Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.

Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K+/H+ exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K+ efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial pathologies.

A framework for optimizing the acquisition protocol multishell diffusion-weighted imaging for multimodel assessment.

Complementary aspects of tissue microstructure can be studied with diffusion-weighted imaging (DWI). However, there is no consensus on how to design a diffusion acquisition protocol for multiple models within a clinically feasible time. The purpose of this study is to provide a flexible framework that is able to optimize the shell acquisition protocol given a set of DWI models. Eleven healthy subjects underwent an extensive DWI acquisition protocol, including 15 candidate shells, ranging from 10 to 3500 s/mm2. The proposed framework aims to determine the optimized acquisition scheme (OAS) with a data-driven procedure minimizing the squared error of model-estimated parameters. We tested the proposed method over five heterogeneous DWI models exploiting both low and high b-values (i.e., diffusion tensor imaging [DTI], free water, intra-voxel incoherent motion [IVIM], diffusion kurtosis imaging [DKI], and neurite orientation dispersion and density imaging [NODDI]). A voxel-level and region of interest (ROI)-level analysis was conducted over the white matter and in 48 fiber bundles, respectively. Results showed that acquiring data for the five abovementioned models via OAS requires 14 min, compared with 35 min for the joint recommended acquisition protocol. The parameters derived from the reference acquisition scheme and the OAS are comparable in terms of estimated values, noise, and tissue contrast. Furthermore, the power analysis showed that the OAS retains the potential sensitivity to group-level differences in the parameters of interest, with the exception of the free water model. Overall, there is a linear correspondence (R2 = 0.91) between OAS and reference-derived parameters. In conclusion, the proposed framework optimizes the shell acquisition scheme for a given set of DWI models (i.e., DTI, free water, IVIM, DKI, and NODDI), combining low and high b-values while saving acquisition time.

Alterations in neural activation in the ventral frontoparietal network during complex magnocellular stimuli in developmental dyslexia associated with READ1 deletion.

BACKGROUND: An intronic deletion within intron 2 of the DCDC2 gene encompassing the entire READ1 (hereafter, READ1d) has been associated in both children with developmental dyslexia (DD) and typical readers (TRs), with interindividual variation in reading performance and motion perception as well as with structural and functional brain alterations. Visual motion perception -- specifically processed by the magnocellular (M) stream -- has been reported to be a solid and reliable endophenotype of DD. Hence, we predicted that READ1d should affect neural activations in brain regions sensitive to M stream demands as reading proficiency changes. METHODS: We investigated neural activations during two M-eliciting fMRI visual tasks (full-field sinusoidal gratings controlled for spatial and temporal frequencies and luminance contrast, and sensitivity to motion coherence at 6%, 15% and 40% dot coherence levels) in four subject groups: children with DD with/without READ1d, and TRs with/without READ1d. RESULTS: At the Bonferroni-corrected level of significance, reading skills showed a significant effect in the right polar frontal cortex during the full-field sinusoidal gratings-M task. Regardless of the presence/absence of the READ1d, subjects with poor reading proficiency showed hyperactivation in this region of interest (ROI) compared to subjects with better reading scores. Moreover, a significant interaction was found between READ1d and reading performance in the left frontal opercular area 4 during the 15% coherent motion sensitivity task. Among subjects with poor reading performance, neural activation in this ROI during this specific task was higher for subjects without READ1d than for READ1d carriers. The difference vanished as reading skills increased. CONCLUSIONS: Our findings showed a READ1d-moderated genetic vulnerability to alterations in neural activation in the ventral attentive and salient networks during the processing of relevant stimuli in subjects with poor reading proficiency.

Magnetic resonance imaging of intracranial anomalies in pregnancies complicated by twin anemia-polycythemia sequence.

PURPOSE: To describe fetal brain Magnetic Resonance Imaging (MRI) findings in a large series of monochorionic (MC) pregnancies complicated by Twin Anemia-Polycythemia Sequence (TAPS) prenatally diagnosed, so to characterize the potential intracranial complications associated with this condition, their frequency and potential treatment options. METHODS: This is a retrospective study of MC twin pregnancies complicated by TAPS and undergone fetal MRI in a single institution from 2006 to 2023. MRI control was performed and post-natal ultrasound (US) or MRI were available. RESULTS: 1250 MC pregnancies were evaluated in our institution. 50 pregnancies (4%) were diagnosed with TAPS, 29 underwent a fetal brain MRI. 13/29 pregnancies (44.8%) demonstrated brain findings at MRI in at least a twin. Neuroradiological findings were detected in 14/57 twins (24.6%). We detected four main categories of findings: hemorrhagic lesions, T2-weighted white-matter hyperintensities (WMH), brain edema-swelling and venous congestion. Nineteen findings were present in the anemic and three in the polycythemic twins, with a statistically significant ratio between the two groups (p-value = 0.01). Intrauterine MRI follow-up demonstrated the sequalae of hemorrhagic lesions. A complete regression of brain swelling, veins prominence and T2-WMHs was demonstrated after treatment. Postnatal imaging confirmed prenatal features. CONCLUSIONS: Our work demonstrates that TAPS-related MRI anomalies consisted in edematous/hemorrhagic lesions that occur mostly in anemic rather than in polycythemic twins. Fetoscopic laser surgery could have a potential decongestant role. Therefore, prenatal MRI may help in counselling and management in TAPS pregnancies, especially for the planning of therapy and the monitoring of its efficacy.

Spontaneous regression of an epidermoid cyst in a pediatric patient-Case report and review of the literature.

Epidermoid cysts are infrequent, benign, slow-growing, space-occupying lesions that account for 0.5-1.8% of primary intracranial tumors. We report the case of a 17-month-old child who presented in 2015 for one episode of pallor associated with hypotonia. Epilepsy was excluded and MRI was recommended. The MRI was performed and there were no focal parenchymal lesions, but it showed an extra-axial ovoid lesion with imaging characteristics consistent with epidermoid cyst. Follow-up MRI at one year was performed and it showed minimal increased in dimensions of the cyst, without changes into the signal of the lesion. Another MRI was performed 7 years after and it showed complete resolution of the cyst. Six months afterwards, another MRI was performed and it confirmed the complete regression of the cyst, without any extra-axial masses reported. The patient did not present any neurological anomalies. No follow-up MRI was recommended afterwards. Spontaneous regression of epidermoid cyst in pediatric population is an extremely rare event, but it should be taken into account when the patient shows no symptoms. This is the third case of spontaneous regression of an epidermoid cyst reported in pediatric patients, and the first one in the temporal region. Careful follow-up and watchful waiting could be an option to surgical treatment in epidermoid cysts.

Progressive Spinal Cord Degeneration in Friedreich's Ataxia: Results from ENIGMA-Ataxia.

BACKGROUND: Spinal cord damage is a hallmark of Friedreich's ataxia (FRDA), but its progression and clinical correlates remain unclear. OBJECTIVE: The objective of this study was to perform a characterization of cervical spinal cord structural damage in a large multisite FRDA cohort. METHODS: We performed a cross-sectional analysis of cervical spinal cord (C1-C4) cross-sectional area (CSA) and eccentricity using magnetic resonance imaging data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched control subjects. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age. RESULTS: Individuals with FRDA, relative to control subjects, had significantly reduced CSA at all examined levels, with large effect sizes (d > 2.1) and significant correlations with disease severity (r < -0.4). Similarly, we found significantly increased eccentricity (d > 1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, although CSA appears to decrease progressively, eccentricity remains stable over time. CONCLUSIONS: Previous research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage, or both. Hence our data support the hypothesis that damage to the DC and damage to CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, while CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cutting-edge applications of fetal MR neuro-imaging in clinical routine: a pictorial essay.

