Association of postoperative delirium with serum and cerebrospinal fluid proteomic profiles: a prospective cohort study in older hip fracture patients.

Biomarkers CXCL9 Cognitive impairment Delirium Hip fracture Neuroinflammation

Journal

GeroScience
ISSN: 2509-2723
Titre abrégé: Geroscience
Pays: Switzerland
ID NLM: 101686284

Informations de publication

Date de publication:
18 Jan 2024
Historique:
received: 26 05 2023
accepted: 08 01 2024
medline: 18 1 2024
pubmed: 18 1 2024
entrez: 18 1 2024
Statut: aheadofprint

Résumé

Postoperative delirium (POD) is a common neuropsychiatric complication in geriatric inpatients after hip fracture surgery and its occurrence is associated with poor outcomes. The purpose of this study was to investigate the relationship between preoperative biomarkers in serum and cerebrospinal fluid (CSF) and the development of POD in older hip fracture patients, exploring the possibility of integrating objective methods into future predictive models of delirium. Sixty hip fracture patients were recruited. Blood and CSF samples were collected at the time of spinal anesthesia when none of the subjects had delirium. Patients were assessed daily using the 4AT scale, and based on these results, they were divided into POD and non-POD groups. The Olink® platform was used to analyze 45 cytokines. Twenty-one patients (35%) developed POD. In the subsample of 30 patients on whom proteomic analyses were performed, a proteomic profile was associated with the incidence of POD. Chemokine (C-X-C motif) ligand 9 (CXCL9) had the strongest correlation between serum and CSF samples in patients with POD (rho = 0.663; p < 0.05). Although several cytokines in serum and CSF were associated with POD after hip fracture surgery in older adults, there was a significant association with lower preoperative levels of CXCL9 in CSF and serum. Despite the small sample size, this study provides preliminary evidence of the potential role of molecular biomarkers in POD, which may provide a basis for the development of new delirium predictive models.

Identifiants

pubmed: 38236313
doi: 10.1007/s11357-024-01071-w
pii: 10.1007/s11357-024-01071-w
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

© 2024. The Author(s), under exclusive licence to American Aging Association.

