Neuroprotective effects of meloxicam on transient brain ischemia in rats:the two faces of anti-inflammatory treatments

The inflammato ry response plays an important role in neuroprotection and regeneration after ischemic insult.The use of non-ste roidal anti-inflammatory drugs has been a matter of debate as to whether they have beneficial or detrimental effects.In this context,the effects of the anti-inflammatory agent meloxicam have been scarcely documented after stro ke,but its ability to inhibit both cyclooxygenase isoforms(1 and 2) could be a promising strategy to modulate postischemic inflammation.This study analyzed the effect of meloxicam in a transient focal cerebral ischemia model in rats,measuring its neuroprotective effect after 48 hours and 7 days of reperfusion and the effects of the treatment on the glial scar and regenerative events such as the generation of new progenitors in the subventricular zone and axonal sprouting at the edge of the damaged area.We show that meloxicam’s neuroprotective effects remained after 7 days of reperfusion even if its administration was restricted to the two first days after ischemia.Moreover,meloxicam treatment modulated glial scar reactivity,which matched with an increase in axonal sprouting.However,this treatment decreased the formation of neuronal progenitor cells.This study discusses the dual role of anti-inflammatory treatments after stro ke and encourages the careful analysis of both the neuroprotective and the regenerative effects in preclinical studies.

The importance of being connected:membrane contact sites and Parkinson’s disease

Membrane contact sites (MCS) occur between closely apposed organelles and are a means to transport ions and macromolecules between themselves,co-ordinate cellular metabolism,and direct organelle fission and transport.While MCS between the endoplasmic reticulum (ER)and mitochondria has long been investigated。

Targeting muscle to treat Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease(CMT)is a hereditary peripheral neuropathy causing muscle weakness/wasting and sensory dysfunction predominantly in limb extremities.CMT patients display gait abnormalities,foot deformities,loss of sensation and decreased/absent deep tendon reflexes,with motor symptoms usually being more prominent than sensory.

Deciphering tau-related dementia using human iPSC lines: electrophysiological perspectives of future studies

To date,no disease-modifying treatment or cure is available for dementia.This disorder is becoming more common as the global population ages.There has been over several decades of extensive research focusing on how the pathology develops and progresses causing memory loss,brain damage,and eventually death-it provides the field with a deep understanding of what proteins,peptides,and signaling molecules contribute to neurodegeneration at the molecular,genetic,and cellular levels.The problem is,however,that there is a wide range of dementia types.A given disease can span heterogeneous clinical syndromes with diverse symptomatology,no matter whether it is“senile dementia”or an early-onset form;moreover,it encompasses the mixed features of many syndromes in later stages of the disease.

Monitoring maturation of neural stem cell grafts within a host microenvironment

Neural stem cells(NSC)act as a versatile tool for neuronal cell replacement strategies to treat neurodegenerative disorders in which functional neurorestorative mechanisms are limited.While the beneficial effects of such cellbased therapy have already been documented in terms of neurodegeneration of various origins,a neurophysiological basis for improvement in the recovery of neurological function is still not completely understood.This overview briefly describes the cumulative evidence from electrophysiological studies of NSCderived neurons,aimed at establishing the maturation of differentiated neurons within a host microenvironment,and their integration into the host circuits,with a particular focus on the neurogenesis of NSC grafts within the post-ischemic milieu.Overwhelming evidence demonstrates that the host microenvironment largely regulates the lineage of NSC grafts.This regulatory role,as yet underestimated,raises possibilities for the favoured maturation of a subset of neural phenotypes in order to gain timely remodelling of the impaired brain tissue and amplify the therapeutic effects of NSC-based therapy for recovery of neurological function.

Real- world evaluation of Brainomix e- Stroke software

Background and purpose Brainomix e-Stroke is an artificial intelligence-based decision support tool that aids the interpretation of CT imaging in the context of acute stroke.While e-Stroke has the potential to improve the speed and accuracy of diagnosis,real-world validation is essential.The aim of this study was to prospectively evaluate the performance of Brainomix e-Stroke in an unselected cohort of patients with suspected acute ischaemic stroke.Methods The study cohort included all patients admitted to the University College London Hospital Hyperacute Stroke Unit between October 2021 and April 2022.For e-ASPECTS and e-CTA,the ground truth was determined by a neuroradiologist with access to all clinical and imaging data.For e-CTP,the values of the core infarct and ischaemic penumbra were compared with those derived from syngo.via,an alternate software used at our institution.Results 1163 studies were performed in 551 patients admitted during the study period.Of these,1130(97.2%)were successfully processed by e-Stroke in an average of 4min.For identifying acute middle cerebral artery territory ischaemia,e-ASPECTS had an accuracy of 77.0%and was more specific(83.5%)than sensitive(58.6%).The accuracy for identifying hyperdense thrombus was lower(69.1%),which was mainly due to many false positives(positive predictive value of 22.9%).Identification of acute haemorrhage was highly accurate(97.8%)with a sensitivity of 100%and a specificity of 97.6%;false positives were typically caused by areas of calcification.The accuracy of e-CTA for large vessel occlusions was 91.5%.The core infarct and ischaemic penumbra volumes provided by e-CTP strongly correlated with those provided by syngo.via(ρ=0.804—0.979).Conclusion Brainomix e-Stroke software provides rapid and reliable analysis of CT imaging in the acute stroke setting although,in line with the manufacturer’s guidance,it should be used as an adjunct to expert interpretation rather than a standalone decision-making tool.

