Publications by authors named "Hermien E Kan"

50 Publications

A split-label design for simultaneous measurements of perfusion in distant slices by pulsed arterial spin labeling.

Magn Reson Med 2021 Jun 9. Epub 2021 Jun 9.

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

Purpose: Multislice arterial spin labeling (ASL) MRI acquisitions are currently challenging in skeletal muscle because of long transit times, translating into low-perfusion SNR in distal slices when large spatial coverage is required. However, fiber type and oxidative capacity vary along the length of healthy muscles, calling for multislice acquisitions in clinical studies. We propose a new variant of flow alternating inversion recovery (FAIR) that generates sufficient ASL signal to monitor exercise-induced perfusion changes in muscle in two distant slices.

Methods: Label around and between two 7-cm distant slices was created by applying the presaturation/postsaturation and selective inversion modules selectively to each slice (split-label multislice FAIR). Images were acquired using simultaneous multislice EPI. We validated our approach in the brain to take advantage of the high resting-state perfusion, and applied it in the lower leg muscle during and after exercise, interleaved with a single-slice FAIR as a reference.

Results: We show that standard multislice FAIR leads to an underestimation of perfusion, while the proposed split-label multislice approach shows good agreement with separate single-slice FAIR acquisitions in brain, as well as in muscle following exercise.

Conclusion: Split-label FAIR allows measuring muscle perfusion in two distant slices simultaneously without losing sensitivity in the distal slice.
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http://dx.doi.org/10.1002/mrm.28879DOI Listing
June 2021

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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http://dx.doi.org/10.1002/jcsm.12711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200430PMC
June 2021

Compartmental diffusion and microstructural properties of human brain gray and white matter studied with double diffusion encoding magnetic resonance spectroscopy of metabolites and water.

Neuroimage 2021 07 21;234:117981. Epub 2021 Mar 21.

C.J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

Double diffusion encoding (DDE) of the water signal offers a unique ability to separate the effect of microscopic anisotropic diffusion in structural units of tissue from the overall macroscopic orientational distribution of cells. However, the specificity in detected microscopic anisotropy is limited as the signal is averaged over different cell types and across tissue compartments. Performing side-by-side water and metabolite DDE spectroscopic (DDES) experiments provides complementary measures from which intracellular and extracellular microscopic fractional anisotropies (μFA) and diffusivities can be estimated. Metabolites are largely confined to the intracellular space and therefore provide a benchmark for intracellular μFA and diffusivities of specific cell types. By contrast, water DDES measurements allow examination of the separate contributions to water μFA and diffusivity from the intra- and extracellular spaces, by using a wide range of b values to gradually eliminate the extracellular contribution. Here, we aimed to estimate tissue and compartment specific human brain microstructure by combining water and metabolites DDES experiments. We performed our DDES measurements in two brain regions that contain widely different amounts of white matter (WM) and gray matter (GM): parietal white matter (PWM) and occipital gray matter (OGM) in a total of 20 healthy volunteers at 7 Tesla. Metabolite DDES measurements were performed at b = 7199 s/mm, while water DDES measurements were performed with a range of b values from 918 to 7199 s/mm. The experimental framework we employed here resulted in a set of insights pertaining to the morphology of the intracellular and extracellular spaces in both gray and white matter. Results of the metabolite DDES experiments in both PWM and OGM suggest a highly anisotropic intracellular space within neurons and glia, with the possible exception of gray matter glia. The water μFA obtained from the DDES results at high b values in both regions converged with that of the metabolite DDES, suggesting that the signal from the extracellular space is indeed effectively suppressed at the highest b value. The μFA measured in the OGM significantly decreased at lower b values, suggesting a considerably lower anisotropy of the extracellular space in GM compared to WM. In PWM, the water μFA remained high even at the lowest b value, indicating a high degree of organization in the interstitial space in WM. Tortuosity values in the cytoplasm for water and tNAA, obtained with correlation analysis of microscopic parallel diffusivity with respect to GM/WM tissue fraction in the volume of interest, are remarkably similar for both molecules, while exhibiting a clear difference between gray and white matter, suggesting a more crowded cytoplasm and more complex cytomorphology of neuronal cell bodies and dendrites in GM than those found in long-range axons in WM.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117981DOI Listing
July 2021

Resting-state functional MRI shows altered default-mode network functional connectivity in Duchenne muscular dystrophy patients.

