Regional structural–functional connectivity decoupling is associated with glymphatic-related dysfunction and cognitive performance in cerebral small vessel disease: a multimodal MRI study

Regional structural–functional connectivity (SC-FC) coupling and glymphatic-related MRI markers may provide complementary insights into cognitive impairment in cerebral small vessel disease (CSVD). However, their interrelationship and cognitive relevance remain unclear. This cross-sectional study included 52 patients with CSVD and 28 healthy controls (HC). Patients with CSVD were classified as cognitively unimpaired (CSVD-CU) or cognitively impaired (CSVD-CI). Structural and functional networks were constructed from diffusion tensor imaging and resting-state functional MRI, followed by regional SC-FC coupling analysis. Glymphatic-related MRI markers were assessed using diffusion tensor image analysis along the perivascular space (DTI-ALPS) and the periventricular diffusivity (PVeD). Group differences were examined using analysis of covariance. Associations among regional SC-FC coupling, glymphatic-related MRI markers, and cognitive performance were evaluated using partial correlation and mediation analyses. Age, sex, and education were included as covariates; mean diffusivity (MD) was additionally included in analyses involving glymphatic-related markers. Compared with HCs, both CSVD groups showed reduced SC-FC coupling in the left superior frontal and left cingulate gyri, whereas the CSVD-CI group showed additional reductions in the right superior frontal and right cingulate gyri. The CSVD-CU group showed increased coupling in the right inferior frontal gyrus. All regional coupling differences survived false discovery rate (FDR) correction ( P FDR <0.05). DTI-ALPS and PVeD differed among groups ( P <0.001 and P =0.011, respectively), whereas only PVeD remained significant after MD adjustment ( P =0.001). In the CSVD-CI group, DTI-ALPS and PVeD were associated with executive and memory performance (all P < 0.05). In the CSVD-CU group, right superior frontal and bilateral cingulate coupling were associated with executive function, memory, and processing speed (all P < 0.05). Mediation analyses showed statistically significant indirect effects of PVeD on Trail Making Test (TMT) scores through left cingulate coupling (TMT-A: indirect effect = − 0.133, 95% CI [− 0.260, − 0.009]; TMT-B: indirect effect = − 0.144, 95% CI [− 0.306, − 0.019]). Regional SC-FC decoupling and glymphatic-related MRI alterations were associated with cognitive function in CSVD. The exploratory indirect effects involving PVeD, left cingulate coupling, and TMT performance suggest that cingulate decoupling may represent a network-level correlate of glymphatic-related dysfunction and early cognitive vulnerability.