Altered perivascular diffusion and elevated circulating cell-derived microparticles among individuals with enlarged perivascular spaces in subclinical cerebral small vessel disease

Enlarged perivascular spaces (ePVS) are increasingly recognized as early markers of cerebral small vessel disease (CSVD), yet their underlying pathophysiology, particularly the role of perivascular fluid dynamics and circulating vascular biomarkers, remains incompletely understood. This study investigated the relationships between ePVS, glymphatic-related diffusion metrics, circulating microparticles (MPs), and cognitive performance in asymptomatic adults with low-to-moderate cardio-cerebrovascular risk (stratified using QRISK3). Sixty participants underwent 3 T MRI, including diffusion tensor imaging–analysis along the perivascular space (DTI-ALPS), neuropsychological assessment, and quantification of circulating MPs and their subtypes. ePVS were graded using STRIVE-2 criteria. Multivariable regression, mediation analysis with bootstrap resampling, and receiver operating characteristic (ROC) analyses were performed to evaluate associations and diagnostic performance. ePVS were present in 43.3% of participants, all restricted to Grade 1 severity. Individuals with ePVS exhibited significantly lower DTI-ALPS index values and higher QRISK3 scores. Leukocytes and platelet-derived MPs (CD62L+ and CD62P⁺, respectively) and total MPs were elevated in the ePVS group. However, only CD62P⁺ MPs were correlated with reduced DTI-ALPS. In multivariable models, ePVS burden and processing speed were independently associated with DTI-ALPS, while CD62P⁺ MPs exerted an indirect effect on ePVS via DTI-ALPS, supporting a full mediation pathway. Diagnostic modelling demonstrated excellent discrimination for ePVS using DTI-ALPS alone (AUC >0.92), outperforming demographic variables, QRISK3, and MPs. Together, these findings suggest that platelet-related microvascular activation may be linked to early perivascular dysfunction through alterations in perivascular fluid dynamics, preceding overt white matter injury or cognitive impairment. While DTI-ALPS does not directly measure glymphatic function, it may represent a sensitive imaging correlate of early perivascular pathology relevant to CSVD risk stratification.