Glymphatic System Dysfunction Contributes to the Pathology of Cerebral Small Vessel Disease
The vasculature becomes dysfunctional with age, and cerebral small vessel disease is a catch-all category that includes a variety of different malfunctions in the biology of smaller blood vessels that act to reduce blood flow to the brain or damage brain tissue. In recent years, attention has turned to the drainage of cerebrospinal fluid from the brain, with the idea that failure of drainage with age contributes to a buildup of molecular waste and consequent pathology in the brain. The glymphatic system is one of the major paths of drainage, and here researchers provide evidence for its dysfunction to be involved in the cognitive decline observed in patients with cerebral small vessel disease.
Cerebral small vessel disease (CSVD) is common among older people. Cognitive impairment is one of the most important manifestations of CSVD. Vascular cognitive impairment and vascular dementia constitute the second most common cause of cognitive impairment. However, the factors causing cognitive impairment remain unknown. White matter lesions (WMLs) and lacunes, which are classical CSVD markers, are related to cognitive impairment in CSVD and could be used to predict cognitive impairment. However, in the clinic, some CSVD patients with mild WMLs have a severe cognitive impairment, which suggests that there are still some important factors that contribute to cognitive impairment in CSVD aside from traditional imaging markers and other imaging markers might enable predictions of cognitive impairment caused by CSVD.
Commonly, cognitive impairment in patients with CSVD occurs due to cerebral hypoperfusion or because other blood components permeate into the brain through a broken blood-brain barrier (BBB). Both of these situations are harmful to neurons and neuroglia. Recently, the glymphatic system was discovered. With the help of Aquaporin 4, cerebrospinal fluid (CSF) flow in the periarterial space enters the brain and becomes interstitial fluid (ISF). It was then drained orderly through the perivenous space, meningeal or olfactory mucosal lymphatics, cervical lymphatic vessel, and finally returned to the peripheral venous. This CSF-ISF exchange system is called the glymphatic system, and its main role includes metabolic product transportation and metabolic waste elimination.
In patients with Alzheimer's disease (AD) and animal models, dysfunction of the glymphatic system contributes to the deposition of amyloid-β and cognitive impairment. CSVD leads to arteriosclerosis and vascular pulsation, which are the driving forces of the glymphatic system. It is difficult to evaluate the glymphatic system in the human body directly. In 2017, based on diffusion tensor imaging (DTI), researchers proposed the DTI analysis along the perivascular space (ALPS) index to evaluate the glymphatic system function. To further explore the reason underlying cognitive impairment in patients with CSVD and identify other new imaging markers of cognitive impairment in patients with CSVD, we studied the relationship of the ALPS index and cognitive impairment in these patients.
We found that the ALPS index was independently linearly correlated with global cognitive function, executive function, attention function, and memory after adjusting for the aforementioned six risk factors or CSVD markers. Our results suggest that glymphatic system impairment is independently related to cognitive impairment in patients with CSVD.