Repeat expansions nested within tandem CNVs: a unique structural change in GLS exemplifies the diagnostic challenges of non-coding pathogenic variation.

Glutaminase deficiency has recently been associated with ataxia and developmental delay due to repeat expansions in the 5'UTR of the glutaminase (GLS) gene. Patients with the described GLS repeat expansion may indeed remain undiagnosed due to the rarity of this variant, the challenge of its detection and the recency of its discovery. In this study, we combined advanced bioinformatics screening of ~3000 genomes and ~1500 exomes with optical genome mapping and long-read sequencing for confirmation studies. We identified two GLS families, previously intensely and unsuccessfully analyzed. One family carries an unusual and complex structural change involving a homozygous repeat expansion nested within a quadruplication event in the 5'UTR of GLS. Glutaminase deficiency and its metabolic consequences were validated by in-depth biochemical analysis. The identified GLS patients showed progressive early-onset ataxia, cognitive deficits, pyramidal tract damage and optic atrophy, thus demonstrating susceptibility of several specific neuron populations to glutaminase deficiency. This large-scale screening study demonstrates the ability of bioinformatics analysis-validated by latest state-of-the-art technologies (optical genome mapping and long-read sequencing)-to effectively flag complex repeat expansions using short-read datasets and thus facilitate diagnosis of ultra-rare disorders.

ZSCAN10 deficiency causes a neurodevelopmental disorder with characteristic oto-facial malformations.

Neurodevelopmental disorders are major indications for genetic referral and have been linked to more than 1500 loci including genes encoding transcriptional regulators. The dysfunction of transcription factors often results in characteristic syndromic presentations; however, at least half of these patients lack a genetic diagnosis. The implementation of machine learning approaches has the potential to aid in the identification of new disease genes and delineate associated phenotypes. Next generation sequencing was performed in seven affected individuals with neurodevelopmental delay and dysmorphic features. Clinical characterization included reanalysis of available neuroimaging datasets and 2D portrait image analysis with GestaltMatcher. The functional consequences of ZSCAN10 loss were modelled in mouse embryonic stem cells (mESCs), including a knockout and a representative ZSCAN10 protein truncating variant. These models were characterized by gene expression and western blot analyses, chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR) and immunofluorescence staining. Zscan10 knockout mouse embryos were generated and phenotyped. We prioritized bi-allelic ZSCAN10 loss-of-function variants in seven affected individuals from five unrelated families as the underlying molecular cause. RNA-sequencing analyses in Zscan10-/- mESCs indicated dysregulation of genes related to stem cell pluripotency. In addition, we established in mESCs the loss-of-function mechanism for a representative human ZSCAN10 protein truncating variant by showing alteration of its expression levels and subcellular localization, interfering with its binding to DNA enhancer targets. Deep phenotyping revealed global developmental delay, facial asymmetry and malformations of the outer ear as consistent clinical features. Cerebral MRI showed dysplasia of the semicircular canals as an anatomical correlate of sensorineural hearing loss. Facial asymmetry was confirmed as a clinical feature by GestaltMatcher and was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations. Our findings provide evidence of a novel syndromic neurodevelopmental disorder caused by bi-allelic loss-of-function variants in ZSCAN10.

Genotype-specific spinal cord damage in spinocerebellar ataxias: an ENIGMA-Ataxia study.

