Monitoring Nusinersen Treatment Effects in Children with Spinal Muscular Atrophy with Quantitative Muscle MRI.

BACKGROUND: Spinal muscular atrophy (SMA) is caused by deficiency of survival motor neuron (SMN) protein. Intrathecal nusinersen treatment increases SMN protein in motor neurons and has been shown to improve motor function in symptomatic children with SMA. OBJECTIVE: We used quantitative MRI to gain insight in microstructure and fat content of muscle during treatment and to explore its use as biomarker for treatment effect. METHODS: We used a quantitative MRI protocol before start of treatment and following the 4th and 6th injection of nusinersen in 8 children with SMA type 2 and 3 during the first year of treatment. The MR protocol allowed DIXON, T2 mapping and diffusion tensor imaging acquisitions. We also assessed muscle strength and motor function scores. RESULTS: Fat fraction of all thigh muscles with the exception of the m. adductor longus increased in all patients during treatment (+3.2%, p = 0.02). WaterT2 showed no significant changes over time (-0.7 ms, p = 0.3). DTI parameters MD and AD demonstrate a significant decrease in the hamstrings towards values observed in healthy muscle. CONCLUSIONS: Thigh muscles of children with SMA treated with nusinersen showed ongoing fatty infiltration and possible normalization of thigh muscle microstructure during the first year of nusinersen treatment. Quantitative muscle MRI shows potential as biomarker for the effects of SMA treatment strategies.

The relationship between quantitative magnetic resonance imaging of the ankle plantar flexors, muscle function during walking and maximal strength in people with neuromuscular diseases.

BACKGROUND: Progression of plantar flexor weakness in neuromuscular diseases is usually monitored by muscle strength measurements, although they poorly relate to muscle function during walking. Pathophysiological changes such as intramuscular adipose tissue affect dynamic muscle function independent from isometric strength. Diffusion tensor imaging and T2 imaging are quantitative MRI measures reflecting muscular pathophysiological changes, and are therefore potential biomarkers to monitor plantar flexor functioning during walking in people with neuromuscular diseases. METHODS: In fourteen individuals with plantar flexor weakness diffusion tensor imaging and T2 scans of the plantar flexors were obtained, and the diffusion indices fractional anisotropy and mean diffusivity calculated. With a dynamometer, maximal isometric plantar flexor strength was measured. 3D gait analysis was used to assess maximal ankle moment and power during walking. FINDINGS: Fractional anisotropy, mean diffusivity and T2 relaxation time all moderately correlated with maximal plantar flexor strength (r > 0.512). Fractional anisotropy and mean diffusivity were not related with ankle moment or power (r < 0.288). T2 relaxation time was strongly related to ankle moment (r = -0.789) and ankle power (r = -0.798), and moderately related to maximal plantar flexor strength (r < 0.600). INTERPRETATION: In conclusion, T2 relaxation time, indicative of multiple pathophysiological changes, was strongly related to plantar flexor function during walking, while fractional anisotropy and mean diffusivity, indicative of fiber size, only related to maximal plantar flexor strength. This indicates that these measures may be suitable to monitor muscle function and gain insights into the pathophysiological changes underlying a poor plantar flexor functioning during gait in people with neuromuscular diseases.

Diffusion Tensor Imaging Shows Differences Between Myotonic Dystrophy Type 1 and Type 2.

