Changes in innervation of lumbar motoneurons and organization of premotor network following training of transected adult rats

International audienceRats with complete spinal cord transection (SCT) can recover hindlimb locomotor function under strategies combining exercise training and 5-HT agonist treatment. This recovery is expected to result from structural and functional reorganization within the spinal cord below the lesion. To begin to understand the nature of this reorganization, we examined synaptic changes to identified gastrocnemius (GS) or tibialis anterior (TA) moto-neurons (MNs) in SCT rats after a schedule of early exercise training and delayed 5-HT agonist treatment. In addition, we analyzed changes in distribution and number of lumbar interneurons (INs) presynaptic to GS MNs using retrograde transneuronal transport of rabies virus. In SCT-untrained rats, we found few changes in the density and size of inhibitory and excitatory inputs impinging on cell bodies of TA and GS MNs compared to intact rats, whereas there was a marked trend for a reduction in the number of premotor INs connected to GS MNs. In contrast, after training of SCT rats, a significant increase of the density of GABAergic and glycinergic axon terminals was observed on both GS and TA motoneuronal cell bodies, as well as of presynaptic P-boutons on VGLUT1 afferents. Despite these changes in innervation the number of premotor INs connected to GS MNs was similar to control values although some new connections to MNs were observed. These results suggest that adaptation of gait patterns in SCT-trained rats was accompanied by changes in the innervation of lumbar MNs while the distribution of the spinal premotor circuitry was relatively preserved

The Matrix Matters: Beverage Carbonation Impacts the Timing of Caffeine Effects on Sustained Attention

Both caffeine and the perception of refreshment delivered by cooling, tingling, and mouth-watering flavors have individually been shown to positively impact cognitive performance and mood, though presently there is limited evidence on their possible combined effects. This study explored the contribution of refreshing compounds in beverages, namely, carbon dioxide and citric acid, on the acute effects of caffeine on sustained attention and self-rated physical and mental energy. A randomized, controlled crossover trial was conducted by testing three products: a carbonated caffeinated beverage; a comparator caffeinated beverage; and a flavor-matched control beverage. Findings from 24 healthy adults revealed product-dependent variations in cognitive performance during a 60-min visual sustained-attention task, suggesting that the carbonated-caffeinated beverage led to faster, greater and more consistent levels of accuracy, compared to the control beverage. Specifically, significant differences were found between: (1) the carbonated-caffeinated beverage and the caffeinated beverage, and (2) between the caffeinated beverage and the control beverage for number of hits, reaction time and false alarm scores. Both caffeinated beverages led to higher physical and mental energy, and lower physical and mental fatigue 60-min post-consumption. These findings suggest beneficial effects on sustained attention through the combination of caffeine with refreshing compounds

Neuropathologie de l’épilepsie

International audienceThe neuropathology of epilepsy aims at diagnosing the cerebral lesions underlying epilepsy that are obtained from epilepsy surgery, or rarely from biopsy or autopsy. The main histopathological and immunohistochemical characteristics of several entities are described: epilepsy-associated hippocampal sclerosis, long-term epilepsy-associated tumours, cortical malformations, vascular malformations, glial scars, encephalitides, and focal neuronal lipofuscinosis. The diagnostic approach, the differential diagnosis and the histochemical and immunohistochemical tools are detailed in order to provide the pathologist with a summarized toolkit to handle the broad range of epileptogenic lesions

GAB1 overexpression identifies Hedgehog‐activated anterior skull base meningiomas

International audienceAimsMutations activating the Hedgehog (Hh) signalling pathway have been described in anterior skull base meningiomas, raising hope for the use of targeted therapies. However, identification of Hh-activated tumours is hampered by the lack of a reliable immunohistochemical marker. We report the evaluation of GAB1, an immunohistochemical marker used to detect Hh pathway activation in medulloblastoma, as a potential marker of Hh-activated meningiomas.MethodsGAB1 staining was compared to SMO mutation detection with Sanger and NGS techniques as well as Hh pathway activation study through mRNA expression level analyses in a discovery set of 110 anterior skull base meningiomas and in a prospective validation set of 21 meningiomas.ResultsUsing an expression score ranging from 0 to 400, we show that a cut-off score of 250 lead to excellent detection of Hh pathway mutations (sensitivity 100%, specificity 86%). The prospective validation set confirmed the excellent negative predictive value of GAB1 to exclude Hedgehog independent meningiomas. We describe a large series of 32 SMO-mutant meningiomas and define multiple ways of Hh activation, either through somatic mutations or associated with mutually co-exclusive SHH (Sonic Hedgehog) or IHH (Indian Hedgehog) overexpression independent of the mutations.ConclusionThe assessment of GAB1 expression by an immunohistochemical score is a fast and cost-efficient tool to screen anterior skull base meningiomas for activation of the Hedgehog pathway. It could facilitate the identification of selected cases amenable to sequencing for hedgehog pathway genes as predictive markers for targeted therapy

Immune Microenvironment and Lineage Tracing Help to Decipher Rosette-Forming Glioneuronal Tumors

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Expression and Prognostic Value of CD80 and CD86 in the Tumor Microenvironment of Newly Diagnosed Glioblastoma.

