Advertisement

The “BIOmarkers associated with Sarcopenia and PHysical frailty in EldeRly pErsons” (BIOSPHERE) study: Rationale, design and methods

      Highlights

      • Physical Frailty & Sarcopenia (PF&S) is a prevalent condition in older adults.
      • No reliable biomarkers are presently available to diagnose or track PF&S.
      • A multi-marker approach may be suitable to capture the complexity of PF&S.
      • BIOSPHERE will test the association of multiple biomarkers with PF&S.
      • The multi-marker panel may be used to frame PF&S in clinics and research.

      Abstract

      Sarcopenia, the progressive and generalised loss of muscle mass and strength/function, is a major health issue in older adults given its high prevalence and burdensome clinical implications. Over the years, this condition has been endorsed as a marker for discriminating biological from chronological age. However, the absence of a unified operational definition has hampered its full appreciation by healthcare providers, researchers and policy-makers. In addition to this unsolved debate, the complexity of musculoskeletal ageing represents a major challenge to the identification of clinically meaningful biomarkers. Here, we illustrate the advantages of biomarker discovery procedures in muscle ageing based on multivariate methodologies as an alternative approach to traditional single-marker strategies. The rationale, design and methods of the “BIOmarkers associated with Sarcopenia and PHysical frailty in EldeRly pErsons” (BIOSPHERE) study are described as an application of a multi-marker strategy for the development of biomarkers for the newly operationalised Physical Frailty & Sarcopenia condition.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • WHO
        Global health and ageing.
        WHO, 2015 (Available at) (Accessed on March 23, 2018)
        • Bien B.
        • McKee K.J.
        • Döhner H.
        • Triantafillou J.
        • Lamura G.
        • Doroszkiewicz H.
        • et al.
        Disabled older people's use of health and social care services and their unmet care needs in six European countries.
        Eur J Public Health. 2013; 23: 1032-1038https://doi.org/10.1093/eurpub/cks190
        • Cesari M.
        • Marzetti E.
        • Thiem U.
        • Pérez-Zepeda M.U.
        • Abellan Van Kan G.
        • Landi F.
        • et al.
        The geriatric management of frailty as paradigm of the end of the disease era.
        Eur J Intern Med. 2016; 31: 11-14https://doi.org/10.1016/j.ejim.2016.03.005
        • Marzetti E.
        • Calvani R.
        • Cesari M.
        • Tosato M.
        • Cherubini A.
        • Di Bari M.
        • et al.
        Operationalization of the physical frailty & sarcopenia syndrome: rationale and clinical implementation.
        Transl. Med. UniSa. 2015; 13: 29-32
        • No authors listed
        Epidemiologic and methodologic problems in determining nutritional status of older persons.
        in: Proceedings of a Conference. Albuquerque, New Mexico, October 19–21, 1988. 50. 1989: 1121-1235 (Am J Clin Nutr)
        • Landi F.
        • Calvani R.
        • Cesari M.
        • Tosato M.
        • Martone A.M.
        • Ortolani E.
        • et al.
        Sarcopenia: an overview on current definitions, diagnosis and treatment.
        Curr Protein Pept Sci. 2017; 18 ([Epub ahead of print])https://doi.org/10.2174/1389203718666170607113459
        • Scott D.
        • Hayes A.
        • Sanders K.M.
        • Aitken D.
        • Ebeling P.R.
        • Jones G.
        Operational definitions of sarcopenia and their associations with 5-year changes in falls risk in community-dwelling middle-aged and older adults.
        Osteoporos Int. 2014; 25: 187-193https://doi.org/10.1007/s00198-013-2431-5
        • Bischoff-Ferrari H.A.
        • Orav J.E.
        • Kanis J.A.
        • Rizzoli R.
        • Schlögl M.
        • Staehelin H.B.
        • et al.
        Comparative performance of current definitions of sarcopenia against the prospective incidence of falls among community-dwelling seniors age 65 and older.
        Osteoporos Int. 2015; 26: 2793-2802https://doi.org/10.1007/s00198-015-3194-y
        • Cao L.
        • Morley J.E.
        Sarcopenia is recognized as an independent condition by an international classification of disease, tenth revision, clinical modification (ICD-10-CM) code.
        J Am Med Dir Assoc. 2016; 17: 675-677https://doi.org/10.1016/j.jamda.2016.06.001
        • Marzetti E.
        • Calvani R.
        • Tosato M.
        • Cesari M.
