Abstract
Objective To determine whether neutrophils contribute to amyotrophic lateral sclerosis (ALS) progression, we tested the association of baseline neutrophil count on ALS survival, whether the effect was sex specific, and whether neutrophils accumulate in the spinal cord.
Methods A prospective cohort study was conducted between June 22, 2011, and October 30, 2019. Blood leukocytes were isolated from ALS participants and neutrophil levels assessed by flow cytometry. Participant survival outcomes were analyzed by groups (<2 × 106, 2–4 × 106, and >4 × 106 neutrophils/mL) with adjustments for relevant ALS covariates and by sex. Neutrophil levels were assessed from CNS tissue from a subset of participants.
Results A total of 269 participants with ALS within 2 years of an ALS diagnosis were included. Participants with baseline neutrophil counts over 4 × 106/mL had a 2.1 times higher mortality rate than those with a neutrophil count lower than 2 × 106/mL (95% CI: 1.3–3.5, p = 0.004) when adjusting for age, sex, and other covariates. This effect was more pronounced in females, with a hazard ratio of 3.8 (95% CI: 1.8–8.2, p = 0.001) in the >4 × 106/mL vs <2 × 106/mL group. Furthermore, ALS participants (n = 8) had increased neutrophils in cervical (p = 0.049) and thoracic (p = 0.022) spinal cord segments compared with control participants (n = 8).
Conclusions Higher neutrophil counts early in ALS associate with a shorter survival in female participants. Furthermore, neutrophils accumulate in ALS spinal cord supporting a pathophysiologic correlate. These data justify the consideration of immunity and sex for personalized therapeutic development in ALS.
Classification of Evidence This study provides Class III evidence that in female participants with ALS, higher baseline neutrophil counts are associated with shorter survival.
Glossary
- ALS=
- amyotrophic lateral sclerosis;
- ALSFRS-R=
- ALS Functional Rating Scale, Revised;
- FBS=
- fetal bovine serum;
- PBS=
- phosphate-buffered saline
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the authors.
- Received August 13, 2020.
- Accepted in final form November 13, 2020.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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