Table 2:

Key gaps in knowledge gaps on perivascular space pathophysiology and limitations of the available literature.

Key knowledge gaps
1) Perivascular space anatomy -What is the exact anatomy of perivascular spaces? -Are there anatomical differences between periarterial, periarteriolar, perivenular (including peripostcapillary venule), and perivenous spaces?
2) Magnetic resonance imaging (MRI)-visible enlarged perivascular space (EPVS) etiopathogenesis -How do EPVS relate to arteries and/or veins? -What is the temporal evolution of EPVS and why do they become enlarged, i.e., MRI-visible? -How do EPVS relate to perivascular spaces around postcapillary venules where immune cell trafficking occurs?
3) Fluid dynamics of perivascular spaces -Is there directional fluid influx along periarterial and outflow along perivenous spaces? -Are fluid dynamics within perivascular spaces disrupted in neuroinflammatory diseases such as multiple sclerosis (MS)?
4) Neuroinflammatory priming within the perivascular space -Which cells serve as antigen-presenting cells in the perivascular space, e.g., macrophages, dendritic cells, B cells? -Which mechanisms govern differences between homeostatic immune-cell trafficking within the perivascular space and the trafficking that occurs during a neuroinflammatory outbreak?
Limitations of the available literature
1) Inconsistent terminology -“Paravascular” versus “perivascular” -Leukocytes “cross the blood-brain barrier”
2) Insufficient anatomical delineation of the perivascular space/compartment, including insufficient definition of locations within the vascular tree (artery, arteriole, venule, vein)
3) Unclear translatability of animal study findings -Caused by anatomical differences, e.g., between human and rodents