        • Di Bari M.
        • Cherubini A.
        • et al.
        Sarcopenia: an overview.
        Aging Clin Exp Res. 2017; 29: 11-17https://doi.org/10.1007/s40520-016-0704-5
        • Clegg A.
        • Young J.
        • Iliffe S.
        • Rikkert M.O.
        • Rockwood K.
        Frailty in elderly people.
        Lancet. 2013; 381: 752-762https://doi.org/10.1016/S0140-6736(12)62167-9
        • Rodríguez-Mañas L.
        • Féart C.
        • Mann G.
        • Viña J.
        • Chatterji S.
        • Chodzko-Zajko W.
        • et al.
        Searching for an operational definition of frailty: a Delphi method based consensus statement. The frailty operative definition-consensus conference project.
        J Gerontol A Biol Sci Med Sci. 2013; 68: 62-67https://doi.org/10.1093/gerona/gls119
        • Theou O.
        • Brothers T.D.
        • Peña F.G.
        • Mitnitski A.
        • Rockwood K.
        Identifying common characteristics of frailty across seven scales.
        J Am Geriatr Soc. 2014; 62: 901-906https://doi.org/10.1111/jgs.12773
        • Rockwood K.
        • Song X.
        • MacKnight C.
        • Bergman H.
        • Hogan D.B.
        • McDowell I.
        • et al.
        A global clinical measure of fitness and frailty in elderly people.
        Can Med Assoc J. 2005; 173: 489-495https://doi.org/10.1503/cmaj.050051
        • Dent E.
        • Kowal P.
        • Hoogendijk E.O.
        Frailty measurement in research and clinical practice: a review.
        Eur J Intern Med. 2016; 31: 3-10https://doi.org/10.1016/j.ejim.2016.03.007
        • Cesari M.
        • Landi F.
        • Vellas B.
        • Bernabei R.
        • Marzetti E.
        Sarcopenia and physical frailty: two sides of the same coin.
        Front Aging Neurosci. 2014; 6: 192https://doi.org/10.3389/fnagi.2014.00192
        • Landi F.
        • Calvani R.
        • Cesari M.
        • Tosato M.
        • Martone A.M.
        • Bernabei R.
        • et al.
        Sarcopenia as the biological substrate of physical frailty.
        Clin Geriatr Med. 2015; 31: 367-374https://doi.org/10.1016/j.cger.2015.04.005
        • Cesari M.
        • Landi F.
        • Calvani R.
        • Cherubini A.
        • Di Bari M.
        • Kortebein P.
        • et al.
        Rationale for a preliminary operational definition of physical frailty and sarcopenia in the SPRINTT trial.
        Aging Clin Exp Res. 2017; 29: 81-88https://doi.org/10.1007/s40520-016-0716-1
        • Studenski S.A.
        • Peters K.W.
        • Alley D.E.
        • Cawthon P.M.
        • McLean R.R.
        • Harris T.B.
        • et al.
        The FNIH sarcopenia project: rationale, study description, conference recommendations, and final estimates.
        J Gerontol A Biol Sci Med Sci. 2014; 69A: 547-558https://doi.org/10.1093/gerona/glu010
        • Guralnik J.M.
        • Simonsick E.M.
        • Ferrucci L.
        • Glynn R.J.
        • Berkman L.F.
        • Blazer D.G.
        • et al.
        A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission.
        J Gerontol. 1994; 49: M85-M94https://doi.org/10.1093/geronj/49.2.M85
        • Newman A.B.
        • Simonsick E.M.
        • Naydeck B.L.
        • Boudreau R.M.
        • Kritchevsky S.B.
        • Nevitt M.C.
        • et al.
        Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability.
        JAMA. 2006; 295: 2018https://doi.org/10.1001/jama.295.17.2018
        • Marzetti E.
        • Calvani R.
        • Landi F.
        • Hoogendijk E.O.
        • Fougère B.
        • Vellas B.
        • et al.
        Innovative medicines initiative: the SPRINTT project.
        J Frailty Aging. 2015; 4: 207-208
        • Calvani R.
        • Marini F.
        • Cesari M.
        • Tosato M.
        • Picca A.
        • Anker S.D.
        • et al.
        Biomarkers for physical frailty and sarcopenia.
        Aging Clin Exp Res. 2017; 29: 29-34https://doi.org/10.1007/s40520-016-0708-1
        • Calvani R.
        • Picca A.
        • Cesari M.
        • Tosato M.