Références

Inouye SK, Westendorp RGJ, Saczynski JS, Naeije G, Pepersack T. Delirium in elderly people. Lancet. 2014;383(9920):911–22. https://doi.org/10.1016/S0140-6736(13)60688-1 .
doi: 10.1016/S0140-6736(13)60688-1 pubmed: 23992774
Marcantonio ER. Delirium in hospitalized older adults. N Engl J Med. 2017;377(15):1456–66. https://doi.org/10.1056/nejmcp1605501 .
doi: 10.1056/nejmcp1605501 pubmed: 29020579 pmcid: 5706782
Bruce AJ, Ritchie CW, Blizard R, Lai R, Raven P. The incidence of delirium associated with orthopedic surgery: a meta-analytic review. Int Psychogeriatrics. 2007;19(2):197–214. https://doi.org/10.1017/S104161020600425X .
doi: 10.1017/S104161020600425X
Zhou J, Liu C, Sun Y, Huang W, Ye K. Cognitive disorders associated with hospitalization of COVID-19: results from an observational cohort study. Brain Behav Immun. 2021;91:383–92. https://doi.org/10.1016/j.bbi.2020.10.019 .
doi: 10.1016/j.bbi.2020.10.019 pubmed: 33148439
Oberai T, Woodman R, Laver K, Crotty M, Kerkhoffs G, Jaarsma R. Is delirium associated with negative outcomes in older patients with hip fracture: analysis of the 4904 patients 2017–2018 from the Australian and New Zealand hip fracture registry. ANZ J Surg. 2022;92(1–2):200–5. https://doi.org/10.1111/ans.17421 .
doi: 10.1111/ans.17421 pubmed: 34904334
Maldonado JR. Neuropathogenesis of delirium: review of current etiologic theories and common pathways. Am J Geriatr Psychiatry. 2013;21(12):1190–222. https://doi.org/10.1016/j.jagp.2013.09.005 .
doi: 10.1016/j.jagp.2013.09.005 pubmed: 24206937
Wilson JE, Mart MF, Cunningham C, Shehabi Y, Girard TD, MacLullich AMJ, Slooter AJC, Ely EW. Delirium. Nat Rev Dis Prim. 2020;6(1). https://doi.org/10.1038/s41572-020-00223-4 .
Wang Y, Shen X. Postoperative delirium in the elderly: the potential neuropathogenesis. Aging Clin Exp Res. 2018;30(11):1287–95. https://doi.org/10.1007/s40520-018-1008-8 .
doi: 10.1007/s40520-018-1008-8 pubmed: 30051417
Alam A, Hana Z, Jin Z, Suen KC, Ma D. Surgery, neuroinflammation and cognitive impairment. EBioMedicine. 2018;37:547–56. https://doi.org/10.1016/j.ebiom.2018.10.021 .
doi: 10.1016/j.ebiom.2018.10.021 pubmed: 30348620 pmcid: 6284418
Subramaniyan S, Terrando N. Neuroinflammation and perioperative neurocognitive disorders. Anesth Analg. 2019;128(4):781–8. https://doi.org/10.1213/ANE.0000000000004053 .
doi: 10.1213/ANE.0000000000004053 pubmed: 30883423 pmcid: 6437083
Liu X, Yu Y, Zhu S. Inflammatory markers in postoperativedelirium (POD) and cognitive dysfunction (POCD): A meta-analysis of observational studies. PLoS One. 2018;13(4). https://doi.org/10.1371/journal.pone.0195659.
Beloosesky Y, Hendel D, Weiss A, Hershkovitz A, Grinblat J, Pirotsky A, et al. Cytokines and C-reactive protein production in hip-fracture-operated elderly patients. Journals Gerontol - Ser A Biol Sci Med Sci. 2007;62(4):420–6. https://doi.org/10.1093/gerona/62.4.420 .
doi: 10.1093/gerona/62.4.420
Hirsch J, Vacas S, Terrando N, Yuan M, Sands LP, Kramer J, et al. Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery. J Neuroinflammation. 2016;13(1):211. https://doi.org/10.1186/s12974-016-0681-9 .
doi: 10.1186/s12974-016-0681-9 pubmed: 27577265 pmcid: 5006595
Miao S, Shen P, Zhang Q, Wang H, Shen J, Wang G, et al. Neopterin and mini-mental state examination scores, two independent risk factors for postoperative delirium in elderly patients with open abdominal surgery. J Cancer Res Ther. 2018;14(6):1234–8. https://doi.org/10.4103/0973-1482.192764 .
doi: 10.4103/0973-1482.192764 pubmed: 30488836
Freter S, Dunbar M, Koller K, MacKnight C, Rockwood K. Risk of pre- and post-operative delirium and the delirium elderly at risk (DEAR) tool in hip fracture patients. Can Geriatr J. 2015;18(4):212–6. https://doi.org/10.5770/cgj.18.185 .
doi: 10.5770/cgj.18.185 pubmed: 26740829 pmcid: 4696448
Zhao S, Sun T, Zhang J, Chen X, Wang X. Risk factors and prognosis of postoperative delirium in nonagenarians with hip fracture. Sci Rep. 2023;13(1):1–7. https://doi.org/10.1038/s41598-023-27829-4 .
