Hermien E. Kan

Quantitative MR imaging of individual muscle involvement in facioscapulohumeral muscular dystrophy

The purpose of this study was to implement a quantitative MR imaging method for the determination of muscular and fat content in individual skeletal muscles of patients with facioscapulohumeral muscular dystrophy (FSHD). Turbo Inversion Recovery Magnitude (TIRM) and multiecho MR images were acquired from seven FSHD patients and healthy volunteers. Signal decay in the multiecho MR images was fitted to a biexponential function with fixed relaxation rates for muscle and fat tissue and used to calculate the degree of fatty infiltration in eight muscles in the lower leg. Considerable differences in fatty infiltration between different muscles were observed in FSHD patients, suggesting that this could be used as a biomarker for disease progression. TIRM imaging indicated an inflammatory component of the disease previously only observed in muscle biopsies. Typically, muscle involvement was non-uniform even within one muscle, indicating that MRI can be used as a valuable tool to study pathophysiology and therapy evaluation in FSHD.

Comparison of dixon and T1-weighted MR methods to assess the degree of fat infiltration in duchenne muscular dystrophy patients

To compare different lipid multipeak spectral models to the single‐peak model in Dixon‐based fat‐water separation and to evaluate differences between visually scored magnetic resonance (MR) images and quantitatively assessed fat fractions in muscle of Duchenne muscular dystrophy patients.

Distinct disease phases in muscles of facioscapulohumeral dystrophy patients identified by MR detected fat infiltration

Facioscapulohumeral muscular dystrophy (FSHD) is an untreatable disease, characterized by asymmetric progressive weakness of skeletal muscle with fatty infiltration. Although the main genetic defect has been uncovered, the downstream mechanisms causing FSHD are not understood. The objective of this study was to determine natural disease state and progression in muscles of FSHD patients and to establish diagnostic biomarkers by quantitative MRI of fat infiltration and phosphorylated metabolites. MRI was performed at 3T with dedicated coils on legs of 41 patients (28 men/13 women, age 34–76 years), of which eleven were re-examined after four months of usual care. Muscular fat fraction was determined with multi spin-echo and T1 weighted MRI, edema by TIRM and phosphorylated metabolites by 3D 31P MR spectroscopic imaging. Fat fractions were compared to clinical severity, muscle force, age, edema and phosphocreatine (PCr)/ATP. Longitudinal intramuscular fat fraction variation was analyzed by linear regression. Increased intramuscular fat correlated with age (p<0.05), FSHD severity score (p<0.0001), inversely with muscle strength (p<0.0001), and also occurred sub-clinically. Muscles were nearly dichotomously divided in those with high and with low fat fraction, with only 13% having an intermediate fat fraction. The intramuscular fat fraction along the muscle’s length, increased from proximal to distal. This fat gradient was the steepest for intermediate fat infiltrated muscles (0.07±0.01/cm, p<0.001). Leg muscles in this intermediate phase showed a decreased PCr/ATP (p<0.05) and the fastest increase in fatty infiltration over time (0.18±0.15/year, p<0.001), which correlated with initial edema (p<0.01), if present. Thus, in the MR assessment of fat infiltration as biomarker for diseased muscles, the intramuscular fat distribution needs to be taken into account. Our results indicate that healthy individual leg muscles become diseased by entering a progressive phase with distal fat infiltration and altered energy metabolite levels. Fat replacement then relatively rapidly spreads over the whole muscle.

Quantitative proton MR techniques for measuring fat.

Accurate, precise and reliable techniques for the quantification of body and organ fat distributions are important tools in physiology research. They are critically needed in studies of obesity and diseases involving excess fat accumulation. Proton MR methods address this need by providing an array of relaxometry‐based (T1, T2) and chemical shift‐based approaches. These techniques can generate informative visualizations of regional and whole‐body fat distributions, yield measurements of fat volumes within specific body depots and quantify fat accumulation in abdominal organs and muscles. MR methods are commonly used to investigate the role of fat in nutrition and metabolism, to measure the efficacy of short‐ and long‐term dietary and exercise interventions, to study the implications of fat in organ steatosis and muscular dystrophies and to elucidate pathophysiological mechanisms in the context of obesity and its comorbidities. The purpose of this review is to provide a summary of mainstream MR strategies for fat quantification. The article succinctly describes the principles that differentiate water and fat proton signals, summarizes the advantages and limitations of various techniques and offers a few illustrative examples. The article also highlights recent efforts in the MR of brown adipose tissue and concludes by briefly discussing some future research directions. Copyright

