Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Neurology: Neuroimmunology & Neuroinflammation COVID-19 Article Hub
    • Diversity, Equity, & Inclusion (DEI)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit New Manuscript
    • Submit Revised Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Neurology: Neuroimmunology & Neuroinflammation COVID-19 Article Hub
    • Diversity, Equity, & Inclusion (DEI)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Topics A-Z
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit New Manuscript
    • Submit Revised Manuscript
    • Author Center
  • Home
  • Articles
  • Issues
  • COVID-19 Article Hub
  • Infographics & Video Summaries

User menu

  • My Alerts
  • Log in

Search

  • Advanced search
Neurology Neuroimmunology & Neuroinflammation
Home
A peer-reviewed clinical and translational neurology open access journal
  • My Alerts
  • Log in
Site Logo
  • Home
  • Articles
  • Issues
  • COVID-19 Article Hub
  • Infographics & Video Summaries

Share

January 2023; 10 (1) Research ArticleOpen Access

Senescent-like Blood Lymphocytes and Disease Progression in Amyotrophic Lateral Sclerosis

Ozlem Yildiz, Johannes Schroth, Timothy Tree, Martin R. Turner, Pamela J. Shaw, Sian M. Henson, Andrea Malaspina
First published November 2, 2022, DOI: https://doi.org/10.1212/NXI.0000000000200042
Ozlem Yildiz
From the Neuroscience and Trauma Centre (O.Y., A.M.), Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London; Queen Square Motor Neuron Disease Centre (A.M.), Neuromuscular Department, Institute of Neurology, University College London; Translational Medicine and Therapeutics (J.S., S.M.H.), William Harvey Research Institute, Barts and the London, Queen Mary University of London; Department of Immunobiology (T.T.), School of Immunology & Microbial Sciences, King's College London; Nuffield Department of Clinical Neurosciences (M.R.T.), University of Oxford; and Sheffield Institute for Translational Neuroscience (P.J.S.), University of Sheffield, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Johannes Schroth
From the Neuroscience and Trauma Centre (O.Y., A.M.), Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London; Queen Square Motor Neuron Disease Centre (A.M.), Neuromuscular Department, Institute of Neurology, University College London; Translational Medicine and Therapeutics (J.S., S.M.H.), William Harvey Research Institute, Barts and the London, Queen Mary University of London; Department of Immunobiology (T.T.), School of Immunology & Microbial Sciences, King's College London; Nuffield Department of Clinical Neurosciences (M.R.T.), University of Oxford; and Sheffield Institute for Translational Neuroscience (P.J.S.), University of Sheffield, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Timothy Tree
From the Neuroscience and Trauma Centre (O.Y., A.M.), Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London; Queen Square Motor Neuron Disease Centre (A.M.), Neuromuscular Department, Institute of Neurology, University College London; Translational Medicine and Therapeutics (J.S., S.M.H.), William Harvey Research Institute, Barts and the London, Queen Mary University of London; Department of Immunobiology (T.T.), School of Immunology & Microbial Sciences, King's College London; Nuffield Department of Clinical Neurosciences (M.R.T.), University of Oxford; and Sheffield Institute for Translational Neuroscience (P.J.S.), University of Sheffield, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin R. Turner
From the Neuroscience and Trauma Centre (O.Y., A.M.), Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London; Queen Square Motor Neuron Disease Centre (A.M.), Neuromuscular Department, Institute of Neurology, University College London; Translational Medicine and Therapeutics (J.S., S.M.H.), William Harvey Research Institute, Barts and the London, Queen Mary University of London; Department of Immunobiology (T.T.), School of Immunology & Microbial Sciences, King's College London; Nuffield Department of Clinical Neurosciences (M.R.T.), University of Oxford; and Sheffield Institute for Translational Neuroscience (P.J.S.), University of Sheffield, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pamela J. Shaw
From the Neuroscience and Trauma Centre (O.Y., A.M.), Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London; Queen Square Motor Neuron Disease Centre (A.M.), Neuromuscular Department, Institute of Neurology, University College London; Translational Medicine and Therapeutics (J.S., S.M.H.), William Harvey Research Institute, Barts and the London, Queen Mary University of London; Department of Immunobiology (T.T.), School of Immunology & Microbial Sciences, King's College London; Nuffield Department of Clinical Neurosciences (M.R.T.), University of Oxford; and Sheffield Institute for Translational Neuroscience (P.J.S.), University of Sheffield, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sian M. Henson
From the Neuroscience and Trauma Centre (O.Y., A.M.), Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London; Queen Square Motor Neuron Disease Centre (A.M.), Neuromuscular Department, Institute of Neurology, University College London; Translational Medicine and Therapeutics (J.S., S.M.H.), William Harvey Research Institute, Barts and the London, Queen Mary University of London; Department of Immunobiology (T.T.), School of Immunology & Microbial Sciences, King's College London; Nuffield Department of Clinical Neurosciences (M.R.T.), University of Oxford; and Sheffield Institute for Translational Neuroscience (P.J.S.), University of Sheffield, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrea Malaspina
From the Neuroscience and Trauma Centre (O.Y., A.M.), Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London; Queen Square Motor Neuron Disease Centre (A.M.), Neuromuscular Department, Institute of Neurology, University College London; Translational Medicine and Therapeutics (J.S., S.M.H.), William Harvey Research Institute, Barts and the London, Queen Mary University of London; Department of Immunobiology (T.T.), School of Immunology & Microbial Sciences, King's College London; Nuffield Department of Clinical Neurosciences (M.R.T.), University of Oxford; and Sheffield Institute for Translational Neuroscience (P.J.S.), University of Sheffield, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Full PDF
Citation
Senescent-like Blood Lymphocytes and Disease Progression in Amyotrophic Lateral Sclerosis
Ozlem Yildiz, Johannes Schroth, Timothy Tree, Martin R. Turner, Pamela J. Shaw, Sian M. Henson, Andrea Malaspina
Neurol Neuroimmunol Neuroinflamm Jan 2023, 10 (1) e200042; DOI: 10.1212/NXI.0000000000200042

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Permissions

Make Comment

See Comments

Downloads
643

Share

  • Article
  • Figures & Data
  • Info & Disclosures
Loading

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.

View Full Text

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

REQUIREMENTS

If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
  • Article
    • Abstract
    • Glossary
    • Methods
    • Results
    • Discussion
    • Study Funding
    • Disclosure
    • Acknowledgment
    • Appendix Authors
    • Footnotes
    • References
  • Figures & Data
  • Info & Disclosures
Advertisement

Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis

Dr. Robert Pitceathly and Dr. William Macken

► Watch

Related Articles

  • No related articles found.

Alert Me

  • Alert me when eletters are published
Neurology - Neuroimmunology Neuroinflammation: 10 (3)

Articles

  • Articles
  • Issues
  • Popular Articles

About

  • About the Journals
  • Ethics Policies
  • Editors & Editorial Board
  • Contact Us
  • Advertise

Submit

  • Author Center
  • Submit a Manuscript
  • Information for Reviewers
  • AAN Guidelines
  • Permissions

Subscribers

  • Subscribe
  • Sign up for eAlerts
  • RSS Feed
Site Logo
  • Visit neurology Template on Facebook
  • Follow neurology Template on Twitter
  • Visit Neurology on YouTube
  • Neurology
  • Neurology: Clinical Practice
  • Neurology: Education
  • Neurology: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

Neurology: Neuroimmunology & Neuroinflammation
Online ISSN: 2332-7812

© 2023 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise