Robert Rehmann

Background: Quantitative muscle MRI (qMRI) is a promising tool for evaluating and monitoring neuromuscular disorders (NMD). However, the application of different imaging protocols and processing pipelines restricts comparison between patient cohorts and disorders. In this qMRI study, we aim to compare dystrophic (limb-girdle muscular dystrophy), inflammatory (inclusion body myositis), and metabolic myopathy (Pompe disease) as well as patients with post-COVID-19 conditions suffering from myalgia to healthy controls. Methods: Ten subjects of each group underwent a 3T lower extremity muscle MRI, including a multi-echo, gradient-echo, Dixon-based sequence, a multi-echo, spin-echo (MESE) T2 mapping sequence, and a spin-echo EPI diffusion-weighted sequence. Furthermore, the following clinical assessments were performed: Quick Motor Function Measure, patient questionnaires for daily life activities, and 6-min walking distance. Results: Different involvement patterns of conspicuous qMRI parameters for different NMDs were observed. qMRI metrics correlated significantly with clinical assessments. Conclusions: qMRI metrics are suitable for evaluating patients with NMD since they show differences in muscular involvement in different NMDs and correlate with clinical assessments. Still, standardisation of acquisition and processing is needed for broad clinical use.

Pompe disease is a rare genetic metabolic disorder caused by mutations in acid-alpha glucoside (GAA) leading to pathological lysosomal glycogen accumulation associated with skeletal muscle weakness, respiratory difficulties and cardiomyopathy, dependent from the GAA residual enzyme activity. This study aimed to investigate early proteomic changes in a mouse model of Pompe disease and identify potential therapeutic pathways using proteomic analysis of skeletal muscles from pre-symptomatic Pompe mice. For this purpose, quadriceps samples of Gaa^6neo/6neo mutant (Pompe) and wildtype mice, at the age of six weeks, were studied with three biological replicates for each group. The data were validated with skeletal muscle morphology, immunofluorescence studies and western blot analysis. Proteomic profiling identified 538 significantly upregulated and 16 significantly downregulated proteins in quadriceps muscles derived from Pompe animals compared to wildtype mice. The majority of significantly upregulated proteins were involved in metabolism, translation, folding, degrading and vesicular transport, with some having crucial roles in the etiopathology of other neurological or neuromuscular diseases. This study highlights the importance of the early diagnosis and treatment of Pompe disease and suggests potential add-on therapeutic strategies targeting protein dysregulations.

Background: Long-term data on ICU-survivors reveal persisting sequalae and a reduced quality-of-life even after years. Major complaints are neuromuscular dysfunction due to Intensive care unit acquired weakness (ICUAW). Quantitative MRI (qMRI) protocols can quantify muscle alterations in contrast to standard qualitative MRI-protocols.Methods: Using qMRI, the aim of this study was to analyse persisting myostructural abnormalities in former ICU patients compared to controls and relate them to clinical assessments. The study was conducted as a cohort/case–control study. Nine former ICU-patients and matched controls were recruited (7 males; 54.8y ± 16.9; controls: 54.3y ± 11.1). MRI scans were performed on a 3T-MRI including a mDTI, T2 mapping and a mDixonquant sequence. Water T2 times, fat-fraction and mean values of the eigenvalue (λ₁), mean diffusivity (MD), radial diffusivity (RD) and fractional anisotropy (FA) were obtained for six thigh and seven calf muscles bilaterally. Clinical assessment included strength testing, electrophysiologic studies and a questionnaire on quality-of-life (QoL). Study groups were compared using a multivariate general linear model. qMRI parameters were correlated to clinical assessments and QoL questionnaire using Pearson´s correlation.Results: qMRI parameters were significantly higher in the patients for fat-fraction (p < 0.001), water T2 time (p < 0.001), FA (p = 0.047), MD (p < 0.001) and RD (p < 0.001). Thighs and calves showed a different pattern with significantly higher water T2 times only in the calves. Correlation analysis showed a significant negative correlation of muscle strength (MRC sum score) with FA and T2-time. The results were related to impairment seen in QoL-questionnaires, clinical testing and electrophysiologic studies.Conclusion: qMRI parameters show chronic next to active muscle degeneration in ICU survivors even years after ICU therapy with ongoing clinical relevance. Therefore, qMRI opens new doors to characterize and monitor muscle changes of patients with ICUAW. Further, better understanding on the underlying mechanisms of the persisting complaints could contribute the development of personalized rehabilitation programs.

To evaluate differences in qMRI parameters of muscle diffusion tensor imaging (mDTI), fat-fraction (FF) and water T2 time in leg muscles of calpainopathy patients (LGMD R1/D4) compared to healthy controls, to correlate those findings to clinical parameters and to evaluate if qMRI parameters show muscle degeneration in not-yet fatty infiltrated muscles. We evaluated eight thigh and seven calf muscles of 19 calpainopathy patients and 19 healthy matched controls. MRI scans were performed on a 3T MRI including a mDTI, T2 mapping and mDixonquant sequence. Clinical assessment was done with manual muscle testing, patient questionnaires (ACTIVLIM, NSS) as well as gait analysis. Average FF was significantly different in all muscles compared to controls (p < 0.001). In muscles with less than 8% FF a significant increase of FA (p < 0.005) and decrease of RD (p < 0.004) was found in high-risk muscles of calpainopathy patients. Water T2 times were increased within the low- and intermediate-risk muscles (p ≤ 0.045) but not in high-risk muscles (p = 0.062). Clinical assessments correlated significantly with qMRI values: QMFM vs. FF: r = − 0.881, p < 0.001; QMFM versus FA: r = − 0.747, p < 0.001; QMFM versus MD: r = 0.942, p < 0.001. A good correlation of FF and diffusion metrics to clinical assessments was found. Diffusion metrics and T2 values are promising candidates to serve as sensitive early and non-invasive methods to capture early muscle degeneration in non-fat-infiltrated muscles in calpainopathies.

