Markers of Oxidative Stress, Other Factors May Predict Disability in ALS

Markers of oxidative stress, iron metabolism in the brain and nerve cell damage may accurately predict disability in patients with amyotrophic lateral sclerosis (ALS), according to new research.

The study, “A ferroptosis-based panel of prognostic biomarkers for Amyotrophic Lateral Sclerosis,” appeared in the journal Scientific Reports.

Phase 2 trials in ALS may benefit from classifying ALS patients based on their prognosis and targeting disease-associated pathways.

Ferroptosis, a form of cell death that involves oxidative damage, is increasingly recognized as a relevant process in ALS. Besides lipid (fat) and iron accumulation, both markers of ferroptosis, other markers in ALS are neurofilament light chain (NfL) and phosphorylated heavy chain (pNfH) — elevated when nerve cells die — interleukin (IL)-6, associated with inflammation, and ferritin, hepcidin, and transferrin, all linked to iron metabolism.

An international team assessed ALS biomarkers in the Roche-sponsored MITOTARGET Phase 3 study (NCT00868166), which assessed olesoxime as add-on therapy to Rilutek (riluzole, by Sanofi) in 15 European centers.

The group of 512 patients (mean age at ALS onset 56.5 years, mean disease duration 17.2 months, 331 men) were first analyzed through the ALS functional rating scale-revised (ALSFRS-r), a measure of disease progression.

Plasma samples were collected at months 1, 6, 12 and 18. Then, in 109 patients (age at ALS onset 54.1 years, disease duration 17.9 months, 69 men) who had completed the 18-month follow-up assessment, the investigators tested a ferroptosis-based panel of prognostic biomarkers, which were compared to clinical predictors.

The results showed no effects of olesoxime and a link between creatine phosphokinase — a marker of muscle damage — and ALSFRS-r score, though without prognostic value.

As for the ferroptosis biomarkers, the scientists observed that higher baseline values of NfL, pNfH, ferritin and 4-HNE and 8-oxo-dG — markers of oxidative stress in lipids and DNA, respectively — were associated with greater functional disability at 18 months.

A subsequent analysis revealed that baseline NfL, 4-HNE, 8-oxo-dG and ferritin were independent predictors of functional decline. Further analysis in two patient groups with fast (55 patients) or slow (54) progression rate from study start to 18 months — a mean monthly ALSFRS-r score reduction of 0.94 and 0.33 points, respectively — found that the differences in biomarker levels preceded functional decline.

However, while the differences in NfL and 4-HNE were attenuated with disease progression, the difference in ferritin became more pronounced as ALS progressed, though with greater variability.

Higher values of both NfL and 4-HNE indicated lower muscle strength and function at follow-up, as assessed by manual muscle testing. A similar negative association was found between NfL levels and pulmonary function, measured through a parameter called slow vital capacity. In contrast, higher baseline levels of ferritin correlated with better pulmonary function and increased body mass index at follow-up.

Although cautioning that the findings need to be confirmed in larger groups of patients, the investigators commented that “markers of neuronal integrity, DNA and lipid oxidation, as well as iron status at baseline are accurate predictors of disability at 18-month follow-up.

“Given the possible predictive value of these biomarkers, they may aid patient stratification for future phase trials.”

From a clinical perspective, they may also contribute to precision care planning, resource allocation, and management of individual patients.