The glymphatic system and cerebral small vessel disease

Abstract

Objectives: Cerebral small vessel disease is a group of pathologies in which alterations of the brain's blood vessels contribute to stroke and neurocognitive changes. Recently, a neurotoxic waste clearance system composed of perivascular spaces abutting the brain's blood vessels, termed the glymphatic system, has been identified as a key player in brain homeostasis. Given that small vessel disease and the glymphatic system share anatomical structures, this review aims to reexamine small vessel disease in the context of the glymphatic system and highlight novel aspects of small vessel disease physiology.

Materials and methods: This review was conducted with an emphasis on studies that examined aspects of small vessel disease and on works characterizing the glymphatic system. We searched PubMed for relevant articles using the following keywords: glymphatics, cerebral small vessel disease, arterial pulsatility, hypertension, blood-brain barrier, endothelial dysfunction, stroke, diabetes.

Results: Cerebral small vessel disease and glymphatic dysfunction are anatomically connected and significant risk factors are shared between the two. These include hypertension, type 2 diabetes, advanced age, poor sleep, obesity, and neuroinflammation. There is clear evidence that CSVD hinders the effective functioning of glymphatic system.

Conclusion: These shared risk factors, as well as the model of cerebral amyloid angiopathy pathogenesis, hint at the possibility that glymphatic dysfunction could independently contribute to the pathogenesis of cerebral small vessel disease. However, the current evidence supports a model of cascading dysfunction, wherein concurrent small vessel and glymphatic injury hinder glymphatic-mediated recovery and promote the progression of subclinical to clinical disease.

Keywords: Cerebrospinal fluid; Dementia; Glymphatic; Perivascular space; Small vessel disease; Stroke.

Figure 1.. The anatomy of the glymphatic system.

(A) Cerebrospinal fluid (CSF) produced in the choroid plexus drains through the ventricular system to the subarachnoid space before entering the parenchyma of the brain. (B) CSF follows the major arteries of the brain via the para-arterial spaces prior to diving deep into the brain along the penetrating arteries. (C) CSF follow the direction of blood upon entering the parenchymal microvasculature. (D) Within the parenchyma, CSF from the para-arterial space flows into the extracellular matrix (ECM) via aquaporin-4 (AQP4) channels on the foot processes of astrocytes, allowing CSF to flow through and collect metabolic waste before draining via the para-venous spaces. (E) Waste CSF flows through the meningeal lymphatic vessels as a continuation of the para-venous drainage. (F) Meningeal lymphatic vessels are located adjacent to the dural sinus which drain to the local lymph nodes, as shown by tracer studies. Flow is represented by the green arrows.

Figure 2.. Cerebral small vessel disease and glymphatic dysfunction share similar risk factors.

(A) Hypertension is a known risk factor for cerebral small vessel disease (CVSD) and is associated with cerebral microbleeds, lacunar infarcts and white matter hyperintensities. In vivo animal studies and patient data have been shown to link hypertension to glymphatic dysfunction through decreased glymphatic influx. (B) Vascular remodeling in type II diabetes (T2D) is a significant cause of CVSD development. Arterial stiffening in T2D models have been linked to glymphatic dysfunction in animal models, highlighting decreased water diffusivity in the perivascular spaces. (C) Patients with disrupted sleep have been seen to suffer from increased white matter hyperintensities and cerebral microbleeds, signs of CVSD. Murine studies show impaired glymphatic influx and clearance of apolipoprotein E (ApoE) isoforms in sleep deprived mice, linking sleep deprivation of glymphatic dysfunction. (D) Decreased arterial pulsatility, vascular remodeling and CSVD are common in older patients. Loss of aquaporin-4 (AQP4) polarization in older mice has been shown to inhibit amyloid-β clearance. Additionally, age-related immunological changes to the central nervous system have been suggested to cause additional glymphatic dysfunction and CVSD. (E) CVSD has been linked to systemic inflammation and reactive astrogliosis. Additionally, murine models of astrogliosis have been shown to possess disrupted AQP4 polarization and impaired glymphatic flow.

Figure 3.. Cerebral small vessel disease plays a possible role as mediator of glymphatic dysfunction.

(A) Animal models of cerebral microinfarcts using cerebrospinal fluid (CSF) tracers have shown trapping within the area of infarction, suggesting a localized area of glymphatic dysfunction. (B) Histopathology of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients have shown dysfunctional cerebrovascular structures associated with the glymphatic system. Patients with CADASIL often show accumulation of granular osmiophilic material (GOM) in their perivascular spaces (PVS) which could lead to glymphatic dysfunction. It is suggested that the elevated iron accumulation in CADASIL patients could also demonstrate a link to a lack of glymphatic clearance. (C) Deposition of amyloid in the cerebral vasculature could mediate glymphatic dysfunction. Brown deposits represent the amyloid in the vasculature that can lead to intracranial hemorrhages, characteristic of cerebral amyloid angiopathy (CAA). CAA rat models have been shown to have increased CSF shunting away from the brain, leading to impaired clearance of metabolic wastes and decreased glymphatic transport.