Evaluation of C-terminal Agrin Fragment as a marker of muscle wasting in patients after acute stroke during early rehabilitation.
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ABSTRACT:
SUBMITTER: Scherbakov N
PROVIDER: S-EPMC4799857 | biostudies-other | 2016 Mar
REPOSITORIES: biostudies-other
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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.
| S-EPMC4668035 | biostudies-literature
Project description: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 and 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 = .028, p = .575, respectively). Plasma CAF concentrations were significantly elevated in sarcopenic individuals compared to nonsarcopenic (p < .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 = .027, p = .003, respectively). In males, those with low grip strength or low ALM had significantly elevated CAF levels (p = .039, p = .027, respectively), while in females, only those with low ALM had significantly raised CAF concentrations, compared to healthy controls (p = .035). Our findings illuminate the potential relevance of CAF as an accessible biomarker for skeletal muscle health. CAF determination may enhance clinical practice 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.
| S-EPMC8599080 | biostudies-literature
Project description:Although physiological data suggest that neuromuscular junction (NMJ) dysfunction is a principal mechanism underpinning sarcopenia, genetic studies have implicated few genes involved in NMJ function. Accordingly, we explored whether genes encoding agrin (AGRN) and neurotrypsin (PRSS12) were associated with sarcopenia phenotypes: muscle mass, strength and plasma C-terminal agrin fragment (CAF). PhenoScanner was used to determine if AGRN and/or PRSS12 variants had previously been implicated with sarcopenia phenotypes. For replication, we combined genotype from whole genome sequencing with phenotypic data from 6715 GenoFit participants aged 18-83 years. Dual energy X-ray absorptiometry assessed whole body lean mass (WBLM) and appendicular lean mass (ALM), hand dynamometry determined grip strength and ELISA measured plasma CAF in a subgroup (n = 260). Follow-up analyses included eQTL analyses, carrier analyses, single-variant and gene-burden tests. rs2710873 (AGRN) and rs71608359 (PRSS12) associate with muscle mass and strength phenotypes, respectively, in the UKBB (p = 8.9 × 10-6 and p = 8.4 × 10-6) and GenoFit cohort (p = 0.019 and p = 0.014). rs2710873 and rs71608359 are eQTLs for AGRN and PRSS12, respectively, in ≥ three tissues. Compared to non-carriers, carriers of rs2710873 had 4.0% higher WBLM and ALM (both p < 0.001), and 9.5% lower CAF concentrations (p < 0.001), while carriers of rs71608359 had 2.3% lower grip strength (p = 0.034). AGRN and PRSS12 are associated with muscle strength and mass in single-variant analyses, while PRSS12 has further associations with muscle strength in gene-burden tests. Our findings provide novel evidence of the relevance of AGRN and PRSS12 to sarcopenia phenotypes and support existing physiological data illustrating the importance of the NMJ in maintaining muscle health during ageing.
| S-EPMC10400504 | biostudies-literature
Project description:Agrin, a multidomain proteoglycan and neurotrypsin, a neuronal serine protease, are important for forming (neuromuscular) synapses. Proteolytical activity of neurotrypsin produces a C-terminal fragment of agrin, termed CAF, of approximately 22 kDA molecular size which also circulates in blood. The presence of CAF in urine suggests either glomerular filtration or secretion into urine. Blood levels of CAF have been identified as a potential novel marker of kidney function. Here we describe that several nephron segments in the mouse kidney express agrin and neutrotrypsin in addition to the localization of both protein in the glomerulum. Agrin mRNA and protein was detected in almost all nephron segments and mRNA abundance was highest in the inner medullary collecting duct. Neurotrypsin mRNA was mostly detected in the thick ascending limb of the loop of Henle, the distal convoluted tubule, and the inner medullary collecting duct. Moreover, we show that the proximal tubule absorbs injected recombinant CAF by a process shared with receptor-mediated and fluid phase endocytosis. Co-injection of CAF with recombinant human transferrin, a substrate of the receptor-mediated endocytic pathway as well as with FITC-labelled dextran (10 kDa), a marker of fluid phase endocytosis, showed partial colocalization of CAF with both markers. Further colocalization of CAF with the lysosomal marker cathepsin B suggested degradation of CAF by the lysosome in the proximal tubule. Thus, the murine kidney expresses agrin and neurotrypsin in nephron segments beyond the glomerulum. CAF is filtered by the glomerulum and is reabsorbed by endocytosis by the proximal tubule. Thus, impaired kidney function could impair glomerular clearance of CAF and thereby increase circulating CAF levels.
| S-EPMC4933355 | biostudies-literature
Project description:C-terminal agrin fragment (tCAF) is a promising biomarker for glomerular filtration. Data regarding biomarkers that have the ability to predict rapid progression of chronic kidney disease (CKD) are sparse but necessary in order to identify patients at high risk for rapid progression. This study addresses the value of tCAF as a predictor of rapid kidney function decline in CKD patients.We measured plasma tCAF in a retrospective observational cohort study of 277 prevalent CKD patients stage I-V. Using multivariable Cox proportional hazards regression analysis, we evaluated the association of tCAF with end-stage-renal-disease (ESRD), ≥30%-decline of estimated glomerular filtration rate (eGFR) and the composite endpoint of both, adjusting for eGFR, age, systolic blood pressure, proteinuria and diabetes.The median age was 58 [interquartile range 47, 71] years, 36% were female. Median tCAF level was 822 [594, 1232] pM, eGFR was 32 [19, 48] ml/min/1.73 m. tCAF was correlated to eGFR and proteinuria (r = -0.76 and r = 0.49, P < .001 resp.). During a follow-up of 57.1 [42.9, 71.9] weeks, 36 (13%) patients developed ESRD and 13 (5%) had an eGFR decline of ≥30% (composite endpoint: 49 (18%)). In multivariable analysis, each 100 pM higher tCAF was independently associated with ESRD (hazard ratio (HR) 1.05 (95%-CI 1.02-1.08)), ≥30% eGFR decline (HR 1.10 (1.03-1.18)) and the composite endpoint (HR 1.07 (1.04-1.1)).Plasma tCAF may identify CKD patients at risk for rapid kidney function decline independent of eGFR and other risk factors for eGFR loss such as proteinuria.
