Citations

ABSTRACT Background and Objectives Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results Variant carriers ( n =147) and familial non-carriers ( n =113) did not differ in age (mean±SD, 25.9±3.2 years), sex (53% female), or number of visits (2.1±1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years ( b =-982.8mm 3 , SE=317.0, p= 0.0046, f 2 =0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines ( b =64.4mm 3 , SE=29.9, p= 0.035, f 2 =0.07). For MAPT and GRN , there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

BACKGROUND AND OBJECTIVES: Endoscopic transnasal surgery offers a minimally invasive alternative to transcranial approaches for accessing midline skull base lesions involving the petrous apex and petroclival region. However, lateral access, particularly behind the petrous internal carotid artery (ICA), remains limited. The contralateral transmaxillary (CTM) approach provides a more direct surgical trajectory, more parallel to the petrous ICA. Yet, lateral access through this approach can be restricted by anatomic barriers, including the pterygoid process and lateral buttress of the maxillary sinus. We aimed to evaluate the contralateral transmaxillary-transpterygoid (CTMP) approach, with and without the lateral buttress removal (CTMP-LBR), to determine whether these modifications could enhance surgical access to the petroclival region. METHODS: Ten sides from 5 formalin-fixed, latex-injected cadaveric specimens were dissected to compare CTM, CTMP, and CTMP-LBR approaches. Petrous bone drilling was directed posterolaterally behind the petrous ICA toward the region medial to the cochlea. In addition, 30 sides from computed tomography angiography scans were analyzed to obtain radiographic measurements for each approach. RESULTS: Compared with CTM, both CTMP and CTMP-LBR significantly increased access for retrocarotid petrous bone drilling ( P < .001) and yielded a wider surgical angle relative to midline ( P < .001), in both cadaveric and radiographic analyses. In dissections, 20% of sides required CTM only, 50% benefited from CTMP, and 30% required CTMP-LBR to achieve adequate lateral access. Radiographic analysis revealed that CTMP required a median of 4 mm of pterygoid drilling, whereas CTMP-LBR required 9 mm and enabled a trajectory parallel to the petrous ICA with only 11 mm of soft tissue displacement. Patients with smaller angles between the petrous ICA and the horizontal plane were significantly more likely to benefit from CTMP over CTM ( P = .005). CONCLUSION: Modification of the CTM approach with pterygoid drilling and optional LBR improves retrocarotid access. Preoperative evaluation of the petrous ICA angle may help optimize patient-specific planning in endoscopic petroclival surgery.

Background. The adoption of technical variant grafts has expanded the donor pool for pediatric liver transplantation, but it also poses a risk of portal vein thrombosis (PVT). This study evaluated risk and prognostic factors of PVT in children undergoing liver transplantation with technical variant grafts. Methods. A total of 3137 pediatric patients from 19 centers were included: 470 received split/reduced deceased donor grafts and 2667 received living donor grafts. Multivariable logistic regression was used to identify risk factors, whereas time-dependent Cox models were used to assess the impact on survival. Results. PVT occurred in 102 patients (3.3%) and was associated with increased mortality (adjusted hazard ratio, 2.86; 95% confidence interval [CI], 1.13-7.25; P = 0.027) and graft loss (adjusted hazard ratio, 9.97; 95% CI, 4.90-20.3; P < 0.001). Risk factors included younger age, lower weight, higher Pediatric End-Stage Liver Disease score, longer cold ischemia and operation times, higher graft-to-recipient weight ratio, increased red blood cell transfusions, and biliary atresia. After adjusting for center, lower weight (odds ratio, 0.84 per kg; 95% CI, 0.71-1.00; P = 0.047) and biliary atresia (odds ratio, 2.34; 95% CI, 1.10-5.00; P = 0.027) remained predictors. Five-year patient (88.4% versus 93.1%) and graft survival (82.7% versus 96.3%) were significantly inferior in patients with PVT. Conclusions. Low-weight children with biliary atresia constituted a high-risk group, highlighting the necessity for early detection and management.

Abstract Background Mono-allelic Dehydrodolichyl Diphosphate Synthase ( DHDDS) variants are associated with juvenile Parkinsonism, developmental delay and seizures. Symptoms are progressive, and various mechanisms, such as defective glycosylation, lysosomal dysfunction and cholesterol accumulation have been hypothesized to underlie disease symptoms. There is no treatment for DHDDS-related disease. Methods Patient-derived cortical forebrain organoids were created to elucidate disease mechanisms and evaluate potential treatments. In these neuronal models, glycosylation, lipidomics, proteomics, cholesterol/ganglioside accumulation, mitochondrial function and electrophysiological activity were assessed. Finally, we investigated the effects of nicotinamide mononucleotide (NMN), identified through a yeast-based drug screen, in neuronal cell models and in six patients in an off-label, N-of-1, observational series. Results DHDDS-patient derived organoids showed visual signs of degeneration after four months of culturing. This was accompanied by significant cholesterol accumulation in astrocytes, decreased mitochondrial respiration and loss of deep-layer neurons. In addition, we identified glycosylation abnormalities, showing for the first time that glycosylation in human tissue is affected by monoallelic DHDDS variants. Proteomic analysis revealed altered protein expression of proteins involved in lipid metabolism, cytoskeletal organization and neuronal development. We found that oral Nicotinamide Mononucleotide supplementation led to significant improvement in mitochondrial respiration and electrophysiological parameters in organoids, concurring with clinical improvements in all of the treated patients, particularly regarding their ataxia and tremor. Conclusion Our findings reveal a progressive phenotype in DHDDS-patient-derived brain organoids, with mitochondrial dysfunction and astrocyte-specific metabolic alterations contributing to disease pathology. Notably, NMN treatment led to clinical improvements in patients with heterozygous DHDDS variants, highlighting its potential as a therapeutic strategy.

