Gray Matter Reserve Modulates the Association between Glymphatic System Function and Cognition in Patients with Type 2 Diabetes Mellitus

Introduction: The glymphatic system is regarded as a key factor in the pathogenesis of neurodegenerative diseases. Given the heightened risk of cognitive impairment in patients with type 2 diabetes mellitus (T2DM), the possible alterations in the glymphatic system in T2DM patients remain to be explored. Diffusion tensor imaging (DTI) analysis along the perivascular space (ALPS) index can be utilized to model the glymphatic system in humans. Our aim was to explore the relationship between the ALPS index and cognitive function in patients with T2DM and whether this relationship is modulated by gray matter (GM) integrity anchored by the ALPS index. Methods: All participants underwent evaluation using a comprehensive cognitive assessment scale to determine their neurocognitive status. The ALPS index was calculated based on DTI data, and the disparity in ALPS index values between patients with T2DM and healthy controls (HCs) was examined. Furthermore, multiple linear regression analysis was conducted in the T2DM group to identify the GM regions associated with the ALPS index, and the volumes of the GM partitions were extracted. The volume of GM partitions was used as the regulating variable, the ALPS index was used as the independent variable, and cognitive test scores were used as the dependent variable in our analysis. Results: The ALPS index differed significantly between the two groups, and the ALPS index in patients with T2DM was significantly lower than that in HCs. In addition, our analysis revealed a correlation between the ALPS index and GM volume in the insular region, consistent with the observed GM atrophy in the patient cohort. Moreover, a significant negative correlation was observed between the ALPS index in patients and performance on the Trail-Making Test-A (TMT-A), and this relationship was moderated by GM integrity. In patients with more severe GM atrophy, the ALPS index was more strongly correlated with cognitive function. Conclusions: In this study, a decreased ALPS index was found in T2DM patients, indicating impaired glymphatic function in this population. Furthermore, a significant association was detected between the ALPS index and cognitive performance in T2DM patients, and this correlation was influenced by GM integrity. Therefore, the ALPS index has the potential to be used as a biomarker of cognitive impairment in diabetic patients. Further studies are needed to investigate the diagnostic and therapeutic implications of glymphatic dysfunction in T2DM patients with cognitive impairment.