Maurizio Grassano1, Umberto Manera1, Fabiola De Marchi2, Enrico Matteoni1, Margherita Daviddi1, Paolo Cugnasco1, Antonio Canosa1, Rosario Vasta1, Letizia Mazzini2, Cristina Moglia1, Andrea Calvo1, Adriano Chio1
1"Rita Levi Montalcini" Department of Neuroscience, University of Torino, 2Azienda Ospedaliera Universitaria Maggiore della CaritÃ
Objective:
To investigate the characteristics of systemic immunity in a population-based Amyotrophic Lateral Sclerosis (ALS) cohort using readily available hematological indexes that reflect changes in innate and adaptive immunity.
Background:
Systemic inflammation has been proposed as a relevant mechanism in ALS. Still, comprehensive data on ALS patients' innate and adaptive immune responses and their effect on the clinical phenotype are lacking.
Design/Methods:
We collected the complete blood count (CBC) at diagnosis in 1451 ALS patients from the Piemonte and Aosta Register for ALS (PARALS) from 2007 to 2019. Leukocyte 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:
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 low lymphocytes (p=0.045) and decreased LMR (p=0.013). ALS patients with cognitive impairment exhibited lower 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).
Conclusions:
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 a reduced monocyte count in ALS patients with greater cognitive impairment. 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.