{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T10:55:03Z","timestamp":1785495303908,"version":"3.56.0"},"reference-count":67,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T00:00:00Z","timestamp":1774051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"King Edward Medical University, Lahore","award":["09\/2023-24\/RGC"],"award-info":[{"award-number":["09\/2023-24\/RGC"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Circulating cytokines and their soluble receptors in body fluids have been implicated in the pathogenesis of multiple sclerosis (MS). Alterations in serum levels of pro- and anti-inflammatory cytokines and\/or their soluble receptors can dysregulate central nervous system (CNS) signaling pathways and, therefore, may serve as potential biomarkers for the diagnosis of MS. Therefore, the primary end-point of this study is to investigate the utility of various cytokines and their soluble receptors as diagnostic biomarkers in MS. The secondary outcome is also to assess whether these cytokines are useful in differentiating the severity of MS. Methods: In this case\u2013control study, we compared a panel of pro-inflammatory interleukins (ILs), including IL18 and tumor necrosis factor-alpha (TNF\u03b1), soluble IL receptors (sIL7R\u03b1 and sIL2R\u03b1), and insulin-like growth factor-1 (IGF-1) in 45 MS patients and in 45 healthy control individuals matched for sex and age. Associations of these biomarkers with age, disease severity (Expanded Disability Status Scale [EDSS]), disease duration, and age at first MS symptom onset were also assessed. Results: Serum levels of cytokines and soluble IL receptors were elevated in MS patients compared to healthy controls. IGF-1 was lower (p &lt; 0.001) in the MS patients than in the healthy individuals. The serum level of IGF-1 was higher (p &lt; 0.01) in the remitting-relapsing phase compared to the primary progression and secondary progression stages. Similarly, only IGF-1 was more elevated (p &lt; 0.01) in the mild stage compared to the moderate stage based on the EDSS score. Receiver operating characteristic (ROC) curve analysis demonstrated that IL18 had excellent discriminatory power for the diagnosis of MS (p &lt; 0.001), with an area under the curve (AUC) of 0.96 \u00b1 0.017, followed by IGF-1 (p &lt; 0.001), which showed strong diagnostic performance (AUC = 0.873 \u00b1 0.037). Soluble (s) IL2R\u03b1 exhibited fair diagnostic accuracy (p &lt; 0.001; AUC = 0.717 \u00b1 0.054). In contrast, sIL7R\u03b1 and TNF\u03b1 showed poor discriminatory power despite statistical significance (p &lt; 0.01), with AUC values of 0.675 \u00b1 0.057 and 0.687 \u00b1 0.056, respectively. Results of regression analysis revealed that EDSS, duration of disease, and use of any treatment had no impact on the cytokines. Similarly, no significant correlations were noted between these confounders and cytokines, except a moderate negative correlation (\u22120.418) between IGF-1 and EDSS. Conclusions: IL18 and IGF-1 have the potential to be used as biomarkers in distinguishing MS from healthy individuals. However, both biomarkers failed to demonstrate the discrimination between various phenotypic patterns of disease, limiting their utility for disease stratification. Future studies with larger, longitudinal cohorts and multi-marker panels are warranted to validate these results and to explore whether combining cytokines with imaging or genetic markers can improve prognostic precision.<\/jats:p>","DOI":"10.3390\/jcm15062397","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T09:48:42Z","timestamp":1774259322000},"page":"2397","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Circulating Proinflammatory Cytokines and Soluble Cytokine Receptors as Diagnostic Biomarkers in Multiple Sclerosis"],"prefix":"10.3390","volume":"15","author":[{"given":"Safia","family":"Bano","sequence":"first","affiliation":[{"name":"Department of Neurology, King Edward Medical University, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nakhshab","family":"Choudhry","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, King Edward Medical University, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahsan","family":"Numan","sequence":"additional","affiliation":[{"name":"Department of Neurology, King Edward Medical University, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4379-0578","authenticated-orcid":false,"given":"Aamir Jamal","family":"Gondal","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, King Edward Medical University, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3783-6093","authenticated-orcid":false,"given":"Nighat","family":"Yasmin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, King Edward Medical University, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1177\/1352458517694432","article-title":"MSCOI Study Group. New insights into the burden and costs of multiple sclerosis in Europe","volume":"23","author":"Kobelt","year":"2017","journal-title":"Mult. Scler. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1002\/acn3.50862","article-title":"Environmental and genetic risk factors for MS: An integrated review","volume":"6","author":"Waubant","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Khan, A.W., Farooq, M., Hwang, M.J., Haseeb, M., and Choi, S.J. (2023). Autoimmune neuroinflammatory diseases: Role of interleukins. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24097960"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.3892\/mmr.2013.1256","article-title":"Cytokine profile in relapsing-remitting multiple sclerosis patients and the association between progression and activity of the disease","volume":"7","author":"Kallaur","year":"2013","journal-title":"Mol. Med. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ihim, S.A., Abubakar, S.D., Zian, Z., Sasaki, T., Saffarioun, M., Maleknia, S., and Azizi, G. (2022). Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.919973"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1186\/s12974-024-03193-6","article-title":"The contribution of tumor necrosis factor to multiple sclerosis: A possible role in progression independent of relapse?","volume":"21","author":"Mazziotti","year":"2024","journal-title":"J. Neuroinflamm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100123","DOI":"10.1016\/j.jtauto.2021.100123","article-title":"The IL-2\u2013IL-2 receptor pathway: Key to understanding multiple sclerosis","volume":"4","author":"Peerlings","year":"2021","journal-title":"J. Transl. Autoimmun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/gene.2012.34","article-title":"Decreased systemic IL-7 and soluble IL-7R\u03b1 in multiple sclerosis patients","volume":"13","author":"Kreft","year":"2012","journal-title":"Genes Immun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1191\/1352458505ms1123oa","article-title":"Serum levels of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in relapsing and primary progressive multiple sclerosis","volume":"11","author":"Wilczak","year":"2005","journal-title":"Mult. Scler. J."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Yaghoobpoor, S., Fathi, M., Vakili, K., Sayehmiri, F., Alipour, M., and Miriran, Z. (2024). Insulin-like growth factor-1 (IGF-1) levels in multiple sclerosis patients: A systematic review and meta-analysis. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0297091"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"137","DOI":"10.13005\/bpj\/2349","article-title":"The role of the proinflammatory and anti-inflammatory cytokines in multiple sclerosis","volume":"15","author":"Vani","year":"2022","journal-title":"Biomed. Pharmacol. J."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Grunwald, C., Kr\u0119towska-Grunwald, A., Adamska-Patruno, E., Kochanowicz, J., Ku\u0142akowska, A., and Chor\u0105\u017cy, M. (2024). The role of selected interleukins in the development and progression of multiple sclerosis\u2014A systematic review. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25052589"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1016\/S0140-6736(18)30481-1","article-title":"Multiple sclerosis","volume":"391","author":"Thompson","year":"2018","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"380","DOI":"10.7861\/clinmed.2020-0292","article-title":"Clinical presentation and diagnosis of multiple sclerosis","volume":"20","author":"Ford","year":"2020","journal-title":"Clin. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"359","DOI":"10.3988\/jcn.2018.14.3.359","article-title":"Clinical presentations and phenotypic spectrum of multiple sclerosis at a University Hospital in Saudi Arabia","volume":"14","author":"Nazish","year":"2018","journal-title":"J. Clin. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Liu, X., and Quan, N. (2018). Microglia and CNS interleukin-1: Beyond immunological concepts. Front. Neurol., 9.","DOI":"10.3389\/fneur.2018.00008"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1034\/j.1600-0404.2001.00356.x","article-title":"IL-18 in patients with multiple sclerosis","volume":"104","author":"Losy","year":"2001","journal-title":"Acta Neurol. Scand."