        • Marini F.
        • Manes-Gravina E.
        • et al.
        Biomarkers for sarcopenia: reductionism vs complexity.
        Curr. Protein Pept. Sci. 2017; ([Epub ahead of print])https://doi.org/10.2174/1389203718666170516115422
        • Calvani R.
        • Marini F.
        • Cesari M.
        • Tosato M.
        • Anker S.D.
        • von Haehling S.
        • et al.
        Biomarkers for physical frailty and sarcopenia: state of the science and future developments.
        J Cachexia Sarcopenia Muscle. 2015; 6: 278-286https://doi.org/10.1002/jcsm.12051
        • Landi F.
        • Cesari M.
        • Calvani R.
        • Cherubini A.
        • Di Bari M.
        • Bejuit R.
        • et al.
        The “sarcopenia and physical fRailty IN older people: multi-componenT treatment strategies” (SPRINTT) randomized controlled trial: design and methods.
        Aging Clin Exp Res. 2017; 29: 89-100https://doi.org/10.1007/s40520-016-0715-2
        • Folstein M.F.
        • Folstein S.E.
        • McHugh P.R.
        "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician.
        J Psychiatr Res. 1975; 12: 189-198
        • Radloff L.S.
        The CES-D scale.
        Appl Psychol Measur. 1977; 1: 385-401https://doi.org/10.1177/014662167700100306
        • Katz S.
        • Ford A.B.
        • Moskowitz R.W.
        • Jackson B.A.
        • Jaffe M.W.
        Studies of illness in the aged. The index of ADL: a standardized measure of biological and psychosocial function.
        JAMA. 1963; 185: 914-919
        • Lawton M.P.
        • Brody E.M.
        Assessment of older people: self-maintaining and instrumental activities of daily living.
        Gerontologist. 1969; 9: 179-186
        • Cesari M.
        • Penninx B.W.J.H.
        • Pahor M.
        • Lauretani F.
        • Corsi A.M.
        • Rhys Williams G.
        • et al.
        Inflammatory markers and physical performance in older persons: the InCHIANTI study.
        J Gerontol A Biol Sci Med Sci. 2004; 59: 242-248
        • Ferrucci L.
        • Penninx B.W.J.H.
        • Volpato S.
        • Harris T.B.
        • Bandeen-Roche K.
        • Balfour J.
        • et al.
        Change in muscle strength explains accelerated decline of physical function in older women with high interleukin-6 serum levels.
        J Am Geriatr Soc. 2002; 50: 1947-1954
        • Stephan A.
        • Mateos J.M.
        • Kozlov S.V.
        • Cinelli P.
        • Kistler A.D.
        • Hettwer S.
        • et al.
        Neurotrypsin cleaves agrin locally at the synapse.
        FASEB J. 2008; 22: 1861-1873https://doi.org/10.1096/fj.07-100008
        • Hettwer S.
        • Dahinden P.
        • Kucsera S.
        • Farina C.
        • Ahmed S.
        • Fariello R.
        • et al.
        Elevated levels of a C-terminal agrin fragment identifies a new subset of sarcopenia patients.
        Exp Gerontol. 2013; 48: 69-75https://doi.org/10.1016/j.exger.2012.03.002
        • Drey M.
        • Sieber C.C.
        • Bauer J.M.
        • Uter W.
        • Dahinden P.
        • Fariello R.G.
        • et al.
        C-terminal Agrin fragment as a potential marker for sarcopenia caused by degeneration of the neuromuscular junction.
        Exp Gerontol. 2013; 48: 76-80https://doi.org/10.1016/j.exger.2012.05.021
        • Marzetti E.
        • Calvani R.
        • Lorenzi M.
        • Marini F.
        • D'Angelo E.
        • Martone A.M.
        • et al.
        Serum levels of C-terminal agrin fragment (CAF) are associated with sarcopenia in older hip fractured patients.
        Exp Gerontol. 2014; 60: 79-82https://doi.org/10.1016/j.exger.2014.10.003
        • Landi F.
        • Calvani R.
        • Lorenzi M.
        • Martone A.M.
        • Tosato M.
        • Drey M.
        • et al.
        Serum levels of C-terminal agrin fragment (CAF) are associated with sarcopenia in older multimorbid community-dwellers: results from the ilSIRENTE study.
        Exp Gerontol. 2016; 79: 31-36https://doi.org/10.1016/j.exger.2016.03.012
        • Tiaden A.N.
