Quantitative Foot Muscle Magnetic Resonance Imaging Reliably Measures Disease Progression in Children and Adolescents with Charcot-Marie-Tooth Disease Type 1A.

Quantitative muscle fat fraction (FF) responsiveness is lower in younger Charcot-Marie-Tooth disease type 1A (CMT1A) patients with lower baseline calf-level FF. We investigated the practicality, validity, and responsiveness of foot-level FF in this cohort involving 22 CMT1A patients and 14 controls. The mean baseline foot-level FF was 25.9 ± 20.3% in CMT1A patients, and the 365-day FF (n = 15) increased by 2.0 ± 2.4% (p < 0.001 vs controls). Intrinsic foot-level FF demonstrated large responsiveness (12-month standardized response mean (SRM) of 0.86) and correlated with the CMT examination score (ρ = 0.58, P = 0.01). Intrinsic foot-level FF has the potential to be used as a biomarker in future clinical trials involving younger CMT1A patients. ANN NEUROL 2024.

Lower limb muscle MRI fat fraction is a responsive outcome measure in CMT X1, 1B and 2A.

OBJECTIVE: With potential therapies for many forms of Charcot-Marie-Tooth disease (CMT), responsive outcome measures are urgently needed for clinical trials. Quantitative lower limb MRI demonstrated progressive calf intramuscular fat accumulation in the commonest form, CMT1A with large responsiveness. In this study, we evaluated the responsiveness and validity in the three other common forms, due to variants in GJB1 (CMTX1), MPZ (CMT1B) and MFN2 (CMT2A). METHODS: 22 CMTX1, 21 CMT1B and 21 CMT2A patients and matched controls were assessed at a 1-year interval. Intramuscular fat fraction (FF) was evaluated using three-point Dixon MRI at thigh and calf level along with clinical measures including CMT examination score, clinical strength assessment, CMT-HI and plasma neurofilament light chain. RESULTS: All patient groups had elevated muscle fat fraction at thigh and calf levels, with highest thigh FF and atrophy in CMT2A. There was moderate correlation between calf muscle FF and clinical measures (CMTESv2 rho = 0.405; p = 0.001, ankle MRC strength rho = -0.481; p < 0.001). Significant annualised progression in calf muscle FF was seen in all patient groups (CMTX1 2.0 ± 2.0%, p < 0.001, CMT1B 1.6 ± 2.1% p = 0.004 and CMT2A 1.6 ± 2.1% p = 0.002). Greatest increase was seen in patients with 10-70% FF at baseline (calf 2.7 ± 2.3%, p < 0.0001 and thigh 1.7 ± 2.1%, p = 0.01). INTERPRETATION: Our results confirm that calf muscle FF is highly responsive over 12 months in three additional common forms of CMT which together with CMT1A account for 90% of genetically confirmed cases. Calf muscle MRI FF should be a valuable outcome measure in upcoming CMT clinical trials.

Quantitative MRI outcome measures in CMT1A using automated lower limb muscle segmentation.

BACKGROUND: Lower limb muscle magnetic resonance imaging (MRI) obtained fat fraction (FF) can detect disease progression in patients with Charcot-Marie-Tooth disease 1A (CMT1A). However, analysis is time-consuming and requires manual segmentation of lower limb muscles. We aimed to assess the responsiveness, efficiency and accuracy of acquiring FF MRI using an artificial intelligence-enabled automated segmentation technique. METHODS: We recruited 20 CMT1A patients and 7 controls for assessment at baseline and 12 months. The three-point-Dixon fat water separation technique was used to determine thigh-level and calf-level muscle FF at a single slice using regions of interest defined using Musclesense, a trained artificial neural network for lower limb muscle image segmentation. A quality control (QC) check and correction of the automated segmentations was undertaken by a trained observer. RESULTS: The QC check took on average 30 seconds per slice to complete. Using QC checked segmentations, the mean calf-level FF increased significantly in CMT1A patients from baseline over an average follow-up of 12.5 months (1.15%±1.77%, paired t-test p=0.016). Standardised response mean (SRM) in patients was 0.65. Without QC checks, the mean FF change between baseline and follow-up, at 1.15%±1.68% (paired t-test p=0.01), was almost identical to that seen in the corrected data, with a similar overall SRM at 0.69. CONCLUSIONS: Using automated image segmentation for the first time in a longitudinal study in CMT, we have demonstrated that calf FF has similar responsiveness to previously published data, is efficient with minimal time needed for QC checks and is accurate with minimal corrections needed.

