Pathogenesis of Cerebral Small Vessel Disease: Role of the Glymphatic System Dysfunction

Abstract

Cerebral small vessel disease (CSVD) is a group of pathologies that affect the cerebral blood vessels. CSVD accounts for 25% of strokes and contributes to 45% of dementia. However, the pathogenesis of CSVD remains unclear, involving a variety of complex mechanisms. CSVD may result from dysfunction in the glymphatic system (GS). The GS contains aquaporin-4 (AQP-4), which is in the perivascular space, at the endfeet of the astrocyte. The GS contributes to the removal of waste products from the central nervous system, occupying perivascular spaces and regulating the exchange and movement of cerebrospinal fluid and interstitial fluid. The GS involves astrocytes and aquaporin channels, which are components of the blood-brain barrier, and problems with them may constitute the pathogenesis of CSVD. Vascular risk factors, including diabetes, dilate the perivascular space, disrupting the glymphatic system and the active regulation of AQP-4. CSVD exacerbation due to disorders of the GS is associated with multiple vasculopathies. Dysfunction of the glymphatic system and AQP-4 interferes with the functioning of the blood-brain barrier, which exacerbates CSVD. In a long-term follow-up of CSVD patients with microbleeds, lacunar infarcts, and white matter hyperintensity, several vascular risk factors, including hypertension, increased the risk of ischemic stroke. Dysfunction of the GS may be the cause of CSVD; however, the underlying treatment needs to be studied further.

Keywords: Virchow–Robin space; cerebral small vessel disease; glymphatic system; magnetic resonance imaging.

Figure 1

In the perivascular space surrounding the artery, there are numerous endfeet of astrocytes. There are many AQP-4 channel proteins there, which are responsible for water transport. CSF: cerebrospinal fluid, ISF: interstitial fluid.

Figure 2

Brain MRI images of patients who have experienced CSVD. WMH, CMB, lacunar infarct, and ICH worsen CSVD due to ischemic or hemorrhagic lesions. The red circles within the brain are cerebral hemorrhage and ischemic conditions identified by WMH, CMB, infarct, and hemorrhage occurrence points, respectively.