“Mind the Gap”—enlarged perivascular spaces as a potential magnetic resonance imaging biomarker of impaired glymphatic clearance in brain disorders

The abundant capillary network penetrating the brain parenchyma is surrounded by potential tubular, fluid-filled regions referred to as perivascular spaces (PVSs). PVSs have a unique and complex history and are believed to act as a pathway for the drainage of waste products from brain interstitial and cerebrospinal fluid (CSF) as part of the glymphatic clearance system. The unique perivascular "gap" spaces are eponymously linked to Virchow and Robin, who argued vigorously in the 1800s over PVSs' exact location and physiology. Currently, debates are ongoing regarding whether PVSs are predominantly periarteriolar, perivenular, or both and how they aid in clearing fluids from the brain parenchyma. In neurodevelopmental, neuropsychiatric, and neuropathological conditions, PVS can enlarge, a phenomenon referred to as enlarged perivascular spaces (ePVSs), which are identifiable on magnetic resonance imaging (MRI), with improved detection and resolution at higher magnetic field strengths. Quantification of ePVS enlargement on MRI using artificial intelligence (AI) imaging algorithms may serve as a potential non-invasive imaging biomarker for impaired glymphatic clearance and brain disorders. This mini-review presents the historical background and pathophysiology of PVSs and ePVSs, current debates regarding their exact location, their potential as neuroimaging biomarkers, and how AI may aid in ePVS quantification.