Year: 2024
Type: article
Study design: Observational Study
Abstract: BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.
Institution: University of Michigan
Language: German
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,450
Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, University of Michigan, Target ALS, Sinai Medical Staff Foundation, National Institutes of Health, Centers for Disease Control and Prevention, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, Agency for Toxic Substances and Disease Registry, National Center for Advancing Translational Sciences
Awards: Mapping the ALS Exposome to Gain New Insights into Disease Risk and Pathogenesis, LINKING LONG-TERM AIR POLLUTION EXPOSURE WITH INFLAMMATION, ALS RISK, AND DISEASE PROGRESSION, Developing novel strategies for personalized treatment and prevention of ALS: Leveraging the global exposome, genome, epigenome, metabolome, and inflammasome with data science in a case/control cohort, Impact of Geospatial Factors and Environmental Pollutants on Amyotrophic Lateral Sclerosis in the State of Michigan, The Role of NK Cells in ALS, Michigan Institute for Clinical and Health Research (MICHR), Creating a foundation for personalized age- and sex-based immune-targeted therapies from an ALS longitudinal cohort by identifying peripheral and central immune signatures, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe)
OpenAlex ID: W4394866198