Over time, fetal MR neuro-imaging has undergone continuous improvement; presently, it plays a pivotal role in the diagnosis of an expanding array of complex neurological conditions. Within this pictorial essay, our focus will be exclusively directed towards those cutting-edge clinical applications, which currently yield valuable diagnostic insights on a single case basis. Specifically, the pictorial examples will center on some abnormal entities and their features at an earlier fetal stage.

Onset of Chiari type 1 malformation: insights from a small series of intrauterine MR imaging cases.

PURPOSE: Morphometric studies on idiopathic Chiari malformation type 1 (CM1) pathogenesis have been mainly based on post-natal neuroimaging. Prenatal clues related to CM1 development are lacking. We present pre- and post-natal imaging time course in idiopathic CM1 and assess fetal skull and brain biometry to establish if clues about CM1 development are present at fetal age. METHODS: Multicenter databases were screened to retrieve intrauterine magnetic resonance (iuMR) of children presenting CM1 features at post-natal scan. Syndromes interfering with skull-brain growth were excluded. Twenty-two morphometric parameters were measured at fetal (average 24.4 weeks; range 21 to 32) and post-natal (average 15.4 months; range 1 to 45) age; matched controls were included. RESULTS: Among 7000 iuMR cases, post-natal scans were available for 925, with postnatal CM1 features reported in seven. None of the fetuses presented CM1 features. Tonsillar descent was clear at a later post-natal scan in all seven cases. Six fetal parameters resulted to be statistically different between CM1 and controls: basal angle (p = 0.006), clivo-supraoccipital angle (p = 0.044), clivus' length (p = 0.043), posterior cranial fossa (PCF) width (p = 0.009), PCF height (p = 0.045), and PCFw/BPDb (p = 0.013). Postnatally, only the clivus' length was significant between CM1 cases and controls. CONCLUSION: Pre- and post-natal CM1 cases did not share striking common features, making qualitative prenatal assessment not predictive; however, our preliminary results support the view that some of the pathogenetic basis of CM1 may be embedded to some extent already in intrauterine life.

Congenital isolated unilateral third nerve palsy in children: the diagnostic contribution of high-resolution MR imaging.

PURPOSE: To describe the neuroanatomical correlates of unilateral congenital isolated oculomotor palsy by means of high-resolution MRI. METHODS: Children with a clinical diagnosis of congenital isolated oculomotr palsy and with a high-resolution MRI acquisition targeted on the orbits and cranial nerves were selected and included in the study. An experienced pediatric neuroradiologist evaluated all the exams, assessing the integrity and morphology of extraocular muscles, oculomotor, trochlear and abducens nerves as well as optic nerves and globes. Clinical data and ophthalmologic evaluations were also collected. RESULTS: Six children (age range: 1-16 years; males: 3) were selected. All patients showed, on the affected side (left:right = 5:1), anomalies of the III nerve and extraocular muscles innervated by the pathological nerve. One patient had complete nerve agenesis, two patients showed a diffuse thinning of the nerve, from the brainstem to the orbit and 3 patients showed a distal thinning of the oculomotor nerve, starting at the level of the cavernous sinus. In all cases atrophy of corresponding muscles was noticed, but the involvement of the affected muscles varied with the nervous pattern of injury. CONCLUSIONS: High-resolution MRI represents a valuable tool for the diagnosis of III nerve anomalies in unilateral congenital IOP, showing different patterns of nerve involvement and muscular atrophy.

SUFU haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum.

BACKGROUND: Joubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%-75%.In 2018, we reported homozygous hypomorphic missense variants of the SUFU gene in two families with mild JS. Recently, heterozygous truncating SUFU variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies. METHODS: We reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes. RESULTS: Heterozygous truncating and splice-site SUFU variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents. CONCLUSION: Heterozygous truncating or splice-site SUFU variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.

Refining the mutational spectrum and gene-phenotype correlates in pontocerebellar hypoplasia: results of a multicentric study.