Camera-based Prospective Motion Correction in Paediatric Epilepsy Patients Enables EEG-fMRI Localization Even in High-motion States.

BACKGROUND: EEG-fMRI is a useful additional test to localize the epileptogenic zone (EZ) particularly in MRI negative cases. However subject motion presents a particular challenge owing to its large effects on both MRI and EEG signal. Traditionally it is assumed that prospective motion correction (PMC) of fMRI precludes EEG artifact correction. METHODS: Children undergoing presurgical assessment at Great Ormond Street Hospital were included into the study. PMC of fMRI was done using a commercial system with a Moiré Phase Tracking marker and MR-compatible camera. For retrospective EEG correction both a standard and a motion educated EEG artefact correction (REEGMAS) were compared to each other. RESULTS: Ten children underwent simultaneous EEG-fMRI. Overall head movement was high (mean RMS velocity < 1.5 mm/s) and showed high inter- and intra-individual variability. Comparing motion measured by the PMC camera and the (uncorrected residual) motion detected by realignment of fMRI images, there was a five-fold reduction in motion from its prospective correction. Retrospective EEG correction using both standard approaches and REEGMAS allowed the visualization and identification of physiological noise and epileptiform discharges. Seven of 10 children had significant maps, which were concordant with the clinical EZ hypothesis in 6 of these 7. CONCLUSION: To our knowledge this is the first application of camera-based PMC for MRI in a pediatric clinical setting. Despite large amount of movement PMC in combination with retrospective EEG correction recovered data and obtained clinically meaningful results during high levels of subject motion. Practical limitations may currently limit the widespread use of this technology.

High-resolution quantitative MRI of multiple sclerosis spinal cord lesions.

PURPOSE: Validation of quantitative MR measures for myelin imaging in the postmortem multiple sclerosis spinal cord. METHODS: Four fixed spinal cord samples were imaged first with a 3T clinical MR scanner to identify areas of interest for scanning, and then with a 7T small bore scanner using a multicomponent-driven equilibrium single-pulse observation of T1 and T2 protocol to produce apparent proton density, T1 , T2 , myelin water, intracellular water, and free-water fraction maps. After imaging, the cords were sectioned and stained with histological markers (hematoxylin and eosin, myelin basic protein, and neurofilament protein), which were quantitatively compared with the MR maps. RESULTS: Excellent correspondence was found between high-resolution MR parameter maps and histology, particularly for apparent proton density MRI and myelin basic protein staining. CONCLUSION: High-resolution quantitative MRI of the spinal cord provides biologically meaningful measures, and could be beneficial to diagnose and track multiple sclerosis lesions in the spinal cord.

Clinically feasible diffusion MRI in muscle: Time dependence and initial findings in Duchenne muscular dystrophy.

PURPOSE: To characterize the diffusion time-dependence in muscle in healthy adult volunteers, boys with Duchenne's muscular dystrophy (DMD), and age-matched controls in a clinically feasible acquisition time for pediatric applications. METHODS: Diffusion data were acquired using a pulsed gradient stimulated echo diffusion preparation at 5 different diffusion times (70, 130, 190, 250, and 330 ms), at 4 different b-values (0, 200, 400, 600, and 800 s/mm2 ) and 6 directions (orthogonal x, y, and z and diagonal xy, xz, and yz) and processed to obtain standard diffusion indices (mean diffusivity [MD] and fractional anisotropy [FA]) at each diffusion time. RESULTS: Time-dependent diffusion was seen in muscle in healthy adult volunteers, boys with DMD, and age-matched controls. Boys with DMD showed reduced MD and increased FA values in comparison to age matched controls across a range of diffusion times. A diffusion time of Δ = 190 ms had the largest effect size. CONCLUSIONS: These results could be used to optimize diffusion imaging in this disease further and imply that these diffusion indices may become an important biomarker in monitoring progression in DMD in the future.

Multiparametric mapping in post-mortem perinatal MRI: a feasibility study.

OBJECTIVES: To demonstrate feasibility of a 3 T multiparametric mapping (MPM) quantitative pipeline for perinatal post-mortem MR (PMMR) imaging. METHODS: Whole body quantitative PMMR imaging was acquired in four cases, mean gestational age 34 weeks, range (29-38 weeks) on a 3 T Siemens Prisma scanner. A multicontrast protocol yielded proton density, T1 and magnetic transfer (MT) weighted multi-echo images obtained from variable flip angle (FA) 3D fast low angle single-shot (FLASH) acquisitions, radiofrequency transmit field map and one B0 field map alongside four MT weighted acquisitions with saturation pulses of 180, 220, 260 and 300 degrees were acquired, all at 1 mm isotropic resolution. RESULTS: Whole body MPM was achievable in all four foetuses, with R1, R2*, PD and MT maps reconstructed from a single protocol. Multiparametric maps were of high quality and show good tissue contrast, especially the MT maps. CONCLUSION: MPM is a feasible technique in a perinatal post-mortem setting, which may allow quantification of post-mortem change, prior to being evaluated in a clinical setting. ADVANCES IN KNOWLEDGE: We have shown that the MPM sequence is feasible in PMMR imaging and shown the potential of MT imaging in this setting.

