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Neurofilaments can differentiate ALS subgroups and ALS from common diagnostic mimics
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.ORCID-id: 0000-0003-2369-4319
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
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2021 (Engelska)Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 11, nr 1, artikel-id 22128Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Delayed diagnosis and misdiagnosis are frequent in people with amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease (MND). Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) are elevated in ALS patients. We retrospectively quantified cerebrospinal fluid (CSF) NFL, CSF pNFH and plasma NFL in stored samples that were collected at the diagnostic work-up of ALS patients (n = 234), ALS mimics (n = 44) and controls (n = 9). We assessed the diagnostic performance, prognostication value and relationship to the site of onset and genotype. CSF NFL, CSF pNFH and plasma NFL levels were significantly increased in ALS patients compared to patients with neuropathies & myelopathies, patients with myopathies and controls. Furthermore, CSF pNFH and plasma NFL levels were significantly higher in ALS patients than in patients with other MNDs. Bulbar onset ALS patients had significantly higher plasma NFL levels than spinal onset ALS patients. ALS patients with C9orf72HRE mutations had significantly higher plasma NFL levels than patients with SOD1 mutations. Survival was negatively correlated with all three biomarkers. Receiver operating characteristics showed the highest area under the curve for CSF pNFH for differentiating ALS from ALS mimics and for plasma NFL for estimating ALS short and long survival. All three biomarkers have diagnostic value in differentiating ALS from clinically relevant ALS mimics. Plasma NFL levels can be used to differentiate between clinical and genetic ALS subgroups.

Ort, förlag, år, upplaga, sidor
Nature Publishing Group, 2021. Vol. 11, nr 1, artikel-id 22128
Nationell ämneskategori
Neurologi
Identifikatorer
URN: urn:nbn:se:umu:diva-189808DOI: 10.1038/s41598-021-01499-6ISI: 000717747400105Scopus ID: 2-s2.0-85118949353OAI: oai:DiVA.org:umu-189808DiVA, id: diva2:1613289
Tillgänglig från: 2021-11-22 Skapad: 2021-11-22 Senast uppdaterad: 2024-03-25Bibliografiskt granskad
Ingår i avhandling
1. Biomarkers for diagnosis and prognosis in amyotrophic lateral sclerosis
Öppna denna publikation i ny flik eller fönster >>Biomarkers for diagnosis and prognosis in amyotrophic lateral sclerosis
2024 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of upper and lower motor neurons, leading to paresis, muscle atrophy, and respiratory failure. ALS can be difficult to diagnose and prognosticate early.

Aim: To investigate the diagnostic and prognostic characteristics of biomarkers in cerebrospinal fluid (CSF), plasma, and skeletal muscle tissue in patients with ALS.

Paper I: Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) were analyzed in CSF using enzyme-linked immunosorbent assay (ELISA), and NFL in plasma was analyzed using single-molecule array (SIMOA). CSF NFL, CSF pNFH, and plasma NFL concentrations can differentiate ALS patients from ALS mimics, and were significantly negatively correlated with the disease duration in ALS patients.

Paper II: Myosin heavy chain (MyHC) isoforms in extraocular muscles were investigated using immunofluorescence. Control donors had significantly higher proportion of myofibers containing MyHCIIa and significantly lower proportion of myofibers containing MyHCeom in the global layer compared to spinal-onset ALS and bulbar-onset ALS donors. Disease duration in the spinal-onset ALS donors was significantly correlated with the proportion of myofibers containing MyHCIIa in the global layer and MyHCeom in the orbital layer.

Paper III: The study combined the neurofilament concentrations from Paper I, with cytokines previously analyzed in CSF and plasma using SIMOA, to investigate distinct molecular phenotypes in ALS. Patients with bulbar-onset ALS had significantly higher concentrations of CSF tumor necrosis factor α (TNF-α) compared to ALS mimics. TNF-α and NFL were significantly correlated with each other in both CSF and plasma in ALS patients. Combined analysis of NFL and IL-6 in plasma identified molecular prognostic subgroups in ALS patients.

Paper IV: Creatine kinase (CK), high-sensitivity cardiac troponin T (hs-cTnT), hs-cTnI, and cystatin C (CysC) were analyzed in plasma in a fully accredited laboratory. CK and hs-cTnT concentrations were significantly elevated in limb-onset ALS compared to controls and bulbar-onset ALS. hs-cTnT concentrations were significantly elevated in truncal-onset ALS compared to controls and bulbar-onset ALS. Multivariable Cox proportional hazards models indicated elevated concentrations of CysC as a significant marker for worse prognosis in ALS.

Conclusions: The papers report diagnostic and prognostic characteristics of biomarkers in CSF, plasma, and muscle tissue in ALS patients. The significant findings for biomarkers in plasma could be of value since plasma sampling does not involve a lumbar puncture.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2024. s. 91
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2290
Nyckelord
amyotrophic lateral sclerosis, biomarkers, neurofilaments, cytokines, troponin, cystatin C
Nationell ämneskategori
Neurologi
Forskningsämne
neurologi
Identifikatorer
urn:nbn:se:umu:diva-222636 (URN)978-91-8070-312-3 (ISBN)978-91-8070-313-0 (ISBN)
Disputation
2024-04-19, Hörsal B, byggnad 1D, 9 trappor, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2024-03-28 Skapad: 2024-03-25 Senast uppdaterad: 2024-03-25Bibliografiskt granskad

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Behzadi, ArvinTjust, Anton E.Wuolikainen, AnnaForsberg, KarinAndersen, Peter M.

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