Phenotype-dependent redox imbalance and neuroaxonal injury in progressive supranuclear palsy

Abstract Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy characterized by marked clinical heterogeneity, yet the contribution of oxidative stress to neurodegeneration and phenotype-specific differences remains unclear. This study investigated the relationship between oxidative stress and neuroaxonal injury in two major PSP phenotypes, PSP-Richardson’s syndrome (PSP-RS) and PSP-parkinsonism (PSP-P), using serum and cerebrospinal fluid biomarkers. Serum and cerebrospinal fluid concentrations of neurofilament light chain (NfL), malondialdehyde (MDA), glutathione peroxidase 1 (GPx1), reduced glutathione (GSH), and oxidized glutathione (GSSG) were assessed in 28 patients with PSP, including 14 with PSP-RS and 14 with PSP-P, as well as control participants using ELISA and colorimetric assays. Results demonstrated that serum and CSF NfL concentrations were significantly elevated in both PSP phenotypes compared with controls. Serum MDA concentrations were also significantly elevated in both PSP phenotypes, whereas in CSF a significant increase in MDA was observed in PSP-RS. Notably, a positive correlation between serum MDA and serum NfL was observed in PSP-RS; however, this finding should be regarded as exploratory. In contrast, redox alterations showed some phenotype-associated differences, with the GSSG/GSH ratio representing the only biomarker that differentiated between PSP phenotypes in serum. These findings indicate that neuroaxonal injury is accompanied by alterations in redox homeostasis in PSP and suggest phenotype-associated differences in systemic redox balance.