Abstract
Background and Objectives Aging is known to exacerbate neuroinflammation, and in the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), an older age is associated with a worse prognosis. We have previously shown the activation of cell senescence pathways in the proteome of peripheral blood mononuclear cells and the increase of proinflammatory cytokines in blood from individuals living with ALS. In this single-center, retrospective study, we investigated the expression of senescent-like blood mononuclear cells in ALS.
Methods We first applied multidimensional cytometry by time-of-flight (CyTOF) to study the senescent immunophenotype of blood mononuclear cells from 21 patients with ALS and 10 healthy controls (HCs). We then used targeted flow cytometry (FC) to investigate frequencies of senescent blood lymphocytes in 40 patients with ALS and 20 HCs. Longitudinal analysis included 2 additional time points in 17 patients with ALS. Frequencies of senescent-like lymphocytes were analyzed in relation to survival.
Results Unsupervised clustering of CyTOF data showed higher frequencies of senescent CD4+CD27−CD57+ T cells in patients with ALS compared with those in HCs (p = 0.0017, false discovery (FDR)-adjusted p = 0.029). Moderate to strong negative correlations were identified between CD4 T central memory–cell frequencies and survival (R = −061, p = 0.01; FDR-adjusted p < 0.1) and between CD95 CD8 cells and ALS functional rating scale revised at baseline (R = −0.72, p = 0.001; FDR-adjusted p < 0.1).Targeted FC analysis showed higher memory T regulatory cells (p = 0.0052) and memory CD8+ T cell (M-Tc; p = 0.0006) in bulbar ALS (A-B) compared with those in limb ALS (A-L), while late memory B cells (LM-B) were also elevated in A-B and fast-progressing ALS (p = 0.0059). Higher M-Tc levels separated A-B from A-L (AUC: 0.887; p < 0.0001). A linear regression model with prespecified clinical independent variables and neurofilament light chain plasma concentration showed that higher frequencies of LM-B predicted a shorter survival (hazard ratio: 1.094, CI: 1.026–1.167; p = 0.006).
Discussion Our data suggest that a systemic elevation of senescent and late memory T and B lymphocytes is a feature of faster progressing ALS and of ALS individuals with bulbar involvement. Lymphocyte senescence and their memory state may be central to the immune dysregulation known to drive disease progression in ALS and a target for biomarkers and therapeutics discovery.
Glossary
- A-B=
- bulbar ALS;
- A-F=
- faster progressing ALS;
- A-L=
- limb ALS;
- ALS=
- amyotrophic lateral sclerosis;
- ALSFRS-R=
- ALS functional rating scale revised;
- ANOVA=
- analysis of variance;
- CD4 T SEN=
- senescent CD4 cells expressing CD57;
- CyTOF=
- cytometry by time-of-flight;
- F-B=
- follicular B cells;
- FC=
- flow cytometry;
- FIt-SNE=
- Fourier transform–accelerated interpolation-based t-Stochastic Neighborhood Embedding;
- HCs=
- healthy controls;
- HR=
- hazard ratio;
- IL=
- interleukin;
- IQR=
- interquartile range;
- KLRG1=
- Killer Cell Lectin-Like Receptor G1;
- LM-B=
- Late memory B cells;
- M-B=
- memory B cells;
- MMI=
- median marker intensities;
- M-Tc=
- memory CD8+ T cell;
- M-Tc=
- memory CD8+ T cells;
- M-Tc=
- Tregs and memory CD8 cells;
- NB GLM=
- negative binomial generalized linear models;
- NfL=
- neurofilament light chain;
- PBMCs=
- peripheral blood mononuclear cells;
- QL=
- quasi-likelihood;
- ROC=
- receiver operating characteristic;
- SASP=
- senescence-associated secretory phenotype;
- SOD1=
- superoxide dismutase 1;
- Tregs=
- T regulatory cells
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.
Submitted and externally peer reviewed. The handling editor was Josep O. Dalmau, MD, PhD, FAAN.
- Received April 18, 2022.
- Accepted in final form August 22, 2022.
- Copyright © 2022 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 License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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