{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T20:08:50Z","timestamp":1792354130558,"version":"4.4.0"},"reference-count":55,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T00:00:00Z","timestamp":1744329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neurology International"],"abstract":"<jats:p>Neurofilament light chain (NfL), an abundant cytoskeletal protein in neurons, has emerged as a promising serum biomarker that indicates non-specific neuronal damage secondary to various neurologic diseases, including multiple sclerosis (MS). Emerging evidence suggests that serum NfL levels correlate with future disability, brain atrophy, predict new disease activity, and decrease in response to various disease-modifying therapies. As research continues to validate NfL\u2019s potential role in clinical practice, the need for a practical model to conceptualize and visualize its relevance to MS pathology becomes evident\u2014not only for healthcare providers but also for patients. To address this, we propose the Neurofoundational Model (NFM), which likens a neuron to a home, with various parts of the home representing distinct regions of the central nervous system (CNS). In this model, the home (neuron) experiences scenarios such as a fire, an earthquake, and a slow flood, representing distinct MS disease states. A fire illustrates an MS relapse with good recovery, where serum NfL levels rise during the relapse and subsequently return near baseline. An earthquake represents an MS relapse with poor recovery, where NfL levels increase and remain elevated above baseline. Finally, a slow flood depicts MS in progressive stages, characterized by sustained and gradually increasing serum NfL levels without abrupt clinical changes. This approach offers a clear and relatable visualization for clinicians and patients alike, illustrating the dynamics of serum NfL levels during CNS damage caused by demyelination. By integrating this model into clinical practice, we aim to enhance understanding and communication regarding the role of NfL in MS pathology and its potential utility as a biomarker.<\/jats:p>","DOI":"10.3390\/neurolint17040056","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T10:05:51Z","timestamp":1744365951000},"page":"56","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Neurofilament Light Chain and Multiple Sclerosis: Building a Neurofoundational Model of Biomarkers and Diagnosis"],"prefix":"10.3390","volume":"17","author":[{"given":"Rany","family":"Aburashed","sequence":"first","affiliation":[{"name":"Insight Hospital and Medical Center, Chicago, IL 60616, USA"},{"name":"Neurogen Biomarking LLC, Dover, DE 19901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9160-3549","authenticated-orcid":false,"given":"Ansam","family":"Eghzawi","sequence":"additional","affiliation":[{"name":"Insight Hospital and Medical Center, Chicago, IL 60616, USA"},{"name":"Neurogen Biomarking LLC, Dover, DE 19901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Long","sequence":"additional","affiliation":[{"name":"Memorial Healthcare, Owosso, MI 48867, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Pace","sequence":"additional","affiliation":[{"name":"Memorial Healthcare, Owosso, MI 48867, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Madha","sequence":"additional","affiliation":[{"name":"Insight Hospital and Medical Center, Chicago, IL 60616, USA"},{"name":"Insight Institute of Neurology and Neurosurgery, Flint, MI 48507, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanie","family":"Cote","sequence":"additional","affiliation":[{"name":"Memorial Healthcare, Owosso, MI 48867, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,11]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Multiple sclerosis","volume":"4","author":"Filippi","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S1474-4422(14)70267-4","article-title":"Environmental risk factors and multiple sclerosis: An umbrella review of systematic reviews and meta-analyses","volume":"14","author":"Belbasis","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2120","DOI":"10.1212\/WNL.0000000000200258","article-title":"Blood neurofilament light in progressive multiple sclerosis","volume":"98","author":"Leppert","year":"2022","journal-title":"Neurology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S1474-4422(13)70233-3","article-title":"Body fluid biomarkers in multiple sclerosis","volume":"13","author":"Comabella","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1474-4422(17)30470-2","article-title":"Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria","volume":"17","author":"Thompson","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e1007","DOI":"10.1212\/WNL.0000000000007032","article-title":"Blood neurofilament light chain as a biomarker of MS disease activity and treatment response","volume":"92","author":"Kuhle","year":"2019","journal-title":"Neurology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.msard.2019.07.025","article-title":"Cerebrospinal fluid neurofilament light chain predicts disease activity after the first demyelinating event suggestive of multiple sclerosis","volume":"35","author":"Gaetani","year":"2019","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/s41582-018-0058-z","article-title":"Neurofilaments as biomarkers in neurological disorders","volume":"14","author":"Khalil","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1002\/acn3.325","article-title":"Neurofilament light chain: A biomarker for genetic frontotemporal dementia","volume":"3","author":"Meeter","year":"2016","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/nan.12511","article-title":"Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with amyotrophic lateral sclerosis","volume":"45","author":"Gille","year":"2019","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1212\/WNL.0000000000003912","article-title":"Serum neurofilament light as a biomarker for mild traumatic brain injury in contact sports","volume":"88","author":"Shahim","year":"2017","journal-title":"Neurology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1111\/ene.13554","article-title":"Serum neurofilament light chain in patients with acute cerebrovascular events","volume":"25","author":"Katan","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1001\/jamaneurol.2015.3037","article-title":"Association of cerebrospinal fluid neurofilament light concentration with Alzheimer disease progression","volume":"73","author":"Zetterberg","year":"2016","journal-title":"JAMA Neurol."