Publications by authors named "Melissa T Hooijmans"

22 Publications

  • Page 1 of 1

A diffusion tensor-based method facilitating volumetric assessment of fiber orientations in skeletal muscle.

PLoS One 2022 27;17(1):e0261777. Epub 2022 Jan 27.

Department of Biomedical Engineering and Physics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: The purpose of this study was to develop a DTI-based method to quantitatively assess fiber angles and changes therein in leg muscles in order to facilitate longitudinal studies on muscle fiber architectural adaptations in healthy subjects.

Methods: The upper legs of five volunteers were scanned twice on the same day. The right lower legs of five volunteers were scanned twice with the ankle in three positions, i.e. -15° dorsiflexion, 0° neutral position, and 30° plantarflexion. The MRI protocols consisted of a noise scan, a 3-point mDixon scan and a DTI scan. Fiber-angle color maps were generated for four muscles in the upper legs and two muscles in the lower leg. Voxel-wise fiber angles (θ) were calculated from the angle between the principal eigenvector of the diffusion tensor and a reference line defined between the origo and insertion points of each muscle. Bland-Altman analysis, intraclass correlation coefficient (ICC), coefficient of variation (CV%), minimal detectable change (MDC), standard error (SE) and Friedman test were used for assessing the feasibility of this method and in order to have an indication of the repeatability and the sensitivity.

Results: Bland-Altman analysis showed good repeatability (CV%<10 and 0.7≤ICC≤0.9) with exception of the Tibialis Anterior (TA) muscle in dorsiflexion position(CV%: 12.2) and the Semitendinosus (ST) muscle (left leg) (CV%: 11.4). The best repeatability metrics were found for the SOL muscle in neutral position (CV%: 2.6). Changes in average θ in TA and SOL with ankle positions were observed in accordance with expected agonist and antagonist functions of both muscles. For example, for the anterior left compartment the change in fiber angle Δθ with respect to the neutral position Δθ = -1.6° ± 0.8° and 2.2° ± 2.8° (p = 0.008), for dorsiflexion and plantarflexion, respectively.

Conclusion: Our method facilitates fast inspection and quantification of muscle fiber angles in the lower and upper leg muscles in rest and detection of changes in lower-leg muscle fiber angles with varying ankle angles.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0261777PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8794095PMC
February 2022

Multi-parametric quantitative magnetic resonance imaging of the upper arm muscles of patients with spinal muscular atrophy.

NMR Biomed 2022 Jan 20:e4696. Epub 2022 Jan 20.

UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Quantitative magnetic resonance imaging (qMRI) is frequently used to map the disease state and disease progression in the lower extremity muscles of patients with spinal muscular atrophy (SMA). This is in stark contrast to the almost complete lack of data on the upper extremity muscles, which are essential for carrying out daily activities. The aim of this study was therefore to assess the disease state in the upper arm muscles of patients with SMA in comparison with healthy controls by quantitative assessment of fat fraction, diffusion indices, and water T2 relaxation times, and to relate these measures to muscle force. We evaluated 13 patients with SMA and 15 healthy controls with a 3-T MRI protocol consisting of DIXON, diffusion tensor imaging, and T2 sequences. qMRI measures were compared between groups and related to muscle force measured with quantitative myometry. Fat fraction was significantly increased in all upper arm muscles of the patients with SMA compared with healthy controls and correlated negatively with muscle force. Additionally, fat fraction was heterogeneously distributed within the triceps brachii (TB) and brachialis muscle, but not in the biceps brachii muscle. Diffusion indices and water T2 relaxation times were similar between patients with SMA and healthy controls, but we did find a slightly reduced mean diffusivity (MD), λ1, and λ3 in the TB of patients with SMA. Furthermore, MD was positively correlated with muscle force in the TB of patients with SMA. The variation in fat fraction further substantiates the selective vulnerability of muscles. The reduced diffusion tensor imaging indices, along with the positive correlation of MD with muscle force, point to myofiber atrophy. Our results show the feasibility of qMRI to map the disease state in the upper arm muscles of patients with SMA. Longitudinal data in a larger cohort are needed to further explore qMRI to map disease progression and to capture the possible effects of therapeutic interventions.
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http://dx.doi.org/10.1002/nbm.4696DOI Listing
January 2022

Baseline fat fraction is a strong predictor of disease progression in Becker muscular dystrophy.

NMR Biomed 2022 Jan 14:e4691. Epub 2022 Jan 14.

