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. 2023 Sep;10(9):1623-1632.
doi: 10.1002/acn3.51853. Epub 2023 Jul 22.

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

Maurizio Grassano #  1 , Umberto Manera #  1   2 , Fabiola De Marchi  3 , Paolo Cugnasco  1 , Enrico Matteoni  1 , Margherita Daviddi  1 , Luca Solero  1 , Alessandro Bombaci  1 , Francesca Palumbo  1 , Rosario Vasta  1 , Antonio Canosa  1   2 , Paolina Salamone  1 , Giuseppe Fuda  1 , Federico Casale  1 , Letizia Mazzini  3 , Andrea Calvo #  1   2 , Cristina Moglia #  1   2 , Adriano Chiò #  1   2
Affiliations

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

Maurizio Grassano et al. Ann Clin Transl Neurol. 2023 Sep.

Abstract

Background: Systemic inflammation has been proposed as a relevant mechanism in amyotrophic lateral sclerosis (ALS). Still, comprehensive data on ALS patients' innate and adaptive immune responses and their effect on the clinical phenotype are lacking. Here, we investigate systemic immunity in a population-based ALS cohort using readily available hematological indexes.

Methods: We collected clinical data and 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. 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.

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 correlated with worse pulmonary function and shorter survival. The prognosis in women also correlated with low lymphocytes (P = 0.045) and a decreased LMR (P = 0.013). ALS patients with cognitive impairment exhibited lower monocytes (P = 0.0415).

Conclusions and relevance: The dysregulation of the systemic immune system plays a multifaceted role in ALS. More specifically, an elevated innate immune response is associated with faster progression and reduced survival. Conversely, ALS patients with cognitive impairment showed a reduction in monocyte count. Additionally, immune response varied according to sex and age, thus suggesting that involved immune pathways are patient specific. Further studies will help translate those findings into clinical practice or targeted treatments.

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Conflict of interest statement

Maurizio Grassano, Umberto Manera, Fabiola De Marchi, Paolo Cugnasco, Enrico Matteoni, Margherita Daviddi, Luca Solero, Alessandro Bombaci, Francesca Palumbo, Rosario Vasta, Antonio Canosa, Paolina Salamone, Giuseppe Fuda, Federico Casale, Letizia Mazzini, Cristina Moglia report nothing to disclose. Andrea Calvo has received a research grant from Cytokinetics. Adriano Chiò serves on scientific advisory boards for Mitsubishi Tanabe, Roche, Denali Pharma, Cytokinetics, and Amylyx.

Figures

Figure 1
Figure 1
Overall association of peripheral immune markers with FVC < 75% of predicted value, ALSFRS‐R progression rate, presence of FTD, and survival. β estimates from linear regression; OR odds ratio from logistic regression, HR hazard ratio from Cox proportional hazard regression, 97.5% CI, 97.55% confidence interval; LMR, lymphocyte‐to‐monocyte ratio; NLR, neutrophil‐to‐lymphocyte ratio; PLR, platelet‐to‐lymphocyte ratio; SII, systemic inflammatory index.
Figure 2
Figure 2
Sex‐stratified association of peripheral immune markers with FVC < 75% of predicted value, ALSFRS‐R progression rate, presence of FTD and survival. β estimates from linear regression; OR odds ratio from logistic regression, HR hazard ratio from Cox proportional hazard regression, 97.5% CI, 97.55% confidence interval; LMR, lymphocyte‐to‐monocyte ratio; NLR, neutrophil‐to‐lymphocyte ratio; PLR, platelet‐to‐lymphocyte ratio; SII, systemic inflammatory index. Male, n = 799; Female, n = 653.
Figure 3
Figure 3
Age‐stratified association of peripheral immune markers with FVC < 75% of predicted value, ALSFRS‐R progression rate, presence of FTD and survival. β estimates from linear regression; OR odds ratio from logistic regression, HR hazard ratio from Cox proportional hazard regression, 97.5% CI, 97.55% confidence interval; LMR, lymphocyte‐to‐monocyte ratio; NLR, neutrophil‐to‐lymphocyte ratio; PLR, platelet‐to‐lymphocyte ratio; SII, systemic inflammatory index. Age < 65 years, n = 497; age 65–75 years, n = 548; age >75 years, n = 406.
Figure 4
Figure 4
Graphical summary of study results. Baseline neutrophil count and increased markers of innate immune response in the peripheral blood are associated with a shorter survival time via multiple potential mechanisms, such as a more rapid motor disease progression and a lower respiratory function. In addition, a reduced monocyte count was observed in patients with more severe cognitive impairment. Lower lymphocyte levels and markers of adaptive immune response correlated with shorter survival, with lower lymphocytes also linked to cognitive decline. However, these effects of lymphocytes and adaptive immunity were only observed in female patients.
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