doi: 10.1038/s41598-023-27829-4
Smith TO, Cooper A, Peryer G, Griffiths R, Fox C, Cross J. Factors predicting incidence of post-operative delirium in older people following hip fracture surgery: a systematic review and meta-analysis. Int J Geriatr Psychiatry. 2017;32(4):386–96. https://doi.org/10.1002/gps.4655 .
doi: 10.1002/gps.4655 pubmed: 28093812
Auer S, Reisberg B. The GDS/FAST staging system. Int Psychogeriatrics. 1997;9(SUPPL. 1):167–71. https://doi.org/10.1017/S1041610297004869 .
doi: 10.1017/S1041610297004869
Barthel M. Functional evaluation: the Barthel Index. Md State Med J. 1965;14:56–61.
Lawton M, Brody E. Assessment of older people: selfmaintaining and instrumental activities of daily living. Gerontologist. 1969;9:179–86.
doi: 10.1093/geront/9.3_Part_1.179 pubmed: 5349366
Woo J, Yu R, Wong M, Yeung F, Wong M, Lum C. Frailty screening in the community using the FRAIL scale. J Am Med Dir Assoc. 2015;16(5):412–9. https://doi.org/10.1016/j.jamda.2015.01.087 .
doi: 10.1016/j.jamda.2015.01.087 pubmed: 25732832
Kaiser MJ, Bauer JM, Ramsh C, Uter W, Guigoz Y, Cederlorm T, et al. Validation of the mini nutritional assessment short-form (MNA®-SF): a practical tool for identification of nutritional status. J Nutr Health Aging. 2009;13(9):782–8 https://doi.org/10.1007/s12603-009-0214-7 .
Herdman M, Badia X, Berra S. EuroQol-5D: a simple alternative for measuring health-related quality of life in primary care. Aten Primaria. 2001;28(6):425–30. https://doi.org/10.1016/s0212-6567(01)70406-4 .
doi: 10.1016/s0212-6567(01)70406-4 pubmed: 11602124 pmcid: 7684037
Yesavage JA. Geriatric depression scale. Psychopharmacol Bull. 1988;24(4):709–10. https://doi.org/10.1007/978-3-319-69892-2_736-1 .
doi: 10.1007/978-3-319-69892-2_736-1 pubmed: 3249773
Tieges Z, Maclullich AMJ, Anand A, Brookes C, Cassarino M, O’connor M, et al. Diagnostic accuracy of the 4AT for delirium detection in older adults: systematic review and meta-analysis. Age Ageing. 2021;50(3):733–43. https://doi.org/10.1093/ageing/afaa224 .
doi: 10.1093/ageing/afaa224 pubmed: 33951145
Delgado-Parada E, Morillo-Cuadrado D, Saiz-Ruiz J, Cebollada-Gracia A, Ayuso-Mateos JL, Cruz-Jentoft AJ. Diagnostic accuracy of the Spanish version of the 4AT scale (4AT-ES) for delirium screening in older inpatients. Eur J Psychiatry. 2022;36(3):182–90. https://doi.org/10.1016/j.ejpsy.2022.01.003 .
doi: 10.1016/j.ejpsy.2022.01.003
Barahona E, Pinhao R, Galindo V, Noguera A. The diagnostic sensitivity of the memorial delirium assessment scale—Spanish version. J Pain Symptom Manage. 2018;55(3):968–72. https://doi.org/10.1016/j.jpainsymman.2017.11.013 .
doi: 10.1016/j.jpainsymman.2017.11.013 pubmed: 29155289
Meagher D, Adamis D, Leonard M, Trzepacz P, Grover S, Jabbar F, et al. Development of an abbreviated version of the delirium motor subtyping scale (DMSS-4). Int Psychogeriatrics. 2014;26(4):693–702. https://doi.org/10.1017/S1041610213002585 .
doi: 10.1017/S1041610213002585
Burton JK, Stott DJ, McShane R, Noel-Storr AH, Swann-Price RS, Quinn TJ. Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) for the early detection of dementia across a variety of healthcare settings. Cochrane Database Syst Rev. 2021;7(7). https://doi.org/10.1002/14651858.CD011333.pub3.
Blandfort S, Gregersen M, Rahbek K, Juul S, Damsgaard EM. The short IQCODE as a predictor for delirium in hospitalized geriatric patients. Aging Clin Exp Res. 2020;32(10):1969–76. https://doi.org/10.1007/s40520-019-01412-2 .
doi: 10.1007/s40520-019-01412-2 pubmed: 31722092
Luo J, Frisken S, Machado I, Zhang M, Pieper S, Golland P, et al. Using the variogram for vector outlier screening: application to feature-based image registration. Int J Comput Assist Radiol Surg. 2018;13(12):1871–80. https://doi.org/10.1007/s11548-018-1840-5 .
doi: 10.1007/s11548-018-1840-5 pubmed: 30097956 pmcid: 6224309