BACKGROUND: Pontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorders characterised by concurrent hypoplasia of the pons and the cerebellum and variable clinical and imaging features. The current classification includes 13 subtypes, with ~20 known causative genes. Attempts have been made to delineate the phenotypic spectrum associated to specific PCH genes, yet clinical and neuroradiological features are not consistent across studies, making it difficult to define gene-specific outcomes. METHODS: We performed deep clinical and imaging phenotyping in 56 probands with a neuroradiological diagnosis of PCH, who underwent NGS-based panel sequencing of PCH genes and MLPA for CASK rearrangements. Next, we conducted a phenotype-based unsupervised hierarchical cluster analysis to investigate associations between genes and specific phenotypic clusters. RESULTS: A genetic diagnosis was obtained in 43 probands (77%). The most common causative gene was CASK, which accounted for nearly half cases (45%) and was mutated in females and occasionally in males. The European founder mutation p.Ala307Ser in TSEN54 and pathogenic variants in EXOSC3 accounted for 18% and 9% of cases, respectively. VLDLR, TOE1 and RARS2 were mutated in single patients. We were able to confirm only few previously reported associations, including jitteriness and clonus with TSEN54 and lower motor neuron signs with EXOSC3. When considering multiple features simultaneously, a clear association with a phenotypic cluster only emerged for EXOSC3. CONCLUSION: CASK represents the major PCH causative gene in Italy. Phenotypic variability associated with the most common genetic causes of PCH is wider than previously thought, with marked overlap between CASK and TSEN54-associated disorders.

DBB - A Distorted Brain Benchmark for Automatic Tissue Segmentation in Paediatric Patients.

T1-weighted magnetic resonance images provide a comprehensive view of the morphology of the human brain at the macro scale. These images are usually the input of a segmentation process that aims detecting the anatomical structures labeling them according to a predefined set of target tissues. Automated methods for brain tissue segmentation rely on anatomical priors of the human brain structures. This is the reason why their performance is quite accurate on healthy individuals. Nevertheless model-based tools become less accurate in clinical practice, specifically in the cases of severe lesions or highly distorted cerebral anatomy. More recently there are empirical evidences that a data-driven approach can be more robust in presence of alterations of brain structures, even though the learning model is trained on healthy brains. Our contribution is a benchmark to support an open investigation on how the tissue segmentation of distorted brains can be improved by adopting a supervised learning approach. We formulate a precise definition of the task and propose an evaluation metric for a fair and quantitative comparison. The training sample is composed of almost one thousand healthy individuals. Data include both T1-weighted MR images and their labeling of brain tissues. The test sample is a collection of several tens of individuals with severe brain distortions. Data and code are openly published on BrainLife, an open science platform for reproducible neuroscience data analysis.

Effects of age and gender on neural correlates of emotion imagery.

Mental imagery is part of people's own internal processing and plays an important role in everyday life, cognition and pathology. The neural network supporting mental imagery is bottom-up modulated by the imagery content. Here, we examined the complex associations of gender and age with the neural mechanisms underlying emotion imagery. We assessed the brain circuits involved in emotion mental imagery (vs. action imagery), controlled by a letter detection task on the same stimuli, chosen to ensure attention to the stimuli and to discourage imagery, in 91 men and women aged 14-65 years using fMRI. In women, compared with men, emotion imagery significantly increased activation within the right putamen, which is involved in emotional processing. Increasing age, significantly decreased mental imagery-related activation in the left insula and cingulate cortex, areas involved in awareness of ones' internal states, and it significantly decreased emotion verbs-related activation in the left putamen, which is part of the limbic system. This finding suggests a top-down mechanism by which gender and age, in interaction with bottom-up effect of type of stimulus, or directly, can modulate the brain mechanisms underlying mental imagery.

Brain Structure and Degeneration Staging in Friedreich Ataxia: Magnetic Resonance Imaging Volumetrics from the ENIGMA-Ataxia Working Group.

