Primary cilia control translation and the cell cycle in medulloblastoma.

The primary cilium, a signaling organelle projecting from the surface of a cell, controls cellular physiology and behavior. The presence or absence of primary cilia is a distinctive feature of a given tumor type; however, whether and how the primary cilium contributes to tumorigenesis are unknown for most tumors. Medulloblastoma (MB) is a common pediatric brain cancer comprising four groups: SHH, WNT, group 3 (G3), and group 4 (G4). From 111 cases of MB, we show that primary cilia are abundant in SHH and WNT MBs but rare in G3 and G4 MBs. Using WNT and G3 MB mouse models, we show that primary cilia promote WNT MB by facilitating translation of mRNA encoding ß-catenin, a major oncoprotein driving WNT MB, whereas cilium loss promotes G3 MB by disrupting cell cycle control and destabilizing the genome. Our findings reveal tumor type-specific ciliary functions and underlying molecular mechanisms. Moreover, we expand the function of primary cilia to translation control and reveal a molecular mechanism by which cilia regulate cell cycle progression, thereby providing new frameworks for studying cilium function in normal and pathologic conditions.

Predicting functional impairments with lesion-derived disconnectome mapping: Validation in stroke patients with motor deficits.

Focal structural damage to white matter tracts can result in functional deficits in stroke patients. Traditional voxel-based lesion-symptom mapping is commonly used to localize brain structures linked to neurological deficits. Emerging evidence suggests that the impact of structural focal damage may extend beyond immediate lesion sites. In this study, we present a disconnectome mapping approach based on support vector regression (SVR) to identify brain structures and white matter pathways associated with functional deficits in stroke patients. For clinical validation, we utilized imaging data from 340 stroke patients exhibiting motor deficits. A disconnectome map was initially derived from lesions for each patient. Bootstrap sampling was then employed to balance the sample size between a minority group of patients exhibiting right or left motor deficits and those without deficits. Subsequently, SVR analysis was used to identify voxels associated with motor deficits (p < .005). Our disconnectome-based analysis significantly outperformed alternative lesion-symptom approaches in identifying major white matter pathways within the corticospinal tracts associated with upper-lower limb motor deficits. Bootstrapping significantly increased the sensitivity (80%-87%) for identifying patients with motor deficits, with a minimum lesion size of 32 and 235 mm3 for the right and left motor deficit, respectively. Overall, the lesion-based methods achieved lower sensitivities compared with those based on disconnection maps. The primary contribution of our approach lies in introducing a bootstrapped disconnectome-based mapping approach to identify lesion-derived white matter disconnections associated with functional deficits, particularly efficient in handling imbalanced data.

Screening for Cognitive Impairment in Bilinguals: What Is the Influence of the Language of Assessment?

BACKGROUND: Bilingualism's impact on cognitive assessment remains underexplored. This study analyzes the efficacy of the Mini-Mental State Examination (MMSE) as a screening tool for bilinguals, specifically examining the influence of language choice on balanced and unbalanced Lebanese bilinguals (Arabic-French) and its implications for diagnosing cognitive impairment. METHODS: Ninety-three bilingual healthy controls (mean age = 67.99 ± 9.3) and 29 Alzheimer's disease patients (mean age = 77.2 ± 5.9), including 26 with mild and 3 with moderate dementia, underwent MMSE assessments in both Arabic and French. The study aimed to assess language impact on cognitive screening outcomes in different bilingual subtypes. RESULTS: Sensitivity in screening for cognitive impairment using the MMSE varied based on language and bilingualism subtype. For unbalanced bilinguals, using the prominent language increased sensitivity. Conversely, in balanced bilinguals, employing the societal majority language enhanced sensitivity. This suggests that the conventional use of the non-prominent language in cognitive screening for foreigners/immigrants may result in a subtle loss of MMSE sensitivity. CONCLUSION: This study emphasizes the critical role of language choice in cognitive assessment for bilinguals. The MMSE's sensitivity is influenced by language selection, with clinical implications for screening procedures. Recommendations include using the prominent language for cognitive screening in dominant bilinguals and the societal majority language for balanced bilinguals. This nuanced approach aims to improve the accuracy and cultural sensitivity of cognitive screening in bilingual populations, addressing the gap in current assessment practices.

