Systemic inflammatory response and neuromuscular involvement in amyotrophic lateral sclerosis.
OBJECTIVE
To evaluate the combined blood expression of neuromuscular and inflammatory biomarkers as predictors of disease progression and prognosis in amyotrophic lateral sclerosis (ALS).


METHODS
Logistic regression adjusted for markers of the systemic inflammatory state and principal component analysis were carried out on plasma levels of creatine kinase (CK), ferritin, and 11 cytokines measured in 95 patients with ALS and 88 healthy controls. Levels of circulating biomarkers were used to study survival by Cox regression analysis and correlated with disease progression and neurofilament light chain (NfL) levels available from a previous study. Cytokines expression was also tested in blood samples longitudinally collected for up to 4 years from 59 patients with ALS.


RESULTS
Significantly higher levels of CK, ferritin, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β, IL-2, IL-8, IL-12p70, IL-4, IL-5, IL-10, and IL-13 and lower levels of interferon (IFN)-γ were found in plasma samples from patients with ALS compared to controls. IL-6, TNF-α, and IFN-γ were the most highly regulated markers when all explanatory variables were jointly analyzed. High ferritin and IL-2 levels were predictors of poor survival. IL-5 levels were positively correlated with CK, as was TNF-α with NfL. IL-6 was strongly associated with CRP levels and was the only marker showing increasing expression towards end-stage disease in the longitudinal analysis.


CONCLUSIONS
Neuromuscular pathology in ALS involves the systemic regulation of inflammatory markers mostly active on T-cell immune responses. Disease stratification based on the prognostic value of circulating inflammatory markers could improve clinical trials design in ALS.
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Ching-Hua
CH
Lu
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Kezia
K
Allen
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Felicia
F
Oei
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Emanuela
E
Leoni
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Jens
J
Kuhle
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Timothy
T
Tree
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Pietro
P
Fratta
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Nikhil
N
Sharma
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Katie
K
Sidle
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Robin
R
Howard
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Richard
R
Orrell
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Mark
M
Fish
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Linda
L
Greensmith
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Neil
N
Pearce
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Valentina
V
Gallo
Centre for Neuroscience & Trauma (C.L., F.O., J.K., A.M.) and Centre of Primary Care and Public Health (V.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London; Sobell Department of Motor Neuroscience and Movement Disorders (C.L., P.F., L.G.), MRC Centre for Neuromuscular Diseases (P.F., L.G.), MRC Unit for Lifelong Health and Ageing (N.S.), Department of Molecular Neuroscience (K.S.), and Department of Clinical Neuroscience (R.O.), UCL Institute of Neurology; Basildon and Thurrock University Hospitals (K.A., A.M.), NHS Foundation Trust, Basildon; William Harvey Hospital (F.O.), Kent; Proteome Sciences plc (E.L.), South Wing Laboratory, Institute of Psychiatry, UK; Neurology (J.K.), University Hospital Basel, Switzerland; Department of Immunobiology (T.T.), King's College London; National Hospital for Neurology and Neurosurgery (N.S., R.H., R.O.), London; Musgrove Park Hospital (M.F.), Taunton; and Department of Medical Statistics (N.P.), London School of Hygiene and Tropical Medicine, UK.
Andrea
A
Malaspina