Integrated Neuronal Injury and Dysregulated Wnt Signaling Are Associated with Chronic Fatigue Syndrome and Psychiatric Symptoms in Parkinson's Disease

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder with complex pathophysiology. The potential of integrating biomarkers of neuronal injury, neuroinflammation, and modulators of Wnt signaling for PD diagnosis remains largely unexplored. Objective: This study aimed to evaluate the diagnostic and clinical predictive value of a ten-biomarker serum panel encompassing markers of neuronal injury (NSE, UCHL1), neuroinflammation (GFAP, HMGB1), synaptic plasticity (BDNF), proteinopathy (α-Synuclein, β-Amyloid-42), and Wnt signaling (R-spondin-1, DKK1, Sclerostin), with a particular focus on chronic fatigue in PD. Methods: In this case-control study, 90 PD patients and 45 healthy controls were enrolled. Serum biomarkers were quantified using ELISA. Clinical severity was assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Fibro-Fatigue (FF) scales. Binary logistic regression and multiple linear regression analyses were used to evaluate the diagnostic and predictive value of biomarkers for PD diagnosis, psychiatric and motoric scores, and an FF score reflecting chronic fatigue syndrome (CFS) severity. Results: A model incorporating NSE, DKK1, and β-Amyloid-42 effectively discriminated PD patients from controls, yielding an area under the curve (AUC) of 0.932 and an overall accuracy of 83.0%. NSE and DKK1 emerged as the main predictors of overall disease severity, motor symptoms, and CFS severity. Regression analyses indicated that 41.3% of the variance in the FF score was explained by increased NSE, DKK1, β-amyloid, and UCHL1, while 42.9% of the variance in psychiatric symptoms was explained by increased NSE, DKK1, and β-amyloid. Increased GFAP levels were significantly associated with motor dysfunction. Conclusion: The combined presence of neuronal injury, Wnt signaling dysregulation, and amyloid pathology may represent a key pathophysiological component underlying PD, CFS-like fatigue, and psychiatric symptoms in PD. Targeting neuronal injury and Wnt signaling pathways may offer novel therapeutic strategies for managing fatigue and psychiatric manifestations in PD.