Background: Long-term data on ICU-survivors reveal persisting sequalae and a reduced quality-of-life even after years. Major complaints are neuromuscular dysfunction due to ICUAW (Intensive care unit acquired weakness). Quantitative MRI (qMRI) protocols can quantify muscle alterations superiorly to standard MRI-protocols. Methods: Using qMRI, the aim of this study was to analyse persisting myostructural abnormalities in former ICU patients compared to controls and relate them to clinical assessments. The study was conducted as a Cohort/Case-control study. Nine former ICU-patients and matched controls were recruited (7 males; 54.8y±16.9; controls: 54.3y±11.1). MRI scans were performed on a 3T-MRI including a mDTI, T2 mapping and mDixonquant sequence. T2 mapping times, fat-fraction and mean values of the eigenvalue (λ1), mean diffusivity (MD), radial diffusivity (RD) and fractional anisotropy (FA) were obtained for six thigh and seven calf muscles bilaterally. Clinical assessment included strength testing, electrophysiologic studies and a questionnaire on quality-of-life (QoL). Study groups were compared using a multivariate general linear model. qMRI parameters were correlated to clinical assessments and QoL questionnaire using Pearson´s correlation. Results: qMRI parameters were significantly higher in the patients for fat-fraction (pConclusion: qMRI parameters show chronic next to active muscle degeneration in ICU survivors even years after ICU therapy with ongoing clinical relevance. Therefore, qMRI opens new doors to characterize and monitor muscle changes of patients with ICUAW. Further, better understanding on the underlying mechanisms of the persisting complaints could contribute the development of personalized rehabilitation programs.

Quantitative MRI combines non-invasive imaging techniques to reveal alterations in muscle pathophysiology. Creating muscle-specific labels manually is time consuming and requires an experienced examiner. Semi-automatic and fully automatic methods reduce segmentation time significantly. Current machine learning solutions are commonly trained on data from healthy subjects using homogeneous databases with the same image contrast. While yielding high Dice scores (DS), those solutions are not applicable to different image contrasts and acquisitions. Therefore, the aim of our study was to evaluate the feasibility of automatic segmentation of a heterogeneous database. To create a heterogeneous dataset, we pooled lower leg muscle images from different studies with different contrasts and fields-of-view, containing healthy controls and diagnosed patients with various neuromuscular diseases. A second homogenous database with uniform contrasts was created as a subset of the first database. We trained three 3D-convolutional neuronal networks (CNN) on those databases to test performance as compared to manual segmentation. All networks, training on heterogeneous data, were able to predict seven muscles with a minimum average DS of 0.75. U-Net performed best when trained on the heterogeneous dataset (DS: 0.80 ± 0.10, AHD: 0.39 ± 0.35). ResNet and DenseNet yielded higher DS, when trained on a heterogeneous dataset (both DS: 0.86), as compared to a homogeneous dataset (ResNet DS: 0.83, DenseNet DS: 0.76). In conclusion, a CNN trained on a heterogeneous dataset achieves more accurate labels for predicting a heterogeneous database of lower leg muscles than a CNN trained on a homogenous dataset. We propose that a large heterogeneous database is needed, to make automated segmentation feasible for different kinds of image acquisitions.

Background: Muscle diffusion tensor imaging (mDTI) is a promising surrogate biomarker in the evaluation of muscular injuries and neuromuscular diseases. Since mDTI metrics are known to vary between different muscles, separation of different muscles is essential to achieve muscle-specific diffusion parameters. The commonly used technique to assess DTI metrics is parameter maps based on manual segmentation (MSB). Other techniques comprise tract-based approaches, which can be performed in a previously defined volume. This so-called volume-based tractography (VBT) may offer a more robust assessment of diffusion metrics and additional information about muscle architecture through tract properties. The purpose of this study was to assess DTI metrics of human calf muscles calculated with two segmentation techniques—MSB and VBT—regarding their inter-rater reliability in healthy and dystrophic calf muscles. Methods: 20 healthy controls and 18 individuals with different neuromuscular diseases underwent an MRI examination in a 3T scanner using a 16-channel Torso XL coil. DTI metrics were assessed in seven calf muscles using MSB and VBT. Coefficients of variation (CV) were calculated for both techniques. MSB and VBT were performed by two independent raters to assess inter-rater reliability by ICC analysis and Bland-Altman plots. Next to analysis of DTI metrics, the same assessments were also performed for tract properties extracted with VBT. Results: For both techniques, low CV were found for healthy controls (≤13%) and neuromuscular diseases (≤17%). Significant differences between methods were found for all diffusion metrics except for λ₁. High inter-rater reliability was found for both MSB and VBT (ICC ≥ 0.972). Assessment of tract properties revealed high inter-rater reliability (ICC ≥ 0.974). Conclusions: Both segmentation techniques can be used in the evaluation of DTI metrics in healthy controls and different NMD with low rater dependency and high precision but differ significantly from each other. Our findings underline that the same segmentation protocol must be used to ensure comparability of mDTI data.