Physiology and Clinical Relevance of Enlarged Perivascular Spaces in the Aging Brain

Abstract

Perivascular spaces (PVS) are fluid-filled compartments that are part of the cerebral blood vessel wall and represent the conduit for fluid transport in and out of the brain. PVS are considered pathologic when sufficiently enlarged to be visible on MRI. Recent studies have demonstrated that enlarged PVS (ePVS) may have clinical consequences related to cognition. Emerging literature points to arterial stiffening and abnormal protein aggregation in vessel walls as 2 possible mechanisms that drive ePVS formation. We describe the clinical consequences, anatomy, fluid dynamics, physiology, risk factors, and in vivo quantification methods of ePVS. Given competing views of PVS physiology, we detail the 2 most prominent theoretical views and review ePVS associations with other common small vessel disease markers. Because ePVS are a marker of small vessel disease and ePVS burden is higher in Alzheimer disease, a comprehensive understanding about ePVS is essential in developing prevention and treatment strategies.

Figure 1. Regional Differences in Morphology of ePVS Visible on Brain MRI

(A) An axial slice depicting enlarged perivascular spaces (ePVS) in the basal ganglia. (B) A sagittal slice of the same participant depicting ePVS in white matter. Note that the ePVS in the basal ganglia appear larger in diameter than the ePVS in the white matter. Such morphologic differences are typical and may be due to the fact that cortical arteries have one layer of pia mater while perforating arteries of the basal ganglia have two. (C) Although less common, ePVS can grow much larger than 3 mm and in some rare cases may present throughout large regions of the brain.

Figure 2. Visible ePVS in Unfixed Brain Tissue

Unfixed brain tissue from a patient with cerebral amyloid angiopathy. The tissue sample displays clear and widespread enlarged perivascular spaces (ePVS) throughout the white matter along with a cortical microhemorrhage (black arrow).

Figure 3. Healthy Perivascular Space Anatomy

Pictured is an example electron microscopy image of a healthy blood vessel lumen (lu) with normal-appearing perivascular spaces (highlighted in blue) which also contain macrophages (m). The pial–glial basement membrane (pgbm) is extended away from the vessel only in the presence of macrophages. Also pictured are normal smooth muscle cells (sm), pia mater (pm), and endothelium (en). Image courtesy of Roxana Carare, MD, PhD.

Figure 4. Theoretical Perivascular Space Anatomy and Physiology

Two theoretical models for perivascular space anatomy and physiology. Pathway 1 is the glymphatic clearance pathway. Pathway 2 is the intramural periarterial drainage pathway. In pathway 2, the perivascular space is occupied by the fused basement membranes of pia mater and glia limitans. © Ikumi Kayama/Studio Kayama LLC. IPAD = intramural periarterial drainage.

Figure 5. Enlarged Perivascular Space Electron Micrograph With Theoretical Models for Perivascular Space Enlargement

(A) Pictured is scanning electron micrograph of an enlarged perivascular space (ePVS) (the outer layer of pia mater is green) surrounding an artery in the basal ganglia. The enlarged perivascular space appears between 2 layers of leptomeninges. Image courtesy of Roy Weller, MD, PhD.²⁰ (B) Increased aortic pulse wave velocity (PWV) results in higher pulse waves travelling to perforating arteries of the basal ganglia, resulting in vessel wall damage and enlarged perivascular spaces. The tissue boxes illustrate the basal ganglia, where the walls of arteries are subject to pulsatile damage, leaving wider spaces that fill with interstitial fluid and possibly CSF (in blue). © Ikumi Kayama/Studio Kayama LLC. (C) Increased vascular amyloid accumulation upstream could create a blockage, resulting in ePVS in the white matter. © Ikumi Kayama/Studio Kayama LLC. CAA = cerebral amyloid angiopathy.