BACKGROUND: Spinal cord damage is a feature of many spinocerebellar ataxias (SCAs), but well-powered in vivo studies are lacking and links with disease severity and progression remain unclear. Here we characterise cervical spinal cord morphometric abnormalities in SCA1, SCA2, SCA3 and SCA6 using a large multisite MRI dataset. METHODS: Upper spinal cord (vertebrae C1-C4) cross-sectional area (CSA) and eccentricity (flattening) were assessed using MRI data from nine sites within the ENIGMA-Ataxia consortium, including 364 people with ataxic SCA, 56 individuals with preataxic SCA and 394 nonataxic controls. Correlations and subgroup analyses within the SCA cohorts were undertaken based on disease duration and ataxia severity. RESULTS: Individuals in the ataxic stage of SCA1, SCA2 and SCA3, relative to non-ataxic controls, had significantly reduced CSA and increased eccentricity at all examined levels. CSA showed large effect sizes (d>2.0) and correlated with ataxia severity (r<-0.43) and disease duration (r<-0.21). Eccentricity correlated only with ataxia severity in SCA2 (r=0.28). No significant spinal cord differences were evident in SCA6. In preataxic individuals, CSA was significantly reduced in SCA2 (d=1.6) and SCA3 (d=1.7), and the SCA2 group also showed increased eccentricity (d=1.1) relative to nonataxic controls. Subgroup analyses confirmed that CSA and eccentricity are abnormal in early disease stages in SCA1, SCA2 and SCA3. CSA declined with disease progression in all, whereas eccentricity progressed only in SCA2. CONCLUSIONS: Spinal cord abnormalities are an early and progressive feature of SCA1, SCA2 and SCA3, but not SCA6, which can be captured using quantitative MRI.

MRI-ARSACS: An Imaging Index for Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) Identification Based on the Multicenter PROSPAX Study.

BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and hereditary spastic paraplegia type 7 (SPG7) represent the most common genotypes of spastic ataxia (SPAX). To date, their magnetic resonance imaging (MRI) features have only been described qualitatively, and a pure neuroradiological differential diagnosis between these two conditions is difficult to achieve. OBJECTIVES: To test the performance of MRI measures to discriminate between ARSACS and SPG7 (as an index of common SPAX disease). METHODS: In this prospective multicenter study, 3D-T1-weighted images of 59 ARSACS (35.4 ± 10.3 years, M/F = 33/26) and 78 SPG7 (54.8 ± 10.3 years, M/F = 51/27) patients of the PROSPAX Consortium were analyzed, together with 30 controls (45.9 ± 16.9 years, M/F = 15/15). Different linear and surface measures were evaluated. A receiver operating characteristic analysis was performed, calculating area under the curve (AUC) and corresponding diagnostic accuracy parameters. RESULTS: The pons area proved to be the only metric increased exclusively in ARSACS patients (P = 0.02). Other different measures were reduced in ARSACS and SPG7 compared with controls (all with P ≤ 0.005). A cut-off value equal to 1.67 of the pons-to-superior vermis area ratio proved to have the highest AUC (0.98, diagnostic accuracy 93%, sensitivity 97%) in discriminating between ARSACS and SPG7. CONCLUSIONS: Evaluation of the pons-to-superior vermis area ratio can discriminate ARSACS from other SPAX patients, as exemplified here by SPG7. Hence, we hereby propose this ratio as the Magnetic Resonance Index for the Assessment and Recognition of patients harboring SACS mutations (MRI-ARSACS), a novel diagnostic tool able to identify ARSACS patients and useful for discriminating ARSACS from other SPAX patients undergoing MRI. © 2024 International Parkinson and Movement Disorder Society.

Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study.

OBJECTIVE: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA-Epilepsy working group. METHODS: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in (1) all epilepsies, (2) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), (3) nonlesional temporal lobe epilepsy, (4) genetic generalized epilepsy, and (5) extratemporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness. RESULTS: Across all epilepsies, reduced total cerebellar volume was observed (d = .42). Maximum volume loss was observed in the corpus medullare (dmax = .49) and posterior lobe gray matter regions, including bilateral lobules VIIB (dmax = .47), crus I/II (dmax = .39), VIIIA (dmax = .45), and VIIIB (dmax = .40). Earlier age at seizure onset ( η ρ max 2 = .05) and longer epilepsy duration ( η ρ max 2 = .06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE, with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls. SIGNIFICANCE: We provide robust evidence of deep cerebellar and posterior lobe subregional gray matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in nonmotor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellar subregional damage into neurobiological models of epilepsy.

GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response.