Sex Differences in Poststroke Cognitive Impairment: A Multicenter Study in 2343 Patients With Acute Ischemic Stroke.

BACKGROUND: Poststroke cognitive impairment (PSCI) occurs in about half of stroke survivors. Cumulative evidence indicates that functional outcomes of stroke are worse in women than men. Yet it is unknown whether the occurrence and characteristics of PSCI differ between men and women. METHODS: Individual patient data from 9 cohorts of patients with ischemic stroke were harmonized and pooled through the Meta-VCI-Map consortium (n=2343, 38% women). We included patients with visible symptomatic infarcts on computed tomography/magnetic resonance imaging and cognitive assessment within 15 months after stroke. PSCI was defined as impairment in ≥1 cognitive domains on neuropsychological assessment. Logistic regression analyses were performed to compare men to women, adjusted for study cohort, to obtain odds ratios for PSCI and individual cognitive domains. We also explored sensitivity and specificity of cognitive screening tools for detecting PSCI, according to sex (Mini-Mental State Examination, 4 cohorts, n=1814; Montreal Cognitive Assessment, 3 cohorts, n=278). RESULTS: PSCI was found in 51% of both women and men. Men had a lower risk of impairment of attention and executive functioning (men: odds ratio, 0.76 [95% CI, 0.61-0.96]), and language (men: odds ratio, 0.67 [95% CI, 0.45-0.85]), but a higher risk of verbal memory impairment (men: odds ratio, 1.43 [95% CI, 1.17-1.75]). The sensitivity of Mini-Mental State Examination (<25) for PSCI was higher for women (0.53) than for men (0.27; P=0.02), with a lower specificity for women (0.80) than men (0.96; P=0.01). Sensitivity and specificity of Montreal Cognitive Assessment (<26.) for PSCI was comparable between women and men (0.91 versus 0.86; P=0.62 and 0.29 versus 0.28; P=0.86, respectively). CONCLUSIONS: Sex was not associated with PSCI occurrence but affected domains differed between men and women. The latter may explain why sensitivity of the Mini-Mental State Examination for detecting PSCI was higher in women with a lower specificity compared with men. These sex differences need to be considered when screening for and diagnosing PSCI in clinical practice.

Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells.

PURPOSE: We and others have demonstrated that MYC-amplified medulloblastoma (MB) cells are susceptible to class I histone deacetylase inhibitor (HDACi) treatment. However, single drug treatment with HDACi has shown limited clinical efficacy. We hypothesized that addition of a second compound acting synergistically with HDACi may enhance efficacy. METHODS: We used a gene expression dataset to identify PLK1 as a second target in MB cells and validated the relevance of PLK1 in MB. We measured cell metabolic activity, viability, and cycle progression in MB cells after treatment with PLK1-specific inhibitors (PLK1i). Chou-Talalay synergy calculations were used to determine the nature of class I HDACi entinostat and PLK1i interaction which was validated. Finally, the clinical potential of the combination was assessed in the in vivo experiment. RESULTS: MYC-amplified tumor cells are highly sensitive towards treatment with ATP-competitive PLK1i as a monotherapy. Entinostat and PLK1i in combination act synergistically in MYC-driven MB cells, exerting cytotoxic effects at clinically relevant concentrations. The downstream effect is exerted via MYC-related pathways, pointing out the potential of MYC amplification as a clinically feasible predictive biomarker for patient selection. While entinostat significantly extended survival of mice implanted with orthotopic MYC-amplified MB PDX, there was no evidence of the improvement of survival when treating the animals with the combination. CONCLUSION: The combination of entinostat and PLK1i showed synergistic interaction in vitro, but not in vivo. Therefore, further screening of blood-brain barrier penetrating PLK1i is warranted to determine the true potential of the combination as no on-target activity was observed after PLK1i volasertib treatment in vivo.

Long-Term Cognitive Decline After Stroke: An Individual Participant Data Meta-Analysis.