C. J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.

In Becker muscular dystrophy (BMD), muscle weakness progresses relatively slowly, with a highly variable rate among patients. This complicates clinical trials, as clinically relevant changes are difficult to capture within the typical duration of a trial. Therefore, predictors for disease progression are needed. We assessed if temporal increase of fat fraction (FF) in BMD follows a sigmoidal trajectory and whether fat fraction at baseline (FFbase) could therefore predict FF increase after 2 years (ΔFF). Thereafter, for two different MR-based parameters, we tested the additional predictive value to FFbase. We used 3-T Dixon data from the upper and lower leg, and multiecho spin-echo MRI and 7-T P MRS datasets from the lower leg, acquired in 24 BMD patients (age: 41.4 [SD 12.8] years). We assessed the pattern of increase in FF using mixed-effects modelling. Subsequently, we tested if indicators of muscle damage like standard deviation in water T (stdT ) and the phosphodiester (PDE) over ATP ratio at baseline had additional value to FFbase for predicting ∆FF. The association between FFbase and ΔFF was described by the derivative of a sigmoid function and resulted in a peak ΔFF around 0.45 FFbase (fourth-order polynomial term: t = 3.7, p < .001). StdT and PDE/ATP were not significantly associated with ∆FF if FFbase was included in the model. The relationship between FFbase and ∆FF suggests a sigmoidal trajectory of the increase in FF over time in BMD, similar to that described for Duchenne muscular dystrophy. Our results can be used to identify muscles (or patients) that are in the fast progressing stage of the disease, thereby facilitating the conduct of clinical trials.
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http://dx.doi.org/10.1002/nbm.4691DOI Listing
January 2022

Magnetic resonance reveals mitochondrial dysfunction and muscle remodelling in spinal muscular atrophy.

Brain 2021 Nov 11. Epub 2021 Nov 11.

Centre for Child Development, Exercise and Physical Literacy, Wilhelmina Children's Hospital, University Medical Centre Utrecht, P.O. Box 85090 3508 AB Utrecht, The Netherlands.

Genetic therapy has changed the prognosis of hereditary proximal spinal muscular atrophy, although treatment efficacy has been variable. There is a clear need for deeper understanding of underlying causes of muscle weakness and exercise intolerance in patients with this disease to further optimize treatment strategies. Animal models suggest that in addition to motor neuron and associated musculature degeneration, intrinsic abnormalities of muscle itself including mitochondrial dysfunction contribute to the disease etiology. To test this hypothesis in patients, we conducted the first in vivo clinical investigation of muscle bioenergetics. We recruited 15 patients and 15 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. MRI and 31phosphorus magnetic resonance spectroscopy, the modality of choice to interrogate muscle energetics and phenotypic fiber type makeup, was performed of the proximal arm musculature in combination with fatiguing arm-cycling exercise and blood lactate testing. We derived bioenergetic parameter estimates including: blood lactate, intramuscular pH and inorganic phosphate accumulation during exercise, and muscle dynamic recovery constants. Linear correlation was used to test for associations between muscle morphological and bioenergetic parameters and clinico-functional measures of muscle weakness. MRI showed significant atrophy of triceps but not biceps muscles in patients. Maximal voluntary contraction force normalized to muscle cross-sectional area for both arm muscles was 1.4-fold lower in patients than in controls, indicating altered intrinsic muscle properties other than atrophy contributed to muscle weakness in this cohort. In vivo 31phosphorus magnetic resonance spectroscopy identified white-to-red remodeling of residual proximal arm musculature in patients on basis of altered intramuscular inorganic phosphate accumulation during arm-cycling in red versus white and intermediate myofibers. Blood lactate rise during arm-cycling was blunted in patients and correlated with muscle weakness and phenotypic muscle makeup. Post-exercise metabolic recovery was slower in residual intramuscular white myofibers in patients demonstrating mitochondrial ATP synthetic dysfunction in this particular fiber type. This study provides first in vivo evidence in patients that degeneration of motor neurons and associated musculature causing atrophy and muscle weakness in 5q spinal muscular atrophy type 3 and 4 is aggravated by disproportionate depletion of myofibers that contract fastest and strongest. Our finding of decreased mitochondrial ATP synthetic function selectively in residual white myofibers provides both a possible clue to understanding the apparent vulnerability of this particular fiber type in 5q spinal muscular atrophy type 3 and 4 as well as a new biomarker and target for therapy.
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http://dx.doi.org/10.1093/brain/awab411DOI Listing
November 2021

Muscle architecture is associated with muscle fat replacement in Duchenne and Becker muscular dystrophies.

