Dysregulated Wnt Signaling in Parkinson’s Disease: Correlation with Motor and Nonmotor Symptom Severity

Background Dysregulation of Wnt signaling and neuroinflammation are critically implicated in Parkinson’s disease (PD) pathogenesis. This study investigates the clinical utility of key circulating biomarkers related to these pathways for diagnosing PD and correlating with symptom severity. Methods In this case-control study, 90 PD patients and 45 healthy controls (HC) were recruited. Serum levels of Wnt-related proteins (DKK1, Sclerostin, RSPO1), HMGB1, and electrolytes were measured using ELISA and colorimetric assays. Participants underwent comprehensive motor (MDS-UPDRS, Hoehn & Yahr) and non-motor (Fibro-Fatigue, NMS Scale) assessments. Statistical analyses included multivariate general linear models, partial correlations, binary logistic regression, and receiver operating characteristic (ROC) analysis. Results Serum levels of DKK1 and HMGB1 were significantly elevated in the PD group compared to HC (p < 0.001). Binary logistic regression identified both as independent predictors of PD (DKK1: OR = 1.280, p < 0.001; HMGB1: OR = 1.000, p = 0.003). ROC analysis confirmed their strong diagnostic accuracy (DKK1 AUC = 0.81; HMGB1 AUC = 0.72). Within the PD cohort, HMGB1 correlated with disease progression (Hoehn & Yahr: r = 0.424, p < 0.01), while RSPO1 correlated with worse motor experiences of daily living (r = 0.286, p = 0.010) and Sclerostin with motor complications (r = 0.229, p = 0.033). However, no biomarker predicted severe motor or non-motor symptom severity in dedicated regression and ROC models. Conclusion DKK1 and HMGB1 are robust diagnostic biomarkers for PD, underscoring the roles of Wnt dysregulation and neuroinflammation. The correlation of Sclerostin and RSPO1 with specific symptom domains suggests their function as disease modulators rather than diagnostic markers. This panel differentiates between biomarkers for diagnosis and those associated with symptom expression.