Plasma Semaphorin 3A as a Potential Biomarker for Cognitive Impairment in Cerebral Small Vessel Disease

Sema3A plays an essential role in the nervous system and is thought to regulate the entire course of the inflammatory response. This study aimed to explore the potential association between plasma Sema3A levels and cerebral small vessel disease (CSVD).

This study enrolled patients with recent small subcortical infarct (RSSI) and 100 healthy controls (HCs). Sema3A levels were measured during the acute phase (≤3 days) and the subacute phase (14-30 days) of RSSI. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Brain magnetic resonance imaging (MRI) was used to evaluate CSVD imaging features. The study analyzed the association between Sema3A, CSVD imaging features, and cognitive impairment.

Plasma Sema3A levels during the acute phase were markedly higher in RSSI patients than in HCs (p = 0.001), with an area under the receiver operating characteristic curve (AUC) of 0.715 (p < 0.01) for differentiating RSSIs from HCs. Levels were higher in the acute than the subacute phase (p < 0.001) but showed no difference between the subacute phase and HCs (p = 0.367).Within the RSSI group, acute-phase Sema3A levels were significantly higher in the CI subgroup (p < 0.001). A strong negative correlation was found between Sema3A and MoCA scores (r = -0.459, p < 0.001). The AUC for distinguishing CI from non-cognitive impairment (NCI) was 0.793 (p < 0.01). In addition, acute-phase plasma Sema3A levels were notably elevated in patients with a high total CSVD burden (p < 0.001), and were positively correlated with the total imaging burden score (r = 0.469, p < 0.001). Mediation analysis showed that white matter hyperintensities (WMH) and lacunar infarcts (LI) significantly mediated the relationship between acute-phase Sema3A and CI (p < 0.001).

Plasma Sema3A levels during the acute phase were elevated in RSSI patients and were linked to cognitive impairment through the mediating roles of WMH and LI.