Peripheral Immune Profiles Predict ALS Progression in an Age- and Sex-Dependent Manner

• Published in: Neurology : neuroimmunology & neuroinflammation 2024-05, Vol.11 (3), p.e200241-e200241
• Main Authors: Murdock, Benjamin J, Zhao, Bangyao, Pawlowski, Kristen D, Famie, Joshua P, Piecuch, Caroline E, Webber-Davis, Ian F, Teener, Samuel J, Feldman, Eva L, Zhao, Lili, Goutman, Stephen A
• Format: Article
• Language: English
• Subjects: Amyotrophic Lateral Sclerosis; Biomarkers; Disease Progression; Female; Humans; Male; Neurodegenerative Diseases; Prognosis
• ISSN: 2332-7812; 2332-7812
• DOI: 10.1212/NXI.0000000000200241

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease whose pathobiology associates with peripheral blood immune cell levels and activation patterns in an age and sex-dependent manner. This study's objective was to identify immune profile associations with ALS progression, whether the associations are age and sex-specific, and whether immune profiles can predict a future disease course. Flow cytometry immune profiles (a combination of 22 peripheral blood immune markers) were generated for 241 participants with ALS and linked to ALS progression, using progression-free survival, which is a composite combining the revised ALS Functional Rating Scale and survival. Participants were first grouped by immune profiles using unsupervised hierarchical clustering, and clusters were associated with subsequent progression-free survival. Next, individual immune markers were associated with progression-free survival using least absolute shrinkage and selection operator-Cox regression. Analyses were stratified by age and sex to identify demographic-specific immune mechanisms. Finally, random forest determined the predictive power of immune profiles on ALS progression in the whole population and again stratified by age and sex. Progression-free survival differed between clusters of participants with similar immune profiles, particularly reduced natural killer (NK)-cell activation associated with slower progression. Individual markers such as neutrophil levels and NK-cell NKp46 expression associated with faster ALS progression while overall NK-cell levels and NK-cell subpopulations associated with slower progression; the strength of these associations varied by age and sex. Adding these immune markers to prediction models dramatically increased short-term prediction compared with routine clinical prognostic variables alone, and the addition of NK-cell markers further improved the prediction accuracy in female participants. Specific immune profiles likely contribute to ALS progression in an age and sex-dependent manner, and peripheral immune markers enhance the prediction of short-term clinical outcomes. These findings suggest a complex milieu of immune profiles associated with ALS progression, and more detailed immunophenotyping in ALS will facilitate personalized immunotherapeutics in ALS.