OBJECTIVETo determine the genetic basis of bottom-of-sulcus dysplasia (BOSD), which is a highly focal and epileptogenic cortical malformation in which the imaging, electrophysiologic, and pathologic ...abnormalities are maximal at the bottom of sulcus, tapering to a normal gyral crown.
METHODSTargeted panel deep sequencing (>500×) was performed on paired blood and brain-derived genomic DNA from 20 operated patients with drug-resistant focal epilepsy and BOSD. Histopathology was assessed using immunohistochemistry.
RESULTSBrain-specific pathogenic somatic variants were found in 6 patients and heterozygous pathogenic germline variants were found in 2. Somatic variants were identified in MTOR and germline variants were identified in DEPDC5 and NPRL3. Two patients with somatic MTOR variants showed a mutation gradient, with higher mutation load at the bottom of sulcus compared to the gyral crown. Immunohistochemistry revealed an abundance of dysmorphic neurons and balloon cells in the bottom of sulcus but not in the gyral crown or adjacent gyri.
CONCLUSIONSBOSD is associated with mTOR pathway dysregulation and shares common genetic etiologies and pathogenic mechanisms with other forms of focal and hemispheric cortical dysplasia, suggesting these disorders are on a genetic continuum.
Despite the available evidence regarding effectiveness of stroke telerehabilitation, there has been little focus on factors influencing its delivery or translation from the research setting into ...practice. There are complex challenges to embedding telerehabilitation into stroke services and generating transferable knowledge about scaling up and routinising this service model. This review aimed to explore factors influencing the delivery of stroke telerehabilitation interventions, including platforms, technical requirements, training, support, access, cost, usability and acceptability.
MEDLINE, EMBASE, CINAHL, Web of Science and Cochrane Library and Central Registry of Clinical Trials were searched to identify full-text articles of randomised controlled trials (RCTs) and protocols for RCTs published since a Cochrane review on stroke telerehabilitation services. A narrative synthesis was conducted, providing a comprehensive description of the factors influencing stroke telerehabilitation intervention delivery.
Thirty-one studies and ten protocols of ongoing studies were included. Interventions were categorised as synchronous telerehabilitation (n = 9), asynchronous telerehabilitation (n = 11) and tele-support (n = 11). Telephone and videoconference were the most frequently used modes of delivery. Usability and acceptability with telerehabilitation were high across all platforms, although access issues and technical challenges may be potential barriers to the use of telerehabilitation in service delivery. Costs of intervention delivery and training requirements were poorly reported.
This review synthesises the evidence relating to factors that may influence stroke telerehabilitation intervention delivery at a crucial timepoint given the rapid deployment of telerehabilitation in response to the COVID-19 pandemic. It recommends strategies, such as ensuring adequate training and technical infrastructure, shared learning and consistent reporting of cost and usability and acceptability outcomes, to overcome challenges in embedding and routinising this service model and priorities for research in this area.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Type II focal cortical dysplasia (FCD) is a neuropathological entity characterised by cortical dyslamination with the presence of dysmorphic neurons only (FCDIIA) or the presence of both dysmorphic ...neurons and balloon cells (FCDIIB). The year 2021 marks the 50th anniversary of the recognition of FCD as a cause of drug resistant epilepsy, and it is now the most common reason for epilepsy surgery. The causes of FCD remained unknown until relatively recently. The study of resected human FCD tissue using novel genomic technologies has led to remarkable advances in understanding the genetic basis of FCD. Mechanistic parallels have emerged between these non-neoplastic lesions and neoplastic disorders of cell growth and differentiation, especially through perturbations of the mammalian target of rapamycin (mTOR) signalling pathway. This narrative review presents the advances through which the aetiology of FCDII has been elucidated in chronological order, from recognition of an association between FCD and the mTOR pathway to the identification of somatic mosaicism within FCD tissue. We discuss the role of a two-hit mechanism, highlight current challenges and future directions in detecting somatic mosaicism in brain and discuss how knowledge of FCD may inform novel precision treatments of these focal epileptogenic malformations of human cortical development.
Since the 1993 White Paper on Growth, Competitiveness and Employment, the Commission has emphasised the importance of trans-European networks (TENs) for the physical completion of the single market. ...Despite the 2004 and 2013 revisions to the TEN-T regulation, redefining and expanding the multimodal network, many projects remain unfinished. This article explores the Commission's enduring role in EU policy coordination from the perspective of hybrid governance, focusing on the mediating role of high-level 'European Coordinators', the use of stakeholders forums, recourse to policy evaluation, and the development of new financial instruments. Drawing on recent audit and evaluations work by the EU institutions, it explores reconfigurations of implementing actors, and engages with notions from the literature on experimentalist governance, including networks, informalism and deliberation. The analysis suggests that the Commission demonstrates resilience as a coordination body in its commitment to 'physically complete' the single market, while recognising limitations to its coordination capacity.
