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Plasma C-Terminal Agrin Fragment as an Early Biomarker for Sarcopenia: Results from the Genofit Study.

ABSTRACT: Barriers associated with direct muscle quantification have prevented a consistent implementation of therapeutic measures for sarcopenia. Recently, the relevance of circulating C-terminal agrin fragment (CAF) as an accessible screening method alternative for sarcopenia has gained credence. Accordingly, this study aimed to verify the pertinence of plasma CAF as a biomarker for sarcopenia. Three-hundred healthy adults aged between 50-83 years took part in this study. Sarcopenia was diagnosed according to the European Working Group on Sarcopenia in Older People criteria. Body composition was assessed using dual-energy x-ray absorptiometry, while muscle strength was examined using hand dynamometry. Plasma CAF concentrations were determined using a commercially available ELISA kit. CAF concentrations were significantly associated with appendicular lean mass (ALM), but not grip strength (p=0.028, p=0.575, respectively). Plasma CAF concentrations were significantly elevated in sarcopenic individuals compared to non-sarcopenic (p<0.001). Overall, individuals with low grip strength or low ALM displayed significantly higher CAF levels compared to healthy controls, after adjusting for age and body mass index (p=0.027, p=0.003, respectively). In males, those with low grip strength or low ALM had significantly elevated CAF levels (p=0.039, p=0.027, respectively), while in females, only those with low ALM had significantly raised CAF concentrations, compared to healthy controls (p=0.035). Our findings illuminate the potential relevance of CAF as an accessible biomarker for skeletal muscle health. CAF determination may enhance clinical practise by facilitating more widespread treatment strategies for sarcopenia. Nevertheless, future research is needed to confirm the diagnostic pertinence of CAF concentrations in screening for sarcopenia.

SUBMITTER: Pratt J

PROVIDER: S-EPMC8599080 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIncreasing interest surrounds the utility of blood-based biomarkers for diagnosing sarcopenia. C-terminal agrin fragment (CAF), a marker of neuromuscular junction stability, is amongst the most promising candidates; however, a dearth of reference data impedes the incorporation of its use in public health settings. This study aimed to establish reference values for plasma CAF concentrations across adulthood in a large, well-characterized cohort of healthy adults; and comprehensively examine the association between plasma CAF levels and skeletal muscle health.MethodsOne thousand people aged between 18 and 87 years took part in this study (mean age = 50.4 years; 51% females). Body composition and muscle strength were examined using DXA and hand dynamometry. Plasma CAF concentrations were measured, in duplicate, using commercially available ELISA kits. Sarcopenia and individual sarcopenia signatures [low skeletal muscle index (SMI) only/low grip strength only] were classified using the EWGSOP2 algorithm.ResultsDetailed reference CAF values, according to sex and age, are presented. A significant but modest age-related increase in plasma CAF concentration was observed (P = 0.018). Across adulthood, CAF concentrations were negatively associated with grip strength and SMI (both P < 0.001). In people ≥50 years old, CAF concentrations were 22.6% higher in those with sarcopenia (P < 0.001), 11.3% higher in those with low SMI (P = 0.006) and 9.6% higher in those with low grip strength (P = 0.0034), compared with controls. People in the highest CAF concentration quartile, had 3.25 greater odds for sarcopenia (95% CI = 1.41-7.49, P = 0.005), 2.76 greater odds for low SMI (95% CI = 1.24-5.22, P = 0.012), and 2.56 greater odds for low grip strength (95% CI = 1.07-5.57, P = 0.037), compared with those in the lowest quartile. People with a CAF Z-score ≥2 had 9.52 greater odds for sarcopenia (95% CI = 3.01-30.05, P < 0.001) compared with a Z-score <1. Plasma CAF concentration had an acceptable level of diagnostic accuracy for sarcopenia (AUC = 0.772, 95% CI = 0.733-0.807, P < 0.001).ConclusionsThe reference values presented herein may guide the clinical interpretation of circulating CAF and help identify people at risk of poor skeletal muscle outcomes for inclusion in therapeutic interventions. Our findings add clarity to existing data, demonstrating a robust relationship between circulating CAF and skeletal muscle integrity in the largest adult cohort to date, and support the use of CAF as an accessible, cost-effective screening tool for sarcopenia. However, further research into the prognostic utility of plasma CAF, and the establishment of normative data from other populations, are urgently needed if routine CAF screening is to be embedded into public healthcare settings.