BACKGROUND: Poststroke cognitive impairment is common, but the trajectory and magnitude of cognitive decline after stroke is unclear. We examined the course and determinants of cognitive change after stroke using individual participant data from the Stroke and Cognition Consortium. METHODS: Nine longitudinal hospital-based cohorts from 7 countries were included. Neuropsychological test scores and normative data were used to calculate standardized scores for global cognition and 5 cognitive domains. One-step individual participant data meta-analysis was used to examine the rate of change in cognitive function and risk factors for cognitive decline after stroke. Stroke-free controls were included to examine rate differences. Based on the literature and our own data that showed short-term improvement in cognitive function after stroke, key analyses were restricted to the period beginning 1-year poststroke to focus on its long-term effects. RESULTS: A total of 1488 patients (mean age, 66.3 years; SD, 11.1; 98% ischemic stroke) were followed for a median of 2.68 years (25th-75th percentile: 1.21-4.14 years). After an initial period of improvement through up to 1-year poststroke, decline was seen in global cognition and all domains except executive function after adjusting for age, sex, education, vascular risk factors, and stroke characteristics (-0.053 SD/year [95% CI, -0.073 to -0.033]; P<0.001 for global cognition). Recurrent stroke and older age were associated with faster decline. Decline was significantly faster in patients with stroke compared with controls (difference=-0.078 SD/year [95% CI, -0.11 to -0.045]; P<0.001 for global cognition in a subgroup analysis). CONCLUSIONS: Patients with stroke experience cognitive decline that is faster than that of stroke-free controls from 1 to 3 years after onset. An increased rate of decline is associated with older age and recurrent stroke.

Determinants of disability at 6 months after stroke: The GRECogVASC Study.

BACKGROUND AND PURPOSE: The aim of this study was to determine the contributions of background disorders responsible for participation restriction as indexed by a structured interview for the modified Rankin Scale (mRS-SI). METHODS: A subset of 256 patients was assessed at 6 months after stroke using the National Institutes of Health Stroke Scale (NIHSS), gait score, comprehensive cognitive battery (yielding a global cognitive Z-score), behavioral dysexecutive disorders (DDs), anxiety and depressive symptoms, epilepsy, and headache. Following bivariate analyses, determinants of participation restriction were selected using ordinal regression analysis with partial odds. RESULTS: Poststroke participation restriction (mRS-SI score > 1) was observed in 59% of the patients. In bivariate analyses, mRS-SI score was associated with prestroke mRS-SI score, 6-month NIHSS score, gait score, global cognitive Z-score, behavioral DDs, and presence of anxiety and depression (all: p = 0.0001; epilepsy: p =0.3; headache: p = 0.7). After logistic regression analysis, NIHSS score was associated with increasing mRS-SI score (p = 0.00001). Prestroke mRS-SI score (p = 0.00001), behavioral DDs (p = 0.0008) and global cognitive Z-score (p = 0.01) were associated with both mRS-SI score > 1 and mRS-SI score > 2. In addition, gait score was associated with mRS-SI score > 2 (p = 0.00001). This model classified 85% of mRS-SI scores correctly (p = 0.001). Structural equation modeling showed the contributions of gait limitation (standardized coefficient [SC]: 0.68; p = 0.01), prestroke mRS-SI (SC: 0.41; p = 0.01), severity of neurological impairment (SC: 0.16; p = 0.01), global cognitive Z-score (SC: -0.14; p = 0.05), and behavioral DDs (SC: 0.13; p = 0.01). CONCLUSION: These results provide a statistical model of weights of determinants responsible for poststroke participation restriction and highlight a new independent determinant: behavioral DDs.

In Individuals With Subjective Cognitive Decline, Age, Memory and Speed Scores at Baseline Predict Progression to Cognitive Impairment.

Some patients with subjective cognitive decline (SCD) progress to neurocognitive disorders (NCD), whereas others remain stable; however, the neuropsychological determinants of this progression have not been identified. Our objective was to examine baseline neuropsychological indicators that could discriminate between stable SCD Versus progression toward an NCD. We retrospectively included patients consulting for SCD at a university medical center's memory center (Amiens, France) who had undergone 3 or more neuropsychological assessments. Among the 80 patients with SCD, 11 had progressed to an NCD. The combination of age, memory, and speed scores at the baseline assessment predicted the progression of SCD with a sensitivity of 91%, and a negative predictive value of 98%. The present results constitute a first step (pending prospective studies) toward helping physicians to identify cases of SCD at risk of progression and, in particular, identifying patients with SCD who will not progress by examining baseline neuropsychological indicators. ClinicalTrials.gov ID: NCT04880252.