Metsalu T, Vilo J. ClustVis: A web tool for visualizing clustering of multivariate data using principal component analysis and heatmap. Nucleic Acids Res. 2015;43(W1):W566–70. https://doi.org/10.1093/nar/gkv468 .
doi: 10.1093/nar/gkv468 pubmed: 25969447 pmcid: 4489295
Torres KCL, de Rezende VB, Lima-Silva ML, de Sousa SLJ, Costa CG, de Melo MJV, et al. Immune senescence and biomarkers profile of Bambuí aged population-based cohort. Exp Gerontol. 2018;103:47–56. https://doi.org/10.1016/j.exger.2017.12.006 .
doi: 10.1016/j.exger.2017.12.006 pubmed: 29247791
Sayed N, Huang Y, Nguyen K, Krejciova-Rajaniemi Z, Grawe AP, Gao T, et al. An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging. Nat Aging. 2021;1(8):748. https://doi.org/10.1038/s43587-021-00102-x .
Phan QT, Chua KY, Jin A, Winkler C, Koh WP. CXCL9 predicts the risk of osteoporotic hip fracture in a prospective cohort of Chinese men—a matched case–control study. J Bone Miner Res. 2022;37(10):1843–9. https://doi.org/10.1002/jbmr.4646 .
doi: 10.1002/jbmr.4646 pubmed: 35810382
de Amorim JSC, Torres KCL, Teixeira-Carvalho A, Martins-Filho OA, Lima-Costa MF, Peixoto SV. Inflammatory markers and occurrence of falls: Bambuí cohort study of aging. Rev Saude Publica. 2019;53:1–11. https://doi.org/10.11606/S1518-8787.2019053000855 .
doi: 10.11606/S1518-8787.2019053000855
de Amorim JSC, Torres KCL, Carvalho AT, Martins-Filho OA, Lima-Costa MF, Peixoto SV. Inflammatory markers associated with fall recurrence and severity: the Bambuí cohort study of aging. Exp Gerontol. 2020;132: 110837. https://doi.org/10.1016/j.exger.2020.110837 .
doi: 10.1016/j.exger.2020.110837 pubmed: 31935439
Watson AES, Goodkey K, Footz T, Voronova A. Regulation of CNS precursor function by neuronal chemokines. Neurosci Lett. 2020;715: 134533. https://doi.org/10.1016/j.neulet.2019.134533 .
doi: 10.1016/j.neulet.2019.134533 pubmed: 31629772
Satarkar D, Patra C. Evolution, expression and functional analysis of CXCR3 in neuronal and cardiovascular diseases: a narrative review. Front Cell Dev Biol. 2022;10(June):1–17. https://doi.org/10.3389/fcell.2022.882017 .
doi: 10.3389/fcell.2022.882017
Lee KS, Chung JH, Lee KH, Shin MJ, Oh BH, Hong CH. Bioplex analysis of plasma cytokines in Alzheimer’s disease and mild cognitive impairment. Immunol Lett. 2008;121(2):105–9. https://doi.org/10.1016/j.imlet.2008.09.004 .
doi: 10.1016/j.imlet.2008.09.004 pubmed: 18930766
Koper OM, Kaminska J, Sawicki K, Kemona H. CXCL9, CXCL10, CXCL11, and their receptor (CXCR3) in neuroinflammation and neurodegeneration. Adv Clin Exp Med. 2018;27(6):849–56. https://doi.org/10.17219/acem/68846 .
doi: 10.17219/acem/68846 pubmed: 29893515
Soares HD, Potter WZ, Pickering E, Kuhn M, Immermann FW, Shera DM, et al. Plasma biomarkers associated with the apolipoprotein E genotype and Alzheimer disease. Arch Neurol. 2012;69(10):1310–7. https://doi.org/10.1001/archneurol.2012.1070 .
doi: 10.1001/archneurol.2012.1070 pubmed: 22801723 pmcid: 3683865
Berchiche YA, Sakmar TP. CXC chemokine receptor 3 alternative splice variants selectively activate different signaling pathways. Mol Pharmacol. 2016;90(4):483–95. https://doi.org/10.1124/mol.116.105502 .
doi: 10.1124/mol.116.105502 pubmed: 27512119
Li H, Wang R. A focus on CXCR4 in Alzheimer’s disease. Brain Circ. 2017;3(4):199. https://doi.org/10.4103/bc.bc_13_17 .
doi: 10.4103/bc.bc_13_17 pubmed: 30276325 pmcid: 6057706
Pellecchia MT, Santangelo G, Picillo M, Pivonello R, Longo K, Pivonello C, et al. Serum epidermal growth factor predicts cognitive functions in early, drug-naive Parkinson’s disease patients. J Neurol. 2013;260(2):438–44. https://doi.org/10.1007/s00415-012-6648-6 .
doi: 10.1007/s00415-012-6648-6 pubmed: 22911513
Yasar Z, Elliott BT, Kyriakidou Y, Nwokoma CT, Postlethwaite RD, Gaffney CJ, et al. Sprint interval training (SIT) reduces serum epidermal growth factor (EGF), but not other inflammatory cytokines in trained older men. Eur J Appl Physiol. 2021;121(7):1909–19. https://doi.org/10.1007/s00421-021-04635-2 .
