Introduction: Inertial sensors generate objective and sensitive metrics of movement disability that may indicate fall risk in many clinical conditions including multiple sclerosis (MS). The Timed-Up-And-Go (TUG) task is used to assess patient mobility because it incorporates clinically-relevant submovements during standing. Most sensor-based TUG research has focused on the placement of sensors at the spine, hip or ankles; an examination of thigh activity in TUG in multiple sclerosis is wanting. Methods: We used validated sensors (x-IMU by x-io) to derive transparent metrics for the sit-to-stand (SI-ST) transition and the stand-to-sit (ST-SI) transition of TUG, and compared effect sizes for metrics from inertial sensors on the thighs to effect sizes for metrics from a sensor placed at the L3 level of the lumbar spine. Twenty-three healthy volunteers were compared to 17 ambulatory persons with MS (PwMS, HAI ≤ 2). Results: During the SI-ST transition, the metric with the largest effect size comparing healthy volunteers to PwMS was the Area Under the Curve of the thigh angular velocity in the pitch direction-representing both thigh and knee extension; the peak of the spine pitch angular velocity during SI-ST also had a large effect size, as did some temporal measures of duration of SI-ST, although less so. During the ST-SI transition the metric with the largest effect size in PwMS was the peak of the spine angular velocity curve in the roll direction. A regression was performed. Discussion: We propose for PwMS that the diminished peak angular velocity during SI-ST directly represents extensor weakness, while the increased roll during ST-SI represents diminished postural control. Conclusions: During the SI-ST transition of TUG, angular velocities can discriminate between healthy volunteers and ambulatory PwMS better than temporal features. Sensor placement on the thighs provides additional discrimination compared to sensor placement at the lumbar spine.

Introduction: Paraspinal muscles are important for gross motor functions. Impairment of these muscles can lead to poor postural control and ambulation difficulty. Little knowledge exists about the involvement of paraspinal muscles in Becker muscular dystrophy. Objective: In this cross-sectional study, we investigated the involvement of paraspinal muscles with quantitative trunk strength measure and quantitative muscle MRI. Methods and Materials: Eighteen patients with Becker muscular dystrophy underwent trunk, hip, and thigh strength assessment using a Biodex dynamometer and an MRI Dixon scan. Fourteen age- and body mass index-matched healthy men were included for comparison. Results: Muscle fat fraction (FF) of the paraspinal muscles (multifidus and erector spinae) was higher in participants with Becker muscular dystrophy vs. healthy controls at all three examined spinal levels (C6, Th12, and L4/L5) (p < 0.05). There was a strong and inverse correlation between paraspinal muscle FF and trunk extension strength (ρ = -0.829, p < 0.001), gluteus maximus FF and hip extension strength (ρ = -0.701, p = 0.005), FF of the knee extensor muscles (quadriceps and sartorius) and knee extension strength (ρ = -0.842, p < 0.001), and FF of the knee flexor muscles (hamstring muscles) and knee flexion strength (ρ = -0.864, p < 0.001). Fat fraction of the paraspinal muscles also correlated with muscle FF of the thigh muscles and lower leg muscles. Conclusion: In conclusion, patients with Becker muscular dystrophy demonstrate severe paraspinal muscular involvement indicated by low back extension strength and high levels of fat replacement, which parallel involvement of lower limb muscles. Assessment of paraspinal muscle strength and fat replacement may serve as a possible biomarker for both the clinical management and further study of the disease.

Quantitative MRI is an increasingly used method to monitor disease progression in muscular disorders due to its ability to measure changes in muscle fat content (reported as fat fraction) over a short period. Being able to objectively measure such changes is crucial for the development of new treatments in clinical trials. However, the analysis of the images involved continues to be a daunting task because of the time needed. Whether a more specific analysis selecting individual muscles or a global one analyzing the whole thigh or compartments could be a suitable alternative has only been marginally studied. In our study we compare three methods of analysis of 2-point-dixon images in a cohort of 34 patients with late onset Pompe disease followed over a period of one year. We measured fat fraction on MRIs obtained at baseline and at year 1, and we calculated the increment of fat fraction. We correlated the results obtained with the results of muscle function tests to investigate whether the three methods of analysis were equivalent or not. We observed significant differences between the three methods in the estimation of the fat fraction at both baseline and year 1, but no difference was found in the increment in fat fraction between baseline and year 1. When we correlated the fat fraction obtained with each method and the muscle function tests, we found a significant correlation with most tests in all three methods, although in most comparisons the highest correlation coefficient was found with the analysis of individual muscles. We conclude that the fastest strategy of analysis assessing compartments or the whole thigh could be reliable for certain cohorts of patients where the variable to study is the fat increment. In other sorts of studies, an individual muscle approach seems the most reliable technique.