Brain Imaging Behav 2021 Jan 3. Epub 2021 Jan 3.

John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.

Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder caused by absence of dystrophin protein. Dystrophin is expressed in muscle, but also in the brain. Difficulties with attention/inhibition, working memory and information processing are well described in DMD patients but their origin is poorly understood. The default mode network (DMN) is one of the networks involved in these processes. Therefore we aimed to assess DMN connectivity in DMD patients compared to matched controls, to better understand the cognitive profile in DMD. T1-weighted and resting state functional MRI scans were acquired from 33 DMD and 24 male age-matched controls at two clinical sites. Scans were analysed using FMRIB Software Library (FSL). Differences in the DMN were assessed using FSL RANDOMISE, with age as covariate and threshold-free cluster enhancement including multiple comparison correction. Post-hoc analyses were performed on the visual network, executive control network and fronto-parietal network with the same methods. In DMD patients, the level of connectivity was higher in areas within the control DMN (hyperconnectivity) and significant connectivity was found in areas outside the control DMN. No hypoconnectivity was found and no differences in the visual network, executive control network and fronto-parietal network. We showed differences both within and in areas outside the DMN in DMD. The specificity of our findings to the DMN can help provide a better understanding of the attention/inhibition, working memory and information processing difficulties in DMD.
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http://dx.doi.org/10.1007/s11682-020-00422-3DOI Listing
January 2021

Quantitative Imaging in Muscle Diseases with Focus on Non-proton MRI and Other Advanced MRI Techniques.

Semin Musculoskelet Radiol 2020 Aug 29;24(4):402-412. Epub 2020 Sep 29.

Department of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany.

The role of neuromuscular imaging in the diagnosis of inherited and acquired muscle diseases has gained clinical relevance. In particular, magnetic resonance imaging (MRI), especially whole-body applications, is increasingly being used for the diagnosis and monitoring of disease progression. In addition, they are considered as a powerful outcome measure in clinical trials. Because many muscle diseases have a distinct muscle involvement pattern, whole-body imaging can be of diagnostic value by identifying this pattern and thus narrowing the differential diagnosis and supporting the clinical diagnosis. In addition, more advanced MRI applications including non-proton MRI, diffusion tensor imaging, perfusion MRI, T2 mapping, and magnetic resonance spectroscopy provide deeper insights into muscle pathophysiology beyond the mere detection of fatty degeneration and/or muscle edema. In this review article, we present and discuss recent data on these quantitative MRI techniques in muscle diseases, with a particular focus on non-proton imaging techniques.
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http://dx.doi.org/10.1055/s-0040-1712955DOI Listing
August 2020

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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http://dx.doi.org/10.3233/JND-200541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902964PMC
January 2020

249th ENMC International Workshop: The role of brain dystrophin in muscular dystrophy: Implications for clinical care and translational research, Hoofddorp, The Netherlands, November 29th-December 1st 2019.

Neuromuscul Disord 2020 Sep 15;30(9):782-794. Epub 2020 Aug 15.

The Dubowitz Neuromuscular Centre, University College London, Great Ormond Street Institute of Child Health, London, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK.

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http://dx.doi.org/10.1016/j.nmd.2020.08.357DOI Listing
September 2020

The feasibility of quantitative MRI of extra-ocular muscles in myasthenia gravis and Graves' orbitopathy.

NMR Biomed 2021 01 7;34(1):e4407. Epub 2020 Sep 7.

CJ Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.