Muscle Nerve 2021 11 25;64(5):576-584. Epub 2021 Aug 25.

C.J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

Introduction/aims: Duchenne and Becker muscular dystrophies (DMD and BMD, respectively) are characterized by fat replacement of different skeletal muscles in a specific temporal order. Given the structural role of dystrophin in skeletal muscle mechanics, muscle architecture could be important in the progressive pathophysiology of muscle degeneration. Therefore, the aim of this study was to assess the role of muscle architecture in the progression of fat replacement in DMD and BMD.

Methods: We assessed the association between literature-based leg muscle architectural characteristics and muscle fat fraction from 22 DMD and 24 BMD patients. Dixon-based magnetic resonance imaging estimates of fat fractions at baseline and 12 (only DMD) and 24 months were related to fiber length and physiological cross-sectional area (PCSA) using age-controlled linear mixed modeling.

Results: DMD and BMD muscles with long fibers and BMD muscles with large PCSAs were associated with increased fat fraction. The effect of fiber length was stronger in muscles with larger PCSA.

Discussion: Muscle architecture may explain the pathophysiology of muscle degeneration in dystrophinopathies, in which proximal muscles with a larger mass (fiber length × PCSA) are more susceptible, confirming the clinical observation of a temporal proximal-to-distal progression. These results give more insight into the mechanical role in the pathophysiology of muscular dystrophies. Ultimately, this new information can be used to help support the selection of current and the development of future therapies.
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http://dx.doi.org/10.1002/mus.27399DOI Listing
November 2021

A MATLAB toolbox for muscle diffusion-tensor MRI tractography.

J Biomech 2021 07 7;124:110540. Epub 2021 Jun 7.

Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, USA; Departments of Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN 37232, USA; Departments of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA; Departments of Electrical Engineering and Computer Science, Vanderbilt University, Nashville, TN 37232, USA.

Diffusion-tensor MRI fiber tractography has been used to reconstruct skeletal muscle architecture, but remains a specialized technique using custom-written data processing routines. In this work, we describe the public release of a software toolbox having the following design objectives: accomplish the pre-processing tasks of file input, image registration, denoising, and diffusion-tensor calculation; allow muscle-specific methods for defining seed points; make fiber-tract architectural measurements referenced to tendinous structures; visualize fiber tracts and other muscle structures of interest; analyze the goodness of outcomes; and provide a programming structure that allows the addition of new capabilities in future versions. The proper function of the code was verified using simulated datasets. The toolbox capabilities for characterizing human muscle structure in vivo were demonstrated in a case study. These capabilities included measurements of muscle morphology; contractile and non-contractile tissue volumes; fiber-tract length, pennation angle, curvature; and the physiological cross-sectional area,. The free public release of this software is a first step in creating of a community of users who use these tools in studies of muscle physiology and biomechanics. Users may further contribute to code development. Along with simulated and actual datasets for benchmarking, these tools will further create mechanisms for enhancing scientific rigor and developing and validating new code features. Planned future developments include additional options for image pre-processing, development of a graphical user interface, analysis of architectural patterns during muscle contraction, and integration of functional imaging data.
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http://dx.doi.org/10.1016/j.jbiomech.2021.110540DOI Listing
July 2021

Selection Approach to Identify the Optimal Biomarker Using Quantitative Muscle MRI and Functional Assessments in Becker Muscular Dystrophy.

Neurology 2021 08 23;97(5):e513-e522. Epub 2021 Jun 23.

From the Department of Neurology (N.M.v.d.V., K.R.K., Z.K., J.J.G.M.V., E.H.N.), C.J. Gorter Center for High-Field MRI, Department of Radiology (M.T.H., A.S.D.S.M., K.R.K., T.T.J.V., J.-W.M.B., H.E.K.), Department of Orthopaedics, Rehabilitation and Physical Therapy (I.A.), Department of Biomedical Data Sciences (E.W.v.Z.), and Department of Ophthalmology (J.-W.M.B.), Leiden University Medical Center, the Netherlands; and Duchenne Center Netherlands (N.M.v.d.V., J.J.G.M.V., H.E.K., E.H.N.), the Netherlands.

Objective: To identify the best quantitative fat-water MRI biomarker for disease progression of leg muscles in Becker muscular dystrophy (BMD) by applying a stepwise approach based on standardized response mean (SRM) over 24 months, correlations with baseline ambulatory tests, and reproducibility.

