Peripheral redox biomarkers in multiple sclerosis: associations with phenotype, cognition, and fatigue

Oxidative stress (OS) plays a pivotal role in MS pathogenesis, but its relationship with cognitive impairment, mood disorders, and fatigue remains underexplored. This study assessed blood OS markers and their association with clinical and symptomatic measures.

This cross-sectional study included 67 adults (>18 years) with definite MS (2017 revised McDonald criteria). Measured oxidative markers included total oxidative status (TOS), TAS (total antioxidant status), prooxidative-antioxidative balance (PAB), malondialdehyde (MDA), advanced oxidation protein products (AOPP), serum paraoxonase-1 (PON1) activity, plasma superoxide dismutase (SOD) activity, and plasma levels of sulhydryl groups (SH) groups. Clinical assessments included Expanded Disability Status Scale (EDSS), Beck Depression Inventory II (BDI-II), Hamilton Depression Rating Scale (HAMD), Symbol Digit Modalities Test (SDMT) and Modified Fatigue Impact Scale (MFIS).

MS patients demonstrated significant redox imbalance compared to controls, with significantly reduced antioxidant capacity (TAS, SOD, PON1 and SH groups) and elevated TOS (p < 0.001), except for PAB. In the overall MS cohort, PAB correlated positively with disease duration and negatively with EDSS. Patients with secondary progressive MS (SPMS) had higher PAB and MDA levels than relapsing remitting MS (RRMS) patients (p < 0.001) in the unadjusted analysis, but the association with PAB was not retained after adjustment for age, disease duration, and therapy in the multivariate model. Cognitive performance (as assessed by SDMT) negatively correlated with AOPP, PAB, and MDA (p < 0.05). Physical fatigue (determined through MFIS) correlated with elevated PAB and SOD levels, whereas psychosocial fatigue was associated with reduced SOD levels (p < 0.05). High-Efficacy disease-modifying therapies (DMTs) were associated with lower EDSS (p = 0.003) and fatigue (p = 0.025), but paradoxically with increased levels of MDA levels compared to low-efficacy therapies. However, after Bonferroni correction for multiple comparisons, the previously reported post-hoc value increased (from p = 0.032 to p = 0.097), and therefore the statistical significance was lost.

Redox biomarkers-particularly PAB and MDA-emerged as promising indicators of clinical heterogeneity in MS, with associations with cognition and fatigue. Although some associations were attenuated after adjustment, the overall pattern supports oxidative stress as a clinically meaningful component of MS and highlights peripheral redox profiling as a promising biomarker approach. These results should be interpreted with caution. Validation in larger, longitudinal studies is required.