Although quantitative MRI can be instrumental in the diagnosis and assessment of disease progression in orbital diseases involving the extra-ocular muscles (EOM), acquisition can be challenging as EOM are small and prone to eye-motion artefacts. We explored the feasibility of assessing fat fractions (FF), muscle volumes and water T2 (T2 ) of EOM in healthy controls (HC), myasthenia gravis (MG) and Graves' orbitopathy (GO) patients. FF, EOM volumes and T2 values were determined in 12 HC (aged 22-65 years), 11 MG (aged 28-71 years) and six GO (aged 28-64 years) patients at 7 T using Dixon and multi-echo spin-echo sequences. The EOM were semi-automatically 3D-segmented by two independent observers. MANOVA and t-tests were used to assess differences in FF, T2 and volume of EOM between groups (P < .05). Bland-Altman limits of agreement (LoA) were used to assess the reproducibility of segmentations and Dixon scans. The scans were well tolerated by all subjects. The bias in FF between the repeated Dixon scans was -0.7% (LoA: ±2.1%) for the different observers; the bias in FF was -0.3% (LoA: ±2.8%) and 0.03 cm (LoA: ± 0.36 cm ) for volume. Mean FF of EOM in MG (14.1% ± 1.6%) was higher than in HC (10.4% ± 2.5%). Mean muscle volume was higher in both GO (1.2 ± 0.4 cm ) and MG (0.8 ± 0.2 cm ) compared with HC (0.6 ± 0.2 cm ). The average T2 for all EOM was 24.6 ± 4.0 ms for HC, 24.0 ± 4.7 ms for MG patients and 27.4 ± 4.2 ms for the GO patient. Quantitative MRI at 7 T is feasible for measuring FF and muscle volumes of EOM in HC, MG and GO patients. The measured T2 was on average comparable with skeletal muscle, although with higher variation between subjects. The increased FF in the EOM in MG patients suggests that EOM involvement in MG is accompanied by fat replacement. The unexpected EOM volume increase in MG may provide novel insights into underlying pathophysiological processes.
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http://dx.doi.org/10.1002/nbm.4407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757175PMC
January 2021

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

The effect of mirabegron on energy expenditure and brown adipose tissue in healthy lean South Asian and Europid men.

Diabetes Obes Metab 2020 11 29;22(11):2032-2044. Epub 2020 Jul 29.

Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands.

Aim: To compare the effects of cold exposure and the β3-adrenergic receptor agonist mirabegron on plasma lipids, energy expenditure and brown adipose tissue (BAT) activity in South Asians versus Europids.

Materials And Methods: Ten lean Dutch South Asian (aged 18-30 years; body mass index [BMI] 18-25 kg/m ) and 10 age- and BMI-matched Europid men participated in a randomized, double-blinded, cross-over study consisting of three interventions: short-term (~ 2 hours) cold exposure, mirabegron (200 mg one dose p.o.) and placebo. Before and after each intervention, we performed lipidomic analysis in serum, assessed resting energy expenditure (REE) and skin temperature, and measured BAT fat fraction by magnetic resonance imaging.

Results: In both ethnicities, cold exposure increased the levels of several serum lipid species, whereas mirabegron only increased free fatty acids. Cold exposure increased lipid oxidation in both ethnicities, while mirabegron increased lipid oxidation in Europids only. Cold exposure and mirabegron enhanced supraclavicular skin temperature in both ethnicities. Cold exposure decreased BAT fat fraction in both ethnicities. After the combination of data from both ethnicities, mirabegron decreased BAT fat fraction compared with placebo.

Conclusions: In South Asians and Europids, cold exposure and mirabegron induced beneficial metabolic effects. When combining both ethnicities, cold exposure and mirabegron increased REE and lipid oxidation, coinciding with a higher supraclavicular skin temperature and lower BAT fat fraction.
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http://dx.doi.org/10.1111/dom.14120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771034PMC
November 2020

Recommendations for the analysis of gene expression data to identify intrinsic differences between similar tissues.

Genomics 2020 09 30;112(5):3157-3165. Epub 2020 May 30.

Department of Human Genetics, Leiden University Medical Center, the Netherlands; Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center. Electronic address:

Identifying genes involved in functional differences between similar tissues from expression profiles is challenging, because the expected differences in expression levels are small. To exemplify this challenge, we studied the expression profiles of two skeletal muscles, deltoid and biceps, in healthy individuals. We provide a series of guides and recommendations for the analysis of this type of studies. These include how to account for batch effects and inter-individual differences to optimize the detection of gene signatures associated with tissue function. We provide guidance on the selection of optimal settings for constructing gene co-expression networks through parameter sweeps of settings and calculation of the overlap with an established knowledge network. Our main recommendation is to use a combination of the data-driven approaches, such as differential gene expression analysis and gene co-expression network analysis, and hypothesis-driven approaches, such as gene set connectivity analysis. Accordingly, we detected differences in metabolic gene expression between deltoid and biceps that were supported by both data- and hypothesis-driven approaches. Finally, we provide a bioinformatic framework that support the biological interpretation of expression profiles from related tissues from this combination of approaches, which is available at github.com/tabbassidaloii/AnalysisFrameworkSimilarTissues.
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http://dx.doi.org/10.1016/j.ygeno.2020.05.026DOI Listing
September 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

Liraglutide decreases energy expenditure and does not affect the fat fraction of supraclavicular brown adipose tissue in patients with type 2 diabetes.

Nutr Metab Cardiovasc Dis 2020 04 13;30(4):616-624. Epub 2019 Dec 13.

Dept. Medicine, Div. Endocrinology, Leiden University Medical Center (LUMC), Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, the Netherlands.

Background And Aims: Several studies have shown that glucagon-like peptide-1 (GLP-1) analogues can affect resting energy expenditure, and preclinical studies suggest that they may activate brown adipose tissue (BAT). The aim of the present study was to investigate the effect of treatment with liraglutide on energy metabolism and BAT fat fraction in patients with type 2 diabetes.

Methods And Results: In a 26-week double-blind, placebo-controlled trial, 50 patients with type 2 diabetes were randomized to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after treatment for 4, 12 and 26 weeks, we assessed resting energy expenditure (REE) by indirect calorimetry. Furthermore, at baseline and after 26 weeks, we determined the fat fraction in the supraclavicular BAT depot using chemical-shift water-fat MRI at 3T. Liraglutide reduced REE after 4 weeks, which persisted after 12 weeks and tended to be present after 26 weeks (week 26 vs baseline: liraglutide -52 ± 128 kcal/day; P = 0.071, placebo +44 ± 144 kcal/day; P = 0.153, between group P = 0.057). Treatment with liraglutide for 26 weeks did not decrease the fat fraction in supraclavicular BAT (-0.4 ± 1.7%; P = 0.447) compared to placebo (-0.4 ± 1.4%; P = 0.420; between group P = 0.911).

Conclusion: Treatment with liraglutide decreases REE in the first 12 weeks and tends to decrease this after 26 weeks without affecting the fat fraction in the supraclavicular BAT depot. These findings suggest reduction in energy intake rather than an increase in REE to contribute to the liraglutide-induced weight loss.

Trial Registry Number: NCT01761318.
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http://dx.doi.org/10.1016/j.numecd.2019.12.005DOI Listing
April 2020

P magnetic resonance spectroscopy in skeletal muscle: Experts' consensus recommendations.

NMR Biomed 2020 Feb 10:e4246. Epub 2020 Feb 10.

Department of Musculoskeletal Biology and Liverpool Magnetic Resonance Imaging Centre (LiMRIC), University of Liverpool, Liverpool, UK.

Skeletal muscle phosphorus-31 P MRS is the oldest MRS methodology to be applied to in vivo metabolic research. The technical requirements of P MRS in skeletal muscle depend on the research question, and to assess those questions requires understanding both the relevant muscle physiology, and how P MRS methods can probe it. Here we consider basic signal-acquisition parameters related to radio frequency excitation, TR, TE, spectral resolution, shim and localisation. We make specific recommendations for studies of resting and exercising muscle, including magnetisation transfer, and for data processing. We summarise the metabolic information that can be quantitatively assessed with P MRS, either measured directly or derived by calculations that depend on particular metabolic models, and we give advice on potential problems of interpretation. We give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting acquisition parameters and experimental results in publications. Reliable examination depends on a reproducible setup, standardised preconditioning of the subject, and careful control of potential difficulties, and we summarise some important considerations and potential confounders. Our recommendations include the quantification and standardisation of contraction intensity, and how best to account for heterogeneous muscle recruitment. We highlight some pitfalls in the assessment of mitochondrial function by analysis of phosphocreatine (PCr) recovery kinetics. Finally, we outline how complementary techniques (near-infrared spectroscopy, arterial spin labelling, BOLD and various other MRI and H MRS measurements) can help in the physiological/metabolic interpretation of P MRS studies by providing information about blood flow and oxygen delivery/utilisation. Our recommendations will assist in achieving the fullest possible reliable picture of muscle physiology and pathophysiology.
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http://dx.doi.org/10.1002/nbm.4246DOI Listing
February 2020

Human Brown Adipose Tissue Estimated With Magnetic Resonance Imaging Undergoes Changes in Composition After Cold Exposure: An MRI Study in Healthy Volunteers.

Front Endocrinol (Lausanne) 2019 9;10:898. Epub 2020 Jan 9.