OBJECTIVE: Friedreich ataxia (FRDA) is an inherited neurological disease defined by progressive movement incoordination. We undertook a comprehensive characterization of the spatial profile and progressive evolution of structural brain abnormalities in people with FRDA. METHODS: A coordinated international analysis of regional brain volume using magnetic resonance imaging data charted the whole-brain profile, interindividual variability, and temporal staging of structural brain differences in 248 individuals with FRDA and 262 healthy controls. RESULTS: The brainstem, dentate nucleus region, and superior and inferior cerebellar peduncles showed the greatest reductions in volume relative to controls (Cohen d = 1.5-2.6). Cerebellar gray matter alterations were most pronounced in lobules I-VI (d = 0.8), whereas cerebral differences occurred most prominently in precentral gyri (d = 0.6) and corticospinal tracts (d = 1.4). Earlier onset age predicted less volume in the motor cerebellum (rmax  = 0.35) and peduncles (rmax  = 0.36). Disease duration and severity correlated with volume deficits in the dentate nucleus region, brainstem, and superior/inferior cerebellar peduncles (rmax  = -0.49); subgrouping showed these to be robust and early features of FRDA, and strong candidates for further biomarker validation. Cerebral white matter abnormalities, particularly in corticospinal pathways, emerge as intermediate disease features. Cerebellar and cerebral gray matter loss, principally targeting motor and sensory systems, preferentially manifests later in the disease course. INTERPRETATION: FRDA is defined by an evolving spatial profile of neuroanatomical changes beyond primary pathology in the cerebellum and spinal cord, in line with its progressive clinical course. The design, interpretation, and generalization of research studies and clinical trials must consider neuroanatomical staging and associated interindividual variability in brain measures. ANN NEUROL 2021;90:570-583.

Get Your Molar Tooth Right: Joubert Syndrome Misdiagnosis Unmasked by Whole-Exome Sequencing.

Joubert syndrome (JS) is a recessively inherited ciliopathy, characterized by a specific cerebellar and brainstem malformation recognizable on brain imaging as the "molar tooth sign" (MTS). Clinical signs include hypotonia, developmental delay, breathing abnormalities, and ocular motor apraxia. Older patients develop ataxia, intellectual impairment, and variable organ involvement. JS is genetically heterogeneous, with over 40 ciliary genes overall accounting for 65-75% cases. Thus, in recent years, the genetic diagnosis of JS has been based on the analysis of next-generation sequencing targeted gene panels. Since clinical features are unspecific and undistinguishable from other neurodevelopmental syndromes, the recognition of the MTS is crucial to address the patient to the appropriate genetic testing. However, the MTS is not always properly diagnosed, resulting either in false negative diagnoses (patients with the MTS not addressed to JS genetic testing) or in false positive diagnoses (patients with a different brain malformation wrongly addressed to JS genetic testing). Here, we present six cases referred for JS genetic testing based on inappropriate recognition of MTS. While the analysis of JS-related genes was negative, whole-exome sequencing (WES) disclosed pathogenic variants in other genes causative of distinct brain malformative conditions with partial clinical and neuroradiological overlap with JS. Reassessment of brain MRIs from five patients by a panel of expert pediatric neuroradiologists blinded to the genetic diagnosis excluded the MTS in all cases but one, which raised conflicting interpretations. This study highlights that the diagnostic yield of NGS-based targeted panels is strictly related to the accuracy of the diagnostic referral based on clinical and imaging assessment and that WES has an advantage over targeted panel analysis when the diagnostic suspicion is not straightforward.

Superior Cerebellar Atrophy: An Imaging Clue to Diagnose ITPR1-Related Disorders.