Quantitative MRI and strength measurements in the assessment of muscle quality in Duchenne muscular dystrophy

The purpose of this study was to assess leg muscle quality and give a detailed description of leg muscle involvement in a series of Duchenne muscular dystrophy patients using quantitative MRI and strength measurements. Fatty infiltration, as well as total and contractile (not fatty infiltrated) cross sectional areas of various leg muscles were determined in 16 Duchenne patients and 11 controls (aged 8-15). To determine specific muscle strength, four leg muscle groups (quadriceps femoris, hamstrings, anterior tibialis and triceps surae) were measured and related to the amount of contractile tissue. In patients, the quadriceps femoris showed decreased total and contractile cross sectional area, attributable to muscle atrophy. The total, but not the contractile, cross sectional area of the triceps surae was increased in patients, corresponding to hypertrophy. Specific strength decreased in all four muscle groups of Duchenne patients, indicating reduced muscle quality. This suggests that muscle hypertrophy and fatty infiltration are two distinct pathological processes, differing between muscle groups. Additionally, the quality of remaining muscle fibers is severely reduced in the legs of Duchenne patients. The combination of quantitative MRI and quantitative muscle testing could be a valuable outcome parameter in longitudinal studies and in the follow-up of therapeutic effects.

Dystrophin levels and clinical severity in Becker muscular dystrophy patients

Objective Becker muscular dystrophy (BMD) is characterised by broad clinical variability. Ongoing studies exploring dystrophin restoration in Duchenne muscular dystrophy ask for better understanding of the relation between dystrophin levels and disease severity. We studied this relation in BMD patients with varying mutations, including a large subset with an exon 45–47 deletion. Methods Dystrophin was quantified by western blot analyses in a fresh muscle biopsy of the anterior tibial muscle. Disease severity was assessed using quantitative muscle strength measurements and functional disability scoring. MRI of the leg was performed in a subgroup to detect fatty infiltration. Results 33 BMD patients participated. No linear relation was found between dystrophin levels (range 3%–78%) and muscle strength or age at different disease milestones, in both the whole group and the subgroup of exon 45–47 deleted patients. However, patients with less than 10% dystrophin all showed a severe disease course. No relation was found between disease severity and age when analysing the whole group. By contrast, in the exon 45–47 deleted subgroup, muscle strength and levels of fatty infiltration were significantly correlated with patients’ age. Conclusions Our study shows that dystrophin levels appear not to be a major determinant of disease severity in BMD, as long as it is above approximately 10%. A significant relation between age and disease course was only found in the exon 45–47 deletion subgroup. This suggests that at higher dystrophin levels, the disease course depends more on the mutation site than on the amount of the dystrophin protein produced.

Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake

•  Creatine (Cr) plays an important role in muscle energy homeostasis as a substrate in the creatine kinase phosphoryl exchange reaction, but the consequences of creatine depletion are incompletely understood. •  We assessed the morphological, metabolic and functional consequences of systemic creatine depletion on skeletal muscle in a mouse model with deficiency of an essential enzyme in the biosynthesis of creatine (AGAT−/− mice). •  We show that Cr depletion leads to several metabolic abnormalities in muscle, including reduced ATP, increased inorganic phosphate levels and reduced activities of proton‐pumping respiratory chain enzymes and an elevated glycolytic contribution in ischaemic circumstances. •  The Cr‐depleted muscle suffers from reduced grip strength, severe atrophy and abnormal mitochondrial structures, increased overall mitochondrial content and an increased number of lipid droplets. •  Oral Cr administration led to rapid accumulation in skeletal muscle (faster than in brain) and reversed all the muscle abnormalities, revealing that the condition of the AGAT−/− mice can be switched between Cr deficient and normal simply by dietary manipulation.