Ataxia due to an autosomal dominant intronic GAA repeat expansion in FGF14 [GAA-FGF14 ataxia, spinocerebellar ataxia 27B (SCA27B)] has recently been identified as one of the most common genetic late-onset ataxias. We here aimed to characterize its phenotypic profile, natural history progression, and 4-aminopyridine (4-AP) treatment response. We conducted a multi-modal cohort study of 50 GAA-FGF14 patients, comprising in-depth phenotyping, cross-sectional and longitudinal progression data (up to 7 years), MRI findings, serum neurofilament light (sNfL) levels, neuropathology, and 4-AP treatment response data, including a series of n-of-1 treatment studies. GAA-FGF14 ataxia consistently presented as late-onset [60.0 years (53.5-68.5), median (interquartile range)] pancerebellar syndrome, partly combined with afferent sensory deficits (55%) and dysautonomia (28%). Dysautonomia increased with duration while cognitive impairment remained infrequent, even in advanced stages. Cross-sectional and longitudinal assessments consistently indicated mild progression of ataxia [0.29 Scale for the Assessment and Rating of Ataxia (SARA) points/year], not exceeding a moderate disease severity even in advanced stages (maximum SARA score: 18 points). Functional impairment increased relatively slowly (unilateral mobility aids after 8 years in 50% of patients). Corresponding to slow progression and low extra-cerebellar involvement, sNfL was not increased relative to controls. Concurrent second diseases (including progressive supranuclear palsy neuropathology) represented major individual aggravators of disease severity, constituting important caveats for planning future GAA-FGF14 trials. A treatment response to 4-AP with relevance for everyday living was reported by 86% of treated patients. A series of three prospective n-of-1 treatment experiences with on/off design showed marked reduction in daily symptomatic time and symptom severity on 4-AP. Our study characterizes the phenotypic profile, natural history progression, and 4-AP treatment response of GAA-FGF14 ataxia. It paves the way towards large-scale natural history studies and 4-AP treatment trials in this newly discovered, possibly most frequent, and treatable late-onset ataxia.

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.

Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy.

Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy.

A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies.

AIMS: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. METHODS: Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. RESULTS: We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. CONCLUSIONS: These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

Event-based modeling in temporal lobe epilepsy demonstrates progressive atrophy from cross-sectional data.

OBJECTIVE: Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multicenter cross-sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) correlate with clinical features. METHODS: We extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1-weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA-Epilepsy consortium, comprising 804 people with MTLE-HS and 1625 healthy controls from 25 centers. Features with a moderate case-control effect size (Cohen d ≥ .5) were used to train an event-based model (EBM), which estimates a sequence of disease-specific biomarker changes from cross-sectional data and assigns a biomarker-based fine-grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance. RESULTS: In MTLE-HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10-16 ), age at onset (ρ = -.18, p = 9.82 × 10-7 ), and ASM resistance (area under the curve = .59, p = .043, Mann-Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE-HS with mild or nondetectable abnormality on T1W MRI. SIGNIFICANCE: From cross-sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE-HS subjects in other cohorts and help establish connections between imaging-based progression staging and clinical features.

GLINT: GlucoCEST in neoplastic tumors at 3 T-clinical results of GlucoCEST in gliomas.

OBJECTIVE: Clinical relevance of dynamic glucose enhanced (DGE) chemical exchange saturation transfer (CEST) imaging has mostly been demonstrated at ultra-high field (UHF) due to low effect size. Results of a cohort study at clinical field strength are shown herein. MATERIALS AND METHODS: Motion and field inhomogeneity corrected T1ρ-based DGE (DGE⍴) images were acquired before, during and after a D-glucose injection with 6.3 s temporal resolution to detect accumulation in the brain. Six glioma patients with clear blood-brain barrier (BBB) leakage, two glioma patients with suspected BBB leakage, and three glioma patients without BBB leakage were scanned at 3 T. RESULTS: In high-grade gliomas with BBB leakage, D-glucose uptake could be detected in the gadolinium (Gd) enhancing region as well as in the tumor necrosis with a maximum increase of ∆DGE⍴ around 0.25%, whereas unaffected white matter did not show any significant DGE⍴ increase. Glioma patients without Gd enhancement showed no detectable DGE⍴ effect within the tumor. CONCLUSION: First application of DGE⍴ in a patient cohort shows an association between BBB leakage and DGE signal irrespective of the tumor grade. This indicates that glucoCEST corresponds more to the disruptions of BBB with Gd uptake than to the molecular tumor profile or tumor grading.