The inositol 1,4,5-triphosphate receptor type 1 (ITPR1) gene encodes an InsP3-gated calcium channel that modulates intracellular Ca2+ release and is particularly expressed in cerebellar Purkinje cells. Pathogenic variants in the ITPR1 gene are associated with different types of autosomal dominant spinocerebellar ataxia: SCA15 (adult onset), SCA29 (early-onset), and Gillespie syndrome. Cerebellar atrophy/hypoplasia is invariably detected, but a recognizable neuroradiological pattern has not been identified yet. With the aim of describing ITPR1-related neuroimaging findings, the brain MRI of 14 patients with ITPR1 variants (11 SCA29, 1 SCA15, and 2 Gillespie) were reviewed by expert neuroradiologists. To further evaluate the role of superior vermian and hemispheric cerebellar atrophy as a clue for the diagnosis of ITPR1-related conditions, the ITPR1 gene was sequenced in 5 patients with similar MRI pattern, detecting pathogenic variants in 4 of them. Considering the whole cohort, a distinctive neuroradiological pattern consisting in superior vermian and hemispheric cerebellar atrophy was identified in 83% patients with causative ITPR1 variants, suggesting this MRI finding could represent a hallmark for ITPR1-related disorders.

Definitions and classification of malformations of cortical development: practical guidelines.

Malformations of cortical development are a group of rare disorders commonly manifesting with developmental delay, cerebral palsy or seizures. The neurological outcome is extremely variable depending on the type, extent and severity of the malformation and the involved genetic pathways of brain development. Neuroimaging plays an essential role in the diagnosis of these malformations, but several issues regarding malformations of cortical development definitions and classification remain unclear. The purpose of this consensus statement is to provide standardized malformations of cortical development terminology and classification for neuroradiological pattern interpretation. A committee of international experts in paediatric neuroradiology prepared systematic literature reviews and formulated neuroimaging recommendations in collaboration with geneticists, paediatric neurologists and pathologists during consensus meetings in the context of the European Network Neuro-MIG initiative on Brain Malformations (https://www.neuro-mig.org/). Malformations of cortical development neuroimaging features and practical recommendations are provided to aid both expert and non-expert radiologists and neurologists who may encounter patients with malformations of cortical development in their practice, with the aim of improving malformations of cortical development diagnosis and imaging interpretation worldwide.

Diaphragm Involvement in Duchenne Muscular Dystrophy (DMD): An MRI Study.

BACKGROUND: Duchenne muscular dystrophy (DMD) is characterized by progressive weakness and wasting of skeletal, cardiac, and respiratory muscles, with consequent cardiopulmonary failure as the main cause of death. Reliable outcome measures able to demonstrate specific trends over disease progression are essential. PURPOSE: To investigate MRI as a noninvasive imaging modality to assess diaphragm impairment in DMD. In particular, we sought to correlate MRI measurement of diaphragm structure and function with pulmonary function tests and with the abdominal volumes (VAB ) measured by optoelectronic plethysmography, being an index of the action of the diaphragm. STUDY TYPE: Cross-sectional study. POPULATION: Twenty-six DMD patients (17.9 ± 6.2 years) and 12 age-matched controls (17.8 ± 5.9 years). FIELD STRENGTH/SEQUENCE: 3-Point gradient echo Dixon sequence at 3T. ASSESSMENT: Images were acquired in breath-hold at full-expiration (EXP) and full-inspiration (INSP). INSP and EXP lung volumes were segmented and the diaphragm surface was reconstructed as the bottom surface of the left and the right lung. The inspiratory and the expiratory diaphragm surfaces were aligned by a nonrigid iterative closest point algorithm. On MRI we measured: 1) craniocaudal diaphragmatic excursion; 2) diaphragm fatty infiltration. STATISTICAL TESTS: Three-parameter sigmoid regression, one-way analysis of variance (ANOVA), Spearman's correlation. RESULTS: In patients, diaphragm excursion decreased with age (r2 = 0.68, P < 0.0001) and fat fraction increased (r2 = 0.51, P = 0.0002). In healthy subjects, diaphragm excursion and fat fraction had no relationship with age. Diaphragm excursion decreased with decreasing FEV1 %pred (r = 0.78, P < 0.0001) and FVC %pred (r = 0.76, P < 0.0001) and correlated with VAB (r = 0.60, P = 0.0002). Fatty infiltration increased with decreasing FEV1 %pred (r = -0.88, P < 0.0001) and FVC %pred (r = -0.88, P < 0.0001). DATA CONCLUSION: The progressive structural and functional diaphragm impairment is highly related to pulmonary function tests and to VAB . The results suggest that MRI might represent a new and noninvasive tool for the functional and structural assessment of the diaphragm. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2020;51:461-471.