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

Magnetic resonance imaging (MRI) is increasingly being used to evaluate brown adipose tissue (BAT) function. Reports on the extent and direction of cold-induced changes in MRI fat fraction and estimated BAT volume vary between studies. Here, we aimed to explore the effect of different fat fraction threshold ranges on outcomes measured by MRI. Moreover, we aimed to investigate the effect of cold exposure on estimated BAT mass and energy content. The effects of cold exposure at different fat fraction thresholding levels were analyzed in the supraclavicular adipose depot of nine adult males. MRI data were reconstructed, co-registered and analyzed in two ways. First, we analyzed cold-induced changes in fat fraction, T2* relaxation time, volume, mass, and energy of the entire supraclavicular adipose depot at different fat fraction threshold levels. As a control, we assessed fat fraction differences of deltoid subcutaneous adipose tissue (SAT). Second, a local analysis was performed to study changes in fat fraction and T2* on a voxel-level. Thermoneutral and post-cooling data were compared using paired-sample -tests ( < 0.05). Global analysis unveiled that the largest cold-induced change in fat fraction occurred within a thermoneutral fat fraction range of 30-100% (-3.5 ± 1.9%), without changing the estimated BAT volume. However, the largest cold-induced changes in estimated BAT volume were observed when applying a thermoneutral fat fraction range of 70-100% (-3.8 ± 2.6%). No changes were observed for the deltoid SAT fat fractions. Tissue energy content was reduced from 126 ± 33 to 121 ± 30 kcal, when using a 30-100% fat fraction range, and also depended on different fat fraction thresholds. Voxel-wise analysis showed that while cold exposure changed the fat fraction across nearly all thermoneutral fat fractions, decreases were most pronounced at high thermoneutral fat fractions. Cold-induced changes in fat fraction occurred over the entire range of thermoneutral fat fractions, and were especially found in lipid-rich regions of the supraclavicular adipose depot. Due to the variability in response between lipid-rich and lipid-poor regions, care should be taken when applying fat fraction thresholds for MRI BAT analysis.
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http://dx.doi.org/10.3389/fendo.2019.00898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964318PMC
January 2020

Twelve weeks of exenatide treatment increases [F]fluorodeoxyglucose uptake by brown adipose tissue without affecting oxidative resting energy expenditure in nondiabetic males.

Metabolism 2020 05 23;106:154167. Epub 2020 Jan 23.

Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.

Aims/hypothesis: Brown adipose tissue (BAT) improves energy metabolism by combusting glucose and lipids into heat. Agonism of the glucagon-like peptide-1 receptor (GLP-1R) within the central nervous system activates BAT in mice. Moreover, in patients with type 2 diabetes, GLP-1R agonism lowers body weight and improves glucose and lipid levels, possibly involving BAT activation. Interestingly, people from South Asian descent are prone to develop cardiometabolic disease. We studied the effect of GLP-1R agonism on BAT in humans, specifically in South Asians and Europids without obesity or type 2 diabetes.

Methods: Twelve Dutch South Asian and 12 age- and BMI-matched Europid nondiabetic men received 12 weeks extended-release exenatide (Bydureon) in this single-arm prospective study. Before and after treatment, BAT was visualized by a cold-induced [F]FDG-PET/CT scan and a thermoneutral MRI scan, and resting energy expenditure (REE), substrate oxidation, body composition and fasting plasma glucose and serum lipids were determined. Appetite was rated using a visual analogue scale.

Results: Since the effect of exenatide on metabolic parameters did not evidently differ between ethnicities, data of all participants were pooled. Exenatide decreased body weight (-1.5 ± 0.4 kg, p < 0.01), without affecting REE or substrate oxidation, and transiently decreased appetite ratings during the first weeks. Exenatide also lowered triglycerides (-15%, p < 0.05) and total cholesterol (-5%, p < 0.05), and tended to lower glucose levels. Notably, exenatide increased BAT metabolic volume (+28%, p < 0.05) and mean standardized uptake value (+11%, p < 0.05) ([F]FDG-PET/CT), without affecting supraclavicular adipose tissue fat fraction (MRI).

Conclusions/interpretation: We show for the first time that GLP-1R agonism increases [F]FDG uptake by BAT in South Asian and Europid men without obesity or type 2 diabetes.

Trial Registry: Clinicaltrials.gov NCT03002675.
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http://dx.doi.org/10.1016/j.metabol.2020.154167DOI Listing
May 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

Water-fat separation in spiral magnetic resonance fingerprinting for high temporal resolution tissue relaxation time quantification in muscle.