},{"key":"ref_14","first-page":"e827","article-title":"NfL as a biomarker for neurodegeneration and survival in Parkinson disease","volume":"95","author":"Linder","year":"2020","journal-title":"Neurology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e33","DOI":"10.1111\/ane.12151","article-title":"Neurofilament light and heavy subunits compared as therapeutic biomarkers in multiple sclerosis","volume":"128","author":"Kuhle","year":"2013","journal-title":"Acta Neurol. Scand."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e422","DOI":"10.1212\/NXI.0000000000000422","article-title":"Neurofilament light chain predicts disease activity in relapsing-remitting MS","volume":"5","author":"Varhaug","year":"2018","journal-title":"Neurol. Neuroimmunol. Neuroinflammation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1002\/acn3.638","article-title":"Neurofilament light chain serum levels correlate with 10-year MRI outcomes in multiple sclerosis","volume":"5","author":"Chitnis","year":"2018","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1212\/WNL.0000000000001491","article-title":"Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis","volume":"84","author":"Kuhle","year":"2015","journal-title":"Neurology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1177\/1352458517715132","article-title":"Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod","volume":"24","author":"Piehl","year":"2018","journal-title":"Mult. Scler."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1212\/WNL.0000000000003653","article-title":"Serum neurofilament is associated with progression of brain atrophy and disability in early MS","volume":"88","author":"Kuhle","year":"2017","journal-title":"Neurology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S24-002","DOI":"10.1212\/WNL.90.15_supplement.S24.002","article-title":"Interim analysis of the OBOE (ocrelizumab biomarker outcome evaluation) study in multiple sclerosis (MS)","volume":"90","author":"Gelfand","year":"2018","journal-title":"Neurology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1093\/brain\/awy154","article-title":"Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis","volume":"141","author":"Barro","year":"2018","journal-title":"Brain"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s12035-008-8033-0","article-title":"Review of the multiple aspects of neurofilament functions, and their possible contribution to neurodegeneration","volume":"38","author":"Perrot","year":"2008","journal-title":"Mol. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1242\/jcs.104729","article-title":"Neurofilaments at a glance","volume":"125","author":"Yuan","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1083\/jcb.133.5.1061","article-title":"Subunit composition of neurofilaments specifies axonal diameter","volume":"133","author":"Xu","year":"1996","journal-title":"J. Cell Biol."},{"key":"ref_26","unstructured":"Skolnick, N., and Alves, W. (2018). The use of blood-based biomarkers to improve the design of clinical trials of traumatic brain injury. Handbook of Neuroemergency Clinical Trials, Academic Press. [2nd ed.]."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1126\/science.279.5350.514","article-title":"A structural scaffolding of intermediate filaments in health and disease","volume":"279","author":"Fuchs","year":"1998","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Varhaug, K.N., Torkildsen, \u00d8., Myhr, K.M., and Vedeler, C.A. (2019). Neurofilament light chain as a biomarker in multiple sclerosis. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.00338"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1136\/jnnp-2018-319190","article-title":"Cerebrospinal fluid neurofilament light chain in multiple sclerosis and its subtypes: A meta-analysis of case-control studies","volume":"90","author":"Martin","year":"2019","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1001\/jamaneurol.2019.3238","article-title":"Serum neurofilament light chain levels in patients with presymptomatic multiple sclerosis","volume":"77","author":"Bjornevik","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_31","first-page":"1308","article-title":"Neurofilament light chain as a biomarker for diagnosis of multiple sclerosis","volume":"20","author":"Kouchaki","year":"2021","journal-title":"EXCLI J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1136\/jnnp-2018-320106","article-title":"Neurofilament light chain as a biomarker in neurological disorders","volume":"90","author":"Gaetani","year":"2019","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ferreira-Atuesta, C., Reyes, S., Giovannoni, G., and Gnanapavan, S. (2021). The evolution of neurofilament light chain in multiple sclerosis. