Perivascular spaces and their role in neuroinflammation, 2022, Ineichen et al.

[SNT Gatchaman]

Perivascular spaces and their role in neuroinflammation
Benjamin V. Ineichen; Serhat V. Okar; Steven T. Proulx; Britta Engelhardt; Hans Lassmann; Daniel S. Reich

It is uncontested that perivascular spaces play critical roles in maintaining homeostasis and priming neuroinflammation. However, despite more than a century of intense research on perivascular spaces, many open questions remain about the anatomical compartment surrounding blood vessels within the CNS.

The goal of this comprehensive review is to summarize the literature on perivascular spaces in human neuroinflammation and associated animal disease models. We describe the cell types taking part in the morphological and functional aspects of perivascular spaces and how those spaces can be visualized. Based on this, we propose a model of the cascade of events occurring during neuroinflammatory pathology. We also discuss current knowledge gaps and limitations of the available evidence. An improved understanding of perivascular spaces could advance our comprehension of the pathophysiology of neuroinflammation and open a new therapeutic window for neuroinflammatory diseases such as multiple sclerosis.

Link | PDF (Neuron) paywalled

 

[SNT Gatchaman]

Review article. Overview of sections —

A Brief History Of Perivascular Spaces

Anatomy And Visualization Of Perivascular Spaces

• Definition of perivascular spaces
• Histopathology and electron microscopy
• Magnetic resonance imaging
• Associations between enlarged perivascular spaces and neuroinflammatory diseases

Fluid Circulation In Perivascular Spaces

• Perivascular fluid dynamics
• Molecular transport in the perivascular space
• The glymphatic hypothesis

Immune Cells And Other Cells In Perivascular Spaces

Functional Aspects Of Perivascular Spaces In Neuroinflammation

• Endothelial barrier
• Sojourn in the perivascular space
• Parenchymal border

Perivascular Spaces And The Central Vein

Translational Aspects Of Perivascular Spaces

Knowledge Gaps

Limitations Of The Available Evidence

Conclusions

 

[SNT Gatchaman]

Key quotes from "Definition of perivascular spaces" —

The perivascular space is defined as the compartment surrounding the brain’s blood vessels — its arteries, arterioles, venules, and veins.

There is a large body of historical and contemporary literature assessing the exact anatomical configuration of perivascular spaces, with considerable inconsistencies across studies, including in nomenclature. Indeed, there is an ongoing debate about whether these are true "spaces" or potential spaces that are normally filled with connective tissue.

(I wonder if white matter hyperintensities may be perivascular spaces that are sometimes T2/FLAIR bright or only FLAIR bright depending on their fluid or cellular content.)

The most acknowledged current anatomical concept suggests that perivascular spaces are the compartments between the parenchymal basement membrane of the glia limitans (the outer boundary, formed by compacted astrocyte foot processes and an overlying parenchymal basement membrane) and the endothelial basement membrane of the blood vessel (inner boundary).

Perivascular spaces are widely considered to be confined by the boundaries of the pia mater (i.e., intracerebrally) and to follow the vascular tree down to the capillary level. At this point, the glial and endothelial basement membranes become closely juxtaposed and thus appearing as one structure and obliterating the space.

 

[SNT Gatchaman]

Key quotes from "Magnetic resonance imaging" —

MRI identifies perivascular spaces as mostly linear structures with a signal intensity similar to cerebrospinal fluid (CSF). This has led to the identification and classification of enlarged perivascular spaces (EPVSs) in specific brain regions into three types.

Type 1 EPVSs are situated in the basal ganglia [...]. Type 2 EPVSs are found in the centrum semiovale, and type 3 in the midbrain (pontomesencephalic junction).

Recently, advanced MRI techniques using high-static magnetic field strengths have improved the detection of even smaller perivascular spaces, enabling the classification of perivascular space location within the vascular tree

Insights from MRI have confirmed previous knowledge from neuropathology by showing associations between EPVSs and certain demographic parameters and/or diseases.

 

[SNT Gatchaman]

Key quotes from "Fluid circulation in perivascular spaces" —

"Perivascular fluid dynamics"

Despite solid evidence of fluid dynamics within perivascular spaces, the potential route of entry for fluid into perivascular spaces is a controversial subject.

The pia mater is the innermost layer of the meninges, coating veins and arteries in the subarachnoid space, and there is some evidence of a separation between the subarachnoid space and the subpial space. The perivascular space containing interstitial fluid also seems to be separated from the subarachnoid space containing CSF.