What do we know about dynamic glucose-enhanced (DGE) MRI and how close is it to the clinics? Horizon 2020 GLINT consortium report.

Cancer is one of the most devastating diseases that the world is currently facing, accounting for 10 million deaths in 2020 (WHO). In the last two decades, advanced medical imaging has played an ever more important role in the early detection of the disease, as it increases the chances of survival and the potential for full recovery. To date, dynamic glucose-enhanced (DGE) MRI using glucose-based chemical exchange saturation transfer (glucoCEST) has demonstrated the sensitivity to detect both D-glucose and glucose analogs, such as 3-oxy-methyl-D-glucose (3OMG) uptake in tumors. As one of the recent international efforts aiming at pushing the boundaries of translation of the DGE MRI technique into clinical practice, a multidisciplinary team of eight partners came together to form the "glucoCEST Imaging of Neoplastic Tumors (GLINT)" consortium, funded by the Horizon 2020 European Commission. This paper summarizes the progress made to date both by these groups and others in increasing our knowledge of the underlying mechanisms related to this technique as well as translating it into clinical practice.

Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients.

OBJECTIVE: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). METHODS: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. RESULTS: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. INTERPRETATION: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251-263.

Natural History of Polymerase Gamma-Related Ataxia.

BACKGROUND: Mutations in the mitochondrial DNA polymerase gamma are causing a wide phenotypic spectrum including ataxia as one of the most common presentations. OBJECTIVE: The objective of this study was to determine the course of disease of polymerase gamma-related ataxia. METHODS: In a prospective natural history study, we assessed 24 adult ataxia patients with biallelic polymerase gamma mutations for (1) severity of cerebellar dysfunction using the Scale for the Assessment and Rating of Ataxia score, (2) presence of nonataxia signs using the Inventory of Non-Ataxia Symptoms, (3) gray- and white-matter changes in brain MRI, and (4) findings in nerve conduction studies. RESULTS: Assessment included follow-up visits up to 11.6 years. The Scale for the Assessment and Rating of Ataxia showed a mean annual increase of 1.02 ± 0.78 points/year. Disease progression was faster in patients with age at onset ≤ 30 years (1.5 Scale for the Assessment and Rating of Ataxia points/year) than with later onset (0.5 points/year); P = 0.008. The Inventory of Non-Ataxia Symptoms count increased by 0.30 ± 0.4 points/year. External ophthalmoplegia, brain stem oculomotor signs, areflexia, and sensory deficits were the most common nonataxic features. On MRI cerebellar atrophy was mild. T2 signal alterations affected mostly cerebellar white matter, middle cerebellar peduncles, thalamus, brain stem, and occipital and frontal white matter. Within 4 years, progression was primarily observed in the context of repeated epileptic seizures. Nerve conduction studies revealed axonal sensory peripheral neuropathy with mild motor nerve involvement. Exploratory sample size calculation implied 38 patients per arm as sufficient to detect a reduction of progression by 50% in hypothetical interventions within a 1-year trial. CONCLUSION: The results recommend the Scale for the Assessment and Rating of Ataxia as a primary outcome measure for future interventional trials in polymerase gamma-related ataxia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3.