Objective: To investigate the clinical features, skeletal muscle imaging, and muscle pathological characteristics of late-onset GSD IIIa caused by mutation of the AGL gene in adults. Methods: The clinical data, skeletal muscle imaging, pathological data, and gene test results of a family with late-onset GSD IIIa in adulthood were collected in detail in November 2019. Results: The proband is a 40-years-old male, who was admitted into our hospital due to a 2-years history of limb weakness. The proband was diagnosed with the following syndrome: he had a 15-years history of elevated muscle enzymes; the cranial nerve examinations showed no abnormal findings; the muscle tension in both upper and lower limbs was low, and tendon reflexes were absent; the proband's muscle strength was 5 in the proximal muscles and 4 in the distal muscles of the upper limbs, with 3 in the proximal muscles and 4 in the distal muscles of the lower limbs; Magnetic Resonance Imaging (MRI) revealed abnormally high signal intensity changes in the posterior thigh muscle group, and the posterior-medial calf muscle group; and vacuoles were evident in some muscle fibers biopsied from the gastrocnemius muscle. Periodic acid-Schiff staining stained the cytoplasm of muscle fibers a dark red color. The proband's older brother exhibited the same clinical features. DNA analysis identified mutations in the AGL gene in the proband, his older brother, and parents. The proband and his older brother both carried two compound heterozygous mutations, c.866G>A and c.2855_2856insT. Pedigree analysis demonstrated that c.866G>A and c.2855_2856insT mutations had been inherited from the mother and father, respectively. Conclusion: Late-onset GSD IIIa in adults is clinically characterized by muscle weakness, muscle atrophy, and mainly occurred in the posterior thigh muscle group. We also identified two novel compound heterozygous mutations (c.866G> A and c.2855_2856insT) in the AGL gene.

Background: Recent studies have found deposition of phosphorylated α-synuclein (p-syn) in Parkinson disease (PD) patients' skin, indicating p-syn may be a potential biomarker of PD. However, the sensitivity of the p-syn detection varied largely from 5. 3 to 100%, this influenced the clinical use of this detection method to some extent. Objective: This study aimed to optimize the skin biopsy method for detecting p-syn deposition in patients with PD. Methods: Ninety PD patients and 30 healthy controls underwent skin biopsies at 2-3 of the following sites: the distal leg, thigh, cervical region, or forearm. Skin biopsy samples were cut to 50- and 15-μm thickness sections. Deposition of p-syn were detected by using double immunofluorescence labeling of protein gene production 9.5 (PGP9.5) /p-syn. Statistical data analysis was performed using SPSS 25.0 software. Results: Deposition of p-syn were found in 75/90 PD patients but not in healthy controls (p < 0.001). The positive deposition rate of p-syn in the single cervical site was significantly higher than that in the distal leg, thigh, and forearm site. Two samples from the cervical region had a higher p-syn positive rate compared to single cervical site (90.5 vs. 66.7%, p = 0.037). There was no significant difference between the p-syn positive rate of samples from the distal leg/cervical sites and 2 samples from cervical region (80 vs. 90.5%, p = 0.261). Next, the p-syn positive deposition rate of 2-biopsy samples including distal leg/cervical sites and double samples in the cervical site were comparable to the 3-biopsy samples. The 50-μm section had a significantly higher p-syn positive rate than the 15-μm section (p = 0.049). Conclusions: Two biopsy sites (cervical/distal leg) or 2 samples from the cervical site were considered to be priority biopsy sites for detecting p-syn in PD patients. Thick sections may provide a higher p-syn positive rate than thin sections for skin biopsies. These findings provide an optimized p-syn detection method, indicate the valuable pathology biomarker of PD and will promote the clinical use of skin biopsy in the future.

