Targeting the brain's glymphatic pathway: A novel therapeutic approach for cerebral small vessel disease

Cerebral small vessel disease encompasses a group of neurological disorders characterized by injury to small blood vessels, often leading to stroke and dementia. Due to its diverse etiologies and complex pathological mechanisms, preventing and treating cerebral small vessel vasculopathy is challenging. Recent studies have shown that the glymphatic system plays a crucial role in interstitial solute clearance and the maintenance of brain homeostasis. Increasing evidence also suggests that dysfunction in glymphatic clearance is a key factor in the progression of cerebral small vessel disease. This review begins with a comprehensive introduction to the structure, function, and driving factors of the glymphatic system, highlighting its essential role in brain waste clearance. Afterwards, cerebral small vessel disease was reviewed from the perspective of the glymphatic system, after which the mechanisms underlying their correlation were summarized. Glymphatic dysfunction may lead to the accumulation of metabolic waste in the brain, thereby exacerbating the pathological processes associated with cerebral small vessel disease. The review also discussed the direct evidence of glymphatic dysfunction in patients and animal models exhibiting two subtypes of cerebral small vessel disease: arteriolosclerosis-related cerebral small vessel disease and amyloid-related cerebral small vessel disease. Diffusion tensor image analysis along the perivascular space is an important non-invasive tool for assessing the clearance function of the glymphatic system. However, the effectiveness of its parameters needs to be enhanced. Among various nervous system diseases, including cerebral small vessel disease, glymphatic failure may be a common final pathway toward dementia. Overall, this review summarizes prevention and treatment strategies that target glymphatic drainage and will offer valuable insight for developing novel treatments for cerebral small vessel disease.