The role of peripheral immunity in ALS: a population-based study

Background Systemic inflammation has been proposed as a relevant mechanism in Amyotrophic Lateral Sclerosis (ALS). Recent evidence shows that an increased inflammatory status correlates with survival in ALS. Still, comprehensive data on ALS patients’ innate and adaptive immune responses and their effect on the clinical phenotype are lacking. Here, we investigate the role and characteristics of systemic immunity in a population-based ALS cohort using readily available hematological indexes that reflect changes in innate and adaptive immunity. Methods We collected the complete blood count (CBC) at diagnosis in ALS patients from the Piemonte and Valle d’Aosta Register for ALS (PARALS) from 2007 to 2019. Demographic and clinical data were collected using registry data. Leukocytes populations, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII) and lymphocyte-to-monocyte ratio (LMR) were derived from CBC. All variables were analyzed for association with clinical features in the entire cohort and then in sex- and age-based subgroups. Logistic, linear and Cox regression models were used as appropriate. Results After adjustment for relevant covariates, neutrophils (p=0.001) and markers of increased innate immunity (NLR, p=0.008 and SII, p=0.006) were associated with a faster disease progression. Similarly, elevated innate immunity markers correlated with worse pulmonary function and shorter survival. Sex-based differences emerged, as the prognosis in women also correlated with a low lymphocyte (p=0.045) and a decreased LMR (p=0.013). ALS patients with cognitive impairment exhibited lower levels of monocytes (p=0.0415) and, although only in later-onset ALS (age at onset > 70 years), lower lymphocytes (p=0.006) and increased NLR (p=0.021) and SII (p=0.030). Conclusions and Relevance Our results confirm that a dysregulated systemic immune system participates in ALS progression. More specifically, an elevated innate immune response is associated with faster progression and reduced survival. The immune response varied according to sex and age, thus prompting the speculation that involved immune pathways are patient-specific. Finally, we observed that ALS patients with greater cognitive impairment showed a reduction in monocytes count. Those data revealed that systemic inflammation plays a multifaceted role in ALS: further studies will help translate those findings into clinical practice or targeted treatments.