Glymphatic dysfunction in HIV: a resting-state fMRI biomarker linking cognitive impairment and immune suppression

Objective: To investigate glymphatic dysfunction in people living with HIV (PLWH) and its associations with immunological status and cognitive function, utilizing the coupling strength of global blood-oxygen-level-dependent and cerebrospinal fluid (gBOLD-CSF). Design: Retrospective study of 75 PLWH and 52 non-HIV controls undergoing neuropsychological tests and resting-state functional magnetic resonance imaging (rs-fMRI). Methods: GBOLD-CSF coupling, Montreal Cognitive Assessment (MoCA) and seven cognitive domain scores were calculated. Group difference in gBOLD-CSF coupling strength was analyzed using a general linear model, adjusting for age, sex, and education. Partial correlation analyses were performed to examine the correlations of cognitive performance and immunological status with gBOLD-CSF coupling. Multivariate regression analysis was utilized to further evaluate the associations of gBOLD-CSF coupling with cognition. Results: PLWH exhibited significantly weaker gBOLD-CSF coupling than non-HIV controls (p = 0.018) and revealed impairments in attention/working memory, speed of information processing, and abstract/executive function (all p < 0.05). Reduced gBOLD-CSF coupling was associated with deficits in MoCA scores (r = -0.332, p = 0.004), verbal fluency (r = 0.245, p = 0.038), attention/working memory (r = 0.240, p = 0.042), speed of information processing (r = 0.245, p = 0.038), and abstract/executive function (r = 0.241, p = 0.042) in PLWH. Multivariate regression analysis showed gBOLD-CSF coupling was the only independent predictor for speed of information processing (β=0.410, p = 0.031) and MoCA scores (β=-0.399, p = 0.037). Weaker gBOLD-CSF coupling was correlated with lower nadir and current CD4 counts(r = -0.379, p = 0.019; r = -0.321, p = 0.049, respectively). Conclusion: Reduced gBOLD-CSF coupling in PLWH suggests glymphatic dysfunction and was associated with cognitive impairment and HIV-related immune suppression. It may serve as a non-invasive biomarker for monitoring cognitive disturbances and disease progression in HIV.