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1212\/WNL.57.2.342","article-title":"Increased serum levels of interleukin-18 in patients with multiple sclerosis","volume":"57","author":"Nicoletti","year":"2001","journal-title":"Neurology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jneuroim.2011.12.008","article-title":"Serum levels of interleukin (IL)-18, IL-23 and IL-17 in Chinese patients with multiple sclerosis","volume":"243","author":"Chen","year":"2012","journal-title":"J. Neuroimmunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"474","DOI":"10.4103\/aian.AIAN_515_18","article-title":"Interleukin 18 polymorphisms and its serum level in patients with multiple sclerosis","volume":"22","author":"Alsahebfosoul","year":"2019","journal-title":"Ann. Indian Acad. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1212\/WNL.53.5.1104","article-title":"Interferon-\u03b3\u2013inducing factor (IL-18) and interferon-\u03b3 in inflammatory CNS diseases","volume":"53","author":"Fassbender","year":"1999","journal-title":"Neurology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.clineuro.2016.04.027","article-title":"The association of IL-18 gene promoter polymorphisms and the levels of serum IL-18 on the risk of multiple sclerosis","volume":"146","author":"Orhan","year":"2016","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1080\/01616412.2017.1420522","article-title":"Circulating levels of interleukin-17A, tumor necrosis factor-alpha, interleukin-18, interleukin-10, and cognitive performance of patients with relapsing-remitting multiple sclerosis","volume":"40","author":"Trenova","year":"2018","journal-title":"Neurol. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1007\/s11033-013-3013-5","article-title":"Interleukin 18 gene polymorphism is a risk factor for multiple sclerosis","volume":"41","author":"Dursun","year":"2014","journal-title":"Mol. Biol. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1590\/S0004-282X2005000600002","article-title":"Cytokines and intrathecal IgG synthesis in multiple sclerosis patients during clinical remission","volume":"63","author":"Ruocco","year":"2005","journal-title":"Arq. Neuro-Psiquiatr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"151","DOI":"10.2298\/VSP1202151O","article-title":"Tumor necrosis factor-alfa and interleukin-4 in cerebrospinal fluid and plasma in different clinical forms of multiple sclerosis","volume":"69","author":"Kataranovski","year":"2012","journal-title":"Vojn. Pregl."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1007\/s00011-019-01286-0","article-title":"Tumor necrosis factor alpha (TNF-\u03b1) and its soluble receptors are associated with disability, disability progression and clinical forms of multiple sclerosis","volume":"68","author":"Ribeiro","year":"2019","journal-title":"Inflamm. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1590\/S0004-282X2001000100005","article-title":"Determination of soluble ICAM-1 and TNFalphaR in the cerebrospinal fluid and serum levels in a population of Brazilian patients with relapsing-remitting multiple sclerosis","volume":"59","author":"Batista","year":"2001","journal-title":"Arq. Neuro-Psiquiatr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1001\/archneur.55.6.793","article-title":"Increased production of tumor necrosis factor \u03b1, and not of interferon \u03b3, preceding disease activity in patients with multiple sclerosis","volume":"55","author":"Barkhof","year":"1998","journal-title":"Arch. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1007\/s00415-006-0090-6","article-title":"TNF\u2013\u03b1 converting enzyme (TACE) protein expression in different clinical subtypes of multiple sclerosis","volume":"253","author":"Comabella","year":"2006","journal-title":"J. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"29","DOI":"10.2478\/v10153-010-0034-x","article-title":"Clinical and laboratory study of pro-inflammatory and anti-inflammatory cytokines in women with multiple sclerosis","volume":"53","author":"Trenova","year":"2011","journal-title":"Folia Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/ng.401","article-title":"Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci","volume":"41","author":"Jia","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1006\/cyto.2002.1984","article-title":"Cerebrospinal fluid and serum protein levels of tumor necrosis factor-alpha (TNF-\u03b1), interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R gp80) in multiple sclerosis patients","volume":"20","author":"Horvat","year":"2002","journal-title":"Cytokine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1056\/NEJM198810133191518","article-title":"Elevated levels of soluble interleukin-2 receptors in multiple sclerosis","volume":"319","author":"Greenberg","year":"1988","journal-title":"N. Eng. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/0022-510X(89)90171-8","article-title":"Immune activation in multiple sclerosis: Study of IL-2, sIL-2R, and \u03b3-IFN levels in serum and cerebrospinal fluid","volume":"92","author":"Gallo","year":"1989","journal-title":"J. Neurol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/S0140-6736(89)90103-7","article-title":"Interleukin-2 receptor levels indicating relapse in multiple sclerosis","volume":"333","author":"Adachi","year":"1989","journal-title":"Lancet"},{"key":"ref_37","first-page":"687","article-title":"Elevated soluble interleukin-2 receptor levels in patients with active multiple sclerosis","volume":"28","author":"Adachi","year":"1990","journal-title":"Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.4049\/jimmunol.182.3.1541","article-title":"Soluble IL-2RA levels in multiple sclerosis subjects and the effect of soluble IL-2RA on immune responses","volume":"182","author":"Maier","year":"2009","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.cyto.2017.04.024","article-title":"Relationship between soluble CD25 and gene expression in healthy individuals and patients with multiple sclerosis","volume":"93","author":"Buhelt","year":"2017","journal-title":"Cytokine"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/0165-5728(91)90031-2","article-title":"Serum cytokine levels in chronic progressive multiple sclerosis: Interleukin-2 levels parallel tumor necrosis factor-\u03b1 levels","volume":"33","author":"Trotter","year":"1991","journal-title":"J. Neuroimmunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"100750","DOI":"10.1016\/j.mgene.2020.100750","article-title":"Association between interleukin 2 receptor A gene polymorphisms (rs2104286 and rs12722489) with susceptibility to multiple sclerosis in Iranian population","volume":"25","author":"Pourakbari","year":"2020","journal-title":"Meta Gene"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Lu, H., Wu, P.F., Zhang, W., and Liao, X. (2021). Circulating interleukins and risk of multiple sclerosis: A Mendelian randomization study. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.647588"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"123461","DOI":"10.1016\/j.jns.2025.123461","article-title":"Association of IL2RA and multiple sclerosis risk: A case control, systematic review, and meta-analysis study","volume":"10","author":"Rangani","year":"2025","journal-title":"J. Neurol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1136\/jnnp.56.2.169","article-title":"Correlation of interleukin-2 and soluble interleukin-2 receptor with clinical activity of multiple sclerosis","volume":"56","author":"Sharief","year":"1993","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"102687","DOI":"10.1016\/j.msard.2020.102687","article-title":"Association between IL7 Receptor Alpha (Il7ra) gene rs6897932 polymorphism and the risk of Multiple Sclerosis: A meta-regression and meta-analysis","volume":"48","author":"Omraninava","year":"2021","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.neulet.2017.01.068","article-title":"The expression of lnc-IL-7R long non-coding RNA dramatically correlated with soluble and membrane-bound isoforms of IL-7Ra gene in multiple sclerosis patients","volume":"642","author":"Bina","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0165-5728(01)00308-3","article-title":"In vivo gene expression revealed by cDNA arrays: The pattern in relapsing\u2013remitting multiple sclerosis patients compared with normal subjects","volume":"116","author":"Ramanathan","year":"2001","journal-title":"J. Neuroimmunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"47","DOI":"10.2147\/ITT.S264149","article-title":"Soluble IL-7R\u03b1\/sCD127 in health, disease, and its potential role as a therapeutic agent","volume":"8","author":"Barros","year":"2021","journal-title":"Immuno. Targets Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.clim.2017.08.023","article-title":"Multiple sclerosis treatment effects on plasma cytokine receptor levels","volume":"187","author":"Bedri","year":"2018","journal-title":"Clin. Immunol."