Methods: Dixon fat-water imaging was performed at baseline (n = 24) and 24 months (n = 20). Fat fractions (FF) were calculated for 3 center slices and the whole muscles for 19 muscles and 6 muscle groups. Contractile cross-sectional area (cCSA) was obtained from the center slice. Functional assessments included knee extension and flexion force and 3 ambulatory tests (North Star Ambulatory Assessment [NSAA], 10-meter run, 6-minute walking test). MRI measures were selected using SRM (≥0.8) and correlation with all ambulatory tests (ρ ≤ -0.8). Measures were evaluated based on intraclass correlation coefficient (ICC) and SD of the difference. Sample sizes were calculated assuming 50% reduction in disease progression over 24 months in a clinical trial with 1:1 randomization.

Results: Median whole muscle FF increased between 0.2% and 2.6% without consistent cCSA changes. High SRMs and strong functional correlations were found for 8 FF but no cCSA measures. All measures showed excellent ICC (≥0.999) and similar SD of the interrater difference. Whole thigh 3 center slices FF was the best biomarker (SRM 1.04, correlations ρ ≤ -0.81, ICC 1.00, SD 0.23%, sample size 59) based on low SD and acquisition and analysis time.

Conclusion: In BMD, median FF of all muscles increased over 24 months. Whole thigh 3 center slices FF reduced the sample size by approximately 40% compared to NSAA.
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http://dx.doi.org/10.1212/WNL.0000000000012233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356376PMC
August 2021

Supervised segmentation framework for evaluation of diffusion tensor imaging indices in skeletal muscle.

NMR Biomed 2021 01 1;34(1):e4406. Epub 2020 Oct 1.

Department of Biomedical Engineering and Physics, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands.

Diffusion tensor imaging (DTI) is becoming a relevant diagnostic tool to understand muscle disease and map muscle recovery processes following physical activity or after injury. Segmenting all the individual leg muscles, necessary for quantification, is still a time-consuming manual process. The purpose of this study was to evaluate the impact of a supervised semi-automatic segmentation pipeline on the quantification of DTI indices in individual upper leg muscles. Longitudinally acquired MRI datasets (baseline, post-marathon and follow-up) of the upper legs of 11 subjects were used in this study. MR datasets consisted of a DTI and Dixon acquisition. Semi-automatic segmentations for the upper leg muscles were performed using a transversal propagation approach developed by Ogier et al on the out-of-phase Dixon images at baseline. These segmentations were longitudinally propagated for the post-marathon and follow-up time points. Manual segmentations were performed on the water image of the Dixon for each of the time points. Dice similarity coefficients (DSCs) were calculated to compare the manual and semi-automatic segmentations. Bland-Altman and regression analyses were performed, to evaluate the impact of the two segmentation methods on mean diffusivity (MD), fractional anisotropy (FA) and the third eigenvalue (λ ). The average DSC for all analyzed muscles over all time points was 0.92 ± 0.01, ranging between 0.48 and 0.99. Bland-Altman analysis showed that the 95% limits of agreement for MD, FA and λ ranged between 0.5% and 3.0% for the transversal propagation and between 0.7% and 3.0% for the longitudinal propagations. Similarly, regression analysis showed good correlation for MD, FA and λ (r = 0.99, p < 60; 0.0001). In conclusion, the supervised semi-automatic segmentation framework successfully quantified DTI indices in the upper-leg muscles compared with manual segmentation while only requiring manual input of 30% of the slices, resulting in a threefold reduction in segmentation time.
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http://dx.doi.org/10.1002/nbm.4406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757256PMC
January 2021

Marathon running transiently depletes the myocardial lipid pool.

