{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T22:22:20Z","timestamp":1773008540801,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T00:00:00Z","timestamp":1719532800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon 2020 research and innovation program","award":["GA101017598"],"award-info":[{"award-number":["GA101017598"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Respiratory dysfunction is an important hallmark of amyotrophic lateral sclerosis (ALS). Elevation of creatine kinase (CK) has been reported in 23\u201375% of ALS patients, but the underlying mechanisms remain unknown. This work aims to enlighten the role of CK as a prognostic factor of respiratory dysfunction in ALS. A retrospective analysis of demographic and clinical variables, CK, functional decline per month (\u0394FS), forced vital capacity (%FVC), and mean amplitude of the phrenic nerve compound motor action potential (pCMAP) in 319 ALS patients was conducted. These measurements were evaluated at study entry, and patients were followed from the moment of first observation until death or last follow-up visit. High CK values were defined as above the 90th percentile (CK \u2265 P90) adjusted to sex. We analyzed survival and time to non-invasive ventilation (NIV) as proxies for respiratory impairment. Linear regression analysis revealed that high CK was associated with male sex (p &lt; 0.001), spinal onset (p = 0.018), and FVC \u2265 80% (p = 0.038). CK was 23.4% higher in spinal-onset ALS patients (p &lt; 0.001). High CK levels were not linked with an increased risk of death (p = 0.334) in Cox multivariate regression analysis. CK \u2265 P90 (HR = 1.001, p = 0.038), shorter disease duration (HR = 0.937, p &lt; 0.001), lower pCMAP (HR = 0.082, p &lt; 0.001), and higher \u0394FS (HR = 1.968, p &lt; 0.001) were risk factors for respiratory failure. The association between high CK levels and poorer respiratory outcomes could derive from cellular metabolic stress or a specific phenotype associated with faster respiratory decline. Our study suggests that CK measurement at diagnosis should be more extensively investigated as a possible marker of poor respiratory outcome in future studies, including a larger population of patients.<\/jats:p>","DOI":"10.3390\/brainsci14070661","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T11:33:53Z","timestamp":1719920033000},"page":"661","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Creatine Kinase and Respiratory Decline in Amyotrophic Lateral Sclerosis"],"prefix":"10.3390","volume":"14","author":[{"given":"Jo\u00e3o Pedro","family":"Correia","sequence":"first","affiliation":[{"name":"Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, 1649-004 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2111-4579","authenticated-orcid":false,"given":"Marta","family":"Gromicho","sequence":"additional","affiliation":[{"name":"Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, 1649-004 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2816-9698","authenticated-orcid":false,"given":"Ana Catarina","family":"Pronto-Laborinho","sequence":"additional","affiliation":[{"name":"Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, 1649-004 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8290-0410","authenticated-orcid":false,"given":"Miguel","family":"Oliveira Santos","sequence":"additional","affiliation":[{"name":"Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, 1649-004 Lisboa, Portugal"},{"name":"Centro de Estudos Egas Moniz, Faculdade de Medicina, Universidade de Lisboa, 1649-004 Lisboa, Portugal"},{"name":"Departamento de Neuroci\u00eancias e Sa\u00fade Mental, Hospital (ULS) de Santa Maria, 1649-028 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7556-0158","authenticated-orcid":false,"given":"Mamede","family":"de Carvalho","sequence":"additional","affiliation":[{"name":"Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, 1649-004 Lisboa, Portugal"},{"name":"Centro de Estudos Egas Moniz, Faculdade de Medicina, Universidade de Lisboa, 1649-004 Lisboa, Portugal"},{"name":"Departamento de Neuroci\u00eancias e Sa\u00fade Mental, Hospital (ULS) de Santa Maria, 1649-028 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5395","DOI":"10.1007\/s00415-022-11195-8","article-title":"Creatine kinase and prognosis in amyotrophic lateral sclerosis: A literature review and multi-centre cohort analysis","volume":"269","author":"Gao","year":"2022","journal-title":"J. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"473","DOI":"10.3109\/21678421.2015.1062516","article-title":"Relationship of creatine kinase to body composition, disease state, and longevity in ALS","volume":"16","author":"Gibson","year":"2015","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/art.1780260212","article-title":"Elevation of creatine kinase in amyotrophic lateral sclerosis","volume":"26","author":"Harrington","year":"1983","journal-title":"Arthritis Rheum."