Magn Reson Med 2020 08 3;84(2):646-662. Epub 2020 Jan 3.

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

Purpose: To minimize the known biases introduced by fat in rapid T and T quantification in muscle using a single-run magnetic resonance fingerprinting (MRF) water-fat separation sequence.

Methods: The single-run MRF acquisition uses an alternating in-phase/out-of-phase TE pattern to achieve water-fat separation based on a 2-point DIXON method. Conjugate phase reconstruction and fat deblurring were applied to correct for B inhomogeneities and chemical shift blurring. Water and fat signals were matched to the on-resonance MRF dictionary. The method was first tested in a multicompartment phantom. To test whether the approach is capable of measuring small in vivo dynamic changes in relaxation times, experiments were run in 9 healthy volunteers; parameter values were compared with and without water-fat separation during muscle recovery after plantar flexion exercise.

Results: Phantom results show the robustness of the water-fat resolving MRF approach to undersampling. Parameter maps in volunteers show a significant (P < .01) increase in T (105 ± 94 ms) and decrease in T (14 ± 6 ms) when using water-fat-separated MRF, suggesting improved parameter quantification by reducing the well-known biases introduced by fat. Exercise results showed smooth T and T recovery curves.

Conclusion: Water-fat separation using conjugate phase reconstruction is possible within a single-run MRF scan. This technique can be used to rapidly map relaxation times in studies requiring dynamic scanning, in which the presence of fat is problematic.
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http://dx.doi.org/10.1002/mrm.28143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217066PMC
August 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

Author Correction: Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy.

Sci Rep 2018 Mar 1;8(1):4058. Epub 2018 Mar 1.

Division of Image Processing, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-22154-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832820PMC
March 2018

Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy.

Sci Rep 2017 10 3;7(1):12575. Epub 2017 Oct 3.

Division of Image Processing, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

Duchenne muscular dystrophy (DMD) is a muscular dystrophy with high incidence of learning and behavioural problems and is associated with neurodevelopmental disorders. To gain more insights into the role of dystrophin in this cognitive phenotype, we performed a comprehensive analysis of the expression patterns of dystrophin isoforms across human brain development, using unique transcriptomic data from Allen Human Brain and BrainSpan atlases. Dystrophin isoforms show large changes in expression through life with pronounced differences between the foetal and adult human brain. The Dp140 isoform was expressed in the cerebral cortex only in foetal life stages, while in the cerebellum it was also expressed postnatally. The Purkinje isoform Dp427p was virtually absent. The expression of dystrophin isoforms was significantly associated with genes implicated in neurodevelopmental disorders, like autism spectrum disorders or attention-deficit hyper-activity disorders, which are known to be associated to DMD. We also identified relevant functional associations of the different isoforms, like an association with axon guidance or neuron differentiation during early development. Our results point to the crucial role of several dystrophin isoforms in the development and function of the human brain.
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http://dx.doi.org/10.1038/s41598-017-12981-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626779PMC
October 2017

Validation of a pharmacological model for mitochondrial dysfunction in healthy subjects using simvastatin: A randomized placebo-controlled proof-of-pharmacology study.

Eur J Pharmacol 2017 Nov 21;815:290-297. Epub 2017 Sep 21.

Centre for Human Drug Research, Zernikedreef 8, 2333 CL Leiden, The Netherlands.