Abstract Oncogenic BRAF alterations occur in a subset of diffuse gliomas across WHO grades and are increasingly identified through modern molecular diagnostics. In addition to standard glioma therapies, targeted treatments are available for patients with BRAF-altered glioma supported by variable evidence spanning randomized trials, single-arm studies, and real-world evidence. This joint consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO) synthesizes current knowledge on the diagnosis and management of BRAF-altered gliomas across age groups, tumor grades, and lines of therapy. Particular emphasis is placed on expert consensus in clinical scenarios where high-quality trial evidence remains limited. The review addresses rationale testing for BRAF alterations, selection, and monitoring of targeted therapies, management of treatment-related toxicities, approaches to resistance, and priorities for future research. It aims to provide practical, evidence-based guidance for clinicians while highlighting gaps to inform prospective studies.

Importance Stool metabolites influencing gut motility and sensation may contribute to fecal incontinence (FI). Objective The objective of this study was to test whether FI is associated with higher levels of butyrate and Clostridiales taxa in stool. Study Design Stool metabolites and microbiota were compared between 96 women with FI and 42 controls. FI frequency and subtype (urgency vs insensible) were measured using a 14-day bowel diary, St. Mark’s score, and the Accidental Bowel Leakage questionnaire. Metabolite analysis included targeted analysis (8 short-chain fatty acids including butyrate, 17 bile acids, and 8 tryptophan derivatives) and untargeted analysis. Stool microbiota were characterized using 16S rRNA gene sequencing. Multivariable and exploratory multiomics factor analysis were performed with statistical significance defined as false discovery rate (FDR) ≤0.10. Results The FI group had a higher proportion of Bristol stool types 2 and 6 than controls ( P = 0.005). The mean number of leaks for the FI group was 1.7 ± 1.7 per day, 38% had urgency FI, and 39% had insensible FI. There was no significant difference between groups in butyrate levels and Clostridiales taxa. Multiomics analysis identified glycerolipids (monoacylglycerols and diacylglycerols) associated with FI (FDR = 0.08). In addition, insensible FI was associated with glycerolipids, long-chain saturated and monounsaturated fatty acids, phospholipids, and dipeptides (FDR = 0.08–0.09). The top weighted microbiota associated with these metabolites were Lachnospiraceae and Ruminococcaceae; however, these taxa were not directly associated with FI. Conclusion Butyrate and Clostridiales were not associated with FI. Novel stool metabolite signatures were identified, suggesting new biological pathways and potential therapeutic targets for FI.

Abstract Objective This study was undertaken to evaluate the safety and effectiveness of responsive thalamic stimulation as adjunctive therapy for drug‐resistant idiopathic generalized epilepsy (IGE) with generalized tonic–clonic seizures (GTCSs). Methods NAUTILUS is a prospective, multicenter, single‐blind, randomized sham‐controlled pivotal trial. Patients were ≥12 years of age with drug‐resistant IGE and ≥2 GTCSs over a 3‐month baseline. Bilateral depth leads were targeted to the centromedian thalamus. One month later, patients were randomized to Active (responsive stimulation, n = 44) or Sham (no stimulation, n = 43). The effectiveness evaluation period (EEP) began 3 months postimplant through 1 year. After a second GTCS in the EEP, patients transitioned to open‐label active stimulation. The primary safety endpoint was the serious adverse device‐related event (SADE) rate at 84 days postimplant. The primary effectiveness endpoint was time‐to‐second‐GTCS during the EEP. Additional endpoints included median percent change in days with any generalized seizure, GTCS frequency, and responder rate (RR). Results Eighty‐seven patients were implanted across 23 US centers. The SADE rate was significantly below the performance goal (6.9%, p < .0001), with no adverse effects on cognition, mood, or sleep. The prespecified primary effectiveness endpoint was not significant. However, a post hoc mixed‐effects model considering all EEP days demonstrated greater GTCS reduction in the originally randomized Active group (61%) compared to patients originally randomized to Sham (49%, p = .030). Eighteen‐month outcomes included 76.8% median GTCS reduction, 62.5% RR, 40% GTCS‐free at that timepoint, and 77.8% median reduction in days with any generalized seizure. More than 90% of patients and 86% of physicians reported improvement on Global Impression of Change scales. Significance NAUTILUS is the first randomized controlled neuromodulation trial in IGE. Responsive thalamic stimulation provided a clinically meaningful and durable reduction in seizures with an acceptable safety profile, offering a much‐needed option for drug‐resistant IGE.