Physiol Rep 2020 09;8(17):e14543

Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Lipids, stored as intracellular triacylglycerol droplets within the myocardium, serve as an important source of energy, particularly in times of prolonged increased energy expenditure. In only a few studies, the acute effects of exercise on such ectopic myocardial lipid storage were investigated. We studied the dynamic behavior of the myocardial lipid pool in response to completing the 2017 Amsterdam Marathon using proton magnetic resonance (MR) spectroscopy ( H-MRS). We hypothesized that the prolonged increased myocardial energy demand of running a marathon could shift the balance of myocardial triacylglycerol turnover from triacylglycerol synthesis toward lipolysis and mitochondrial fatty acid β-oxidation, and decrease the myocardial lipid pool. We employed two 3 Tesla MR systems in parallel to noninvasively examine endurance-trained healthy men (n = 8; age 50.7 [50.1-52.7] y) at 1 week prior (baseline), <6 hr after finishing the marathon (post-marathon), and 2 weeks thereafter (recovery). Exercise intensity was 89 ± 6% of the age-predicted maximal heart rate, with a finish time of 3:56 [3:37-4:42] h:min. Myocardial lipid content was 0.66 [0.58-0.87]% of the total myocardial water signal at baseline, was lower post-marathon (0.47 [0.41-0.63]% of the total myocardial water signal), and had restored to 0.55 [0.49-0.83]% of the total myocardial water signal at recovery, representing a transient marathon running-induced depletion of 29 ± 24% (p = .04). The magnitude of this myocardial lipid pool depletion did not correlate with exercise intensity (r = -0.39; p = .39), nor with marathon finishing time (ρ = 0.57; p = .15). Our data show that prolonged high-intensity exercise can induce a transient depletion of the myocardial lipid pool, reinforcing the dynamic nature of ectopic triacylglycerol storage under real-life conditions of extreme endurance exercise.
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http://dx.doi.org/10.14814/phy2.14543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460059PMC
September 2020

Multi-parametric MR in Becker muscular dystrophy patients.

NMR Biomed 2020 11 5;33(11):e4385. Epub 2020 Aug 5.

C.J. Gorter Center, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

Quantitative MRI and MRS of muscle are increasingly being used to measure individual pathophysiological processes in Becker muscular dystrophy (BMD). In particular, muscle fat fraction was shown to be highly associated with functional tests in BMD. However, the muscle strength per unit of contractile cross-sectional area is lower in patients with BMD compared with healthy controls. This suggests that the quality of the non-fat-replaced (NFR) muscle tissue is lower than in healthy controls. Consequently, a measure that reflects changes in muscle tissue itself is needed. Here, we explore the potential of water T relaxation times, diffusion parameters and phosphorus metabolic indices as early disease markers in patients with BMD. For this purpose, we examined these measures in fat-replaced (FR) and NFR lower leg muscles in patients with BMD and compared these values with those in healthy controls. Quantitative proton MRI (three-point Dixon, multi-spin-echo and diffusion-weighted spin-echo echo planar imaging) and 2D chemical shift imaging P MRS data were acquired in 24 patients with BMD (age 18.8-66.2 years) and 13 healthy controls (age 21.3-63.6 years). Muscle fat fractions, phosphorus metabolic indices, and averages and standard deviations (SDs) of the water T relaxation times and diffusion tensor imaging (DTI) parameters were assessed in six individual leg muscles. Phosphodiester levels were increased in the NFR and FR tibialis anterior, FR peroneus and FR gastrocnemius lateralis muscles. No clear pattern was visible for the other metabolic indices. Increased T SD was found in the majority of FR muscles compared with NFR and healthy control muscles. No differences in average water T relaxation times or DTI indices were found between groups. Overall, our results indicate that primarily muscles that are further along in the disease process showed increases in T heterogeneity and changes in some metabolic indices. No clear differences were found for the DTI indices between groups.
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http://dx.doi.org/10.1002/nbm.4385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687231PMC
November 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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http://dx.doi.org/10.1002/mrm.28290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496817PMC
November 2020

Quantitative MRI Reveals Microstructural Changes in the Upper Leg Muscles After Running a Marathon.

J Magn Reson Imaging 2020 08 7;52(2):407-417. Epub 2020 Mar 7.

Amsterdam University Medical Centers, University of Amsterdam, Department of Biomedical Engineering and Physics, Amsterdam Movement Sciences, Amsterdam, Netherlands.

Background: The majority of sports-related injuries involve skeletal muscle. Unlike acute trauma, which is often caused by a single traumatic event leading to acute symptoms, exercise-induced microtrauma may remain subclinical and difficult to detect. Therefore, novel methods to detect and localize subclinical exercise-induced muscle microtrauma are desirable.

Purpose: To assess acute and delayed microstructural changes in upper leg muscles with multiparametric quantitative MRI after running a marathon.

Study Type: Longitudinal; 1-week prior, 24-48 hours postmarathon and 2-week follow-up POPULATION: Eleven men participants (age: 47-68 years).

Field Strength/sequence: Spin-echo echo planar imaging (SE-EPI) with diffusion weighting, multispin echo, Dixon, and fat-suppressed turbo spin-echo (TSE) sequences at 3T. MR datasets and creatine kinase (CK) concentrations were obtained at three timepoints.

Assessment: Diffusion parameters, perfusion fractions, and quantitative (q)T values were determined for hamstring and quadriceps muscles, TSE images were scored for acute injury. The vastus medialis and biceps femoris long head muscles were divided and analyzed in five segments to assess local damage.