Celeboxib-mediated neuroprotection in focal cerebral ischemia: an interplay between unfolded protein response and inflammation

Ischemic stroke results from the temporary or permanent lack of blood supply in the brain due to the occlusion of a brain blood vessel. Around 85% of patients with cerebrovascular accidents suffer from ischemic strokes.

A novel variant of GALC in a familial case of Krabbe disease:Insights from structural bioinformatics and molecular dynamics simulation

Krabbe disease or globoid cell leukodystrophy(GLD;MIM#245200)is a rare and fatal lysosomal storage disease with an autosomal recessive mode of inheritance that results from the deficiency of galactocerebrosidase(GALC;E.C.3.2.1.46),a lysosomal enzyme encoded by the GALC gene.1 GALC breaks down galactosylceramide,a cerebroside located mainly in the myelin sheath.Defects in GALC cause the accumulation of a cytotoxic metabolite,galactosylsphingosine or psychosine,which can be toxic to oligodendrocytes and Schwann cells.2 The failure to digest galactosylceramide triggers the formation of multi-nucleated globoid cells,causing severe demyelination,axonopathy,and neuronal death.3 The reported frequency of Krabbe disease is 1 in 100,000 live births with symptoms including irritability,loss of motor ability,spasticity,ataxia,visual dysfunction,seizures,andcognitive impairment.

Efficacy and safety of bridging therapy and direct mechanical thrombectomy in large vessel occlusions:a meta-analysis

To the Editor:Acute large vessel occlusion(LVO)is responsible for most acute ischemic stroke(AIS),a common cause of disability and death worldwide.Randomized controlled clinical trials(RCTs)provided evidence endorsing intravenous thrombolysis(IVT,also termed bridging therapy[IVT])and endovascular thrombectomy over IVT alone as the current standard treatment for people with LVO in the anterior circulation.[1]The current American and European guidelines recommend using IVT for all eligible individuals with LVO before direct mechanical thrombectomy(d-MT)(class of recommendation-I).Recent RCTs suggest that MT was noninferior to BT in terms of efficacy and safety,[2,3]which contradict the results from multiple meta-analyses favoring BT over d-MT.[4]The benefit of routine IVT for eligible individuals before thrombectomy has become controversial.BT is associated with complications,including the risk of vasospasm,distal emboli,or symptomatic intracranial hemorrhage.

Ex vivo 100 μm isotropic diffusion MRI-based tractography of connectivity changes in the end-stage R6/2 mouse model of Huntington's disease

Background:Huntington's disease is a progressive neurodegenerative disorder.Brain atrophy,as measured by volumetric magnetic resonance imaging(MRI),is a downstream consequence of neurodegeneration,but microstructural changes within brain tissue are expected to precede this volumetric decline.The tissue microstructure can be assayed non-invasively using diffusion MRI,which also allows a tractographic analysis of brain connectivity.Methods:We here used ex vivo diffusion MRI(11.7 T)to measure microstructural changes in different brain regions of end-stage(14 weeks of age)wild type and R6/2 mice(male and female)modeling Huntington's disease.To probe the microstructure of different brain regions,reduce partial volume effects and measure connectivity between different regions,a 100μm isotropic voxel resolution was acquired.Results:Although fractional anisotropy did not reveal any difference between wild-type controls and R6/2 mice,mean,axial,and radial diffusivity were increased in female R6/2 mice and decreased in male R6/2 mice.Whole brain streamlines were only reduced in male R6/2 mice,but streamline density was increased.Region-to-region tractography indicated reductions in connectivity between the cortex,hippocampus,and thalamus with the striatum,as well as within the basal ganglia(striatum—globus pallidus—subthalamic nucleus—substantia nigra—thalamus).Conclusions:Biological sex and left/right hemisphere affected tractographic results,potentially reflecting different stages of disease progression.This proof-of-principle study indicates that diffusion MRI and tractography potentially provide novel biomarkers that connect volumetric changes across different brain regions.In a translation setting,these measurements constitute a novel tool to assess the therapeutic impact of interventions such as neuroprotective agents in transgenic models,as well as patients with Huntington's disease.