BACKGROUND: Myotonic Dystrophies type 1 and type 2 are hereditary myopathies with dystrophic muscle degeneration in varying degrees. Differences in muscle diffusion between both diseases have not been evaluated yet. OBJECTIVE: To evaluate the ability of muscle diffusion tensor imaging (mDTI) and Dixon fat-quantification to distinguish between Myotonic Dystrophy (DM) type 1 and type 2 and if both diseases show distinct muscle involvement patterns. METHODS: We evaluated 6 thigh and 7 calf muscles (both legs) of 10 DM 1, 13 DM 2 and 28 healthy controls (HC) with diffusion tensor imaging, T1w and mDixonquant sequences in a 3T MRI scanner. The quantitative mDTI-values axial diffusivity (λ1), mean diffusivity (MD), radial diffusivity (RD) and fractional anisotropy (FA) as well as fat-fraction were analysed. CTG-triplet repeat-length of DM 1 patients was correlated with diffusion metrics and fat-fraction. RESULTS: mDTI showed significant differences between DM 1 and DM 2 vs. healthy controls in diffusion parameters of the thigh (all p < 0.001) except for FA (p = 0.0521 / 0.8337). In calf muscles mDTI showed significant differences between DM 1 and DM 2 patients (all p < 0.0001) as well as between DM 1 patients and controls (all p = 0.0001). Thigh muscles had a significant higher fat-fraction in both groups vs. controls (p < 0.05). There was no correlation of CTG triplet length with mDTI values and fat-fraction. DISCUSSION: mDTI reveals specific changes of the diffusion parameters and fat-fraction in muscles of DM 1 and DM 2 patients. Thus, the quantitative MRI methods presented in this study provide a powerful tool in differential diagnosis and follow-up of DM 1 and DM 2, however, the data must be validated in larger studies.

Muscle diffusion tensor imaging in glycogen storage disease V (McArdle disease).

PURPOSE: To evaluate differences in diffusion parameters in thigh muscles in patients with glycogen storage disease type V (McArdle disease) using muscle diffusion tensor imaging (mDTI) compared to healthy controls METHODS: In this prospective study, we evaluated thigh muscles from hip to knee of 10 McArdle patients (5 female, mean age 33.7 ± 14.4 years) and 10 healthy age- and gender-matched volunteers. MRI scans were performed at 3 T and comprised mDTI, T1-weighted and T2-weighted imaging between May 2015 and May 2017. Needle biopsy of the vastus lateralis muscle was performed in three McArdle patients. The muscle tissue was analyzed by using histochemical and enzyme-histochemical techniques for glycogen content and histopathological changes. Mean values of the eigenvalues (λ1-λ3), fractional anisotropy (FA), and mean diffusivity (MD) were obtained for the vastus lateralis, vastus medialis, rectus femoris, biceps femoris, semitendinosus, and semimembranosus and compared between groups using Student's t tests, as well as ANCOVA; significance level was set at p < 0.05. RESULTS: Needle biopsy showed intracellular glycogen accumulation in skeletal muscle fibers of three McArdle patients. Extracellular histopathological changes were not found. Muscle DTI analysis did not show statistically significant differences between patients and controls for any of the muscles. CONCLUSION: Despite intracellular glycogen accumulation in the three biopsy samples, mDTI parameters were not altered in McArdle patients compared to controls. We conclude that the currently used mDTI acquisition and processing lack the sensitivity to detect intracellular changes due to accumulated glycogen in this cohort of McArdle patients. KEY POINTS: • Despite intracellular glycogen accumulation in three examined biopsy samples, mDTI parameters were not altered in McArdle patients compared to controls. • In its current form, diffusion MR does not provide additional information in quantifying intracellular glycogen accumulations within skeletal muscle fibers in McArdle patients.

Evaluation of skeletal muscle DTI in patients with duchenne muscular dystrophy.

Diffusion tensor imaging (DTI) is a popular method to assess differences in fiber organization in diseased and healthy muscle tissue. Previous work has shown that muscle DTI measurements depend on signal-to-noise ratio (SNR), %fat, and tissue T2. The goal of this study was to evaluate the potential biasing effects of these factors on skeletal muscle DTI data in patients with Duchenne Muscular Dystrophy (DMD). MR images were obtained of the right lower leg of 21 DMD patients and 12 healthy controls on a Philips 3T system. DTI measurements were combined with quantitative in-vivo measures of mean water T2, %fat and SNR to evaluate their effect on DTI parameter estimation. All outcome measures were determined within ROIs drawn for six lower leg muscles. Between group analysis, using all ROIs, revealed a significantly elevated FA in the GCL, SOL and PER muscles (p<0.05) and an increased mean diffusivity (p<0.05) and λ3 (p<0.05) in the TA muscle of DMD patients. In-vivo evaluation of the individual confounders showed behaviour in line with predictions from previous simulation work. To account for these confounders, subsequent analysis used only ROIs with SNR greater than 20. With this criterion we found significantly greater MD in the TA muscle of DMD patient (p<0.009) and λ3 in the TA and GCL muscles (p<0.001) of DMD patients, but no differences in FA. As both increased %fat and lower SNR are expected to reduce the apparent MD and λ3, these between-group differences are likely due to pathophysiology. However, the increased FA, observed when using all ROIs, likely reflects the effect of low SNR and %fat on the DTI parameter estimation. These findings suggest that measuring mean water T2, %fat and SNR is essential to ascribe changes in DTI measures to intrinsic diffusion changes or to confounding influences.