Statistical Tests: Differences between timepoints in MR parameters were assessed with a multilevel linear mixed model and in CK concentrations with a Friedman test. Mean diffusivity (MD) and qT for whole muscle and muscle segments were compared using a multivariate analysis of covariance (MANCOVA).

Results: CK concentrations were elevated (1194 U/L [166-3906], P < 0.001) at 24-48 hours postmarathon and returned to premarathon values (323 U/L [56-2216]) at 2-week follow-up. Most of the MRI diffusion indices in muscles without acute injury changed at 24-48 hours postmarathon and returned to premarathon values at follow-up (MD, RD, and λ3; P < 0.006). qT values (P = 0.003) and perfusion fractions (P = 0.003) were higher at baseline compared to follow-up. Local assessments of MD and qT revealed more pronounced changes than whole muscle assessment (2-3-fold; P < 0.01).

Data Conclusion: Marathon running-induced microtrauma was detected with MRI in individual whole upper leg muscles and even more pronounced on local segments.

Level Of Evidence: 2 TECHNICAL EFFICACY STAGE: 3 J. Magn. Reson. Imaging 2020;52:407-417.
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http://dx.doi.org/10.1002/jmri.27106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496541PMC
August 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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http://dx.doi.org/10.1212/WNL.0000000000008939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274919PMC
March 2020

The repeatability of bilateral diffusion tensor imaging (DTI) in the upper leg muscles of healthy adults.

Eur Radiol 2020 Mar 8;30(3):1709-1718. Epub 2019 Nov 8.

Amsterdam UMC, Radiology & Nuclear Medicine, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.

Objectives: Assessment of the repeatability of diffusion parameter estimations in the upper leg muscles of healthy adults over the time course of 2 weeks, from a simultaneous bilateral upper leg DTI measurement.

Methods: SE-EPI DTI datasets were acquired at 3 T in the upper legs of 15 active adults at a time interval of 2 weeks. ROIs were manually drawn for four quadriceps and three hamstring muscles of both legs. The following DTI parameters were analyzed: 1st, 2nd, and 3rd eigenvalue (λ, λ, and λ), mean diffusivity (MD), and fractional anisotropy (FA). DTI parameters per muscle were calculated with and without intravoxel incoherent motion (IVIM) correction together with SNR levels per muscle. Bland-Altman plots and within-subject coefficient of variation (wsCV) were calculated. Left-right differences between muscles were assessed.

Results: The Bland-Altman analysis showed good repeatability of all DTI parameters except FA for both the IVIM-corrected and standard data. wsCV values show that MD has the highest repeatability (4.5% IVIM; 5.6% standard), followed by λ (4.9% IVIM; 5.5% standard), λ (5.3% IVIM; 7.5% standard), and λ (5.7% IVIM; 5.7% standard). wsCV values of FA were 15.2% for the IVIM-corrected data and 13.9% for the standard analysis. The SNR (41.8 ± 16.0 right leg, 41.7 ± 17.1 left leg) and wsCV values were similar for the left and right leg and no left-right bias was detected.

Conclusions: Repeatability was good for standard DTI data and slightly better for IVIM-corrected DTI data. Our protocol is suitable for DTI of the upper legs with overall good SNR.

Key Points: • The presented DTI protocol is repeatable and therefore suitable for bilateral DT imaging of the upper legs. • Additional B1calibrations improve SNR and repeatability. • Correcting for perfusion effects improves repeatability.
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http://dx.doi.org/10.1007/s00330-019-06403-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033061PMC
March 2020

Multi-center evaluation of stability and reproducibility of quantitative MRI measures in healthy calf muscles.

NMR Biomed 2019 09 17;32(9):e4119. Epub 2019 Jul 17.

Department of Radiology, University Medical Centre Utrecht, Utrecht, The Netherlands.

