Insulin Resistance and Cognitive Function in Nondiabetic Patients With Cerebral Small Vessel Disease: Role of Brain Glymphatic Function.

OBJECTIVE: Both insulin sensitivity and brain glymphatic function were linked to cognitive function in nondiabetic patients with cerebral small vessel disease (CSVD). This study aims to elucidate these complex associations through mediation analysis. METHODS: Patients who underwent multimodal magnetic resonance imaging (MRI) scans were recruited. Global cognitive assessment was performed by Mini-Mental State Examination (MMSE), four isolated cognitive domains were assessed simultaneously. Glymphatic function was assessed using the diffusion tensor imaging along the perivascular space (DTI-ALPS) index, insulin sensitivity was assessed by the homeostasis model assessment-estimated insulin resistance index (HOMA-IR), and HOMA-IR≥2.80 was defined as insulin resistance (IR). Mediation analysis was conducted to examine the effect of the DTI-ALPS on insulin sensitivity and cognitive function. RESULTS: 110 CSVD patients were recruited, 40 patients were IR and 70 patients were non-IR. Both the HOMA-IR and DTI-ALPS index were significant predictors of cognitive function, with B = -0.592, 95%CI, -0.939 to -0.244, p = 0.001 and B = 9.378, 95% CI, 3.376 to 15.381, p = 0.003, respectively, after adjusting for age, sex, and other confounding factors. Mediation analysis revealed that the DTI-ALPS index served as a significant partial mediator in the relationship between HOMA-IR and cognitive function, with direct effect = -0.649 (95% CI, -1.015 to -0.282, p < 0.001), total effect = -0.743 (95% CI, -1.106 to -0.380, p < 0.001), and the indirect effect = -0.094 (95% CI, -0.236 to -0.006, p = 0.029), accounting for 12.66% of the total effect. CONCLUSION: Both the HOMA-IR and the DTI-ALPS index are independent risk factors for cognitive function. Furthermore, the DTI-ALPS index significantly and partially mediates the relationship between the HOMA-IR and cognitive function.