Evaluation of the female pelvic floor in pelvic organ prolapse using 3.0-Tesla diffusion tensor imaging and fibre tractography.

OBJECTIVES: To prospectively explore the clinical application of diffusion tensor imaging (DTI) and fibre tractography in evaluating the pelvic floor. METHODS: Ten patients with pelvic organ prolapse, ten with pelvic floor symptoms and ten asymptomatic women were included. A two-dimensional (2D) spin-echo (SE) echo-planar imaging (EPI) sequence of the pelvic floor was acquired. Offline fibre tractography and morphological analysis of pelvic magnetic resonance imaging (MRI) were performed. Inter-rater agreement for quality assessment of fibre tracking results was evaluated using weighted kappa (κ). From agreed tracking results, eigen values (λ1, λ2, λ3), mean diffusivity (MD) and fractional anisotropy (FA) were calculated. MD and FA values were compared using ANOVA. Inter-rater reliability of DTI parameters was interpreted using the intra-class correlation coefficient (ICC). RESULTS: Substantial inter-rater agreement was found (κ = 0.71 [95% CI 0.63-0.78]). Four anatomical structures were reliably identified. Substantial inter-rater agreement was found for MD and FA (ICC 0.60-0.91). No significant differences between groups were observed for anal sphincter, perineal body and puboperineal muscle. A significant difference in FA was found for internal obturator muscle between the prolapse group and the asymptomatic group (0.27 ± 0.05 vs 0.22 ± 0.03; P = 0.015). CONCLUSION: DTI with fibre tractography permits identification of part of the clinically relevant pelvic structures. Overall, no significant differences in DTI parameters were found between groups. KEY POINTS: Diffusion tensor MRI offers new insights into female pelvic floor problems. DTI allows 3D visualisation and quantification of female pelvic floor anatomy. DTI parameters from pelvic floor structures can be reliably determined. No significant differences in DTI parameters between groups with/without prolapse.

Feasibility of diffusion tensor imaging (DTI) with fibre tractography of the normal female pelvic floor.

OBJECTIVES: To prospectively determine the feasibility of diffusion tensor imaging (DTI) with fibre tractography as a tool for the three-dimensional (3D) visualisation of normal pelvic floor anatomy. METHODS: Five young female nulliparous subjects (mean age 28 ± 3 years) underwent DTI at 3.0T. Two-dimensional diffusion-weighted axial spin-echo echo-planar (SP-EPI) pulse sequence of the pelvic floor was performed, with additional T2-TSE multiplanar sequences for anatomical reference. Fibre tractography for visualisation of predefined pelvic floor and pelvic wall muscles was performed offline by two observers, applying a consensus method. Three eigenvalues (λ1, λ2, λ3), fractional anisotropy (FA) and mean diffusivity (MD) were calculated from the fibre trajectories. RESULTS: In all subjects fibre tractography resulted in a satisfactory anatomical representation of the pubovisceral muscle, perineal body, anal - and urethral sphincter complex and internal obturator muscle. Mean FA values ranged from 0.23 ± 0.02 to 0.30 ± 0.04, MD values from 1.30 ± 0.08 to 1.73 ± 0.12 × 10(-)³ mm²/s. Muscular structures in the superficial layer of the pelvic floor could not be satisfactorily identified. CONCLUSIONS: This study demonstrates the feasibility of visualising the complex three-dimensional pelvic floor architecture using 3T-DTI with fibre tractography. DTI of the deep female pelvic floor may provide new insights into pelvic floor disorders.