Serum Cystatin C and 90-Day Neurological Functional Prognosis in Acute Ischemic Stroke: Insights from a Prospective Cohort and Mendelian Randomization

Yongxing Deng,1,2,* Qing Zhu,1,2,* Jianan Wu,3 Jiale Gan,1,2 Xinyi Yang,1,2 Tonglong Jin,1,2 Peiyi Mo,1,2 Peian Liu,1,2 Lianhong Ji,1,2 Hui Jiang,1,2 Yunfei Han,1,2 Zhaoyao Chen,1,2 Wenlei Li,1,2 Yuan Zhu,1,2 Minghua Wu1,2 1Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China; 2Department of Neurology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China; 3Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, People’s Republic of China*These authors contributed equally to this workCorrespondence: Minghua Wu; Yuan Zhu, Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210029, People’s Republic of China, Email [email protected]; [email protected]: The relationship between cystatin C levels and 90-day neurological functional prognosis in acute ischemic stroke (AIS) is not fully understood. This study investigated this association prospectively and employed Mendelian randomization (MR) analysis to assess potential causality.Methods: A prospective cohort study enrolled 786 patients with AIS admitted to a tertiary Stroke Center between 2021 and 2023. Serum cystatin C levels were measured within 48 hours of admission. Associations with adverse 90-day neurological functional outcome (modified Rankin Scale score > 2) were assessed using univariate and multivariable logistic regression. Cox regression models evaluated all-cause mortality during long-term follow-up. Mediation analysis examined the role of inflammatory mediators (Monocyte-to-Lymphocyte Ratio [MLR], Neutrophil-to-Lymphocyte Ratio [NLR], Systemic Inflammatory Response Index [SIRI], Systemic Immune-Inflammation Index [SII]) in the cohort. Causality was further evaluated using a two-sample MR approach with genetic instruments to infer the effect of cystatin C on ischemic stroke risk.Results: Elevated cystatin C levels were independently associated with higher odds of adverse 90-day functional outcome (adjusted odds ratio [OR] = 2.13, 95% CI: 1.34– 3.38, p=0.001) and increased mortality risk (adjusted hazard ratio [HR] = 1.97, 95% CI: 1.09– 3.54, p=0.024). Mediation analysis identified systemic inflammation markers as significant mediators, accounting for 16.1% to 20.2% of the total effect of cystatin C on adverse prognosis. MR analysis provided evidence supporting a causal relationship, indicating that genetically predicted higher cystatin C levels were associated with an increased risk of ischemic stroke (OR = 1.10, 95% CI: 1.02– 1.18, p=0.011).Conclusion: Elevated cystatin C levels demonstrated a significant association with worse 90-day functional outcome and higher mortality in these patients, partially mediated through systemic inflammation. MR findings suggested a potential causal role of cystatin C in ischemic stroke pathogenesis. Cystatin C may represent a valuable integrated biomarker for both prognosticating outcomes in AIS and predicting ischemic stroke risk.Keywords: cystatin c, acute ischemic stroke, 90-day neurological functional prognosis, Mendelian randomization, systemic inflammation