Characterization of plasma misfolded superoxide dismutase 1 in amyotrophic lateral sclerosis

To characterize the dynamics of plasma misfolded superoxide dismutase 1 (mSOD1) and evaluate its utility as a state-dependent biomarker for patient stratification and therapeutic monitoring in amyotrophic lateral sclerosis (ALS).

We utilized an SOD1/G93A mouse model and a cohort of 160 ALS patients, including four with SOD1 mutations, 12 with non-SOD1 mutations (C9orf72, TARDBP, FUS, OPTN), and 144 with nongenetic ALS. Chemical precipitation and enzyme-linked immunosorbent assay were used to quantify mSOD1 levels in plasma, spinal cord extracts, and cerebrospinal fluid (CSF). Clinical outcomes were assessed by the annual reduction in the revised ALS Functional Rating Scale (ALSFRS-R) score and ventilator-free survival.

In mice, plasma mSOD1 increased at the late symptomatic stage with subsequent numerical decline at the humane endpoint, accompanied by progressive motor neuron loss and increasing mSOD1-associated pathology. In humans, mSOD1 was elevated in 100% of SOD1-mutant, 25% of non-SOD1-mutant, and 22.2% of nongenetic ALS patients. Elevation was state-dependent, enriched in patients with moderate disability (ALSFRS-R 17-45). Plasma and CSF mSOD1 levels were correlated across the overall ALS cohort, but this association was no longer significant after exclusion of SOD1-mutant ALS cases. In one tofersen-treated patient, plasma mSOD1 showed rapid, parallel, and sustained reduction with CSF levels. No significant differences in clinical outcomes were observed in nongenetic ALS based on mSOD1 status.

Approximately 22% of nongenetic ALS patients exhibit elevated plasma mSOD1, primarily during the moderate disease stage. Plasma mSOD1 is a candidate state-dependent biomarker for biological stratification and may have potential for treatment monitoring.