Medulloblastoma recurrence and metastatic spread are independent of colony-stimulating factor 1 receptor signaling and macrophage survival.

PURPOSE: Tumor infiltration by immunosuppressive myeloid cells or tumor-associated macrophages (TAMs) contributes to tumor progression and metastasis. In contrast to their adult counterparts, higher TAM signatures do not correlate with aggressive tumor behavior in pediatric brain tumors. While prominent TAM infiltrates exist before and after radiation, the degree to which irradiated macrophages and microglia support progression or leptomeningeal metastasis remains unclear. Patients with medulloblastoma often present with distant metastases and tumor recurrence is largely incurable, making them prime candidates for the study of novel approaches to prevent neuroaxis dissemination and recurrence. METHODS: Macrophage depletion was achieved using CSF-1 receptor inhibitors (CSF-1Ri), BLZ945 and AFS98, with or without whole brain radiation in a variety of medulloblastoma models, including patient-derived xenografts bearing Group 3 medulloblastoma and a transgenic Sonic Hedgehog (Ptch1+/-, Trp53-/-) medulloblastoma model. RESULTS: Effective reduction of microglia, TAM, and spinal cord macrophage with CSF-1Ri resulted in negligible effects on the rate of local and spinal recurrences or survival following radiation. Results were comparable between medulloblastoma subgroups. While notably few tumor-infiltrating lymphocytes (TILs) were detected, average numbers of CD3+ TILs and FoxP3+ Tregs did not differ between groups following treatment and tumor aggressiveness by Ki67 proliferation index was unaltered. CONCLUSION: In the absence of other microenvironmental influences, medulloblastoma-educated macrophages do not operate as tumor-supportive cells or promote leptomeningeal recurrence in these models. Our data add to a growing body of literature describing a distinct immunophenotype amid the medulloblastoma microenvironment and highlight the importance of appropriate pediatric modeling prior to clinical translation.

Phenyl-Glutarimides: Alternative Cereblon Binders for the Design of PROTACs.

Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis-targeting chimera (PROTAC) approaches, owing to favorable drug-like properties of CRBN ligands, immunomodulatory imide drugs (IMiDs). However, IMiDs are known to be inherently unstable, readily undergoing hydrolysis in body fluids. Here we show that IMiDs and IMiD-based PROTACs rapidly hydrolyze in commonly utilized cell media, which significantly affects their cell efficacy. We designed novel CRBN binders, phenyl glutarimide (PG) analogues, and showed that they retained affinity for CRBN with high ligand efficiency (LE >0.48) and displayed improved chemical stability. Our efforts led to the discovery of PG PROTAC 4 c (SJ995973), a uniquely potent degrader of bromodomain and extra-terminal (BET) proteins that inhibited the viability of human acute myeloid leukemia MV4-11 cells at low picomolar concentrations (IC50 =3 pM; BRD4 DC50 =0.87 nM). These findings strongly support the utility of PG derivatives in the design of CRBN-directed PROTACs.

Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource.

Pediatric brain tumors are the leading cause of cancer-related death in children. Patient-derived orthotopic xenografts (PDOX) of childhood brain tumors have recently emerged as a biologically faithful vehicle for testing novel and more effective therapies. Herein, we provide the histopathological and molecular analysis of 37 novel PDOX models generated from pediatric brain tumor patients treated at St. Jude Children's Research Hospital. Using a combination of histopathology, whole-genome and whole-exome sequencing, RNA-sequencing, and DNA methylation arrays, we demonstrate the overall fidelity and inter-tumoral molecular heterogeneity of pediatric brain tumor PDOX models. These models represent frequent as well as rare childhood brain tumor entities, including medulloblastoma, ependymoma, atypical teratoid rhabdoid tumor, and embryonal tumor with multi-layer rosettes. PDOX models will be valuable platforms for evaluating novel therapies and conducting pre-clinical trials to accelerate progress in the treatment of brain tumors in children. All described PDOX models and associated datasets can be explored using an interactive web-based portal and will be made freely available to the research community upon request.

Sensitivity of the Montreal Cognitive Assessment in screening for cognitive impairment in patients with newly diagnosed high-grade glioma.