Although the mechanism of Aβ action in the pathogenesis of Alzheimer's disease (AD) has remained elusive, it is known to increase the expression of the antagonist of canonical wnt signalling, ...Dickkopf-1 (Dkk1), whereas the silencing of Dkk1 blocks Aβ neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Aβ/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Aβ toxicity and DKK1 upregulation and, conversely, Aβ increased intracellular clusterin and decreased clusterin protein secretion, resulting in the p53-dependent induction of DKK1. To further elucidate how the clusterin-dependent induction of Dkk1 by Aβ mediates neurotoxicity, we measured the effects of Aβ and Dkk1 protein on whole-genome expression in primary neurons, finding a common pathway suggestive of activation of wnt-planar cell polarity (PCP)-c-Jun N-terminal kinase (JNK) signalling leading to the induction of genes including EGR1 (early growth response-1), NAB2 (Ngfi-A-binding protein-2) and KLF10 (Krüppel-like factor-10) that, when individually silenced, protected against Aβ neurotoxicity and/or tau phosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Aβ-induced pathway and resulted in age-dependent increases in tau phosphorylation in hippocampus and cognitive impairment. Furthermore, we show that this Dkk1/wnt-PCP-JNK pathway is active in an Aβ-based mouse model of AD and in AD brain, but not in a tau-based mouse model or in frontotemporal dementia brain. Thus, we have identified a pathway whereby Aβ induces a clusterin/p53/Dkk1/wnt-PCP-JNK pathway, which drives the upregulation of several genes that mediate the development of AD-like neuropathologies, thereby providing new mechanistic insights into the action of Aβ in neurodegenerative diseases.
Bottom-of-sulcus dysplasia (BOSD) is increasingly recognized as a cause of drug-resistant, surgically-remediable, focal epilepsy, often in seemingly MRI-negative patients. We describe the clinical ...manifestations, morphological features, localization patterns and genetics of BOSD, with the aims of improving management and understanding pathogenesis. We studied 85 patients with BOSD diagnosed between 2005-2022. Presenting seizure and EEG characteristics, clinical course, genetic findings and treatment response were obtained from medical records. MRI (3 T) and 18F-FDG-PET scans were reviewed systematically for BOSD morphology and metabolism. Histopathological analysis and tissue genetic testing were performed in 64 operated patients. BOSD locations were transposed to common imaging space to study anatomical location, functional network localization and relationship to normal MTOR gene expression. All patients presented with stereotyped focal seizures with rapidly escalating frequency, prompting hospitalization in 48%. Despite 42% patients having seizure remissions, usually with sodium channel blocking medications, most eventually became drug-resistant and underwent surgery (86% seizure-free). Prior developmental delay was uncommon but intellectual, language and executive dysfunction were present in 24%, 48% and 29% when assessed preoperatively, low intellect being associated with greater epilepsy duration. BOSDs were missed on initial MRI in 68%, being ultimately recognized following repeat MRI, 18F-FDG-PET or image postprocessing. MRI features were grey-white junction blurring (100%), cortical thickening (91%), transmantle band (62%), increased cortical T1 signal (46%) and increased subcortical FLAIR signal (26%). BOSD hypometabolism was present on 18F-FDG-PET in 99%. Additional areas of cortical malformation or grey matter heterotopia were present in eight patients. BOSDs predominated in frontal and pericentral cortex and related functional networks, mostly sparing temporal and occipital cortex, and limbic and visual networks. Genetic testing yielded pathogenic mTOR pathway variants in 63% patients, including somatic MTOR variants in 47% operated patients and germline DEPDC5 or NPRL3 variants in 73% patients with familial focal epilepsy. BOSDs tended to occur in regions where the healthy brain normally shows lower MTOR expression, suggesting these regions may be more vulnerable to upregulation of MTOR activity. Consistent with the existing literature, these results highlight (i) clinical features raising suspicion of BOSD; (ii) the role of somatic and germline mTOR pathway variants in patients with sporadic and familial focal epilepsy associated with BOSD; and (iii) the role of 18F-FDG-PET alongside high-field MRI in detecting subtle BOSD. The anatomical and functional distribution of BOSDs likely explain their seizure, EEG and cognitive manifestations and may relate to relative MTOR expression.