doi: 10.1007/s00421-021-04635-2 pubmed: 33723630 pmcid: 8192388
Sanchez-Ramos J, Song S, Sava V. Granulocyte colony stimulating factor (G-CSF) decreases brain amyloid burden and reverses cognitive impairment in Alzheimer’s mice. Neuroscience. 2009;163(1):55–72. https://doi.org/10.1016/j.neuroscience.2009.05.071 .
doi: 10.1016/j.neuroscience.2009.05.071 pubmed: 19500657
Tuo M, Xiao Y, Xu Y, Wang L, Wei X, Zhang L. Role of granulocyte-colony stimulating factor in the protection of cerebral vascular endothelium, white matter, and cognition. Curr Neurovasc Res. 2019;16(5):425–32. https://doi.org/10.2174/1567202616666191029115113 .
doi: 10.2174/1567202616666191029115113 pubmed: 31660819
Khedr EM, Gomaa AMS, Ahmed OG, Sayed HMM, Gamea A. Cognitive impairment, P300, and transforming growth factor β1 in different forms of dementia. J Alzheimer’s Dis. 2020;78(2):837–45. https://doi.org/10.3233/JAD-200885 .
doi: 10.3233/JAD-200885
Estrada LD, Oliveira-Cruz L, Cabrera D. Transforming growth factor beta type I role in neurodegeneration: implications for Alzheimer´s disease. Curr Protein Pept Sci. 2018;19(12):1180–8. https://doi.org/10.2174/1389203719666171129094937 .
doi: 10.2174/1389203719666171129094937 pubmed: 29189146
Khan SH, Lindroth H, Jawed Y, Wang S, Nasser J, Seyffert S, et al. Serum biomarkers in postoperative delirium after esophagectomy. Ann Thorac Surg. 2022;113(3):1000–7. https://doi.org/10.1016/j.athoracsur.2021.03.035 .
doi: 10.1016/j.athoracsur.2021.03.035 pubmed: 33774004
Culjak M, Perkovic MN, Uzun S, Strac DS, Erjavec GN, Leko MB, et al. The association between TNF-alpha, IL-1 alpha and IL-10 with Alzheimer’s disease. Curr Alzheimer Res. 2020;17(11):972–84. https://doi.org/10.2174/1567205017666201130092427 .
doi: 10.2174/1567205017666201130092427 pubmed: 33256580
Ahmad MA, Kareem O, Khushtar M, Akbar M, Haque MR, Iqubal A, et al. Neuroinflammation: a potential risk for dementia. Int J Mol Sci. 2022;23(2):616. https://doi.org/10.3390/ijms23020616.
Lee WJ, Liao YC, Wang YF, Lin IF, Wang SJ, Fuh JL. Plasma MCP-1 and cognitive decline in patients with Alzheimer’s disease and mild cognitive impairment: a two-year follow-up study. Sci Rep. 2018;8(1):4–11. https://doi.org/10.1038/s41598-018-19807-y .
doi: 10.1038/s41598-018-19807-y
Smith RJ, Lachner C, Singh VP, Trivedi S, Khatua B, Cartin-Ceba R. Cytokine profiles in intensive care unit delirium. Acute Crit Care. 2022;37(3):415–28. https://doi.org/10.4266/acc.2021.01508 .
doi: 10.4266/acc.2021.01508 pubmed: 35791660 pmcid: 9475146
Perna L, Trares K, Perneczky R, Tato M, Stocker H, Möllers T, et al. Risk of late-onset depression and cognitive decline: results from inflammatory proteome analyses in a prospective population-based cohort study. Am J Geriatr Psychiatry. 2022;30(6):689–700. https://doi.org/10.1016/j.jagp.2021.12.001 .
doi: 10.1016/j.jagp.2021.12.001 pubmed: 34961662
Lindqvist D, Hall S, Surova Y, Nielsen HM, Janelidze S, Brundin L, et al. Cerebrospinal fluid inflammatory markers in Parkinson’s disease - associations with depression, fatigue, and cognitive impairment. Brain Behav Immun. 2013;33:183–9. https://doi.org/10.1016/j.bbi.2013.07.007 .
doi: 10.1016/j.bbi.2013.07.007 pubmed: 23911592
Dogrul RT, Dogrul AB, Konan A, Caglar O, Sumer F, Caliskan H, et al. Does preoperative comprehensive geriatric assessment and frailty predict postoperative complications? World J Surg. 2020;44(11):3729–36. https://doi.org/10.1007/s00268-020-05715-8 .
doi: 10.1007/s00268-020-05715-8 pubmed: 32737555
Yang Y, Zhao X, Gao L, Wang Y, Wang J. Incidence and associated factors of delirium after orthopedic surgery in elderly patients: a systematic review and meta-analysis. Aging Clin Exp Res. 2021;33(6):1493–506. https://doi.org/10.1007/s40520-020-01674-1 .
doi: 10.1007/s40520-020-01674-1 pubmed: 32772312