Optimal repetition time reduction for single subject event-related functional magnetic resonance imaging.

PURPOSE: Short TRs are increasingly used for fMRI as fast sequences such as simultaneous multislice excitation become available. These have been associated with apparent sensitivity improvements, although greater temporal autocorrelation at shorter TRs can inflate sensitivity measurements leading to uncertainty regarding the optimal approach. METHODS: In volunteers (n = 10), the optimal TR was assessed at the single subject level for event-related designs (visual stimulation) with 4 frequencies of presentation at 4 TR values (412-2550 ms). T-values in the visual cortex localized in each individual were obtained and receiver operating characteristics (ROC) analysis was performed by counting voxels within and outside expected task active regions at different thresholds. This analysis was repeated using 4 different autoregressive (AR) models; SPM AR(1) and SPM AR(fast) which globally estimate autocorrelation, and fMRIstat AR(1) and AR(5) that use a local estimate. RESULTS: The use of modest multiband factors of 2 or 3 with a reduction in TR to 1000 ± 200 ms had greater sensitivity and specificity as shown by higher T-values in visual cortex and ROC analysis. At these TRs, the ROC analysis demonstrated that a local AR model fit improved performance while high order AR models were unnecessary. CONCLUSIONS: Modest TR reductions (to 1000 ± 200 ms) optimally improved event-related fMRI performance independent of design frequency. Autoregressive models with a local as opposed to global fit performed better, while low order autoregressive models were sufficient at the optimal TR.

Flexible proton density (PD) mapping using multi-contrast variable flip angle (VFA) data.

Quantitative proton density (PD) maps measure the amount of free water, which is important for non-invasive tissue characterization in pathology and across lifespan. PD mapping requires the estimation and subsequent removal of factors influencing the signal intensity other than PD. These factors include the T1, T2* relaxation effects, transmit field inhomogeneities, receiver coil sensitivity profile (RP) and the spatially invariant factor that is required to scale the data. While the transmit field can be reliably measured, the RP estimation is usually based on image post-processing techniques due to limitations of its measurement at magnetic fields higher than 1.5 T. The post-processing methods are based on unified bias-field/tissue segmentation, fitting the sensitivity profile from images obtained with different coils, or on the linear relationship between T1 and PD. The scaling factor is derived from the signal within a specific tissue compartment or reference object. However, these approaches for calculating the RP and scaling factor have limitations particularly in severe pathology or over a wide age range, restricting their application. We propose a new approach for PD mapping based on a multi-contrast variable flip angle acquisition protocol and a data-driven estimation method for the RP correction and map scaling. By combining all the multi-contrast data acquired at different echo times, we are able to fully correct the MRI signal for T2* relaxation effects and to decrease the variance and the entropy of PD values within tissue class of the final map. The RP is determined from the corrected data applying a non-parametric bias estimation, and the scaling factor is based on the median intensity of an external calibration object. Finally, we compare the signal intensity and homogeneity of the multi-contrast PD map with the well-established effective PD (PD*) mapping, for which the RP is based on concurrent bias field estimation and tissue classification, and the scaling factor is estimated from the mean white matter signal. The multi-contrast PD values homogeneity and accuracy within the cerebrospinal fluid (CSF) and deep brain structures are increased beyond that obtained using PD* maps. We demonstrate that the multi-contrast RP approach is insensitive to anatomical or a priori tissue information by applying it in a patient with extensive brain abnormalities and for whole body PD mapping in post-mortem foetal imaging.

High resolution isotropic diffusion imaging in post-mortem neonates: a feasibility study.

