The relationship between plasma FOXO3 and cognitive impairment and depressive symptoms in cerebral small vessel disease.
BACKGROUND AND PURPOSE Cerebral small vessel disease (CSVD) is a leading cause of post-stroke cognitive impairment, depression, and disability in older adults. Forkhead box O3 (FOXO3) is a key transcription factor that plays important roles in neurodegenerative and vascular diseases. This study investigated the correlation of acute-phase plasma FOXO3 levels with cognitive and depressive symptoms in CSVD patients. METHODS This prospective cohort study recruited 183 patients with recent small subcortical infarct (RSSI) and 150 healthy controls. Plasma FOXO3 levels were measured by enzyme-linked immunosorbent assay at the acute phase (≤3 days) and day 7. Cognitive and depressive symptoms were assessed at discharge. The brain MRI was used to evaluate CSVD imaging characteristics. Mediation analysis assessed the effect of CSVD on the association between FOXO3 and cognitive function. RESULTS Among the participants, 76 (41.53%) had cognitive impairment, and 40 (21.9%) had depressive symptoms. Plasma FOXO3 levels were profoundly higher in patients at both the acute phase (≤3 days) and day 7 compared with controls (both P < 0.001), with higher levels observed in the acute phase than at day 7 (P < 0.001). Acute-phase plasma FOXO3 was higher in patients with cognitive impairment than in those without (P < 0.001), showing a predictive area under the curve of 0.747. After adjustment, FOXO3 remained unassociated with depressive symptoms (P = 0.232). Total CSVD burden was associated with cognitive impairment (odds ratio: 1.728, 95%CI 1.084-2.756, P = 0.022). Mediation analysis showed that total CSVD burden, prominently white matter hyperintensities, mediated 36.96% of the association between FOXO3 and cognitive impairment. CONCLUSIONS Acute-phase FOXO3 levels are associated with early cognitive impairment at discharge, whereas its long-term prognostic value requires validation in future longitudinal follow-up studies.