Perivascular spaces as a potential biomarker of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a highly damaging disease that affects one’s cognition and memory and presents an increasing societal and economic burden globally. Considerable research has gone into understanding AD; however, there is still a lack of effective biomarkers that aid in early diagnosis and intervention. The recent discovery of the glymphatic system and associated Perivascular Spaces (PVS) has led to the theory that enlarged PVS (ePVS) may be an indicator of AD progression and act as an early diagnostic marker. Visible on Magnetic Resonance Imaging (MRI), PVS appear to enlarge when known biomarkers of AD, amyloid-β and tau, accumulate. The central goal of ePVS and AD research is to determine when ePVS occurs in AD progression and if ePVS are causal or epiphenomena. Furthermore, if ePVS are indeed causative, interventions promoting glymphatic clearance are an attractive target for research. However, it is necessary first to ascertain where on the pathological progression of AD ePVS occurs. This review aims to examine the knowledge gap that exists in understanding the contribution of ePVS to AD. It is essential to understand whether ePVS in the brain correlate with increased regional tau distribution and global or regional Amyloid-β distribution and to determine if these spaces increase proportionally over time as individuals experience neurodegeneration. This review demonstrates that ePVS are associated with reduced glymphatic clearance and that this reduced clearance is associated with an increase in amyloid-β. However, it is not yet understood if ePVS are the outcome or driver of protein accumulation. Further, it is not yet clear if ePVS volume and number change longitudinally. Ultimately, it is vital to determine early diagnostic criteria and early interventions for AD to ease the burden it presents to the world; ePVS may be able to fulfill this role and therefore merit further research.

Cerebrospinal fluid efflux through dynamic paracellular pores on venules as a missing piece of the brain drainage system

“…Previous works have suggested inadequate drainage of CSF‐ISF might contribute to the Aβ accumulation in AD. [ 30,31 ] Hereby, the observations in transgenic AD model mice (Figure 4 and Supplementary Videos 4–6) revealed the interactions between the glymphatic clearance and the pathological factor Aβ. Elevated Aβ is one important aspect of AD pathology recapitulated in the APP/PS1 model.…”

“…Remarkably, even once the blood flow was fully recovered (Supplementary Video 6), the tracer appeared to be partially retained, with an uneven, “gurgling” flow near the wall. Therefore, despite increased numbers of pores in AD model mice, the viscous, high Aβ‐content CSF could exceed the drainage capacity of even pore‐enriched vessels, which may lead to CSF retention that could be associated with the perivascular space dilation, a known indicator of AD progression [ 30 ] due to declined glymphatic clearance prior to the formation of amyloid plaques. [ 31 ]…”

The etiology and evolution of magnetic resonance imaging-visible perivascular spaces: Systematic review and meta-analysis

“…In addition, two studies found an association of MVPVS with tau by employing flortaucipir PET ( Sepehrband et al, 2021 ; Wang et al, 2021 ) or CSF analysis ( Wang et al, 2022 ). It is also noteworthy that it is still under debate whether MVPVS formation is the consequence or driver of vascular protein deposition ( Lynch et al, 2022 ).…”

A trichotomy method for defining homogeneous subgroups in a dementia population

“…Inclusion of other vascular measures, such as lacunar infarcts, perivascular space enlargement, and microbleeds would have provided additional validity to the VDF. Recent work has reviewed the role of perivascular spaces in AD, 32 and elucidated its contribution to early cognitive decline based on the ADNI data 33 . The methods for automatic quantification of PVS are being developed by different groups, but these methods need to be evaluated for consistency 34–36 .…”