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Myofiber type shift in extraocular muscles in amyotrophic lateral sclerosis
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0002-9347-0364
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0003-2369-4319
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).ORCID iD: 0000-0003-2508-9921
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0003-0094-5429
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2023 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 64, no 5, article id 15Article in journal (Refereed) Published
Abstract [en]

Purpose: To investigate changes in myofiber composition in the global layer (GL) and orbital layer (OL) of extraocular muscles (EOMs) from terminal amyotrophic lateral sclerosis (ALS) donors.

Methods: Medial recti muscles collected postmortem from spinal-onset ALS, bulbar-onset ALS, and healthy control donors were processed for immunofluorescence with antibodies against myosin heavy chain (MyHC) IIa, MyHCI, MyHCeom, laminin, neurofilaments, synaptophysin, acetylcholine receptor γ-subunit, and α-bungarotoxin.

Results: The proportion of myofibers containing MyHCIIa was significantly smaller and MyHCeom was significantly larger in the GL of spinal-onset ALS and bulbar-onset ALS donors compared to control donors. Changes in the GL were more prominent in the bulbar-onset ALS donors, with a significantly larger proportion of myofibers containing MyHCeom being present compared to spinal-onset ALS donors. There were no significant differences in the myofiber composition in the OL. In the spinal-onset ALS donors, the proportions of myofibers containing MyHCIIa in the GL and MyHCeom in the OL were significantly correlated with the disease duration. Neurofilament and synaptophysin were present at motor endplates of myofibers containing MyHCeom in ALS donors.

Conclusions: The EOMs of terminal ALS donors displayed changes in the fast-type myofiber composition in the GL, with a more pronounced alteration in bulbar-onset ALS donors. Our results align with the worse prognosis and subclinical changes in eye movement function previously observed in bulbar-onset ALS patients and suggest that the myofibers in the OL might be more resistant to the pathological process in ALS.

Place, publisher, year, edition, pages
Association for Research in Vision and Ophthalmology (ARVO) , 2023. Vol. 64, no 5, article id 15
National Category
Ophthalmology
Identifiers
URN: urn:nbn:se:umu:diva-210285DOI: 10.1167/iovs.64.5.15PubMedID: 37200039Scopus ID: 2-s2.0-85159762499OAI: oai:DiVA.org:umu-210285DiVA, id: diva2:1772292
Available from: 2023-06-21 Created: 2023-06-21 Last updated: 2024-03-26Bibliographically approved
In thesis
1. Biomarkers for diagnosis and prognosis in amyotrophic lateral sclerosis
Open this publication in new window or tab >>Biomarkers for diagnosis and prognosis in amyotrophic lateral sclerosis
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. p. 91
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2290
Keywords
amyotrophic lateral sclerosis, biomarkers, neurofilaments, cytokines, troponin, cystatin C
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-222636 (URN)978-91-8070-312-3 (ISBN)978-91-8070-313-0 (ISBN)
Public defence
2024-04-19, Hörsal B, byggnad 1D, 9 trappor, Umeå, 09:00 (English)
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Available from: 2024-03-28 Created: 2024-03-25 Last updated: 2024-03-25Bibliographically approved

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Behzadi, ArvinTjust, Anton ErikLiu, Jing-XiaAndersen, Peter Munch

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