"Molecular transport in the perivascular space"

Tracer experiments have shown that molecules of up to 150 kDa can be transported within the intramural drainage pathway, whereas larger molecules, particularly cells or particulate material, track outside of arteries, adjacent to the glia limitans.

It has also been shown that tracers can be taken up by smooth muscle cells and perivascular macrophages along their passage. It is possible that antigenic CNS material is delivered to perivascular macrophages in a similar fashion for presentation to trafficking lymphocytes.

Finally, it has been shown that ß-amyloid is drained along this fluid drainage system but that its drainage becomes impaired with aging. This impairment leaves insoluble ß-amyloid deposits within basement membranes of the vessel walls, potentially further impeding efficient perivascular fluid exchange

"The glymphatic hypothesis"

CSF influx through perivascular spaces penetrating the CNS parenchyma was reported to be dependent on aquaporin-4 expressed on astrocyte endfeet.

This process was originally termed convective tracer influx, but the concept was then extended and renamed the "glymphatic system."

Although this is an interesting concept, several lines of evidence do not support the glymphatic hypothesis

 

[SNT Gatchaman]

Key quotes from "Immune Cells And Other Cells In Perivascular Spaces" —

The presence of myeloid cells with macrophage-like properties or dendritic cells in the perivascular space has two potential implications: first, it provides an opportunity for foreign antigens to be taken up and processed by these resident antigen-presenting cells (APCs); second, it allows for interactions between antigen-loaded macrophages/dendritic cells and lymphocytes from adjacent blood vessels or CSF.

Lymphocytes such as activated or effector/memory T cells can enter the meninges and perivascular spaces independently of their antigen specificity and are further activated when they recognize their cognate antigen present on local border-associated macrophages or dendritic cells in the subarachnoid space.

Importantly, during BBB disturbance, immune cell recruitment occurs at postcapillary venules. This is in contrast to the diffusion of soluble molecules across the cerebral endothelium [...] which is mostly controlled at the capillary level.

 

[SNT Gatchaman]

Key quotes from "Functional Aspects Of Perivascular Spaces In Neuroinflammation" —

The opening of the BBB is a key process of neuroinflammation. Although traditionally considered a single entity, the BBB comprises two anatomical layers, the endothelial cell/endothelial basement membrane layer and the glia limitans (formed by compacted astrocyte foot processes and an overlying parenchymal basement membrane), which are separated by a distinct perivascular space except at the capillary level.

Interestingly, data suggest that penetration of immune cells through the endothelial layer and their process of parenchymal invasion across the glia limitans are distinct processes, independent of one another. Thus, for leukocytes, perivascular spaces are not merely another compartment to cross to access the CNS parenchyma; rather, they provide the critical components needed to initiate neuroinflammation and CNS immune surveillance.

 

[SNT Gatchaman]

Key quotes from "Knowledge Gaps" —

There are [four] critical gaps in knowledge about perivascular space anatomy and function.[/QUOTE]

First, despite over a century of study, the exact anatomy of perivascular spaces is still debated, and the literature is hampered by inconsistent terminology. Open questions include whether there are anatomical differences between perivascular spaces at different levels along the CNS vascular tree, [...], between perivascular spaces in the centrum semiovale and the basal ganglia, or between cerebral and spinal cord

MRI studies have identified several neuroinflammatory disorders with greater numbers of [Enlarged Perivascular Spaces], mostly MS and, to a lesser extent, systemic lupus erythematosus. Yet, a second gap in knowledge surrounds the continuing debate over the exact role of these imaging biomarkers. Based on longitudinal MRI data, one study hypothesized that the dilation of EPVSs might represent a local accumulation of immune cells prior to the emergence of a neuroinflammatory lesion. However, these findings have yet to be reproduced.

a third gap in knowledge is the current uncertainty about whether fluid circulation within perivascular spaces is also altered in neuroinflammation and, if this were the case, whether this is a primary cause of neuroinflammatory pathology or a bystander effect.

Fourth, even though several molecules have been identified as governing the priming of immune cells in perivascular spaces, this process, including the exact type of APCs, is still a matter of debate. Both dendritic cells and perivascular macrophages have been implicated as those APCs, but resident microglia may also play this role by extending their processes to take part in the neurovascular unit.

 

[Hutan]

Are there pictures?

 

[SNT Gatchaman]

Sure are, seeing as you asked so nicely



Imaging-histological correlation. I imagine I - and most of us here - have MRIs that look a little similar to the second row (though hopefully without the atrophy of a presumed neurodegenerative case). Third row is a postmortem correlation. Rows 1 and 4 are mouse studies, with row 4 being in vivo and ex vivo equivalents showing tracer around the vessels.

 

[Hutan]

Very helpful, thank you.