INTRODUCTION: Cognitive impairment is frequent in patients with high-grade glioma and requires cognitive follow-up. Cognitive screening tools such as the Montreal Cognitive Assessment (MoCA) have been used to assess cognition in these patients. Here we assessed the sensitivity of the MoCA in screening for cognitive impairment in a cohort of 156 patients with newly-diagnosed high-grade glioma, after surgery and before radiochemotherapy. METHODS: We assessed cognitive performance with the MoCA and a neuropsychological battery. Cognitive scores were analyzed in terms of a previously validated framework designed to control false positives and data for 1003 control participants from the GRECOGVASC study. After comparison of performance on the tests, we used stepwise logistic regression to produce a cognitive summary score from the neuropsychological battery. Then we analyzed sensitivity and specificity of the MoCA with receiver operator characteristic (ROC) curve analysis. RESULTS: Both raw and adjusted MoCA scores showed only moderate sensitivity. The area under the ROC curve was 0.759 (95% CI 0.703-0.815) for the raw score and 0.788 (95% CI 0.734-0.842) for the adjusted score. Optimal discrimination was obtained with a raw score ≤ 25 (sensitivity: 0.526; specificity: 0.832; positive predictive value: 0.2; negative predictive value: 0.96) and an adjusted score - 0.603 (sensitivity: 0.716; specificity: 0.768; positive predictive value: 0.24; negative predictive value: 0.96). CONCLUSION: The moderate sensitivity of MoCA indicates that it is not a suitable screening tool for detecting cognitive impairment in patients with newly-diagnosed high-grade glioma.

Is Reaction Time Slowing an Early Sign of Alzheimer's Disease? A Meta-Analysis.

BACKGROUND: Although simple reaction time (SRT) slowing is associated with dementia in Alzheimer's disease (AD), its presence in individuals with mild cognitive impairment (MCI) is subject to debate. OBJECTIVE: The aim of this study was to perform a systematic review and meta-analysis of the literature data on SRT slowing in MCI. METHODS: Publications with data on SRT, age, and educational level in participants with MCI were included. After calculating the log SRT and its variance for each study, we took interstudy heterogeneity into account by conducting a random effects (restricted maximum likelihood estimation) meta-analysis. RESULTS: The 7 selected studies featured a total of 327 participants with MCI and 468 healthy controls (HCs). The mean age was 68.2 years for participants with MCI and 72.3 years for HCs. The weighted mean Mini-Mental State Examination score was 26.4 in the MCI group, and 28.4 in the HC group. The mean SRT was significantly (p = 0.0217) longer in the MCI group (by 11%) than in the HC group. CONCLUSION: This meta-analysis showed that SRTs are longer in individuals with MCI. Further studies are needed to determine the mechanism of SRT slowing, its anatomical correlates, and a threshold value for diagnosing prodromal AD.

CNS Penetration of Cyclophosphamide and Metabolites in Mice Bearing Group 3 Medulloblastoma and Non-Tumor Bearing Mice.

PURPOSE: Cyclophosphamide is widely used to treat children with medulloblastoma; however, little is known about its brain penetration. We performed cerebral microdialysis to characterize the brain penetration of cyclophosphamide (130 mg/kg, IP) and its metabolites [4-hydroxy-cyclophosphamide (4OH-CTX) and carboxyethylphosphoramide mustard (CEPM)] in non-tumor bearing mice and mice bearing orthotopic Group 3 medulloblastoma. METHODS: A plasma pharmacokinetic study was performed in non-tumor-bearing CD1- nude mice, and four cerebral microdialysis studies were performed in non-tumor-bearing (M1 and M3) and tumor- bearing mice (M2 and M4). Plasma samples were collected up to 6-hours post-dose, and extracellular fluid (ECF) samples were collected over 60-minute intervals for 24-hours post-dose. To stabilize and quantify 4OH-CTX, a derivatizing solution was added in blood after collection, and either directly in the microdialysis perfusate (M1 and M2) or in ECF collection tubes (M3 and M4). Plasma/ECF cyclophosphamide and CEPM, and 4OH-CTX concentrations were separately measured using different LC-MS/MS methods. RESULTS: All plasma/ECF concentrations were described using a population-based pharmacokinetic model. Plasma exposures of cyclophosphamide, 4OH-CTX, and CEPM were similar across studies (mean AUC=112.6, 45.6, and 80.8 µmol∙hr/L). Hemorrhage was observed in brain tissue when the derivatizing solution was in perfusate compared with none when in collection tubes, which suggested potential sample contamination in studies M1 and M2. Model-derived unbound ECF to plasma partition coefficients (Kp,uu) were calculated to reflect CNS penetration of the compounds. Lower cyclophosphamide Kp,uu was obtained in tumor-bearing mice versus non-tumor bearing mice (mean 0.15 versus 0.22, p=0.019). No differences in Kp,uu were observed between these groups for 4OH- CTX and CEPM (overall mean 0.10 and 0.07). CONCLUSIONS: Future studies will explore potential mechanisms at the brain-tumor barrier to explain lower cyclophosphamide brain penetration in tumor-bearing mice. These results will be used to further investigate exposure-response relationships in medulloblastoma xenograft models.