Introduction: Nusinersen is a recent promising therapy approved for the treatment of spinal muscular atrophy (SMA), a rare disease characterized by the degeneration of alpha motor neurons (αMN) in the spinal cord (SC) leading to progressive muscle atrophy and dysfunction. Muscle and cervical SC quantitative magnetic resonance imaging (qMRI) has never been used to monitor drug treatment in SMA. The aim of this pilot study is to investigate whether qMRI can provide useful biomarkers for monitoring treatment efficacy in SMA. Methods: Three adult SMA 3a patients under treatment with nusinersen underwent longitudinal clinical and qMRI examinations every 4 months from baseline to 21-month follow-up. The qMRI protocol aimed to quantify thigh muscle fat fraction (FF) and water-T2 (w-T2) and to characterize SC volumes and microstructure. Eleven healthy controls underwent the same SC protocol (single time point). We evaluated clinical and imaging outcomes of SMA patients longitudinally and compared SC data between groups transversally. Results: Patient motor function was stable, with only Patient 2 showing moderate improvements. Average muscle FF was already high at baseline (50%) and progressed over time (57%). w-T2 was also slightly higher than previously published data at baseline and slightly decreased over time. Cross-sectional area of the whole SC, gray matter (GM), and ventral horns (VHs) of Patients 1 and 3 were reduced compared to controls and remained stable over time, while GM and VHs areas of Patient 2 slightly increased. We found altered diffusion and magnetization transfer parameters in SC structures of SMA patients compared to controls, thus suggesting changes in tissue microstructure and myelin content. Conclusion: In this pilot study, we found a progression of FF in thigh muscles of SMA 3a patients during nusinersen therapy and a concurrent slight reduction of w-T2 over time. The SC qMRI analysis confirmed previous imaging and histopathological studies suggesting degeneration of αMN of the VHs, resulting in GM atrophy and demyelination. Our longitudinal data suggest that qMRI could represent a feasible technique for capturing microstructural changes induced by SMA in vivo and a candidate methodology for monitoring the effects of treatment, once replicated on a larger cohort.

Diagnosis of peripheral neuropathies relies on neurological examinations, electrodiagnostic studies, and since recently magnetic resonance neurography (MRN). The aim of this study was to develop and evaluate a fully-automatic segmentation method of peripheral nerves of the thigh. T2-weighted sequences without fat suppression acquired on a 3 T MR scanner were retrospectively analyzed in 10 healthy volunteers and 42 patients suffering from clinically and electrophysiologically diagnosed sciatic neuropathy. A fully-convolutional neural network was developed to segment the MRN images into peripheral nerve and background tissues. The performance of the method was compared to manual inter-rater segmentation variability. The proposed method yielded Dice coefficients of 0.859 ± 0.061 and 0.719 ± 0.128, Hausdorff distances of 13.9 ± 26.6 and 12.4 ± 12.1 mm, and volumetric similarities of 0.930 ± 0.054 and 0.897 ± 0.109, for the healthy volunteer and patient cohorts, respectively. The complete segmentation process requires less than one second, which is a significant decrease to manual segmentation with an average duration of 19 ± 8 min. Considering cross-sectional area or signal intensity of the segmented nerves, focal and extended lesions might be detected. Such analyses could be used as biomarker for lesion burden, or serve as volume of interest for further quantitative MRN techniques. We demonstrated that fully-automatic segmentation of healthy and neuropathic sciatic nerves can be performed from standard MRN images with good accuracy and in a clinically feasible time.

Introduction: Duchenne (DMD) and Becker (BMD) muscular dystrophy are X-linked muscular disorders produced by mutations in the DMD gene which encodes the protein dystrophin. Both diseases are characterized by progressive involvement of skeletal, cardiac, and respiratory muscles. As new treatment strategies become available, reliable biomarkers and outcome measures that can monitor disease progression are needed for clinical trials. Methods: We collected clinical and functional data and blood samples from 19 DMD patients, 13 BMD patients, and 66 healthy controls (8 pediatric and 58 adult controls), and blood samples from 15 patients with dysferlinopathy (DYSF) and studied the serum concentration of 4 growth factors involved in the process of muscle fibrosis. We correlated the serum concentration of these growth factors with several muscle function tests, spirometry results and fat fraction identified by quantitative Dixon muscle MRI. Results: We found significant differences in the serum concentration of Platelet Derived Growth Factor-AA (PDGF-AA) between DMD patients and pediatric controls, in Connective Tissue Growth Factor (CTGF) between BMD patients and adult controls, and in and Transforming Growth Factor- β1 (TGF-β1) between BMD and DYSF patients. PDGF-AA showed a good correlation with several muscle function tests for both DMD and BMD patients and with thigh fat fraction in BMD patients. Moreover, PDGF-AA levels were increased in muscle biopsies of patients with DMD and BMD as was demonstrated by immunohistochemistry and Real-Time PCR studies. Conclusion: Our study suggests that PDGF-AA should be further investigated in a larger cohort of DMD and BMD patients because it might be a good biomarker candidate to monitor the progression of these diseases.

