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ObjectiveParoxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.MethodsConfounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses.ResultsOur analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations.SignificanceOur results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.

This is a single arm, open label perioperative trial to assess the feasibility, pharmacokinetics and pharmacodynamics of treatment with safusidenib following biopsy, and prior to surgical resection in patients with IDH1 mutated glioma who have not received radiation therapy or chemotherapy. Fifteen participants will receive treatment in two parts. First, biopsy followed by one cycle (28 days) of safusidenib, an orally available, small molecular inhibitor of mutated IDH1, then maximal safe resection of the tumor (Part A). Second, after recovery from surgery, safusidenib until disease progression or unacceptable toxicity (Part B). This research will enable objective measurement of biological activity of safusidenib in patients with IDH1 mutated glioma. Anti-tumor activity will be assessed by progression free survival and time to next intervention. Clinical Trial Registration:NCT05577416 (ClinicalTrials.gov) Plain Language Summary Adult low-grade gliomas (aLGG) are primary brain cancers, defined by mutations in IDH1 or IDH2. When the IDH gene becomes abnormal (mutated), production of a metabolite that causes cancer cells to grow is increased. These tumors grow slowly but invade the normal functioning brain, making them nearly impossible to cure. The current standard of care treatment includes surgery, followed by radiation therapy and chemotherapy, the timing of which depends on the risk of cancer regrowth. Some patients may be suitable for monitoring with MRI scans alone, however recurrences will inevitably occur. Recently developed targeted mutant IDH inhibitors for aLGG patients may be beneficial both at diagnosis and recurrence. Notably, early treatment prior to radiation therapy and chemotherapy delays growth of aLGG and the need for subsequent radiation therapy and chemotherapy. Nevertheless, most patients will eventually suffer further tumor growth and the optimal timing and sequencing of these therapies remains an area of active research. This research investigates the mutant IDH1 inhibitor safusidenib. The researchers are conducting an innovative clinical trial where patients with aLGG, who have not received radiation therapy or chemotherapy, are treated with safusidenib following a biopsy and prior to surgical removal of their tumor. In this study they investigate whether this trial design is safe and feasible, and how safusidenib works; with the goal to better understand the optimal use of IDH inhibitors for patients with aLGG. Article highlights Introduction Background & rationale Adult low-grade gliomas (aLGGs) are defined by IDH1/2 mutations which lead to accumulation of 2-HG, an oncometabolite affecting tumorigenesis. 2-HG inhibits α-KG-dependent enzymes, affecting epigenetic regulation, collagen synthesis and cell signaling, hindering progenitor cell differentiation and promoting cancer. In addition, 2-HG promotes angiogenesis, an immunosuppressive tumor microenvironment and oxidative damage. aLGGs grow slowly, diffusely infiltrating the brain and are difficult to cure. Emergence of targeted mutant IDH inhibitors has shifted focus toward identifying prognostic markers and future combination studies. Current treatment of aLGG Treatment includes maximal safe surgical resection, radiation therapy and sequential chemotherapy. Early, extensive surgery improves overall survival. Active surveillance with MRI is suitable for some patients to delay side effects. Mutant IDH inhibitors for glioma Multiple mutant IDH inhibitors have shown promise in glioma. Vorasidenib (IDH1/2 inhibitor) improved progression-free survival in the INDIGO Phase III trial. Safusidenib (DS-1001b, AB-218) is an orally available small molecule inhibitor of mutant IDH1 with demonstrated brain penetration and clinical activity in Phase I trials. Perioperative trials There have been few therapeutic advances in glioma due to challenges in measuring drug penetration and pharmacodynamic (PD) evaluation. Perioperative trials, including biopsy to obtain pre-treatment tissue, are feasible and offer a means to examine the direct effects of new drugs. These studies allow evaluation of drug pharmacokinetics (PK) and PD outcomes. Objectives Hypothesis: Treatment with safusidenib following biopsy and prior to resection in newly diagnosed IDH1 mutated glioma is feasible. Estimate: >60% of screened patients completing planned investigations and procedures. Primary objective: Assess feasibility and acceptability of a perioperative study in IDH1 mutated aLGG patients. Secondary end points: Determine safusidenib toxicity, safety of two-stage surgery and biological activity by changes in 2-HG levels. Methods Participants, interventions, & outcomes Key inclusion: Adults ≥18 years with aLGG diagnosis not requiring urgent resection. Key exclusion: prior chemotherapy/radiation, cerebellar/brainstem tumors. Procedures: Open biopsy, oral safusidenib, second-stage resection, continued safusidenib post-resection. Data collection: tumor tissue, CSF and blood samples processed per protocols. PK/PD relationships: Evaluated by blood, tumor and CSF samples. Biological activity: Assessed by changes in 2-HG levels and IDH1 ctDNA. Data collection, management, & analysis Tumor tissue, CSF and blood samples collected for research. Safusidenib PK will be investigated to evaluate PK/PD relationships. Translational end points include paired whole-genome transcriptome profiling, single nuclei RNA sequencing, bulk metabolomics and DNA methylation. Spatial transcriptomics using in situ digital sequencing and spatial metabolomics on sections pre- and post-safusidenib treatment. Descriptive statistics for demographics, safety, PK, PD, efficacy and biomarker data by dose and time. Monitoring Toxicity: Monitored by adverse events, clinical tests and vital signs. Safety of surgery: 30-day morbidity and mortality recorded post-biopsy and resection. Radiological response: Determined by MRI changes and LGG-RANO criteria. Progression-free survival and time to treatment failure: Calculated from biopsy date. Conclusion Perioperative studies in aLGG offer a unique opportunity to study drug effects and are feasible, ethical and acceptable to patients. [ABSTRACT FROM AUTHOR]