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1111\/ene.12995","article-title":"Creatine kinase enzyme level correlates positively with serum creatinine and lean body mass, and is a prognostic factor for survival in amyotrophic lateral sclerosis","volume":"23","author":"Rafiq","year":"2016","journal-title":"Eur. J. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1152\/physrev.00031.2010","article-title":"Fiber types in Mammalian skeletal muscles","volume":"91","author":"Schiaffino","year":"2011","journal-title":"Physiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1007\/s00726-011-0851-0","article-title":"Neuroprotective effects of creatine","volume":"40","author":"Beal","year":"2011","journal-title":"Amino Acids"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1007\/s00726-011-0854-x","article-title":"Systems bioenergetics of creatine kinase networks: Physiological roles of creatine and phosphocreatine in regulation of cardiac cell function","volume":"40","author":"Guzun","year":"2011","journal-title":"Amino Acids"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s12017-008-8053-y","article-title":"Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases","volume":"10","author":"Adhihetty","year":"2008","journal-title":"NeuroMolecular Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Hertel, N., Kuzma-Kozakiewicz, M., Gromicho, M., Grosskreutz, J., de Carvalho, M., Uysal, H., Dengler, R., Petri, S., and K\u00f6rner, S. (2022). Analysis of routine blood parameters in patients with amyotrophic lateral sclerosis and evaluation of a possible correlation with disease progression\u2014A multicenter study. Front. Neurol., 13.","DOI":"10.3389\/fneur.2022.940375"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1016\/j.clinph.2018.01.071","article-title":"Creatine kinase level and its relationship with quantitative electromyographic characteristics in amyotrophic lateral sclerosis","volume":"129","author":"Tai","year":"2018","journal-title":"Clin. Neurophysiol."},{"key":"ref_11","first-page":"189","article-title":"Increased creatine kinase and spontaneous activity on electromyography, in amyotrophic lateral sclerosis","volume":"43","author":"Lima","year":"2003","journal-title":"Electromyogr. Clin. Neurophysiol."},{"key":"ref_12","first-page":"293","article-title":"El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis","volume":"1","author":"Brooks","year":"2000","journal-title":"Amyotroph. Lateral Scler."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1212\/01.wnl.0000194316.91908.8a","article-title":"Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS","volume":"66","author":"Kimura","year":"2006","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1136\/jnnp-2015-310998","article-title":"Rate of disease progression: A prognostic biomarker in ALS","volume":"87","author":"Labra","year":"2016","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1093\/ajcn\/72.3.694","article-title":"Healthy percentage body fat ranges: An approach for developing guidelines based on body mass index","volume":"72","author":"Gallagher","year":"2000","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1016\/j.clnu.2018.08.014","article-title":"Resting energy expenditure equations in amyotrophic lateral sclerosis, creation of an ALS-specific equation","volume":"38","author":"Marin","year":"2019","journal-title":"Clin. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1183\/09031936.00080312","article-title":"Report of the Global Lung Function Initiative (GLI), ERS Task Force to establish improved Lung Function Reference Values, includng supplement","volume":"40","author":"Quanjer","year":"2013","journal-title":"Eur. Respir. J"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1080\/21678421.2021.1895842","article-title":"Phrenic nerve study as outcome in clinical trials for amyotrophic lateral sclerosis","volume":"22","author":"Pinto","year":"2021","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.clinph.2009.02.170","article-title":"Predicting respiratory insufficiency in amyotrophic lateral sclerosis: The role of phrenic nerve studies","volume":"120","author":"Pinto","year":"2009","journal-title":"Clin. Neurophysiol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis, Andersen, P.M., Abrahams, S., Borasio, G.D., de Carvalho, M., Chio, A., Van Damme, P., Hardiman, O., Kollewe, K., and Morrison, K.E. (2012). EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis (MALS)\u2014Revised report of an EFNS task force. Eur. J. Neurol., 19, 360\u2013375.","DOI":"10.1111\/j.1468-1331.2011.03501.x"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1212\/WNL.24.9.834","article-title":"Serum creatine phosphokinase in amyotrophic lateral sclerosis: Correlation with sex, duration, and skeletal muscle biopsy","volume":"24","author":"Achari","year":"1974","journal-title":"Neurology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1002\/mus.21310","article-title":"Serum creatine kinase levels in spinobulbar muscular atrophy and amyotrophic lateral sclerosis","volume":"40","author":"Chahin","year":"2009","journal-title":"Muscle Nerve"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4425","DOI":"10.1093\/brain\/awad202","article-title":"Skeletal muscle in amyotrophic lateral sclerosis","volume":"146","author":"Shefner","year":"2023","journal-title":"Brain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1007\/s00415-019-09507-6","article-title":"Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis","volume":"266","author":"Ito","year":"2019","journal-title":"J. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ceccanti, M., Pozzilli, V., Cambieri, C., Libonati, L., Onesti, E., Frasca, V., Fiorini, I., Petrucci, A., Garibaldi, M., and Palma, E. (2020). Creatine Kinase and Progression Rate in Amyotrophic Lateral Sclerosis. Cells, 9.","DOI":"10.3390\/cells9051174"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s13760-022-01936-x","article-title":"Clinical and electrophysiological characteristics of respiratory onset amyotrophic lateral sclerosis: A single-centre study","volume":"123","author":"Chang","year":"2022","journal-title":"Acta Neurol. Belg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1111\/ene.15765","article-title":"Respiratory phenotypes in amyotrophic lateral sclerosis as determined by respiratory questions on the Amyotrophic Lateral Sclerosis Functional Rating Scale\u2013Revised and their relation to respiratory tests","volume":"30","author":"Pinto","year":"2023","journal-title":"Eur. J. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0003-9993(86)90064-X","article-title":"Amyotrophic lateral sclerosis: Relationship between serum creatine kinase level and patient survival","volume":"67","author":"Sinaki","year":"1986","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S30","DOI":"10.1016\/S0022-510X(98)00195-6","article-title":"Creatine kinase values in amyotrophic lateral sclerosis","volume":"160","author":"Felice","year":"1998","journal-title":"J. Neurol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.neulet.2003.09.018","article-title":"Amyotrophic lateral sclerosis: Disease stage related changes of tau protein and S100 beta in cerebrospinal fluid and creatine kinase in serum","volume":"353","author":"Tumani","year":"2003","journal-title":"Neurosci. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1007\/s10072-003-0158-3","article-title":"Creatine kinase activity in amyotrophic lateral sclerosis patients","volume":"24","author":"Stelmasiak","year":"2003","journal-title":"Neurol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1001\/jamaneurol.2014.1129","article-title":"Amyotrophic lateral sclerosis outcome measures and the role of albumin and creatinine: A population-based study","volume":"71","author":"Calvo","year":"2014","journal-title":"JAMA Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e244","DOI":"10.1212\/NXI.0000000000000244","article-title":"Systemic inflammatory response and neuromuscular involvement in amyotrophic lateral sclerosis","volume":"3","author":"Lu","year":"2016","journal-title":"Neurol.\u2013Neuroimmunol. Neuroinflammation"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Tai, H., Cui, L., Guan, Y., Liu, M., Li, X., Shen, D., Li, D., Cui, B., Fang, J., and Ding, Q. (2017). Correlation of creatine kinase levels with clinical features and survival in amyotrophic lateral sclerosis. Front. Neurol., 8.","DOI":"10.3389\/fneur.2017.00322"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Ong, M.L., Tan, P.F., and Holbrook, J.D. (2017). Predicting functional decline and survival in amyotrophic lateral sclerosis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174925"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"965","DOI":"10.14336\/AD.2017.1016","article-title":"Prognostic Nomogram Associated with Longer Survival in Amyotrophic Lateral Sclerosis Patients","volume":"9","author":"Wei","year":"2018","journal-title":"Aging Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1002\/acn3.51299","article-title":"Decreased serum creatinine levels predict short survival in amyotrophic lateral sclerosis","volume":"8","author":"Guo","year":"2021","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"591","DOI":"10.4103\/1673-5374.293159","article-title":"Creatine kinase in the diagnosis and prognostic prediction of amyotrophic lateral sclerosis: A retrospective case-control study","volume":"16","author":"Shang","year":"2021","journal-title":"Neural Regen. Res."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/14\/7\/661\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:07:25Z","timestamp":1760108845000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/14\/7\/661"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,28]]},"references-count":38,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["brainsci14070661"],"URL":"https:\/\/doi.org\/10.3390\/brainsci14070661","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,28]]}}}