@article{b50b1f05f21c4efbbc105b4f17290de2,
title = "The temporal and causal relationship between inflammation and neurodegeneration in multiple sclerosis",
abstract = "It is currently incompletely understood whether inflammation and neurodegeneration are causally related in multiple sclerosis (MS). The sequence of a potential causal relationship is also unknown. Inflammation is present in rather all clinical stages of MS. Its role in the pathogenesis of MS is supported by histopathological analyses, genetic data, and numerous animal models of MS. All approved disease-modifying therapies that reduce clinical relapses and diminish the accumulation of lesions on neuroimaging are anti-inflammatory. Axonal loss and accelerated brain volume loss can also be detected from clinical disease onset throughout all stages. The expression of neurofilament light chain in cerebrospinal fluid and serum, a scaffolding protein in axons and dendrites, is a biomarker of neuronal injury associated with clinical relapses and reflects neuronal loss during episodes of acute inflammation. The recent association of human endogenous retrovirus (HERV) and its envelope proteins with MS illustrates a pathogenic pathway that causally links central nervous system (CNS)–intrinsic proinflammatory effects and inhibition of myelin repair and neuroregeneration. A review of current data on the causal relationship between inflammation and neurodegeneration in MS identified numerous plausible pathomechanisms that link the two events. Observations from most experimental models appear to favor a pathogenesis in which inflammation precedes neurodegeneration.",
keywords = "Multiple sclerosis, autoimmunity, drugs, experimental autoimmune encephalomyelitis, genetics, inflammation, neurodegeneration, pathology, therapy, treatment",
author = "Ron Milo and Korczyn, {Amos D.} and Navid Manouchehri and Olaf St{\"u}ve",
note = "Funding Information: Milo Ron Department of Neurology, Barzilai Medical Center, Ashkelon, Israel/Faculty of Health Sciences, Ben-Gurion University of the Negev, Be{\textquoteright}er Sheva, Israel Korczyn Amos D Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Manouchehri Navid Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX, USA St{\"u}ve Olaf Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX, USA/Neurology Section, Medical Service, VA North Texas Health Care System, Dallas, TX, USA/Department of Neurology, Klinikum rechts der Isar, Technische Universit{\"a}t M{\"u}nchen, M{\"u}nchen, Germany Neurology Section, Medical Service, VA North Texas Health Care System, 4500 South Lancaster Rd., Dallas, TX 75216, USA. olaf.stuve@utsouthwestern.edu 11 2019 1352458519886943 5 7 2019 26 9 2019 9 10 2019 {\textcopyright} The Author(s), 2019 2019 SAGE Publications It is currently incompletely understood whether inflammation and neurodegeneration are causally related in multiple sclerosis (MS). The sequence of a potential causal relationship is also unknown. Inflammation is present in rather all clinical stages of MS. Its role in the pathogenesis of MS is supported by histopathological analyses, genetic data, and numerous animal models of MS. All approved disease-modifying therapies that reduce clinical relapses and diminish the accumulation of lesions on neuroimaging are anti-inflammatory. Axonal loss and accelerated brain volume loss can also be detected from clinical disease onset throughout all stages. The expression of neurofilament light chain in cerebrospinal fluid and serum, a scaffolding protein in axons and dendrites, is a biomarker of neuronal injury associated with clinical relapses and reflects neuronal loss during episodes of acute inflammation. The recent association of human endogenous retrovirus (HERV) and its envelope proteins with MS illustrates a pathogenic pathway that causally links central nervous system (CNS)–intrinsic proinflammatory effects and inhibition of myelin repair and neuroregeneration. A review of current data on the causal relationship between inflammation and neurodegeneration in MS identified numerous plausible pathomechanisms that link the two events. Observations from most experimental models appear to favor a pathogenesis in which inflammation precedes neurodegeneration. Multiple sclerosis experimental autoimmune encephalomyelitis autoimmunity genetics pathology neurodegeneration inflammation therapy treatment drugs edited-state corrected-proof Authors{\textquoteright} Note This opinion article resulted from debates and discussions held with many of our esteemed colleagues at the 11th World Congress on Controversies in Neuro-logy in Athens in March 2017 ( http://www.comtecmed.com/cony/2017/about_athens.aspx ) and the 13th World Congress on Controversies in Neurology in Madrid in March 2019 ( https://www.comtecmed.com/Cony/2019/default.aspx ). Author Contributions RM, ADK, NM,and OS made substantial contributions to conception and design, drafting the manuscript and revising it critically for important intellectual content. RM, ADK, NM, and OS gave final approval of the version to be published. Each author participated sufficiently in the work to take public responsibility for appropriate portions of the content, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: O.S. serves on the editorial boards of the Multiple Sclerosis Journal and Therapeutic Advances in Neurological Disorders . O.S. has served on data monitoring committees for Pfizer and TG Therapeutics without monetary compensation; advised EMD Serono, Genzyme, and Novartis; and currently receives grant support from Teva Pharmaceuticals and Opexa Therapeutics. RM, ADK and NM report no competing interests. Funding The author(s) received no financial support for the research, authorship, and/or publication of this article. Publisher Copyright: {\textcopyright} The Author(s), 2019.",
year = "2020",
month = jul,
day = "1",
doi = "10.1177/1352458519886943",
language = "English (US)",
volume = "26",
pages = "876--886",
journal = "Multiple Sclerosis Journal",
issn = "1352-4585",
publisher = "SAGE Publications Ltd",
number = "8",
}