},{"key":"ref_50","first-page":"E1761","article-title":"Soluble IL7R\u03b1 potentiates IL-7 bioactivity and promotes autoimmunity","volume":"110","author":"Highfill","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1007\/s00580-015-2064-5","article-title":"The expression of IL-7RA in Egyptian patients with multiple sclerosis","volume":"24","author":"Elshafie","year":"2015","journal-title":"Comp. Clin. Pathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"19260","DOI":"10.1038\/s41598-021-98691-5","article-title":"Expression and clinical significance of IL7R, NFATc2, and RNF213 in familial and sporadic multiple sclerosis","volume":"11","author":"Imani","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.clineuro.2005.11.014","article-title":"Growth hormone and insulin growth factor-I levels in plasma and cerebrospinal fluid of patients with multiple sclerosis","volume":"108","author":"Poljakovic","year":"2006","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.msard.2017.02.002","article-title":"Novel functional polymorphism in IGF-1 gene associated with multiple sclerosis: A new insight to MS","volume":"13","author":"Shahbazi","year":"2017","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1212\/WNL.50.3.772","article-title":"The peripheral insulin-like growth factor system in amyotrophic lateral sclerosis and in multiple sclerosis","volume":"50","author":"Barrios","year":"1998","journal-title":"Neurology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/S0304-3940(98)00829-5","article-title":"Insulin-like growth factor system in serum and cerebrospinal fluid in patients with multiple sclerosis","volume":"257","author":"Wilczak","year":"1998","journal-title":"Neurosci. Lett."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1111\/j.1468-1331.2011.03433.x","article-title":"Insulin-like growth factor (IGF)-I and IGF-binding protein-3 serum levels in relapsing\u2013remitting and secondary progressive multiple sclerosis patients","volume":"18","author":"Lanzillo","year":"2011","journal-title":"Eur. J. Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1080\/01616412.2017.1321711","article-title":"Circulating IGF-1, IGFB-3, GH and TSH levels in multiple sclerosis and their relationship with treatment","volume":"39","author":"Akcali","year":"2017","journal-title":"Neurol. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.ghir.2007.06.002","article-title":"Circulating insulin-like growth factors and related binding proteins are selectively altered in amyotrophic lateral sclerosis and multiple sclerosis","volume":"17","author":"Hosback","year":"2007","journal-title":"Growth Horm. IGF Res."},{"key":"ref_60","first-page":"68","article-title":"Evaluation of insulin-like growth factor 1 (IGF-1) and selected biochemical markers in Iraqi patients with multiple sclerosis","volume":"42","author":"Ghassan","year":"2017","journal-title":"Int. J. Pharm. Sci. Rev. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"106281","DOI":"10.1016\/j.msard.2025.106281","article-title":"Circulating insulin-like growth factor-1 and the risk of multiple sclerosis: A prospective cohort study","volume":"94","author":"Pang","year":"2025","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_62","first-page":"836486","article-title":"Growth hormone and disease severity in early stage of multiple sclerosis","volume":"2013","author":"Gironi","year":"2013","journal-title":"Mult. Scler. Int."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s41983-018-0026-y","article-title":"Serum insulin-like growth factor 1 (IGF-1) in multiple sclerosis: Relation to cognitive impairment and fatigue","volume":"54","author":"Nageeb","year":"2018","journal-title":"Egypt. J. Neurol. Psychiatry Neurosurg."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/0896-6273(93)90173-O","article-title":"Insulin-like growth factor I increases brain growth and central nervous system myelination in Transgenic mice","volume":"10","author":"Carson","year":"1993","journal-title":"Neuron"},{"key":"ref_65","first-page":"35","article-title":"Mouse models of IGF-I deficiency generated by gene targeting","volume":"5","author":"Warburton","year":"1995","journal-title":"Receptor"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.1600-0404.2004.00223.x","article-title":"Cerebrospinal fluid insulin-like growth factor-1, insulin growth factor binding protein-2 or nitric oxide are not increased in MS or ALS","volume":"109","author":"Vanhatalo","year":"2004","journal-title":"Acta Neurol. Scand."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.expneurol.2005.04.016","article-title":"Immunosuppressants: Neuroprotection and promoting neurological recovery following peripheral nerve and spinal cord lesions","volume":"195","author":"Sosa","year":"2005","journal-title":"Exp. Neurol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/6\/2397\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T10:10:49Z","timestamp":1774260649000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/6\/2397"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,21]]},"references-count":67,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["jcm15062397"],"URL":"https:\/\/doi.org\/10.3390\/jcm15062397","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,21]]}}}