Auteurs

Lucía Lozano-Vicario (L)

Department of Geriatric Medicine, Hospital Universitario de Navarra (HUN), Pamplona, Spain. lucia.lozanovicario@gmail.com.

Ángel Javier Muñoz-Vázquez (ÁJ)

Department of Orthopaedic Surgery and Traumatology, Clínica Universidad de Navarra, Pamplona, Spain.

Robinson Ramírez-Vélez (R)

Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.

Arkaitz Galbete-Jiménez (A)

Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.

Joaquín Fernández-Irigoyen (J)

Proteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain.

Enrique Santamaría (E)

Proteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain.

Bernardo Abel Cedeno-Veloz (BA)

Department of Geriatric Medicine, Hospital Universitario de Navarra (HUN), Pamplona, Spain.

Fabricio Zambom-Ferraresi (F)

Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
CIBER of Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain.

Barbara C Van Munster (BC)

Department of Geriatric Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

José Ramón Ortiz-Gómez (JR)

Department of Anesthesiology and Reanimation, Hospital Universitario de Navarra (HUN), Pamplona, Spain.

Ángel Manuel Hidalgo-Ovejero (ÁM)

Department of Orthopaedic Surgery and Traumatology, Hospital Universitario de Navarra (HUN), Pamplona, Spain.

Román Romero-Ortuno (R)

Discipline of Medical Gerontology, School of Medicine, Trinity College Dublin, Dublin, Ireland.

Mikel Izquierdo (M)

Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.

Nicolás Martínez-Velilla (N)

Department of Geriatric Medicine, Hospital Universitario de Navarra (HUN), Pamplona, Spain.
Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
CIBER of Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain.

Classifications MeSH