The purpose of this study was to evaluate temporal stability, multi-center reproducibility and the influence of covariates on a multimodal MR protocol for quantitative muscle imaging and to facilitate its use as a standardized protocol for evaluation of pathology in skeletal muscle. Quantitative T2, quantitative diffusion and four-point Dixon acquisitions of the calf muscles of both legs were repeated within one hour. Sixty-five healthy volunteers (31 females) were included in one of eight 3-T MR systems. Five traveling subjects were examined in six MR scanners. Average values over all slices of water-T2 relaxation time, proton density fat fraction (PDFF) and diffusion metrics were determined for seven muscles. Temporal stability was tested with repeated measured ANOVA and two-way random intraclass correlation coefficient (ICC). Multi-center reproducibility of traveling volunteers was assessed by a two-way mixed ICC. The factors age, body mass index, gender and muscle were tested for covariance. ICCs of temporal stability were between 0.963 and 0.999 for all parameters. Water-T2 relaxation decreased significantly (P < 10 ) within one hour by ~ 1 ms. Multi-center reproducibility showed ICCs within 0.879-0.917 with the lowest ICC for mean diffusivity. Different muscles showed the highest covariance, explaining 20-40% of variance for observed parameters. Standardized acquisition and processing of quantitative muscle MRI data resulted in high comparability among centers. The imaging protocol exhibited high temporal stability over one hour except for water T2 relaxation times. These results show that data pooling is feasible and enables assembling data from patients with neuromuscular diseases, paving the way towards larger studies of rare muscle disorders.
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http://dx.doi.org/10.1002/nbm.4119DOI Listing
September 2019

Exploration of New Contrasts, Targets, and MR Imaging and Spectroscopy Techniques for Neuromuscular Disease - A Workshop Report of Working Group 3 of the Biomedicine and Molecular Biosciences COST Action BM1304 MYO-MRI.

J Neuromuscul Dis 2019;6(1):1-30

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

Neuromuscular diseases are characterized by progressive muscle degeneration and muscle weakness resulting in functional disabilities. While each of these diseases is individually rare, they are common as a group, and a large majority lacks effective treatment with fully market approved drugs. Magnetic resonance imaging and spectroscopy techniques (MRI and MRS) are showing increasing promise as an outcome measure in clinical trials for these diseases. In 2013, the European Union funded the COST (co-operation in science and technology) action BM1304 called MYO-MRI (www.myo-mri.eu), with the overall aim to advance novel MRI and MRS techniques for both diagnosis and quantitative monitoring of neuromuscular diseases through sharing of expertise and data, joint development of protocols, opportunities for young researchers and creation of an online atlas of muscle MRI and MRS. In this report, the topics that were discussed in the framework of working group 3, which had the objective to: Explore new contrasts, new targets and new imaging techniques for NMD are described. The report is written by the scientists who attended the meetings and presented their data. An overview is given on the different contrasts that MRI can generate and their application, clinical needs and desired readouts, and emerging methods.
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http://dx.doi.org/10.3233/JND-180333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398566PMC
January 2020

Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies.

J Cachexia Sarcopenia Muscle 2018 08 16;9(4):715-726. Epub 2018 Apr 16.

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Background: Analysis of muscle biopsies allowed to characterize the pathophysiological changes of Duchenne and Becker muscular dystrophies (D/BMD) leading to the clinical phenotype. Muscle tissue is often investigated during interventional dose finding studies to show in situ proof of concept and pharmacodynamics effect of the tested drug. Less invasive readouts are needed to objectively monitor patients' health status, muscle quality, and response to treatment. The identification of serum biomarkers correlating with clinical function and able to anticipate functional scales is particularly needed for personalized patient management and to support drug development programs.

Methods: A large-scale proteomic approach was used to identify serum biomarkers describing pathophysiological changes (e.g. loss of muscle mass), association with clinical function, prediction of disease milestones, association with in vivo P magnetic resonance spectroscopy data and dystrophin levels in muscles. Cross-sectional comparisons were performed to compare DMD patients, BMD patients, and healthy controls. A group of DMD patients was followed up for a median of 4.4 years to allow monitoring of individual disease trajectories based on yearly visits.

Results: Cross-sectional comparison enabled to identify 10 proteins discriminating between healthy controls, DMD and BMD patients. Several proteins (285) were able to separate DMD from healthy, while 121 proteins differentiated between BMD and DMD; only 13 proteins separated BMD and healthy individuals. The concentration of specific proteins in serum was significantly associated with patients' performance (e.g. BMP6 serum levels and elbow flexion) or dystrophin levels (e.g. TIMP2) in BMD patients. Analysis of longitudinal trajectories allowed to identify 427 proteins affected over time indicating loss of muscle mass, replacement of muscle by adipose tissue, and cardiac involvement. Over-representation analysis of longitudinal data allowed to highlight proteins that could be used as pharmacodynamic biomarkers for drugs currently in clinical development.

Conclusions: Serum proteomic analysis allowed to not only discriminate among DMD, BMD, and healthy subjects, but it enabled to detect significant associations with clinical function, dystrophin levels, and disease progression.
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http://dx.doi.org/10.1002/jcsm.12304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104105PMC
August 2018

Improved olefinic fat suppression in skeletal muscle DTI using a magnitude-based dixon method.

