Introduction

Cerebral small vessel disease (CSVD) refers to a series of clinical, imaging, and pathological syndromes caused by various factors affecting cerebral small vessels and is the most common cause of vascular dementia and mixed dementia ¹. The glymphatic system is a highly organized fluid transport system that facilitates brain metabolic waste clearance through the perivascular network of glia ^2,3. Impairment of glymphatic clearance can lead to the accumulation of brain waste, leading to cognitive decline. Diffusion tensor imaging along the perivascular space (DTI-ALPS) ⁴ is a noninvasive imaging method to explore human glymphatic system function and can be quantified by the DTI-ALPS index ⁵. Currently, few studies have demonstrated the effect of CSVD on glymphatic function. The aim of this study was to investigate the effects of different burdens of CSVD on left/right glymphatic function based on DTI-ALPS.

Methods

This cross-sectional study included 79 patients with severe CSVD (CSVD-S), 125 patients with mild CSVD (CSVD-M), and 100 healthy controls (HCs). Magnetic resonance imaging (MRI) data, including DTI, were acquired with a 3.0-T MR System (Siemens Healthcare, Erlangen, Germany) equipped with a 32-channel head coil for receiving signals. DTI-ALPS was used to measure water diffusivity in the perivenous space indirectly. The Stroop Color-Word Test was performed to assess the cognitive function of all participants. The Kruskal‒Wallis H test was used to evaluate the differences in the bilateral DTI-ALPS index among the three groups. Ordinal multinomial logistic regression was used to explore the hazard factors that affect the DTI-ALPS index. The association between cognitive function and the DTI-ALPS index was further investigated.

Results

There were significant differences in cognitive test results among the three groups (P < 0.001), and the CSVD-S group took a longer time to complete the test than the CSVD-M and HC groups (Figure 1). There were significant differences among the three groups in the right DTI-ALPS index (P = 0.028, FDR correction), and the DTI-ALPS indexes in the CSVD groups were lower than those in the HC group. There was no significant difference in the left DTI-ALPS (P = 0.091, FDR correction) (Figure 2). The right DTI-ALPS was associated with Stroop test (C-B) (P = 0.029) (Figure 3). In addition, the right DTI-ALPS index was significantly correlated with CSVD-M (P = 0.025) and sex (P = 0.011) (Figure 4). However, the ordinal multinomial logistic regression (Figure 5) showed no significant correlation (P = 0.139) between Stroop test (C-B) and the DTI-ALPS index. The Stroop test (C-B) results were influenced by age (P < 0.001) and diabetes (P = 0.012).

Discussion

In this study, we utilized DTI-ALPS to assess bilateral glymphatic function in different burdens of CSVD. Our findings included the following: (I) Cognitive performance decreased with the presence and severity of CSVD; (II) There were significant differences in the right DTI-ALPS index among the three groups, but there was no significant difference in the left DTI-ALPS index among the three groups; (III) Hazard factors for right DTI-ALPS included CSVD-M and sex; (IV) The results of Stroop test (C-B) were influenced by age and diabetes but had no correlation with the bilateral DTI-ALPS index.
We found that the DTI-ALPS indexes of the CSVD groups were significantly lower than those of the HC group, indicating impaired glymphatic function in patients with CSVD, which is consistent with the result of a previous study ⁶. The right DTI-ALPS index was associated with mild CSVD but not with severe CSVD. We speculate that severe CSVD causes functional disruption of the glymphatic system through multiple mechanisms ⁷. Further studies are needed to explore its mechanism. Unexpectedly, there was no significant correlation between the bilateral DTI-ALPS index and cognitive decline in patients with CSVD. Although Spearman rank correlation analysis showed a significant correlation between the right DTI-ALPS index and Stroop test (C-B), the regression results were not significant when other factors, such as age, were included. Since the DTI-ALPS index was calculated from the diffusion images, age may affect white matter fiber status ⁵. In addition, CSVD is a highly age-related disease, and perhaps the effect of age is too large to mask the effect of the glymphatic system on cognition.

Conclusion

Cognitive decline and glymphatic dysfunction coexist in patients with CSVD, but there is no definite correlation between them. Cognitive decline in patients with CSVD is negatively correlated with age and diabetes. Therefore, aggressive glycemic control may reduce the risk of cognitive impairment in patients with CSVD. Further studies are needed to explore the pathophysiological mechanisms of glymphatic dysfunction in CSVD.

References

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