BACKGROUND: Strategies to modulate the tumor microenvironment (TME) have opened new therapeutic avenues with dramatic yet heterogeneous intertumoral efficacy in multiple cancers, including glioblastomas (GBMs). Therefore, investigating molecular actors of TME may help understand the interactions between tumor cells and TME. Immune checkpoint proteins such as a Cluster of Differentiation 80 (CD80) and CD86 are expressed on the surface of tumor cells and infiltrative tumor lymphocytes. However, their expression and prognostic value in GBM microenvironment are still unclear. METHODS: In this study, we investigated, in a retrospective local discovery cohort and a validation TCGA dataset, expression of CD80 and CD86 at mRNA level and their prognostic significance in response to standard of care. Furthermore, CD80 and CD86 at the protein level were investigated in the discovery cohort. RESULTS: Both CD80 and CD86 are expressed heterogeneously in the TME at mRNA and protein levels. In a univariate analysis, the mRNA expression of CD80 and CD86 was not significantly correlated with OS in both local OncoNeuroTek dataset and TCGA datasets. CD80 and CD86 mRNA high expression was significantly associated with shorter progression free survival (PFS) (p < 0.05). These findings were validated using the TCGA cohort; higher CD80 and CD86 expressions were correlated with shorter PFS (p < 0.05). In multivariate analysis, CD86 mRNA expression was an independent prognostic factor for PFS in the TCGA dataset only (p < 0.05). CONCLUSION: CD86 could be used as a potential biomarker for the prognosis of GBM patients treated with immunotherapy; however, additional studies are needed to validate these findings

Clinical, molecular, and radiomic profile of gliomas with FGFR3-TACC3 fusions

International audienceAbstract Background Actionable fibroblast growth factor receptor 3 (FGFR3)–transforming acidic coiled-coil protein 3 fusions (F3T3) are found in approximately 3% of gliomas, but their characteristics and prognostic significance are still poorly defined. Our goal was to characterize the clinical, radiological, and molecular profile of F3T3 positive diffuse gliomas. Methods We screened F3T3 fusion by real-time (RT)-PCR and FGFR3 immunohistochemistry in a large series of gliomas, characterized for main genetic alterations, histology, and clinical evolution. We performed a radiological and radiomic case control study, using an exploratory and a validation cohort. Results We screened 1162 diffuse gliomas (951 unselected cases and 211 preselected for FGFR3 protein immunopositivity), identifying 80 F3T3 positive gliomas. F3T3 was mutually exclusive with IDH mutation (P &lt; 0.001) and EGFR amplification (P = 0.01), defining a distinct molecular cluster associated with CDK4 (P = 0.04) and MDM2 amplification (P = 0.03). F3T3 fusion was associated with longer survival for the whole series and for glioblastomas (median overall survival was 31.1 vs 19.9 mo, P = 0.02) and was an independent predictor of better outcome on multivariate analysis. F3T3 positive gliomas had specific MRI features, affecting preferentially insula and temporal lobe, and with poorly defined tumor margins. F3T3 fusion was correctly predicted by radiomics analysis on both the exploratory (area under the curve [AUC] = 0.87) and the validation MRI (AUC = 0.75) cohort. Using Cox proportional hazards models, radiomics predicted survival with a high C-index (0.75, SD 0.04), while the model combining clinical, genetic, and radiomic data showed the highest C-index (0.81, SD 0.04). Conclusion F3T3 positive gliomas have distinct molecular and radiological features, and better outcome

Hippocampal and neocortical BRAF mutant non‐expansive lesions in focal epilepsies

International audienceAbstract Objective Mesial Temporal Lobe Epilepsy‐associated Hippocampal Sclerosis (MTLE‐HS) is a syndrome associated with various aetiologies. We previously identified CD34‐positive extravascular stellate cells (CD34+ cells) possibly related to BRAF V600E oncogenic variant in a subset of MTLE‐HS. We aimed to identify the BRAF V600E oncogenic variants and characterise the CD34+ cells. Methods We analysed BRAF V600E oncogenic variant by digital droplet Polymerase Chain Reaction in 53 MTLE‐HS samples (25 with CD34+ cells) and nine non‐expansive neocortical lesions resected during epilepsy surgery (five with CD34+ cells). Ex vivo multi‐electrode array recording, immunolabelling, methylation microarray and single nuclei RNAseq were performed on BRAF wildtype MTLE‐HS and BRAF V600E mutant non‐expansive lesion of hippocampus and/or neocortex. Results We identified a BRAF V600E oncogenic variant in five MTLE‐HS samples with CD34+ cells (19%) and in five neocortical samples with CD34+ cells (100%). Single nuclei RNAseq of resected samples revealed two unique clusters of abnormal cells (including CD34+ cells) associated with senescence and oligodendrocyte development in both hippocampal and neocortical BRAF V600E mutant samples. The co‐expression of the oncogene‐induced senescence marker p16 INK4A and the outer subventricular zone radial glia progenitor marker HOPX in CD34+ cells was confirmed by multiplex immunostaining. Pseudotime analysis showed that abnormal cells share a common lineage from progenitors to myelinating oligodendrocytes. Epilepsy surgery led to seizure freedom in eight of the 10 patients with BRAF mutant lesions. Interpretation BRAF V600E underlies a subset of MTLE‐HS and epileptogenic non‐expansive neocortical focal lesions. Detection of the oncogenic variant may help diagnosis and open perspectives for targeted therapies