Objectives: Magnetization transfer (MT) imaging exploits the interaction between bulk water protons and protons contained in macromolecules to induce signal changes through a special radiofrequency pulse. MT detects muscle damage in patients with neuromuscular conditions, such as limb-girdle muscular dystrophies or Charcot-Marie-Tooth disease, which are characterized by progressive fiber loss and replacement by fatty tissue. In Pompe disease, in which there is, in addition, an accumulation of glycogen inside the muscle fibers, MT has not been tested yet. Our aim is to estimate MT ratio (MTR) in the skeletal muscle of these patients and correlate it with intramuscular fat fraction (FF) and results of muscle function tests. Methods: We obtained two-point axial Dixon and Dixon-MT sequences of the right thigh on a 1.5 Teslas MRI scanner in 60 individuals, including 29 late onset Pompe disease patients, 2 patients with McArdle disease, and 29 age and sex matched healthy controls. FF and MTR were estimated. Muscle function using several muscle function tests, including quantification of muscle strength, timed test quality of life scales, conventional spirometry obtaining forced vital capacity while sitting and in the supine position, were assessed in all patients. Results: MTR was significantly lower in Pompe patients compared with controls (45.5 ± 8.5 vs. 51.7 ± 2.3, Student T-test, p < 0.05). There was a negative correlation between the MTR and FF muscles studied (correlation coefficient: -0.65, Spearman test: p < 0.05). MTR correlated with most of the muscle function test results. We analyzed if there was any difference in MTR values between Pompe patients and healthy controls in those muscles that did not have an increase in fat, a measure that could be related to the presence of glycogen in skeletal muscles, but we did not identify significant differences except in the adductor magnus muscle (48.4 ± 3.6 in Pompe vs. 51 ± 1.3 in healthy controls, Student T-test = 0.023). Conclusions: MTR is a sensitive tool to identify muscle loss in patients with Pompe disease and shows a good correlation with muscle function tests. Therefore, the MT technique can be useful in monitoring muscle degeneration in Pompe disease in clinical trials or natural history studies.

Objective: To investigate the clinical manifestations, underlying diseases, pathological features, and therapeutic responses in patients with muscular tuberculosis (MT), which is rare and often misdiagnosed in clinical practice. Methods: This study describes a rare MT case that was recently diagnosed in our department. Additionally, 18 other MT cases retrieved from the PubMed database from 2,000 to date are included in this study. The clinical manifestations, areas of residence, underlying diseases, laboratory test results, pathology results, and outcomes of the patients were recorded and analyzed. Results: The MT patients in this study included 13 males and six females with an average age of 34.58 years old. Eight patients were from Asia, and six patients were from Africa, accounting for the majority of patients, at 73.68%. Underlying diseases included flu-like illness in one patient; chronic kidney disease (CKD) in one patient; Sjögren's syndrome in one patient; systemic lupus erythematosus (SLE), lupus nephropathy, and deep vein thrombosis in one patient; and Alzheimer's disease (AD) and Paget's disease in one patient. Two patients had a previous history of tuberculosis, and two patients had contact with suspected tuberculosis patients. All patients presented chronic occult onset, with an average of 3 (1.75, 5) months. Six cases had local masses, and 13 cases had swelling as the main clinical manifestations. Twelve patients (63.2%) presented manifestations at single sites, and seven patients presented manifestations at multiple sites, including the thigh, calf, arm, chest wall, dorsal, psoas, gluteal, and forehead muscles. Of the 19 total patients, 13 (68.4%) reported pain, and only 8 (42.1%) patients presented tuberculosis symptoms. All patients received laboratory results associated with Mycobacterium tuberculosis infection. Fourteen (73.7%) of the 19 patients underwent skeletal muscle biopsy, where granulomatous inflammation was observed. Eighteen patients were treated with anti-tuberculosis therapies. Sixteen patients improved or recovered after anti-tuberculosis treatment, and unfortunately, two patients died. Conclusion: As a kind of systemic disease, MT is mainly characterized by painful or painless muscle masses and swelling at a single site or at multiple sites. Patients with a history of tuberculosis and immune system disease are susceptible to MT. A diagnosis is mainly made on the basis of the results of pathological biopsy and bacteriological culture. Early diagnosis and timely standardized anti-tuberculosis treatment can improve the prognosis.