Improved signal to noise in proton spectroscopy of the human calf muscle at 7 T using localized B1 calibration

Large variations of tip angle within a slice can lead to suboptimal pulse power optimization using standard techniques, which measure the average tip angle over a slice; this effect is especially pronounced at fields of 7 T and above. A technique was introduced that performed a volume‐selective power optimization in less than 10 sec and automatically calibrates the radiofrequency pulses for subsequent spectroscopy scans. Using this technique, MR spectra were acquired in the human calf of seven healthy volunteers with a partial volume Tx/Rx coil. Increases in signal‐to‐noise ratio based upon the unsuppressed water signal between 22 ± 5% and 166 ± 42%, compared to spectra obtained with the conventional power calibration technique, were measured in different regions of the calf muscle. This new technique was able to measure the inhomogeneous radiofrequency field at 7 T and its use resulted in a considerable signal‐to‐noise ratio increase. Magn Reson Med, 2010.

Improvements in high-field localized MRS of the medial temporal lobe in humans using new deformable high-dielectric materials

The intrinsic nonuniformities in the transmit radiofrequency field from standard quadrature volume resonators at high field are particularly problematic for localized MRS in areas such as the temporal lobe, where a low signal‐to‐noise ratio and poor metabolite quantification result from destructive B  1+ field interference, in addition to line broadening and signal loss from strong susceptibility gradients. MRS of the temporal lobe has been performed in a number of neurodegenerative diseases at clinical fields, but a relatively low signal‐to‐noise ratio has prevented the reliable quantification of, for example, glutamate and glutamine, which are thought to play a key role in disease progression. Using a recently developed high‐dielectric‐constant material placed around the head, localized MRS of the medial temporal lobe using the stimulated echo acquisition mode sequence was acquired at 7 T. The presence of the material increased the signal‐to‐noise ratio of MRS by a factor of two without significantly reducing the sensitivity in other areas of the brain, as shown by the measured B  1+ maps. An increase in the receive sensitivity B  1− was also measured close to the pads. The spectral linewidth of the unsuppressed water peak within the voxel of interest was reduced slightly by the introduction of the dielectric pads (although not to a statistically significant degree), a result confirmed by using a pad composed of lipid. Using LCmodel for quantitative analysis of metabolite concentrations, the increase in signal‐to‐noise ratio and the slight decrease in spectral linewidth contributed to statistically significant reductions in the Cramer–Rao lower bounds (CRLBs), also allowing the levels of glutamate and glutamine to be quantified with CRLBs below 20%. Copyright

Only fat infiltrated muscles in resting lower leg of FSHD patients show disturbed energy metabolism.

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by asymmetric dysfunctioning of individual muscles. Currently, it is unknown why specific muscles are affected before others and more particularly what pathophysiology is causing this differential progression. The aim of our study was to use a combination of 31P magnetic resonance spectroscopic imaging (MRSI) and T1‐weighted MRI to uncover metabolic differences in fat infiltrated and not fat infiltrated muscles in patients with FSHD. T1‐weighted images and 3D 31P MRSI were obtained from the calf muscles of nine patients with diagnosed FSHD and nine healthy age and sex matched volunteers. Muscles of patients were classified as fat infiltrated (PFM) and non fat‐infiltrated (PNM) based on visual assessment of the MR images. Ratios of phosphocreatine (PCr), phosphodiesters (PDE) and inorganic phosphate (Pi) over ATP and tissue pH were compared between PFM and PNM and the same muscles in healthy volunteers. Of all patients, seven showed moderate to severe fatty infiltration in one or more muscles. In these muscles, decreases in PCr/ATP and increases in tissue pH were observed compared to the same muscles in healthy volunteers. Interestingly, these differences were absent in the PNM group. Our data show that differences in metabolite ratios and tissue pH in skeletal muscle between healthy volunteers and patients with FSHD appear to be specific for fat infiltrated muscles. Normal appearing muscles on T1 weighted images of patients showed normal phosphoryl metabolism, which suggests that in FSHD disease progression is truly muscle specific. Copyright