Proof-of-pharmacology models to study compounds in healthy subjects offer multiple advantages. Simvastatin is known to induce mitochondrial dysfunction at least partly by depletion of co-enzyme Q10. The goal of this study was to evaluate a model of simvastatin-induced mitochondrial dysfunction in healthy subjects and to determine whether mitochondrial dysfunction could be pharmacologically reversed by treatment with co-enzyme Q10 (ubiquinol). Subjects received simvastatin 40mg/day for 8 weeks. After 4 weeks, subjects were randomized to receive ubiquinol 300mg/day or placebo in a double-blinded fashion. Mitochondrial function was assessed by measuring the phosphocreatine recovery time (τ-PCr) using phosphorous Magnetic Resonance Spectroscopy (P-MRS) after in-magnet exercise. After 4 weeks of simvastatin treatment, τ-PCr prolonged with 15.2% compared to baseline, (95%CI, 2.5-29.4%; P = 0.018, Fig. 3). After 8 weeks, τ-PCr further prolonged to 37.27s in the placebo group (prolongation of 18.5% compared to baseline, still significantly prolonged, 95%CI, 1.1-38.9%; P = 0.037), but shortened to 33.81s in the ubiquinol group (prolongation of 9.1% compared to baseline, no longer significantly prolonged, 95%CI, -7.9 to 29.2%; P = 0.31). At 8 weeks, there was no significant difference between groups (difference of 8.2%, 95%CI, -14.5 to 37.0%; P = 0.51). Simvastatin induces subclinical mitochondrial dysfunction in healthy subjects, which can be partly reversed by treatment with ubiquinol. This model of pharmacologically induced and reversed mitochondrial dysfunction can be used to study the effects of compounds that enhance mitochondrial function in healthy subjects.
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http://dx.doi.org/10.1016/j.ejphar.2017.09.031DOI Listing
November 2017

Quantifying fat replacement of muscle by quantitative MRI in muscular dystrophy.

J Neurol 2017 Oct 1;264(10):2053-2067. Epub 2017 Jul 1.

Newcastle Magnetic Resonance Centre, Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.

The muscular dystrophies are rare orphan diseases, characterized by progressive muscle weakness: the most common and well known is Duchenne muscular dystrophy which affects young boys and progresses quickly during childhood. However, over 70 distinct variants have been identified to date, with different rates of progression, implications for morbidity, mortality, and quality of life. There are presently no curative therapies for these diseases, but a range of potential therapies are presently reaching the stage of multi-centre, multi-national first-in-man clinical trials. There is a need for sensitive, objective end-points to assess the efficacy of the proposed therapies. Present clinical measurements are often too dependent on patient effort or motivation, and lack sensitivity to small changes, or are invasive. Quantitative MRI to measure the fat replacement of skeletal muscle by either chemical shift imaging methods (Dixon or IDEAL) or spectroscopy has been demonstrated to provide such a sensitive, objective end-point in a number of studies. This review considers the importance of the outcome measures, discusses the considerations required to make robust measurements and appropriate quality assurance measures, and draws together the existing literature for cross-sectional and longitudinal cohort studies using these methods in muscular dystrophy.
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http://dx.doi.org/10.1007/s00415-017-8547-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617883PMC
October 2017

Cortical glutamate in migraine.

Brain 2017 Jul;140(7):1859-1871

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

Cortical hyperexcitability due to enhanced glutamatergic activity has been implicated in migraine pathophysiology but direct evidence is lacking. Here we assessed glutamate levels and intracellular mobility of glutamate in the visual cortex of migraineurs in-between attacks. We included 50 migraineurs (23 with aura and 27 without aura) and 24 age- and gender-matched non-headache controls. We used proton magnetic resonance spectroscopy (1H-MRS) and diffusion weighted spectroscopy at 7 T with a single volume of interest (2 × 2 × 3 cm) located in the primary and secondary visual cortex. For 1H-MRS we used a semi-LASER sequence with water referencing for absolute quantification. For diffusion weighted spectroscopy we used an adapted PRESS sequence with gradients applied in three directions and two different gradient amplitudes. Between-group differences were evaluated using analysis of covariance with the grey matter fraction in the volume of interest as covariate and post hoc comparisons with Bonferroni correction. Glutamate concentrations differed between groups (P = 0.047) and were higher in migraineurs without aura (mean ± standard deviation: 7.02 ± 0.50 mM) compared to controls (mean ± standard deviation: 6.40 ± 0.78 mM, P = 0.042). The apparent diffusion coefficient of glutamate was similar among groups (P = 0.129) suggesting similar inter- and intracellular mobility of glutamate in all three study groups. No differences were observed for concentrations and diffusion constants of other metabolites. The present study suggests that interictal glutamate levels are increased in the visual cortex of migraineurs without aura, supporting the hypothesis of cortical hyperexcitability in migraine.
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http://dx.doi.org/10.1093/brain/awx130DOI Listing
July 2017

Proton Magnetic Resonance Spectroscopy Indicates Preserved Cerebral Biochemical Composition in Duchenne Muscular Dystrophy Patients.

J Neuromuscul Dis 2017 ;4(1):53-58

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

Background: Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin. DMD is associated with specific learning and behavioural disabilities. In the brain, dystrophin is associated with GABAA receptors and aquaporin-4 in neurons and astrocytes, respectively, but little is known about its function.

