Publications by authors named "Karin J Naarding"

4 Publications

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Preserved thenar muscles in non-ambulant Duchenne muscular dystrophy patients.

J Cachexia Sarcopenia Muscle 2021 Jun 8;12(3):694-703. Epub 2021 May 8.

Duchenne Center, Leiden, Netherlands.

Background: Clinical trials in Duchenne muscular dystrophy (DMD) focus primarily on ambulant patients. Results cannot be extrapolated to later disease stages due to a decline in targeted muscle tissue. In non-ambulant DMD patients, hand function is relatively preserved and crucial for daily-life activities. We used quantitative MRI (qMRI) to establish whether the thenar muscles could be valuable to monitor treatment effects in non-ambulant DMD patients.

Methods: Seventeen non-ambulant DMD patients (range 10.2-24.1 years) and 13 healthy controls (range 9.5-25.4 years) underwent qMRI of the right hand at 3 T at baseline. Thenar fat fraction (FF), total volume (TV), and contractile volume (CV) were determined using 4-point Dixon, and T2 was determined using multiecho spin-echo. Clinical assessments at baseline (n = 17) and 12 months (n = 13) included pinch strength (kg), performance of the upper limb (PUL) 2.0, DMD upper limb patient reported outcome measure (PROM), and playing a video game for 10 min using a game controller. Group differences and correlations were assessed with non-parametric tests.

Results: Total volume was lower in patients compared with healthy controls (6.9 cm , 5.3-9.0 cm vs. 13.0 cm , 7.6-15.8 cm , P = 0.010). CV was also lower in patients (6.3 cm , 4.6-8.3 cm vs. 11.9 cm , 6.9-14.6 cm , P = 0.010). FF was slightly elevated (9.7%, 7.3-11.4% vs. 7.7%, 6.6-8.4%, P = 0.043), while T2 was higher (31.5 ms, 30.0-32.6 ms vs. 28.1 ms, 27.8-29.4 ms, P < 0.001). Pinch strength and PUL decreased over 12 months (2.857 kg, 2.137-4.010 to 2.243 kg, 1.930-3.339 kg, and 29 points, 20-36 to 23 points, 17-30, both P < 0.001), while PROM did not (49 points, 36-57 to 44 points, 30-54, P = 0.041). All patients were able to play for 10 min at baseline or follow-up, but some did not comply with the study procedures regarding this endpoint. Pinch strength correlated with TV and CV in patients (rho = 0.72 and rho = 0.68) and controls (both rho = 0.89). PUL correlated with TV, CV, and T2 (rho = 0.57, rho = 0.51, and rho = -0.59).

Conclusions: Low thenar FF, increased T2 , correlation of muscle size with strength and function, and the decrease in strength and function over 1 year indicate that the thenar muscles are a valuable and quantifiable target for therapy in later stages of DMD. Further studies are needed to relate these data to the loss of a clinically meaningful milestone.
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June 2021

Decision-Making And Selection Bias in Four Observational Studies on Duchenne and Becker Muscular Dystrophy.

J Neuromuscul Dis 2020 ;7(4):433-442

Duchenne Center Netherlands.

Background: Natural history data are essential for trial design in Duchenne (DMD) and Becker muscular dystrophy (BMD), but recruitment for observational studies can be challenging.

Objective: We reviewed reasons why patients or caregivers declined participation, and compared characteristics of participants and non-participants to assess possible selection bias in four observational studies, three on DMD and one on BMD.

Methods: Three pediatric DMD studies focused on cross-sectional cognitive function and brain MRI (DMDbrain, n = 35 and DMDperfusion, n = 12), and on longitudinal upper extremity function and muscle MRI (DMDarm, n = 22). One adult BMD study assessed longitudinal functioning (n = 36). Considerations for non-participation were retrospectively reviewed from screening logs. Age, travel-time, DMD gene mutations and age at loss of ambulation (DMDarm and BMD study only), of participants and non-participants were derived from the Dutch Dystrophinopathy Database and compared using nonparametric tests (p < 0.05).

Results: The perceived burden of the protocol (38.2%), use of MRI (30.4%), and travel-time to the study site (19.1%) were the most frequently reported considerations for non-participation. Only few patients reported lack of personal gain (0.0- 5.9%). Overall, participating patients were representative for the studied sub-populations, except for a younger age of DMDarm study participants and a complete lack of participants with a mutation beyond exon 63.

