{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T20:14:23Z","timestamp":1787170463829,"version":"build-2736575974"},"reference-count":48,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["MS190096"],"award-info":[{"award-number":["MS190096"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>To evaluate frailty in severe progressive multiple sclerosis (PMS) and to investigate the underlying mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This prospective, cross\u2010sectional, multicenter study enrolled a late severe PMS group requiring skilled nursing (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200953) and an age, sex, and disease duration\u2010matched control PMS group (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200953). Participants received neurological and MRI assessments and provided blood samples. Frailty was measured on the Edmonton Frail Scale. Disability was measured on the Expanded Disability Status Scale (EDSS), and fatigue was assessed on the Fatigue Severity Scale. The inflammatory vulnerability index (IVX) and metabolic vulnerability index (MVX) were computed from nuclear magnetic resonance spectroscopy\u2010derived metabolomic profiling. Serum neurofilament (sNfL), glial fibrillary acidic protein (GFAP), and growth differentiation factor 15 (GDF15) levels were obtained.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The late severe PMS group had a higher median EDSS (8.0 vs. 6.0,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) than the matched control PMS group. The late severe PMS group had a higher prevalence of frailty (73.1% vs. 23.1%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and higher frailty scores (8.87 vs. 5.52,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) than the control PMS group. EFS was associated with EDSS in both PMS groups. Positive frailty status was associated with a 1.19\u2010point greater EDSS (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.012) in the control PMS group and a 0.436\u2010point greater EDSS in the late severe PMS group (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.002). In PMS controls, the EFS and frailty status were associated with IVX (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.044 for EFS) and MVX (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.036 for EFS).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Frailty is positively associated with MS disability. Inflammatory and metabolic vulnerability are associated with frailty in PMS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70243","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T11:52:56Z","timestamp":1763121176000},"page":"654-664","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Frailty Exacerbates Disability in Progressive Multiple Sclerosis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5803-6222","authenticated-orcid":false,"given":"Taylor R.","family":"Wicks","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences University at Buffalo, The State University of New York  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Wolska","sequence":"additional","affiliation":[{"name":"Lipoprotein Metabolism Laboratory, National Heart, Lung, and Blood Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diala","family":"Ghazal","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University at Buffalo, The State University of New York  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dejan","family":"Jakimovski","sequence":"additional","affiliation":[{"name":"Jacobs Multiple Sclerosis Center University at Buffalo, The State University of New York  Buffalo New York USA"},{"name":"Department of Imaging Sciences Strong Memorial Hospital, University of Rochester  Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Weinstock\u2010Guttman","sequence":"additional","affiliation":[{"name":"Jacobs Multiple Sclerosis Center University at Buffalo, The State University of New York  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Burnham","sequence":"additional","affiliation":[{"name":"The Boston Home  Dorchester Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7792-0433","authenticated-orcid":false,"given":"Niels","family":"Bergsland","sequence":"additional","affiliation":[{"name":"Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences University at Buffalo, The State University of New York  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4684-4658","authenticated-orcid":false,"given":"Michael G.","family":"Dwyer","sequence":"additional","affiliation":[{"name":"Jacobs Multiple Sclerosis Center University at Buffalo, The State University of New York  Buffalo New York USA"},{"name":"Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences University at Buffalo, The State University of New York  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan T.","family":"Remaley","sequence":"additional","affiliation":[{"name":"Lipoprotein Metabolism Laboratory, National Heart, Lung, and Blood Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7799-1485","authenticated-orcid":false,"given":"Robert","family":"Zivadinov","sequence":"additional","affiliation":[{"name":"Jacobs Multiple Sclerosis Center University at Buffalo, The State University of New York  Buffalo New York USA"},{"name":"Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences University at Buffalo, The State University of New York  Buffalo New York USA"},{"name":"Center for Biomedical Imaging University at Buffalo, State University of New York  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9943-150X","authenticated-orcid":false,"given":"Murali","family":"Ramanathan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University at Buffalo, The State University of New York  Buffalo New York USA"},{"name":"Jacobs Multiple Sclerosis Center University at Buffalo, The State University of New York  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/56.3.m146"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2024.106157"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2301292"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000000753"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468\u20102667(18)30091\u20104"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458520925369"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458520924595"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaf254"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2023.105345"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1177\/0269216307076333"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/0269216306075112"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cger.2010.08.009"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357\u2010024\u201001101\u20107"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2016.08.006"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12979\u2010023\u201000410\u20103"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2019.11.019"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12883\u2010025\u201004145\u20100"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2666\u20107568(23)00001\u20106"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2023.578268"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2019.116429"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(17)30470\u20102"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000560"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/ageing\/afl041"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1989.00520460115022"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415\u2010024\u201012420\u20102"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1006\/nimg.2002.1040"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2017.06.022"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102318\u20108\u201024"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0271688"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac016"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.3310\/hta4270"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinph.2009.12.013"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacl.2019.06.003"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0218075"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458512458010"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2022.5250"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.52054"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2021.103090"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010020\u201014612\u20106"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl\u20102014\u2010206225"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13513"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu16172866"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu17040640"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.103295"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glu057"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2018.06.032"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jamda.2019.09.001"},{"issue":"2","key":"e_1_2_10_49_1","first-page":"341","article-title":"Regional Brain Atrophy Evolves Differently in Patients With Multiple Sclerosis According to Clinical Phenotype","volume":"26","author":"Pagani E.","year":"2005","journal-title":"AJNR. American Journal of Neuroradiology"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.70243","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acn3.70243","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.70243","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T04:16:57Z","timestamp":1776053817000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.70243"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,14]]},"references-count":48,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/acn3.70243"],"URL":"https:\/\/doi.org\/10.1002\/acn3.70243","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,14]]},"assertion":[{"value":"2025-08-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}