| S-EPMC6531159 | biostudies-literature
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.
| S-EPMC11294022 | biostudies-literature
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.
| S-EPMC10570065 | biostudies-literature
Project description:The new tendency in rehabilitation involves non-invasive tools that, if applied early after stroke, promote neurorecovery. Repetitive transcranial magnetic stimulation and transcranial direct current stimulation may correct the disruption of cortical excitability and effectively contribute to the restoration of movement and speech. The present paper analyses the results of non-invasive brain stimulation (NIBS) trials, highlighting different aspects related to the repetitive transcranial magnetic stimulation frequency, transcranial direct current stimulation polarity, the period and stimulation places in acute and subacute ischemic strokes. The risk of adverse events, the association with motor or language recovery specific training, and the cumulative positive effect evaluation are also discussed.
| S-EPMC4564042 | biostudies-other
Project description:BackgroundIron deficiency (ID) is a common co-morbidity in patients with cardiovascular disease and contributes to impaired functional capacity. The relevance of ID in patients in recovery after acute stroke is not known. We assessed the prevalence of ID and anaemia in relation to functional capacity and to recovery during early rehabilitation after stroke.MethodsThis observational study enrolled consecutively 746 patients with ischaemic or haemorrhagic stroke at in-patient early rehabilitation (age 68 ± 13 years, female 47%, ischaemic stroke 87%). Functional capacity was assessed before and after rehabilitation using Barthel index (reha-BI), motricity index (MI), trunk control test (TCT), and functional ambulatory category (FAC). ID was defined as ferritin <100 μg/L or as transferrin saturation (TSAT) < 20% if ferritin was 100- < 300 μg/L or if CrP > 5 mg/L. Anaemia was defined as Hb < 12 g/dL (women) and <13 g/dL (men).ResultsThe prevalence of ID and anaemia before rehabilitation were 45% and 46%, respectively, and remained high at discharge (after 27 ± 17 days) at 40% and 48%, respectively. Patients with ID had lower functional capacity compared with patients without ID (reha-BI 20 [±86] vs. 40 [±80], MI 64 [±66] vs. 77 [±41], TCT 61 [±76] vs. 100 [±39], FAC 1 [±4] vs. 4 [±4]; median [IQR], all P < 0.001). ID was related to inflammation (OR 2.68 [95% CI 1.98-3.63], P < 0.001), female sex (OR 2.13 [95% CI 1.59-2.85], P < 0.001), haemorrhagic stroke (OR 1.70 [95% CI 1.11-2.61], P = 0.015), initial treatment on stroke unit (OR 3.59 [95% CI 1.08-11.89], P < 0.001), and anaemia (OR 2.94 [95% CI 2.18-3.96], P < 0.001), while age, BMI, and renal function were not related to ID. In adjusted analysis, ID was associated with low functional capacity in all functional scores: reha-BI (OR 1.66 [95% CI 1.08-2.54], P = 0.02), motricity index (OR 1.94 [95% CI 1.36-2.76], P < 0.001), trunk control test (OR 2.34 [95% CI] 1.64-3.32, P < 0.001) and functional ambulatory category (OR 1.77 [95% CI 1.2-2.63], P < 0.02). Functional capacity improved during rehabilitation regardless of presence of ID, but functional outcome remained significantly lower in patients with ID at the end of rehabilitation (rehab BI and MI, both P < 0.001).ConclusionsIron deficiency and anaemia are common and persistent findings in patients after acute stroke. ID and anaemia are independently related to lower functional capacity after acute stroke and to poor functional outcome after rehabilitation. Regular assessment of iron status may identify patients at risk of low functional recovery.
| S-EPMC8977949 | biostudies-literature
Project description:BackgroundStroke patients are often inactive outside of structured therapy sessions - an enduring international challenge despite large scale organizational changes, national guidelines and performance targets. We examined whether experienced-based co-design (EBCD) - an improvement methodology - could address inactivity in stroke units.AimsTo evaluate the feasibility and impact of patients, carers, and staff co-designing and implementing improvements to increase supervised and independent therapeutic patient activity in stroke units and to compare use of full and accelerated EBCD cycles.MethodsMixed-methods case comparison in four stroke units in England.ResultsInterviews were held with 156 patients, staff, and carers in total; ethnographic observations for 364 hours, behavioral mapping of 68 patients, and self-report surveys from 179 patients, pre- and post-implementation of EBCD improvement cycles.Three priority areas emerged: (1) 'Space' (environment); (2) 'Activity opportunities' and (3) 'Communication'. More than 40 improvements were co-designed and implemented to address these priorities across participating units. Post-implementation interview and ethnographic observational data confirmed use of new social spaces and increased activity opportunities. However, staff interactions remained largely task-driven with limited focus on enabling patient activity. Behavioral mapping indicated some increases in social, cognitive, and physical activity post-implementation, but was variable across sites. Survey responses rates were low at 12-38% and inconclusive.ConclusionIt was feasible to implement EBCD in stroke units. This resulted in multiple improvements in stroke unit environments and increased activity opportunities but minimal change in recorded activity levels. There was no discernible difference in experience or outcome between full and accelerated EBCD; this methodology could be used across hospital stroke units to assist staff and other stakeholders to co-design and implement improvement plans.
| S-EPMC8366168 | biostudies-literature