Neuroimaging Determinants of Poststroke Cognitive Performance.

Background and Purpose- We aimed to define the neuroimaging determinants of poststroke cognitive performance and their relative contributions among a spectrum of magnetic resonance imaging markers, including lesion burden and strategic locations. Methods- We prospectively included patients with stroke from the GRECogVASC study (Groupe de Réflexion pour l'Évaluation Cognitive Vasculaire) who underwent 3-T magnetic resonance imaging and a comprehensive standardized battery of neuropsychological tests 6 months after the index event. An optimized global cognitive score and neuroimaging markers, including stroke characteristics, cerebral atrophy markers, and small vessel diseases markers, were assessed. Location of strategic strokes was determined using a specifically designed method taking into account stroke size and cerebral atrophy. A stepwise multivariable linear regression model was used to identify magnetic resonance imaging determinants of cognitive performance. Results- Data were available for 356 patients (mean age: 63.67±10.6 years; 326 [91.6%] of the patients had experienced an ischemic stroke). Six months poststroke, 50.8% of patients presented with a neurocognitive disorder. Strategic strokes (right corticospinal tract, left antero-middle thalamus, left arcuate fasciculus, left middle frontal gyrus, and left postero-inferior cerebellum; R2=0.225; P=0.0001), medial temporal lobe atrophy ( R2=0.077; P=0.0001), total brain tissue volume ( R2=0.028; P=0.004), and stroke volume ( R2=0.013; P=0.005) were independent determinants of cognitive performance. Strategic strokes accounted for the largest proportion of the variance in the cognitive score (22.5%). The white matter hyperintensity burden, brain microbleeds, and dilated perivascular spaces were not independent determinants. Conclusions- Optimized global cognitive score and combined approach of both quantitative measures related to structure loss and qualitative measures related to the presence of strategic lesion are required to improve the determination of structure-function relationship of cognitive performance after stroke.

Prevalence of Poststroke Neurocognitive Disorders Using National Institute of Neurological Disorders and Stroke-Canadian Stroke Network, VASCOG Criteria (Vascular Behavioral and Cognitive Disorders), and Optimized Criteria of Cognitive Deficit.

BACKGROUND AND PURPOSE: The prevalence of poststroke neurocognitive disorder (NCD) has yet to be accurately determined. The primary objective of the present study was to optimize operationalization of the criterion for NCD by using an external validity criterion. METHODS: The GRECOG-VASC cohort (Groupe de Réflexion pour l'Évaluation Cognitive Vasculaire) of 404 stroke patients with cerebral infarct (91.3%) or hemorrhage (18.7%) was assessed 6 months poststroke and 1003 healthy controls, with the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network standardized battery. Three dimensions of the criterion for cognitive impairment were systematically examined by using the false-positive rate as an external validity criterion. Diagnosis of mild and major NCD was based on the VASCOG criteria (Vascular Behavioral and Cognitive Disorders). The mechanisms of functional decline were systematically assessed. RESULTS: The optimal criterion for cognitive impairment was the shortened summary score (ie, averaged performance for action speed, executive functions, and language) because it was associated with the highest (P=0.0001) corrected true-positive rate (43.5%) and a false-positive rate ≤5%. Using this criterion, the mean (95% confidence interval) prevalence of poststroke NCD was 49.5% (44.6-54.4), most of which corresponded to mild NCD (39.1%; 95% confidence interval, 34.4-43.9) rather than dementia (10.4%; 95% confidence interval, 7.4-13.4). CONCLUSIONS: This study is the first to have optimized the operationalization of the criterion for poststroke cognitive impairment. It documented the prevalence of poststroke NCD in the GRECOG-VASC cohort and showed that mild cognitive impairment accounts for 80% of the affected patients. Finally, the method developed in the present study offers a means of harmonizing the diagnosis of NCD. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01339195.