Objective And Methods: In this study we aimed to compare the biochemical composition between patients and healthy controls in brain regions that are naturally rich in dystrophin using magnetic resonance spectroscopy. Given previous conflicting results obtained at clinical field strengths, we obtained data using a 7 Tesla system with associated higher signal-to-noise ratio and spectral resolution.

Results: Results indicated unchanged biochemical composition in all regions investigated, and increased variance in glutamate in the frontal cortex.
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http://dx.doi.org/10.3233/JND-160201DOI Listing
March 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

Quantitative Dixon MRI sequences to relate muscle atrophy and fatty degeneration with range of motion and muscle force in brachial plexus injury.

Magn Reson Imaging 2017 Feb 27;36:98-104. Epub 2016 Oct 27.

Department of Orthopaedics, Leiden University Medical Center, The Netherlands.

Background: Assessment of muscle atrophy and fatty degeneration in brachial plexus injury (BPI) could yield valuable insight into pathophysiology and could be used to predict clinical outcome. The objective of this study was to quantify and relate fat percentage and cross-sectional area (CSA) of the biceps to range of motion and muscle force of traumatic brachial plexus injury (BPI) patients.

Methods: T1-weighted TSE sequence and three-point Dixon images of the affected and non-affected biceps brachii were acquired on a 3 Tesla magnetic resonance scanner to determine the fat percentage, total and contractile CSA of 20 adult BPI patients. Regions of interest were drawn by two independent investigators to determine the inter-observer reliability. Paired Students' t-test and multivariate analysis were used to relate fat percentage, total and contractile CSA to active flexion and biceps muscle force.

Results: The mean fat percentage 12±5.1% of affected biceps was higher than 6±1.0% of the non-affected biceps (p<0.001). The mean contractile CSA 8.1±5.1cm of the affected biceps was lower than 19.4±4.9cm of the non-affected biceps (p<0.001). The inter-observer reliability was excellent (ICC 0.82 to 0.96). The contractile CSA contributed most to the reduction in active flexion and muscle force.

Conclusion: Quantitative measurement of fat percentage, total and contractile CSA using three-point Dixon sequences provides an excellent reliability and relates with active flexion and muscle force in BPI.
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http://dx.doi.org/10.1016/j.mri.2016.10.020DOI Listing
February 2017

Decreased cerebral perfusion in Duchenne muscular dystrophy patients.

Neuromuscul Disord 2017 Jan 17;27(1):29-37. Epub 2016 Oct 17.

Department of Radiology, C.J. Gorter Center for High Field MRI, Leiden University Medical Center, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden, The Netherlands.

Duchenne muscular dystrophy is caused by dystrophin gene mutations which lead to the absence of the protein dystrophin. A significant proportion of patients suffer from learning and behavioural disabilities, in addition to muscle weakness. We have previously shown that these patients have a smaller total brain and grey matter volume, and altered white matter microstructure compared to healthy controls. Patients with more distal gene mutations, predicted to affect dystrophin isoforms Dp140 and Dp427, showed greater grey matter reduction. Now, we studied if cerebral blood flow in Duchenne muscular dystrophy patients is altered, since cerebral expression of dystrophin also occurs in vascular endothelial cells and astrocytes associated with cerebral vasculature. T1-weighted anatomical and pseudo-continuous arterial spin labeling cerebral blood flow images were obtained from 26 patients and 19 age-matched controls (ages 8-18 years) on a 3 tesla MRI scanner. Group comparisons of cerebral blood flow were made with and without correcting for grey matter volume using partial volume correction. Results showed that patients had a lower cerebral blood flow than controls (40.0 ± 6.4 and 47.8 ± 6.3 mL/100 g/min respectively, p = 0.0002). This reduction was independent of grey matter volume, suggesting that they are two different aspects of the pathophysiology. Cerebral blood flow was lowest in patients lacking Dp140. There was no difference in CBF between ambulant and non-ambulant patients. Only three patients showed a reduced left ventricular ejection fraction. No correlation between cerebral blood flow and age was found. Our results indicate that cerebral perfusion is reduced in Duchenne muscular dystrophy patients independent of the reduced grey matter volume.
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http://dx.doi.org/10.1016/j.nmd.2016.10.005DOI Listing
January 2017