VGLL-fusions define a new class of intraparenchymal CNS schwannoma

Background: Intracerebral schwannomas are rare tumors resembling their peripheral nerve sheath counterparts but localized in the CNS. They are not classified as a separate tumor type in the 2021 WHO classification. This study aimed to compile and characterize these rare neoplasms morphologically and molecularly. // Methods: We analyzed 20 tumor samples by histology, RNA Next-Generation Sequencing, DNA-methylation profiling, copy number analyses, and single nucleus RNA sequencing (snRNA-seq). Clinical data, including age, sex, and disease progression, were collected. MRI series were included when available. // Results: All cases with tissue available for histology review (n=13) were morphologically consistent with intracerebral schwannoma, but differed in their extent of GFAP staining. All (n=20) shared DNA-methylation profiles distinct from other CNS tumors, as well as from VGLL-altered peripheral nerve sheath tumors. Most cases (n=14/17) harbored fusions of either VGLL3 or VGLL1 (CHD7::VGLL3 (n=9/17) and EWSR1::VGLL1 (n=5/17)). In two cases the presence of a VGLL3 fusion was also confirmed by CNA analyses (n=2/17). MRI (n=4) showed well-defined, nodular tumors with strong, homogeneous enhancement and no diffusion restriction. Tumors were located throughout the neuroaxis [supratentorial (n=15), infratentorial (n=4), and spinal (n=1)]. snRNA-seq of a VGLL1-fused tumor indicated VGLL1 upregulation in 28.6% of tumor cells (n=1). During median follow-up of 1.8 years (range 3 months-9 years), none of the tumors recurred (n=10). // Conclusions: We identify and define a new benign tumor class, designated VGLL-altered intraparenchymal CNS schwannomas. These tumors feature VGLL alterations and a specific DNA-methylation profile, with schwannoma-like histopathology and CNS localization, akin to previously classified intracerebral schwannomas

Suicidal ideation in a European Huntington's disease population

BACKGROUND: Previous studies indicate increased prevalences of suicidal ideation, suicide attempts, and completed suicide in Huntington's disease (HD) compared with the general population. This study investigates correlates and predictors of suicidal ideation in HD. METHODS: The study cohort consisted of 2106 HD mutation carriers, all participating in the REGISTRY study of the European Huntington's Disease Network. Of the 1937 participants without suicidal ideation at baseline, 945 had one or more follow-up measurements. Participants were assessed for suicidal ideation by the behavioural subscale of the Unified Huntington's Disease Rating Scale (UHDRS). Correlates of suicidal ideation were analyzed using logistic regression analysis and predictors were analyzed using Cox regression analysis. RESULTS: At baseline, 169 (8.0%) mutation carriers endorsed suicidal ideation. Disease duration (odds ratio [OR]=0.96; 95% confidence interval [CI]: 0.9-1.0), anxiety (OR=2.14; 95%CI: 1.4-3.3), aggression (OR=2.41; 95%CI: 1.5-3.8), a previous suicide attempt (OR=3.95; 95%CI: 2.4-6.6), and a depressed mood (OR=13.71; 95%CI: 6.7-28.0) were independently correlated to suicidal ideation at baseline. The 4-year cumulative incidence of suicidal ideation was 9.9%. Longitudinally, the presence of a depressed mood (hazard ratio [HR]=2.05; 95%CI: 1.1-4.0) and use of benzodiazepines (HR=2.44; 95%CI: 1.2-5.0) at baseline were independent predictors of incident suicidal ideation, whereas a previous suicide attempt was not predictive. LIMITATIONS: As suicidal ideation was assessed by only one item, and participants were a selection of all HD mutation carriers, the prevalence of suicidal ideation was likely underestimated. CONCLUSIONS: Suicidal ideation in HD frequently occurs. Assessment of suicidal ideation is a priority in mutation carriers with a depressed mood and in those using benzodiazepines