A new genetically engineered mouse model of choroid plexus carcinoma.

Choroid plexus carcinomas (CPCs) are highly malignant brain tumours predominantly found in children and associated to poor prognosis. Improved therapy for these cancers would benefit from the generation of animal models. Here we have created a novel mouse CPC model by expressing a stabilised form of c-Myc (MycT58A) and inactivating Trp53 in the choroid plexus of newborn mice. This induced aberrant proliferation of choroid plexus epithelial cells, leading to aggressive tumour development and death within 150 days. Choroid plexus tumours occurred with a complete penetrance in all brain ventricles, with prevalence in the lateral and fourth ventricles. Histological and cellular analysis indicated that these tumours were CPCs resembling their human counterparts. Comparison of gene expression profiles of CPCs and non-neoplastic tissues revealed profound alterations in cell cycle regulation and DNA damage responses, suggesting that dysregulation of cell division and DNA checkpoint pathways may represent key vulnerabilities. This novel animal model of CPC provides an invaluable tool to elucidate the mechanism of CPC formation and to develop successful therapies against this devastating paediatric cancer.

Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas.

Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.

Epigenetic Drivers in Pediatric Medulloblastoma.

Epigenetics is the process by which gene expression is regulated by events other than alterations of the genome. This includes DNA methylation, histone modifications, chromatin remodeling, microRNAs, and long non-coding RNAs. Methylation of DNA, chromatin remodeling, and histone modifications regulate the chromatin and access of transcription factors to DNA and in turn gene transcription. Alteration of chromatin is now recognized to be deregulated in many cancers. Medulloblastoma is an embryonal tumor of the cerebellum and the most common malignant brain tumor in children, that occurs only rarely in adults. Medulloblastoma is characterized by four major molecularly and histopathologically distinct groups, wingless (WNT), sonic hedgehog (SHH), group 3 (G3), and group 4 (G4), that, except for WNT, are each now subdivided in several subgroups. Gene expression array, next-generation sequencing, and methylation profiling of several hundred primary tumors by several consortia and independent groups revealed that medulloblastomas harbor a paucity of mutations most of which occur in epigenetic regulators, genetic alterations in oncogenes and tumor suppressors, in addition to copy number alterations and chromosome gains and losses. Remarkably, some tumors have no reported mutations, suggesting that some genes required for oncogenesis might be regulated by epigenetic mechanisms which are still to be uncovered and validated. This review will highlight several epigenetic regulators focusing mainly on histone modifiers identified in medulloblastoma.

Systematic Review and Meta-Analysis of Prevalence in Post-Stroke Neurocognitive Disorders in Hospital-Based Studies.

BACKGROUND/AIMS: Post-stroke neurocognitive disorders (post-stroke NCD) have been reported with a very variable prevalence. METHODS: Based on a systematic literature search, hospital-based studies published between January 1990 and September 2015 were selected when they reported the prevalence of total, mild, and major post-stroke NCD diagnosed by using specified criteria. Factors affecting prevalence were assessed using meta-regression analysis. RESULTS: Among the 7,440 references evaluated, 16 hospital-based studies were selected, corresponding to a total of 3,087 patients. The overall prevalence of total post-stroke NCD was 53.4% (95% CI: 46.9-59.8): 36.4% for mild post-stroke NCD (95% CI: 29-43.8) and 16.5% (95% CI: 12.1-20.8) for major post-stroke NCD. The overall prevalence was mainly influenced by the threshold score used for categorization (p = 0.0001) and, in the subgroup of studies using a conservative threshold (i.e., ≤7th percentile), by the recurrent stroke rate (p = 0.0005). The prevalence of major post-stroke NCD was mainly influenced by age (p = 0.003). CONCLUSION: More than half of stroke survivors experience post-stroke NCD, corresponding to mild post-stroke NCD in two-thirds of cases and major post-stroke NCD in one-third of cases. Harmonization of stroke assessment and cognitive score thresholds is urgently needed to allow more accurate estimation of post-stroke NCD prevalence, especially mild post-stroke NCD.