        • Richards P.J.
        The emerging roles of HTRA1 in musculoskeletal disease.
        Am J Pathol. 2013; 182: 1482-1488https://doi.org/10.1016/j.ajpath.2013.02.003
        • Oka C.
        • Tsujimoto R.
        • Kajikawa M.
        • Koshiba-Takeuchi K.
        • Ina J.
        • Yano M.
        • et al.
        HtrA1 serine protease inhibits signaling mediated by Tgfbeta family proteins.
        Development. 2004; 131: 1041-1053https://doi.org/10.1242/dev.00999
        • Skorko-Glonek J.
        • Zurawa-Janicka D.
        • Koper T.
        • Jarzab M.
        • Figaj D.
        • Glaza P.
        • et al.
        HtrA protease family as therapeutic targets.
        Curr. Pharm. Des. 2013; 19: 977-1009https://doi.org/10.2174/1381612811319060003
        • Lorenzi M.
        • Lorenzi T.
        • Marzetti E.
        • Landi F.
        • Vetrano D.L.
        • Settanni S.
        • et al.
        Association of frailty with the serine protease HtrA1 in older adults.
        Exp Gerontol. 2016; 81: 8-12https://doi.org/10.1016/j.exger.2016.03.019
        • Fried L.P.
        • Tangen C.M.
        • Walston J.
        • Newman A.B.
        • Hirsch C.
        • Gottdiener J.
        • et al.
        Frailty in older adults: evidence for a phenotype.
        J Gerontol A Biol Sci Med Sci. 2001; 56: M146-M156https://doi.org/10.1093/gerona/56.3.M146
        • Ogawa K.
        • Kim H.
        • Shimizu T.
        • Abe S.
        • Shiga Y.
        • Calderwood S.K.
        Plasma heat shock protein 72 as a biomarker of sarcopenia in elderly people.
        Cell Stress Chaperones. 2012; 17: 349-359https://doi.org/10.1007/s12192-011-0310-6
        • Berry S.D.
        • Ramachandran V.S.
        • Cawthon P.M.
        • Gona P.
        • McLean R.R.
        • Cupples L.A.
        • et al.
        Procollagen type III N-terminal peptide (P3NP) and lean mass: a cross-sectional study.
        J Frailty Aging. 2013; 2: 129-134
        • Marzetti E.
        • Landi F.
        • Marini F.
        • Cesari M.
        • Buford T.W.
        • Manini T.M.
        • et al.
        Patterns of circulating inflammatory biomarkers in older persons with varying levels of physical performance: a partial least squares-discriminant analysis approach.
        Front Med. 2014; 127https://doi.org/10.3389/fmed.2014.00027
        • Shaffer R.E.
        Multi- and megavariate data analysis. Principles and applications.
        in: Eriksson I. Johansson E. Kettaneh-Wold N. Wold S. Umetrics Academy, Umeå, 2001. 16. J Chemom, 2002: 261-262 (ISBN 91-973730-1-X, 533pp)
        • Barker M.
        • Rayens W.
        Partial least squares for discrimination.
        J Chemometr. 2003; 17: 166-173https://doi.org/10.1002/cem.785
        • Westerhuis J.A.
        • Hoefsloot H.C.J.
        • Smit S.
        • Vis D.J.
        • Smilde A.K.
        • van Velzen E.J.J.
        • et al.
        Assessment of PLSDA cross validation.
        Metabolomics. 2008; 4: 81-89https://doi.org/10.1007/s11306-007-0099-6
        • Westerhuis J.A.
        • van Velzen E.J.J.
        • Hoefsloot H.C.J.
        • Smilde A.K.
        Discriminant Q2 (DQ2) for improved discrimination in PLSDA models.
        Metabolomics. 2008; 4: 293-296https://doi.org/10.1007/s11306-008-0126-2
        • Szymańska E.
        • Saccenti E.
        • Smilde A.K.
        • Westerhuis J.A.
        Double-check: validation of diagnostic statistics for PLS-DA models in metabolomics studies.
        Metabolomics. 2012; 8: 3-16https://doi.org/10.1007/s11306-011-0330-3
        • Calvani R.
        • Marini F.
        • Cesari M.
        • Buford T.W.
        • Manini T.M.
        • Pahor M.
        • et al.
        Systemic inflammation, body composition, and physical performance in old community-dwellers.
        J Cachexia Sarcopenia Muscle. 2017; 8: 69-77https://doi.org/10.1002/jcsm.12134