Friedreich ataxia (FRDA) is due to a triplet repeat expansion in
FXN
, resulting in deficiency of the mitochondrial protein frataxin. Resveratrol is a naturally occurring polyphenol, identified to ...increase frataxin expression in cellular and mouse models of FRDA and has anti-oxidant properties. This open-label, non-randomized trial evaluated the effect of two different doses of resveratrol on peripheral blood mononuclear cell (PBMC) frataxin levels over a 12-week period in individuals with FRDA. Secondary outcome measures included PMBC
FXN
mRNA, oxidative stress markers, and clinical measures of disease severity. Safety and tolerability were studied. Twenty-four participants completed the study; 12 received low-dose resveratrol (1 g daily) and 12 high-dose resveratrol (5 g daily). PBMC frataxin levels did not change in either dosage group low-dose group change: 0.08 pg/μg protein (95 % CI −0.05, 0.21,
p
= 0.21); high-dose group change: 0.03 pg/μg protein (95 % CI −0.10, 0.15,
p
= 0.62). Improvement in neurologic function was evident in the high-dose group change in Friedreich Ataxia Rating Scale −3.4 points, 95 % CI (−6.6, −0.3),
p
= 0.036, but not the low-dose group. Significant improvements in audiologic and speech measures, and in the oxidative stress marker plasma F
2
-isoprostane were demonstrated in the high-dose group only. There were no improvements in cardiac measures or patient-reported outcome measures. No serious adverse events were recorded. Gastrointestinal side-effects were a common, dose-related adverse event. This open-label study shows no effect of resveratrol on frataxin levels in FRDA, but suggests that independent positive clinical and biologic effects of high-dose resveratrol may exist. Further assessment of efficacy is warranted in a randomized placebo-controlled trial.
To describe a child meeting diagnostic criteria for tuberous sclerosis complex (TSC) carrying a pathogenic somatic variant in
, but no pathogenic variants in the 2 known TSC genes,
or
.
We present ...the clinical and imaging findings in a child presenting with drug-resistant focal seizures and multiple cortical tubers, a subependymal giant cell astrocytoma and multiple subependymal nodules in 1 cerebral hemisphere. Targeted panel sequencing and exome sequencing were performed on genomic DNA derived from blood and resected tuber tissue.
The child satisfied clinical diagnostic criteria for TSC, having 3 major features, only 2 of which are required for diagnosis. Genetic testing did not identify pathogenic variants or copy number variations in
or
but identified a pathogenic somatic
variant (NM_005614.4:c.104_105delACinsTA p.Tyr35Leu) in the cortical tuber.
RHEB is a partner of the TSC1/2 complex in the mechanistic target of rapamycin pathway. Somatic variants in
are associated with focal cortical dysplasia and hemimegalencephaly. We propose that variants in
may explain some of the genetically undiagnosed TSC cases and may be the third gene for TSC, or
.
Pathogenic variants in the gene encoding the small GTPase Ras analogue in Brain 39b (RAB39B) are associated with early-onset parkinsonism. In this study we investigated the expression and ...localization of RAB39B (RNA and protein) in mouse brain tissue to gain a better understanding of its normal physiological function(s) and role in disease.We developed novel resources, including monoclonal antibodies directed against RAB39B and mice with Rab39b knockout, and performed real-time PCR and western blot analysis on whole brain lysates. To determine the spatial localization of Rab39b RNA and protein, we performed in-situ hybridization and immunohistochemistry on fresh frozen and fixed brain tissue. Our results show that RAB39B is localized throughout the cortex, hippocampus and substantia nigra of mice throughout postnatal life. We found high levels of RAB39B within MAP2 positive cortical and hippocampal neurons, and TH positive dopaminergic neurons in the substantia nigra pars compacta.Our studies support and extend current knowledge of the localization of RAB39B. We validate RAB39B as a neuron-enriched protein and demonstrate that it is present throughout the mouse cortex and hippocampus. Further, we observe high levels in the substantia nigra pars compacta, the brain region most affected in Parkinson's disease pathology. The distribution of Rab39b is consistent with human disease associations with parkinsonism and cognitive impairment. We also describe and validate novel resources, including monoclonal antibodies directed against RAB39B and mice with Rab39b knockout, both of which are valuable tools for future studies of the molecular function of RAB39B.
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