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.642384"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1002\/ana.24954","article-title":"Serum neurofilament light: A biomarker of neuronal damage in multiple sclerosis","volume":"81","author":"Disanto","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Lee, S., Plavina, T., Singh, C.M., Xiong, K., Qiu, X., Rudick, R.A., Calabresi, P.A., Stevenson, L., Graham, D., and Raitcheva, D. (2022). Development of a highly sensitive neurofilament light chain assay on an automated immunoassay platform. Front. Neurol., 13.","DOI":"10.3389\/fneur.2022.935382"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.jim.2004.11.015","article-title":"An enzyme immunoassay to quantify neurofilament light chain in cerebrospinal fluid","volume":"296","author":"Rosengren","year":"2005","journal-title":"J. Immunol. Methods"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Schubert, S., Arendt, L.M., Zhou, W., Baig, S., Walter, S.R., Buchsbaum, R.J., Kuperwasser, C., and Walt, D.R. (2015). Ultra-sensitive protein detection via single molecule arrays towards early stage cancer monitoring. Sci. Rep., 5.","DOI":"10.1038\/srep11034"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1136\/jnnp.60.1.27","article-title":"A study of oligoclonal band negative multiple sclerosis","volume":"60","author":"Zeman","year":"1996","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1136\/jnnp-2012-304695","article-title":"Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically isolated syndromes: A meta-analysis of prevalence, prognosis, and effect of latitude","volume":"84","author":"Dobson","year":"2013","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.2147\/NDT.S173280","article-title":"Neurofilament light chain as a biological marker for multiple sclerosis: A meta-analysis study","volume":"14","author":"Cai","year":"2018","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e200052","DOI":"10.1212\/NXI.0000000000200052","article-title":"Serum GFAP and NfL Levels Differentiate Subsequent Progression and Disease Activity in Patients with Progressive multiple sclerosis","volume":"10","author":"Barro","year":"2022","journal-title":"Neurol. Neuroimmunol. Neuroinflammation"},{"key":"ref_42","unstructured":"(2024, December 26). Cleveland Clinic. (n.d.). Neurofilament Light Chain Fact Sheet. Available online: https:\/\/my.clevelandclinic.org\/departments\/neurological\/depts\/multiple-sclerosis\/ms-approaches\/neurofilament-light-chain."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1177\/1352458515623365","article-title":"Serum neurofilament light chain in early relapsing-remitting MS is increased and correlates with CSF levels and with MRI measures of disease severity","volume":"22","author":"Kuhle","year":"2016","journal-title":"Mult. Scler. J."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Coppens, S., Lehmann, S., Hopley, C., and Hirtz, C. (2023). Neurofilament-light, a promising biomarker: Analytical, metrological, and clinical challenges. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241411624"},{"key":"ref_45","first-page":"e733","article-title":"Prognostic value of serum neurofilaments in patients with clinically isolated syndromes","volume":"92","author":"Martinelli","year":"2019","journal-title":"Neurology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1001\/jamaneurol.2023.3997","article-title":"Neurofilament light chain elevation and disability progression in multiple sclerosis","volume":"80","author":"Abdelhak","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1177\/1352458509359725","article-title":"Neurofilament light as a prognostic marker in multiple sclerosis","volume":"16","author":"Salzer","year":"2010","journal-title":"Mult. Scler. J."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Bar-Or, A., Thanei, G.-A., Harp, C., Bernasconi, C., Bonati, U., Cross, A.H., Fischer, S., Gaetano, L., Hauser, S.L., and Hendricks, R. (2023). Blood neurofilament light levels predict non-relapsing progression following anti-CD20 therapy in relapsing and primary progressive multiple sclerosis: Findings from the ocrelizumab randomized, double-blind phase 3 clinical trials. EBioMedicine, 93.","DOI":"10.1016\/j.ebiom.2023.104662"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1212\/WNL.0000000000010346","article-title":"Serum neurofilament light as a biomarker in progressive multiple sclerosis","volume":"95","author":"Kapoor","year":"2020","journal-title":"Neurology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1002\/acn3.51234","article-title":"Blood neurofilament light: A critical review of its application to neurologic disease","volume":"7","author":"Barro","year":"2020","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e000395","DOI":"10.1136\/bmjno-2022-000395","article-title":"Neurofilament light oligomers in neurodegenerative diseases: Quantification by homogeneous immunoassay in cerebrospinal fluid","volume":"5","author":"Meda","year":"2023","journal-title":"BMJ Neurol. Open"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"986","DOI":"10.2337\/dc23-2208","article-title":"Longitudinal change in serum neurofilament light chain in type 2 diabetes and early diabetic polyneuropathy: ADDITION-Denmark","volume":"47","author":"Andersen","year":"2024","journal-title":"Diabetes Care"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Meeker, K.L., Butt, O.H., Gordon, B.A., Fagan, A.M., Schindler, S.E., Morris, J.C., Benzinger, T.L.S., and Ances, B.M. (2022). Cerebrospinal fluid neurofilament light chain is a marker of aging and white matter damage. Neurobiol. Dis., 166.","DOI":"10.1016\/j.nbd.2022.105662"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e279","DOI":"10.1212\/NXI.0000000000000279","article-title":"The topographical model of multiple sclerosis: A dynamic visualization of disease course. Neurol","volume":"3","author":"Krieger","year":"2016","journal-title":"Neuroimmunol. Neuroinflamm."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1177\/1352458518765666","article-title":"Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis","volume":"25","author":"Siller","year":"2019","journal-title":"Mult. Scler. J."}],"container-title":["Neurology International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2035-8377\/17\/4\/56\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:12:53Z","timestamp":1760029973000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2035-8377\/17\/4\/56"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,11]]},"references-count":55,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["neurolint17040056"],"URL":"https:\/\/doi.org\/10.3390\/neurolint17040056","relation":{},"ISSN":["2035-8377"],"issn-type":[{"value":"2035-8377","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,11]]}}}