Project description:BackgroundDiabetes is the leading cause of CKD in the developed world. C-terminal fragment of agrin (CAF) is a novel kidney function and injury biomarker. We investigated whether serum CAF predicts progression of kidney disease in type 2 diabetics.MethodsSerum CAF levels were measured in 71 elderly patients with diabetic nephropathy using a newly developed commercial ELISA kit (Neurotune®). Estimated glomerular filtration rate (eGFR) and proteinuria in spot urine were assessed at baseline and after 12 months follow up. The presence of end stage renal disease (ESRD) was evaluated after 24 months follow-up. Correlation and logistic regression analyses were carried out to explore the associations of serum CAF levels with GFR, proteinuria, GFR loss and incident ESRD. Renal handling of CAF was tested in neurotrypsin-deficient mice injected with recombinant CAF.ResultsWe found a strong association of serum CAF levels with eGFR and a direct association with proteinuria both at baseline (r = 0.698, p<0.001 and r = 0. 287, p = 0.02) as well as after 12 months follow-up (r = 0.677, p<0.001 and r = 0.449, p<0.001), respectively. Furthermore, in multivariate analysis, serum CAF levels predicted eGFR decline at 12 months follow-up after adjusting for known risk factors (eGFR, baseline proteinuria) [OR (95%CI) = 4.2 (1.2-14.5), p = 0.024]. In mice, injected CAF was detected in endocytic vesicles of the proximal tubule.ConclusionSerum CAF levels reflect renal function and are highly associated with eGFR and proteinuria at several time points. Serum CAF was able to predict subsequent loss of renal function irrespective of baseline proteinuria in diabetic nephropathy. CAF is likely removed from circulation by glomerular filtration and subsequent endocytosis in the proximal tubule. These findings may open new possibilities for clinical trial design, since serum CAF levels may be used as a selection tool to monitor kidney function in high-risk patients with diabetic nephropathy.

Project description:BackgroundC-terminal agrin fragment (CAF) is a biomarker for neuromuscular junction degradation. This study aimed to investigate whether 110-kDa CAF (CAF110) was associated with the presence and incidence of low muscle mass and strength.MethodsThis cross-sectional retrospective cohort study comprised women aged ≥65 years. We measured muscle mass using a dual-energy X-ray absorptiometry scanner, hand-grip strength, and blood sampling between 2011 and 2012. A follow-up study with the same measurements was conducted between 2015 and 2017. Low muscle mass and strength were defined as an appendicular skeletal muscle mass index <5.4 kg/m2 and hand-grip strength <18 kg, respectively. The CAF110 level was measured using enzyme-linked immunosorbent assay kits.ResultsIn total, 515 women (74.3 ± 6.3 years) were included in this cross-sectional analysis. Of these, 101 (19.6%) and 128 (24.9%) women presented with low muscle mass and strength, respectively. For low muscle mass, the odds ratios (ORs) of the middle and highest CAF110 tertile groups, compared with the lowest group, were 1.93 (95% confidence interval: 1.09-3.43; P = 0.024) and 2.15 (1.22-3.80; P = 0.008), respectively. After adjusting for age, the ORs remained significant: 1.98 (1.11-3.52; P = 0.020) and 2.27 (1.28-4.03; P = 0.005), respectively. Low muscle strength ORs of all the CAF110 tertile groups were not significant. In the longitudinal analysis, 292 and 289 women were assessed for incidents of low muscle mass and strength, respectively. Of those, 34 (11.6%) and 20 (6.9%) women exhibited low muscle mass and strength, respectively. For incident low muscle mass, the crude OR of the CAF110 ≥ the median value group was marginally higher than that of the CAF110 < median value group (median [interquartile range]: 1.98 [0.94-4.17] (P = 0.072). After adjusting for age and baseline muscle mass, the OR was 2.22 [0.97-5.06] (P = 0.058). All low muscle strength ORs of the median categories of CAF110 were not significant.ConclusionsCAF110 was not associated with low muscle strength. However, CAF110 may be a potential marker for the incidence of low muscle mass.

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Plasma C-Terminal Agrin Fragment as an Early Biomarker for Sarcopenia: Results from the Genofit Study.

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