BACKGROUND: Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease-related alterations, in particular, in the preataxic stage, in which clinical scales are lacking sensitivity. OBJECTIVE: The objective of this study was to quantify regional brain volumes and upper cervical spinal cord areas in spinocerebellar ataxia type 3 in vivo across the entire time course of the disease. METHODS: We applied a brain segmentation approach that included a lobular subsegmentation of the cerebellum to magnetic resonance images of 210 ataxic and 48 preataxic spinocerebellar ataxia type 3 mutation carriers and 63 healthy controls. In addition, cervical cord cross-sectional areas were determined at 2 levels. RESULTS: The metrics of cervical spinal cord segments C3 and C2, medulla oblongata, pons, and pallidum, and the cerebellar anterior lobe were reduced in preataxic mutation carriers compared with controls. Those of cervical spinal cord segments C2 and C3, medulla oblongata, pons, midbrain, cerebellar lobules crus II and X, cerebellar white matter, and pallidum were reduced in ataxic compared with nonataxic carriers. Of all metrics studied, pontine volume showed the steepest decline across the disease course. It covaried with ataxia severity, CAG repeat length, and age. The multivariate model derived from this analysis explained 46.33% of the variance of pontine volume. CONCLUSION: Regional brain and spinal cord tissue loss in spinocerebellar ataxia type 3 starts before ataxia onset. Pontine volume appears to be the most promising imaging biomarker candidate for interventional trials that aim at slowing the progression of spinocerebellar ataxia type 3. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA-Epilepsy study.

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analysed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182) and non-lesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fibre tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P < 0.001). Across 'all epilepsies' lower fractional anisotropy was observed in most fibre tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. There were also less robust increases in mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Individuals with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced reductions in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and increased mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of diffusion abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibres in a large multicentre study of epilepsy. Overall, patients with epilepsy showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding more detailed insights into pathological substrates that may explain cognitive and psychiatric co-morbidities and be used to guide biomarker studies of treatment outcomes and/or genetic research.

Technical limitations and pitfalls of diffusion-weighted imaging in intraoperative high-field MRI.

OBJECTIVE: Image quality in high-field intraoperative MRI (iMRI) is often influenced negatively by susceptibility artifacts. While routine sequences are rather robust, advanced imaging such as diffusion-weighted imaging (DWI) is very sensitive to susceptibility resulting in insufficient imaging data. This study aims to analyze intraoperatively acquired DWI to identify the main factors for susceptibility, to compare results with postoperative images and to identify technical aspects for improvement of intraoperative DWI. METHODS: 100 patients with intraaxial lesions operated in a high-field iMRI were analyzed retrospectively for the quality of intraoperative DWI in comparison to the postoperative scan. General quality of the MR scan, individual diffusion restrictions, artifacts, and their causes were analyzed. RESULTS: Inclusion criteria were met in 78 patients, 124 diffusion restrictions were included in the comparative analysis. PPV and NPV for the detection of DWI changes intraoperatively were 0.94 and 0.56, respectively (SEN 0.94; SPE 0.56). Image quality was rated significantly (p < 0.0001) worse intraoperatively compared to the postoperative MRI. The main reasons for reduced image quality intraoperatively were air (64%) and artificial material (e.g., compress) (38%) in the resection cavity, as well as positioning of patient's head outside the MR's isocenter 37%. Analysis of surgical approaches showed that frontal craniotomies have the highest risk of limited image quality (40%), whereat better results (15% limited image quality) were seen for all other approaches (p = 0.059). CONCLUSION: Intraoperative DWI showed reliable results in this analysis. However, image-quality was limited severely in many cases leading to uncertainty in the interpretation. Susceptibility-causing factors might be prevented in many cases, if the surgical team is aware of them. The most important factors are good filling of the resection cavity with irrigation fluid, not placing artificial materials in the resection cavity and adequate positioning of patient's head according to the MR isocenter.

DeepCEST 3T: Robust MRI parameter determination and uncertainty quantification with neural networks-application to CEST imaging of the human brain at 3T.

