Glymphopathy and Reduced Processing Speed in Community-Dwelling Adults with Silent Cerebral Small Vessel Disease: A...

Background/Objectives: Cerebral small vessel disease (CSVD) often manifests as enlarged perivascular spaces (ePVS), which are linked to reduced processing speed even in asymptomatic individuals. Glymphatic dysfunction (or glymphopathy) has been proposed as a mechanism underlying ePVS, with the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index serving as a potential non-invasive surrogate marker. This study aimed to examine the association between DTI-ALPS index, ePVS burden, and processing speed in community-dwelling adults without overt neurological symptoms, stratified by QRISK3 cardio-cerebrovascular risk prediction score. Methods: Sixty young-to-middle-aged adults (aged 25-65 years), classified as low-to-moderate QRISK3 scores, underwent brain 3T diffusion magnetic resonance imaging (MRI) to evaluate ePVS burden and calculate DTI-ALPS indices. Processing speed index (PSI) was assessed using the Wechsler Adult Intelligence Scale-Version IV (WAIS-IV). Results: Approximately 43% of subjects reported having ePVS with significantly lower DTI-ALPS indices and PSI compared to those without ePVS. The DTI-ALPS index was inversely correlated with ePVS burden and positively correlated with PSI. Mediation analysis showed that the lower DTI-ALPS partially mediated the association between ePVS burden and slower processing speed. Conclusions: Visible ePVS in our cohort may reflect early glymphopathy and subtle cognitive slowing, while the DTI-ALPS index may serve as an early biomarker for preclinical CSVD-related cognitive vulnerability, supporting targeted prevention strategies.