Blood–Brain Barrier Disruption and Perivascular Spaces in Small Vessel Disease and Neurodegenerative Diseases: A Review on MRI Methods and Insights

Abstract

Perivascular spaces (PVS) and blood–brain barrier (BBB) disruption are two key features of cerebral small vessel disease (cSVD) and neurodegenerative diseases that have been linked to cognitive impairment and are involved in the cerebral waste clearance system. Magnetic resonance imaging (MRI) offers the possibility to study these pathophysiological processes noninvasively in vivo. This educational review provides an overview of the MRI techniques used to assess PVS functionality and BBB disruption. MRI‐visible PVS can be scored on structural images by either (subjectively) counting or (automatically) delineating the PVS. We highlight emerging (diffusion) techniques to measure proxies of perivascular fluid and its movement, which may provide a more comprehensive understanding of the role of PVS in diseases. For the measurement of BBB disruption, we explain the most commonly used MRI technique, dynamic contrast‐enhanced (DCE) MRI, as well as a more recently developed technique based on arterial spin labeling (ASL). DCE MRI and ASL are thought to measure complementary characteristics of the BBB. Furthermore, we describe clinical studies that have utilized these MRI techniques in cSVD and neurodegenerative diseases, particularly Alzheimer's disease (AD). These studies demonstrate the role of PVS and BBB dysfunction in these diseases and provide insight into the large overlap, but also into the differences between cSVD and AD. Overall, MRI techniques may provide valuable insights into the pathophysiological mechanisms underlying these diseases and have the potential to be used as markers for disease progression and treatment response.Level of Evidence3Technical EfficacyStage 2

Heterogeneous blood‐brain barrier dysfunction in cerebral small vessel diseases

“…As GBCAs passively traverse BBB mainly via the paracellular pathway, an increase in K trans (when Vp does not change) indicates damage of endothelial cells (ECs), tight junctions (TJs), or pericytes. 20 , 21 In contrast, water passes across BBB through various pathways, including passive transport, aquaporin‐4 (AQP4) assisted exchange, and some cotransport proteins. 22 , 23 , 24 , 25 Therefore, k w may be altered in a range of BBB pathologies.…”

Pathophysiology of cerebral small vessel disease: a journey through recent discoveries

“…Nonetheless, studies in CADASIL patients have produced contradictory results ( 125 , 130 ). Analyzing water exchange across the BBB using arterial spin labeling MRI is another promising approach for assessing subtle BBB dysfunction since water’s molecular weight (~18 Da) is much smaller than that of gadolinium-based contrast agents ( 131 , 132 ). Using arterial spin labeling MRI, Yang and colleagues recently reported a diffuse alteration (in the whole brain) in the water exchange rate across the BBB in patients with CADASIL or HTRA1-related cSVD, suggestive of an increase in the BBB’s permeability to water ( 133 ).…”

Parenchymal CSF fraction is a measure of brain glymphatic clearance and positively associated with amyloid beta deposition on PET

“… 4 Although the pathophysiology of the enlargement of PVS is still not fully understood, it has been shown to be associated with a higher level of aquaporin‐4, breakdown of the blood–brain barrier (BBB), cerebral amyloid angiopathy (CAA), hypertension, and small vessel disease (SVD). 5 , 6 , 7 , 8 , 9 We hypothesized an impaired drainage could be a potential cause of enlarged PVS due to fluid residue and stasis. The enlargement of PVS might further decrease the CSF flow due to more fluid away from the vessel wall and fluid accumulation.…”