PURPOSE: Calculation of sophisticated MR contrasts often requires complex mathematical modeling. Data evaluation is computationally expensive, vulnerable to artifacts, and often sensitive to fit algorithm parameters. In this work, we investigate whether neural networks can provide not only fast model fitting results, but also a quality metric for the predicted values, so called uncertainty quantification, investigated here in the context of multi-pool Lorentzian fitting of CEST MRI spectra at 3T. METHODS: A deep feed-forward neural network including a probabilistic output layer allowing for uncertainty quantification was set up to take uncorrected CEST-spectra as input and predict 3T Lorentzian parameters of a 4-pool model (water, semisolid MT, amide CEST, NOE CEST), including the B0 inhomogeneity. Networks were trained on data from 3 subjects with and without data augmentation, and applied to untrained data from 1 additional subject and 1 brain tumor patient. Comparison to conventional Lorentzian fitting was performed on different perturbations of input data. RESULTS: The deepCEST 3T networks provided fast and accurate predictions of all Lorentzian parameters and were robust to input perturbations because of noise or B0 artifacts. The uncertainty quantification detected fluctuations in input data by increase of the uncertainty intervals. The method generalized to unseen brain tumor patient CEST data. CONCLUSIONS: The deepCEST 3T neural network provides fast and robust estimation of CEST parameters, enabling online reconstruction of sophisticated CEST contrast images without the typical computational cost. Moreover, the uncertainty quantification indicates if the predictions are trustworthy, enabling confident interpretation of contrast changes.

Association of dynamic susceptibility magnetic resonance imaging at initial tumor diagnosis with the prognosis of different molecular glioma subtypes.

PURPOSE: The updated 2016 CNS World Health Organization classification differentiates three main groups of diffuse glioma according to their molecular characteristics: astrocytic tumors with and without isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deleted oligodendrogliomas. The present study aimed to determine whether dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) is an independent prognostic marker within the molecular subgroups of diffuse glioma. METHODS: Fifty-six patients with treatment-naive gliomas and advanced preoperative MRI examination were assessed retrospectively. The mean and maximal normalized cerebral blood volume values from DSC-MRI within the tumors were measured. Optimal cutoff values for the 1-year progression-free survival (PFS) were defined, and Kaplan-Meier analyses were performed separately for the three glioma subgroups. RESULTS: IDH wild-type astrocytic tumors had a higher mean and maximal perfusion than IDH-mutant astrocytic tumors and oligodendrogliomas. Patients with IDH wild-type astrocytic tumors and a low mean or maximal perfusion had a significantly shorter PFS than patients of the same group with high perfusion (p = 0.0159/0.0112). Furthermore, they had a significantly higher risk for early progression (hazard ratio = 5.6/5.1). This finding was independent of the methylation status of O6-methylguanin-DNA-methyltransferase and variations of the therapy. Within the groups of IDH-mutant astrocytic tumors and oligodendrogliomas, the PFS of low and highly perfused tumors did not differ. CONCLUSION: High perfusion upon initial diagnosis is not compellingly associated with worse short-term prognosis within the different molecular subgroups of diffuse glioma. Particularly, the overall highly perfused group of IDH wild-type astrocytic tumors contains tumors with low perfusion but unfavorable prognosis.

Identification of tumor residuals in pituitary adenoma surgery with intraoperative MRI: do we need gadolinium?

OBJECTIVE: To evaluate the diagnostic accuracy of high-resolution T2w intraoperative magnetic resonance imaging (iMRI) for detecting pituitary adenoma remnants compared to contrast-enhanced T1-weighted images. METHODS: 42 patients underwent iMRI-guided resection of large pituitary macroadenomas and fulfilled the inclusion criteria for this retrospective analysis. Intraoperative and postoperative imaging evaluation of tumor residuals and localization were assessed by two experienced neuroradiologists in a blinded fashion. The diagnostic accuracy of T2w and contrast-enhanced T1w images were evaluated. RESULTS: The diagnostic accuracy for detecting tumor residuals of high-resolution T2w images showed highly significant association to contrast-enhanced T1w images (p < 0.0001). Furthermore, identification rate of tumor remnants in different compartments, e.g., cavernous sinus, was comparable. In total, coronal T2w images provided a diagnostic sensitivity of 97.7% and specificity of 100% compared to the gold standard of contrast-enhanced T1w images. The postoperatively expected extent of resection proved to be true in 97.6% according to MRI 3 months after resection. CONCLUSIONS: High-resolution T2w intraoperative MR images provide excellent diagnostic accuracy for detecting tumor remnants in macroadenoma surgery with highly significant association compared to T1w images with gadolinium. The routine-use and need of gadolinium in these patients should be questioned critically in each case in the future.