Deep brain stimulation for psychiatric disorders: roleof imaging in identifying/confirming DBS targets,predicting, and optimizing outcome and unravellingmechanisms of action

Following the established application of deep brain stimulation(DBS)in the treatment of movement disorders,new non-neurological indications have emerged,such as for obsessive–compulsive disorders,major depressive disorder,dementia,Gilles de la Tourette Syndrome,anorexia nervosa,and addictions.As DBS is a network mod-ulation surgical treatment,the development of DBS for both neurological and psychiatric disorders has been partly driven by advances in neuroimaging,which has helped explain the brain networks implicated.Advances in magnetic resonance imaging connectivity and electrophysiology have led to the development of the con-cept of modulating widely distributed,complex brain networks.Moreover,the increasing number of targets for treating psychiatric disorders have indicated that there may be a convergence of the effect of stimulating dif-ferent targets for the same disorder,and the effect of stimulating the same target for different disorders.The aim of this paper is to review the imaging studies of DBS for psychiatric disorders.Imaging,and particularly connectivity analysis,offers exceptional opportunities to better understand and even predict the clinical out-comes of DBS,especially where there is a lack of objective biomarkers that are essential to properly guide DBS pre-and post-operatively.In future,imaging might also prove useful to individualize DBS treatment.Finally,one of the most important aspects of imaging in DBS is that it allows us to better understand the brain through observing the changes of the functional connectome under neuromodulation,which may in turn help explain the mechanisms of action of DBS that remain elusive.

N-terminally truncated Aβ4-x proteoforms and their relevance for Alzheimer’s pathophysiology

Background:The molecular heterogeneity of Alzheimer’s amyloid-β(Aβ)deposits extends well beyond the clas-sic Aβ1-40/Aβ1-42 dichotomy,substantially expanded by multiple post-translational modifications that increase the proteome diversity.Numerous truncated fragments consistently populate the brain Aβpeptidome,and their homeo-static regulation and potential contribution to disease pathogenesis are largely unknown.Aβ4-x peptides have been reported as major components of plaque cores and the limited studies available indicate their relative abundance in Alzheimer’s disease(AD).Methods:Immunohistochemistry was used to assess the topographic distribution of Aβ4-x species in well-char-acterized AD cases using custom-generated monoclonal antibody 18H6-specific for Aβ4-x species and blind for full-length Aβ1-40/Aβ1-42-in conjunction with thioflavin-S and antibodies recognizing Aβx-40 and Aβx-42 proteo-forms.Circular dichroism,thioflavin-T binding,and electron microscopy evaluated the biophysical and aggregation/oligomerization properties of full-length and truncated synthetic homologues,whereas stereotaxic intracerebral injections of monomeric and oligomeric radiolabeled homologues in wild-type mice were used to evaluate their brain clearance characteristics.Results:All types of amyloid deposits contained the probed Aβepitopes,albeit expressed in different proportions.Aβ4-x species showed preferential localization within thioflavin-S-positive cerebral amyloid angiopathy and cored plaques,strongly suggesting poor clearance characteristics and consistent with the reduced solubility and enhanced oligomerization of their synthetic homologues.In vivo clearance studies demonstrated a fast brain efflux of N-termi-nally truncated and full-length monomeric forms whereas their oligomeric counterparts-particularly of Aβ4-40 and Aβ4-42-consistently exhibited enhanced brain retention.Conclusions:The persistence of aggregation-prone Aβ4-x proteoforms likely contributes to the process of amyloid formation,self-perpetuating the amyloidogenic loop and exacerbating amyloid-mediated pathogenic pathways.

The prevalence,characteristics and outcome of seizure in tuberculous meningitis

Seizures are a common finding in patients with tuberculous meningitis(TBM),and associate with four times increased risk of death and neurological disability,especially in children.It has been reported that brain inflammation,diffuse neuronal injury,and reactive gliosis may all contribute to the pathogenesis of seizures in TBM.Early seizure onset may be associated with meningeal irritation and cerebral oedema;while,the late seizures are usually due to infarction,hydrocephalus,tuberculoma and paradoxical response.Moreover,recurrent uncontrolled seizures can evolve to status epileptics resulting in an increased risk of chronic epilepsy and poor prognosis.Therefore,this review aimed to assess the frequency of seizures in patients with TBM,and discuss the etiologies,mechanisms,and characteristics of seizures in TBM.Besides,we have searched the literature to identify the prognostic factors for chronic epilepsy after TBM.

新型冠状病毒肺炎中急性症状性痫性发作及其危险因素:多中心回顾性研究

背景自2019年12月,新型冠状病毒肺炎在武汉被首次报告以来,新冠病毒开始在全球蔓延。该疾病由新型冠状病毒,即重症急性呼吸综合征冠状病毒2(Severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)引起,2020年3月12日,世界卫生组织(World Health Organization,WHO)正式宣布了该病毒感染引起的综合征为“大流行”(Pandemic)。根据WHO在2020年4月7日的统计报告,当时全球已报告了超过120万例确诊病例,及超过7.2万死亡病例。早期研究提示,新型冠状病毒肺炎可感染所有年龄段人群,在重症患者,将导致呼吸困难、低氧、急性呼吸窘迫综合征和败血性休克等。