Multi-center evaluation of stability and reproducibility of quantitative MRI measures in healthy calf muscles.

The purpose of this study was to evaluate temporal stability, multi-center reproducibility and the influence of covariates on a multimodal MR protocol for quantitative muscle imaging and to facilitate its use as a standardized protocol for evaluation of pathology in skeletal muscle. Quantitative T2, quantitative diffusion and four-point Dixon acquisitions of the calf muscles of both legs were repeated within one hour. Sixty-five healthy volunteers (31 females) were included in one of eight 3-T MR systems. Five traveling subjects were examined in six MR scanners. Average values over all slices of water-T2 relaxation time, proton density fat fraction (PDFF) and diffusion metrics were determined for seven muscles. Temporal stability was tested with repeated measured ANOVA and two-way random intraclass correlation coefficient (ICC). Multi-center reproducibility of traveling volunteers was assessed by a two-way mixed ICC. The factors age, body mass index, gender and muscle were tested for covariance. ICCs of temporal stability were between 0.963 and 0.999 for all parameters. Water-T2 relaxation decreased significantly (P < 10-3 ) within one hour by ~ 1 ms. Multi-center reproducibility showed ICCs within 0.879-0.917 with the lowest ICC for mean diffusivity. Different muscles showed the highest covariance, explaining 20-40% of variance for observed parameters. Standardized acquisition and processing of quantitative muscle MRI data resulted in high comparability among centers. The imaging protocol exhibited high temporal stability over one hour except for water T2 relaxation times. These results show that data pooling is feasible and enables assembling data from patients with neuromuscular diseases, paving the way towards larger studies of rare muscle disorders.

The spectrum of brainstem malformations associated to mutations of the tubulin genes family: MRI and DTI analysis.

OBJECTIVES: To describe the spectrum of brainstem malformations associated to mutations in the tubulin genes taking advantage of magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). METHODS: Fifteen patients (six males; median age, 1.25 years; range, 1 month to 31 years) with mutations in the tubulin genes (TUBA1A = 8, TUBB2B = 4, TUBB3 = 3) studied with MRI and DTI were included in the study. Brain MR exams were reviewed to describe the malformative aspects of the brainstem. Malformations of the supratentorial brain and cerebellum were also recorded. Tractography was performed in seven selected cases. RESULTS: Fourteen patients (93%) showed complex malformations of the brainstem. Most common findings, apparent on anatomical MR sequences, were brainstem asymmetry (12 cases, 5 of which with a crossed pattern characterised by a hypertrophic right medulla oblongata and hypertrophic left pons), short and small pons on midline (10 cases) and anterior brainstem clefting (6 cases). DTI revealed abnormal transverse pontine fibres (13 cases), fusion of corticospinal tracts and medial lemnisci (9 cases) and a small decussation of the superior cerebellar peduncles (7 cases). CONCLUSIONS: Conventional/anatomical MRI and DTI reveal a complex pattern of brainstem malformations associated with tubulin genes mutations. KEY POINTS: • Brainstem malformations affect 93% patients with mutated tubulin genes • MRI shows homolateral and crossed brainstem asymmetries, clefts and pons hypoplasia • DTI demonstrates irregular representation of transverse pontine fibres and fusion of corticospinal tracts.