacerbate the detrimental effects of humoral immunity with a subsequent major impact on the integrity of the cortical structures.

Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology.

The glymphatic system is a recently discovered macroscopic waste clearance system that utilizes a unique system of perivascular tunnels, formed by astroglial cells, to promote efficient elimination of soluble proteins and metabolites from the central nervous system. Besides waste elimination, the glymphatic system also facilitates brain-wide distribution of several compounds, including glucose, lipids, amino acids, growth factors, and neuromodulators. Intriguingly, the glymphatic system function mainly during sleep and is largely disengaged during wakefulness. The biological need for sleep across all species may therefore reflect that the brain must enter a state of activity that enables elimination of potentially neurotoxic waste products, including β-amyloid. Since the concept of the glymphatic system is relatively new, we will here review its basic structural elements, organization, regulation, and functions. We will also discuss recent studies indicating that glymphatic function is suppressed in various diseases and that failure of glymphatic function in turn might contribute to pathology in neurodegenerative disorders, traumatic brain injury and stroke.

/pdf/the-glymphatic-system-a-beginner-s-guide-1r0mryf143.pdf

The Glymphatic System: A Beginner’s Guide

Evidence for a ‘Paravascular’ fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space

Solutes in CSF have rapid access to ECS throughout the CNS (within 5-10 min). This occurs by solute/fluid influx through PVS around penetrating arteries, followed by longitudinal spread along the BL of capillaries to reach venules and veins. These paravascular pathways can be demonstrated light-microscopically by infusion of the tracer protein, HRP, into SAS and the subsequent localization of this probe molecule in brain sections using the sensitive histochemical method based on TMB. This unidirectional tracer/fluid movement along the intraparenchymal vascular network, with accompanying spread into the cerebral interstitium, appears to be facilitated by the pulsation of penetrating arterioles within their PVS with each cardiac contraction.

Rapid solute transport throughout the brain via paravascular fluid pathways.

Cerebral blood vessels are accompanied by longitudinal paravascular fluid pathways that communicate with the subarachnoid space. After infusion into the subarachnoid space, the tracer protein, HRP, distributes throughout the brain with such rapidity as to suggest that the paravascular fluid transport system serves to flush the entire brain parenchyma. However, it was found that the tracer is largely excluded from regions of experimental vasogenic brain edema as well as from remotely situated white matter in the cold-lesioned hemisphere. The results suggest that the persistence and spread of vasogenic edema may be related to an impairment or disruption of the normal paravascular fluid transport system of the brain.

Patricia A. Grady

Papers

Evidence for a ‘Paravascular’ fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space

Rapid solute transport throughout the brain via paravascular fluid pathways.

Focal cerebral edema impedes convective fluid/tracer movement through paravascular pathways in cat brain.

Physiologic parameters of the Cushing reflex.

Experimental cerebral vasospasm: resolution by chlorpromazine.