OBJECTIVE:: To investigate the potential of advanced diffusion weighted imaging (DWI) in post-mortem MRI (PMMR) at 3T. METHODS:: We acquired PMMR brain and body imaging in 12 neonates, mean gestational age 33.4 weeks (range 29-37 weeks) at 3T and 1.5T. Head and body diffusion imaging at 1.5T consisted of bipolar diffusion encoding and single-shot spin-echo echo-planar imaging (SE-EPI) for acquisition (echo time (TE) 96 ms; repetition time (TR) 2700 ms; voxel size 1.8 x 1.8 mm in-plane with slice thickness 5 mm; b-values of 500 and 1000 s/mm2 applied in three orthogonal directions; total acquisition time 2:12). A whole-body 3T diffusion imaging protocol using monopolar diffusion encoding and simultaneous multislice EPI acquisition with gradients applied in 12 uniformly distributed directions was obtained (TE 53.4 ms; TR 5600 ms; 1.8 mm isotropic; multiband factor 2; b-values of 250, 750, 1250 and 1750 s/mm2; acquisition time 2:09 for a single b-value). RESULTS:: There was significant improvement in image quality in multiband, multislice diffusion PMMR protocol. On visual assessment of image quality, 1.5T DWI scored poorly (mean 2.4 SD ± 0.47), and all 3T b-values individually scored significantly higher (p < 0.001) apart from b = 250 s/mm2 which was not significantly different. CONCLUSION:: Recent advances in diffusion sequences and hardware utilising higher field strengths and gradient performance allows whole-body diffusion PMMR imaging at high resolution with improved image quality compared to the current clinical approach. ADVANCES IN KNOWLEDGE:: We have demonstrated feasibility of a multislice, multiband quantitative diffusion imaging sequence in the perinatal post-mortem setting. This will allow more detailed and quantitative clinical PMMR investigations using diffusion MRI in the future.

The value of semiquantitative analysis in identifying diffuse bone marrow involvement in follicular lymphoma.

AIM: The aim of the study was to investigate the value of fluorine-18-fluorodeoxyglucose ((18)F-FDG)-PET/computed tomography (CT) in identifying diffuse bone marrow (BM) involvement in follicular lymphoma using semiquantitative assessment. METHODS: This is a retrospective analysis of 41 patients with grade 1-3a follicular lymphoma who underwent (18)F-FDG-PET/CT, contrast-enhanced CT and bone marrow trephine biopsy (BMB) as part of staging. BM involvement on PET/CT was assessed by visual and semiquantitative analysis. Standardized uptake values (SUVmax) were measured at the sternum, at both iliac blades and at the T12 vertebra. An average of these four measurements was recorded as SUVav. The single highest overall SUVmax for the four bone sites, the SUVav and the ratios SUVav/mediastinal blood pool (MBP) and SUVav/liver were compared with the BMB result. RESULTS: Focal bone uptake was identified on (18)F-FDG-PET/CT by visual analysis in six patients, including two cases in which the BMB was negative. Assessment of diffuse BM involvement on (18)F-FDG-PET/CT by visual analysis had a sensitivity and specificity of 31 and 92%, respectively. Semiquantitative analysis resulted in an improved sensitivity and specificity of 58 and 96%, respectively, when using SUVav greater than or equal to 2 as the cutoff. Using the ratio SUVav/MBP greater than or equal to 1 the sensitivity of (18)F-FDG-PET/CT to detect BM involvement improved to 83%. CONCLUSION: Visual analysis is useful in determining focal bone involvement, whereas semiquantitative analysis using SUVav/MBP has a high sensitivity and specificity for predicting BM involvement in patients lacking focal bone lesions.

Airway deposition of nebulized gene delivery nanocomplexes monitored by radioimaging agents.

Receptor-targeted nanocomplexes are nonviral vectors developed for gene delivery to the airway epithelium for the treatment of pulmonary disease associated with cystic fibrosis. The present study aimed to optimize the delivery of the nanocomplex by nebulization, and to monitor the in vivo deposition of radiolabeled vector in the airways of a large animal model by γ-camera scintigraphy. Large White weaner pigs were nebulized with nanocomplexes mixed with technetium-99m radiopharmaceuticals. The aerosol deposition scans suggested that the nebulized radiovectors were deposited mainly in the trachea-main bronchi and in the midregion of the lungs. The plasmid biodistribution, assessed by real-time PCR, correlated with the scintigraphy images. The highest plasmid copy numbers were found in the bronchial areas and in the tissues proximal to the main bronchi bifurcation. Immunohistochemistry detected transgene expression in the tracheal and bronchial ciliated epithelium. Histological analysis of lung tissue showed no evidence of inflammation, and no increase in inflammatory cytokines or inflammatory cells was detected in the bronchoalveolar lavage. The deposition of nebulized nanocomplexes coassociated with technetium-99m can be monitored by nuclear medicine techniques. The use of a noninvasive strategy to follow the delivery of the vector could improve the clinical management of patients undergoing cystic fibrosis gene therapy.