Conclusion: Optimizing patient involvement in protocol design, improving MRI experiences, and integrating research into clinics are important factors to decrease burden and facilitate participation. Nationwide registries are essential to compare participants and non-participants and ensure representative observational research. Specific effort is needed to include patients with distal mutations in cognitive studies.
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January 2020

T relaxation-time mapping in healthy and diseased skeletal muscle using extended phase graph algorithms.

Magn Reson Med 2020 11 19;84(5):2656-2670. Epub 2020 Apr 19.

Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands.

Purpose: Multi-echo spin-echo (MSE) transverse relaxometry mapping using multi-component models is used to study disease activity in neuromuscular disease by assessing the T of the myocytic component (T ). Current extended phase graph algorithms are not optimized for fat fractions above 50% and the effects of inaccuracies in the T calibration remain unexplored. Hence, we aimed to improve the performance of extended phase graph fitting methods over a large range of fat fractions, by including the slice-selection flip angle profile, a through-plane chemical-shift displacement correction, and optimized calibration of T .

Methods: Simulation experiments were used to study the influence of the slice flip-angle profile with chemical-shift and T estimations. Next, in vivo data from four neuromuscular disease cohorts were studied for different T calibration methods and T estimations.

Results: Excluding slice flip-angle profiles or chemical-shift displacement resulted in a bias in T up to 10 ms. Furthermore, a wrongly calibrated T caused a bias of up to 4 ms in T . For the in vivo data, one-component calibration led to a lower T compared with a two-component method, and T decreased with increasing fat fractions.

Conclusion: In vivo data showed a decline in T for increasing fat fractions, which has important implications for clinical studies, especially in multicenter settings. We recommend using an extended phase graph-based model for fitting T from MSE sequences with two-component T calibration. Moreover, we recommend including the slice flip-angle profile in the model with correction for through-plane chemical-shift displacements.
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November 2020

MRI vastus lateralis fat fraction predicts loss of ambulation in Duchenne muscular dystrophy.

Neurology 2020 03 14;94(13):e1386-e1394. Epub 2020 Jan 14.

From the Department of Neurology (K.J.N., E.H.N.), Department of Biostatistics (E.W.v.Z), and C.J. Gorter Center for High Field MRI (M.T.H., H.E.K.), Department of Radiology, Leiden University Medical Center, Zuid-Holland; Duchenne Center Netherlands (K.J.N., H.E.K., E.H.N.); AIM and CEA NMR Laboratory (H.R., J.L.L., P.G.C.), Neuromuscular Investigation Center, Institute of Myology, Paris, France; and Department of Neurology (C.T., I.R., K.C.S., B.L.W.), Cincinnati Children's Hospital Medical Center, OH.

Objective: We studied the potential of quantitative MRI (qMRI) as a surrogate endpoint in Duchenne muscular dystrophy by assessing the additive predictive value of vastus lateralis (VL) fat fraction (FF) to age on loss of ambulation (LoA).

Methods: VL FFs were determined on longitudinal Dixon MRI scans from 2 natural history studies in Leiden University Medical Center (LUMC) and Cincinnati Children's Hospital Medical Center (CCHMC). CCHMC included ambulant patients, while LUMC included a mixed ambulant and nonambulant population. We fitted longitudinal VL FF values to a sigmoidal curve using a mixed model with random slope to predict individual trajectories. The additive value of VL FF over age to predict LoA was calculated from a Cox model, yielding a hazard ratio.

Results: Eighty-nine MRIs of 19 LUMC and 15 CCHMC patients were included. At similar age, 6-minute walking test distances were smaller and VL FFs were correspondingly higher in LUMC compared to CCHMC patients. Hazard ratio of a percent-point increase in VL FF for the time to LoA was 1.15 for LUMC (95% confidence interval [CI] 1.05-1.26; = 0.003) and 0.96 for CCHMC (95% CI 0.84-1.10; = 0.569).

Conclusions: The hazard ratio of 1.15 corresponds to a 4.11-fold increase of the instantaneous risk of LoA in patients with a 10% higher VL FF at any age. Although results should be confirmed in a larger cohort with prospective determination of the clinical endpoint, this added predictive value of VL FF to age on LoA supports the use of qMRI FF as an endpoint or stratification tool in clinical trials.
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March 2020