Exome sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other neurodevelopmental diseases for which rare, often de novo, mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene. By pooling genetic findings across multiple studies, we have identified six individuals with severe developmental delay (6/6), refractory seizures (5/6), and similar dysmorphic features (3/6), each harboring a de novo mutation in PPP3CA. PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin encodes a calcium- and calmodulin-dependent serine/threonine protein phosphatase that plays a role in a wide range of biological processes, including being a key regulator of synaptic vesicle recycling at nerve terminals. Five individuals with de novo PPP3CA mutations were identified among 4,760 trio probands with neurodevelopmental diseases; this is highly unlikely to occur by chance (p = 1.2 × 10-8) given the size and mutability of the gene. Additionally, a sixth individual with a de novo mutation in PPP3CA was connected to this study through GeneMatcher. Based on these findings, we securely implicate PPP3CA in early-onset refractory epilepsy and further support the emerging role for synaptic dysregulation in epilepsy.

Objective: Betahistine is frequently used in the pharmacotherapy for Menière's Disease (MD). Little is known about its mode of action and prescribed dosages vary. While betahistine had an increasing effect on cochlear microcirculation in earlier studies, low dose betahistine of 0.01 mg/kg bw or less was not able to effect this. Selegiline inhibits monoaminooxidase B and therefore potentially the breakdown of betahistine. The goal of this study was to examine whether the addition of selegiline to low dose betahistine leads to increased cochlear blood flow. Methods: Twelve Dunkin-Hartley guinea pigs were anesthetized, the cochlea was exposed and a window opened to the stria vascularis. Blood plasma was visualized by injecting fluoresceinisothiocyanate-dextrane and vessel diameter and erythrocyte velocity were evaluated over 20 minutes. One group received low dose betahistine (0.01 mg/kg bw) and selegiline (1 mg/kg bw) i.v. while the other group received only selegiline (1 mg/kg bw) and saline (0.9% NaCl) as placebo i.v. Results: Cochlear microcirculation increased significantly (P <.001) in guinea pigs treated with low dose betahistine combined with selegiline by up to 58.3 ± 38.7% above baseline over a period of up to 11 minutes. In one guinea pig, the increase was 104.6%. Treatment with Selegiline alone did not affect microcirculation significantly. Conclusions: Low dose betahistine increased cochlear microcirculation significantly when combined with selegiline. This should be investigated in further studies regarding dose-effect relation in comparison to betahistine alone. Side effects, in particular regarding circulation, should be considered carefully in view of the clinical applicability of a combination therapy in patients with MD. [ABSTRACT FROM AUTHOR]