Impairment of Glymphatic Cerebrospinal Fluid Drainage is a Feature of Cerebral Small Vessel Disease
The glymphatic system parallels blood vessels where they enter the brain, providing a path for drainage of cerebrospinal fluid from the brain into the body. The other well described path is through channels in the cribriform plate bone. These drainage routes become dysfunctional with age, allowing metabolic waste to build up in the brain, and thus contributing to the dysfunctional environment that causes pathology and neurodegeneration.
An approach to measure drainage of cerebrospinal fluid through the glymphatic system via magnetic resonance imaging was developed relatively recently, known by the unwieldy name of diffusion tensor imaging analysis along the perivascular space (DTI-ALPS). DTI-ALPs has been having its time in the sun over the past few years, with numerous research groups working to expand the body of data for this measurement in various patient populations. Today's open access paper is an example of this sort of work, focused on patients with cerebral small vessel disease.
Cerebral small vessel disease, also known as microangiopathy, emerges from a combination of endothelial dysfunction in microvessels, a loss of microvessel density that impairs blood flow, and other issues that affect the integrity and function of the smallest vessels that support brain tissue. It is worth considering that the aspects of aging that harm the vasculature likely also harm the near neighbor glymphatic system. That patients with cerebral small vessel disease also exhibit impaired glymphatic drainage of cerebrospinal fluid doesn't necessarily mean that one condition causes the other. They may both be emergent properties of the cell and tissue damage of aging, and likely each makes the other worse in a variety of different ways.
Cerebral small vessel disease (CSVD) is a progressive cerebrovascular disease characterized by diverse clinical manifestations, especially neurocognitive dysfunction, a primary contributor to vascular cognitive impairment. The glymphatic system, a brain waste clearance system first described in 2012, facilitates the exchange of cerebrospinal fluid (CSF) with interstitial fluid (ISF). In this process, CSF enters the brain parenchyma via para-arterial perivascular spaces, passes through astrocytic aquaporin-4 (AQP4) water channels, and mixes with ISF before being cleared along perivenous routes, thereby promoting the removal of metabolic waste.
Recent evidence suggests that impaired glymphatic function may represent a final common pathway in the pathogenesis of dementia and has been increasingly implicated in the pathophysiology of CSVD. However, the relationship between glymphatic dysfunction and CSVD is likely bidirectional and multifactorial. On one hand, CSVD-related pathologies, such as endothelial dysfunction, blood-brain barrier disruption, and reduced arterial pulsatility, may impair glymphatic flow by compromising perivascular pumping mechanisms and fluid transport. On the other hand, impaired glymphatic clearance may exacerbate CSVD by allowing the accumulation of neurotoxic waste products, such as amyloid-β and tau proteins, and pro-inflammatory molecules within perivascular spaces, further damaging vascular integrity and promoting white matter injury.
We enrolled 120 CSVD patients [52 with no cognitive impairment (CSVD-NCI) and 68 with mild cognitive impairment (CSVD-MCI)] and 40 healthy controls. Glymphatic function was assessed using the left ALPS index derived from diffusion tensor imaging analysis along the perivascular space (DTI-ALPS). Group comparisons in the ALPS index and perivascular space (PVS) volume fraction (VF), and correlations among glymphatic function, perivascular burden, and cognition were analyzed.
Compared to healthy controls, CSVD patients showed decreased ALPS index and increased PVS VF in basal ganglia, caudate, putamen, and hippocampus, with more pronounced alterations in the left hemisphere. The ALPS index was inversely correlated with PVS VF in the basal ganglia (r = -0.232), thalamus (r = -0.213), caudate (r = -0.221), and putamen (r = -0.210) in CSVD. Furthermore, a lower ALPS index was associated with poorer performance in global cognition (r = 0.312), executive function (r = 0.242), processing speed (r = 0.264), and visuospatial function (r = 0.272). Finally, the ALPS index partially mediated the association between putamen-PVS VF and global cognitive function, especially in the left hemisphere. Our findings demonstrate that impaired glymphatic function was associated with enlarged basal ganglia PVS, especially in the putamen, and worse cognitive performance, highlighting its potential role in disease progression and cognitive decline in CSVD.