Magn Reson Med 2018 Jan 5;79(1):152-159. Epub 2017 Mar 5.

C.J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: To develop a method of suppressing the multi-resonance fat signal in diffusion-weighted imaging of skeletal muscle. This is particularly important when imaging patients with muscular dystrophies, a group of diseases which cause gradual replacement of muscle tissue by fat.

Theory And Methods: The signal from the olefinic fat peak at 5.3 ppm can significantly confound diffusion-tensor imaging measurements. Dixon olefinic fat suppression (DOFS), a magnitude-based chemical-shift-based method of suppressing the olefinic peak, is proposed. It is verified in vivo by performing diffusion tensor imaging (DTI)-based quantification in the lower leg of seven healthy volunteers, and compared to two previously described fat-suppression techniques in regions with and without fat contamination.

Results: In the region without fat contamination, DOFS produces similar results to existing techniques, whereas in muscle contaminated by subcutaneous fat signal moved due to the chemical shift artefact, it consistently showed significantly higher (P = 0.018) mean diffusivity (MD). Because fat presence lowers MD, this suggests improved fat suppression.

Conclusion: DOFS offers superior fat suppression and enhances quantitative measurements in the muscle in the presence of fat. DOFS is an alternative to spectral olefinic fat suppression. Magn Reson Med 79:152-159, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
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http://dx.doi.org/10.1002/mrm.26655DOI Listing
January 2018

T2 relaxation times are increased in Skeletal muscle of DMD but not BMD patients.

Muscle Nerve 2016 Jan 26;53(1):38-43. Epub 2015 Nov 26.

C.J. Gorter Centre for high field MRI, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

Introduction: Exon-skipping drugs in Duchenne muscular dystrophy (DMD) aim to restore truncated dystrophin expression, which is present in the milder Becker muscular dystrophy (BMD). MRI skeletal muscle T2 relaxation times as a representation of edema/inflammation could be quantitative outcome parameters for such trials.

Methods: We studied T2 relaxation times, adjusted for muscle fat fraction using Dixon MRI, in lower leg muscles of DMD and BMD patients and healthy controls.

Results: T2 relaxation times correlated significantly with fat fractions in patients only (P < 0.001). After adjusting for muscle fat, T2 relaxation times were significantly increased in 6 muscles of DMD patients (P < 0.01), except for the extensor digitorum longus. In BMD, T2 relaxation times were unchanged.

Conclusions: T2 relaxation times could be a useful outcome parameter in exon-skipping trials in DMD but are influenced by fat despite fat suppression. This should be accounted for when using quantitative T2 mapping to investigate edema/inflammation.
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http://dx.doi.org/10.1002/mus.24679DOI Listing
January 2016

Fast multistation water/fat imaging at 3T using DREAM-based RF shimming.

J Magn Reson Imaging 2015 Jul 21;42(1):217-23. Epub 2014 Oct 21.

Department of Radiology, C.J. Gorter Center for High Field MRI, LUMC, Leiden, the Netherlands.

Purpose: To show the effect, efficiency, and image quality improvements achievable by Dual Refocusing Echo Acquisition Mode (DREAM)-based B1+ shimming in whole-body magnetic resonance imaging (MRI) at 3T using the example of water/fat imaging.

Materials And Methods: 3D multistation, dual-echo mDixon gradient echo imaging was performed in 10 healthy subjects on a clinical 3T dual-transmit MRI system using station-to-station adapted B1+ shimming based on fast DREAM B1+ mapping. Whole-body data were obtained using conventional quadrature excitation and station-by-station adapted DREAM-based B1+ shimmed excitation, along with the corresponding B1+ maps for both excitation modes to assess image quality and radiofrequency (RF) performance.

Results: Station-dependent DREAM-based B1+ shimming showed significantly improved image quality in the stations covering the upper legs, pelvis, and upper body region for all subjects (P < 0.02). This finding is supported by corresponding B1+ maps showing an improved B1+ homogeneity and a more precise flip angle in the DREAM-based B1+ shimmed excitation (P < 0.01). Furthermore, the very short dual-channel DREAM B1+ mapping times of less than 2 seconds facilitate quick B1+ shimming.

Conclusion: Station-dependent DREAM-based B1+ shimming improved RF performance and image quality and is therefore a promising technique for whole-body multistation imaging applications.
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http://dx.doi.org/10.1002/jmri.24775DOI Listing
July 2015
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