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Background: Early intramuscular administration of SARS-CoV-2-neutralising monoclonal antibody combination, tixagevimab–cilgavimab, to non-hospitalised adults with mild to moderate COVID-19 has potential to prevent disease progression. We aimed to evaluate the safety and efficacy of tixagevimab–cilgavimab in preventing progression to severe COVID-19 or death. Methods: TACKLE is an ongoing, phase 3, randomised, double-blind, placebo-controlled study conducted at 95 sites in the USA, Latin America, Europe, and Japan. Eligible participants were non-hospitalised adults aged 18 years or older with a laboratory-confirmed SARS-CoV-2 infection (determined by RT-PCR or an antigen test) from any respiratory tract specimen collected 3 days or less before enrolment and who had not received a COVID-19 vaccination. A WHO Clinical Progression Scale score from more than 1 to less than 4 was required for inclusion and participants had to receive the study drug 7 days or less from self-reported onset of mild to moderate COVID-19 symptoms or measured fever. Participants were randomly assigned (1:1) to receive either a single tixagevimab–cilgavimab 600 mg dose (two consecutive 3 mL intramuscular injections, one each of 300 mg tixagevimab and 300 mg cilgavimab) or placebo. Randomisation was stratified (using central blocked randomisation with randomly varying block sizes) by time from symptom onset, and high-risk versus low-risk of progression to severe COVID-19. Participants, investigators, and sponsor staff involved in the treatment or clinical evaluation and monitoring of the participants were masked to treatment-group assignments. The primary endpoints were severe COVID-19 or death from any cause through to day 29, and safety. This study is registered with ClinicalTrials.gov, NCT04723394. Findings: Between Jan 28, 2021, and July 22, 2021, 1014 participants were enrolled, of whom 910 were randomly assigned to a treatment group (456 to receive tixagevimab–cilgavimab and 454 to receive placebo). The mean age of participants was 46·1 years (SD 15·2). Severe COVID-19 or death occurred in 18 (4%) of 407 participants in the tixagevimab–cilgavimab group versus 37 (9%) of 415 participants in the placebo group (relative risk reduction 50·5% [95% CI 14·6–71·3]; p=0·0096). The absolute risk reduction was 4·5% (95% CI 1·1–8·0; p Interpretation: A single intramuscular tixagevimab–cilgavimab dose provided statistically and clinically significant protection against progression to severe COVID-19 or death versus placebo in unvaccinated individuals and safety was favourable. Treating mild to moderate COVID-19 earlier in the disease course with tixagevimab–cilgavimab might lead to more favourable outcomes.

Depression is highly prevalent in Alzheimer Disease (AD); however, there is paucity of studies that focus specifically on the assessment of depression-relevant phenotypes in AD mouse models. Conditional doxycycline-dependent transgenic mouse models reproducing amyloidosis (TetOffAPPsi) and/or tau (TetOffTauP301L) pathology starting at middle age (6 months) were used in this study. As AD patients can experience depressive symptoms relatively early in disease, testing was conducted at early, pre-pathology stages of Aβ and/or tau accumulation (starting from 45 days of transgenes expression). Tau-related differences were detected in the Novelty Suppressed Feeding task (NSF), whereas APP-related differences were observed predominantly in measures of the Open Field (OF) and Forced Swim tasks (FST). Effects of combined production of Aβ and tau were detected in immobility during the 1st half of the Tail Suspension task (TST). These data demonstrate that results from different tasks are difficult to reconcile using task/variable-centered interpretations in which a single task/variable is assigned an ad-hoc meaning relevant to depression. An alternative, concept-oriented, approach is based on multiple variables/tests, with an understanding of their possible inter-dependence and utilization of statistical approaches that handle correlated data sets. The existence of strong correlations within and between some of the tasks supported utilization of factor analyses (FA). FA explained a similar amount of variability across the genotypes (∼80%) and identified two factors stable across genotypes and representing motor activity and anxiety measures in OF. In contrast, variables related to FST, TST, and NSFT did not demonstrate a structure of factor loadings that would support the existence of a single integral factor of "depressive state" measured by these tasks. In addition, factor loadings varied between genotypes, indicating that genotype-specific between-task correlations need to be considered for interpretations of findings in any single task. In general, this study demonstrates that utilization of multiple tasks to characterize behavioral phenotypes, an approach that is finally gaining more widespread adoption, requires a step of data integration across different behavioral tests for appropriate interpretations.

Summary: Mutations of SHANK3 cause Phelan-McDermid syndrome (PMS), and these individuals can exhibit sensitivity to stress, resulting in behavioral deterioration. Here, we examine the interaction of stress with genotype using a mouse model with face validity to PMS. In Shank3ΔC/+ mice, swim stress produces an altered transcriptomic response in pyramidal neurons that impacts genes and pathways involved in synaptic function, signaling, and protein turnover. Homer1a, which is part of the Shank3-mGluR-N-methyl-D-aspartate (NMDA) receptor complex, is super-induced and is implicated in the stress response because stress-induced social deficits in Shank3ΔC/+ mice are mitigated in Shank3ΔC/+;Homer1a−/− mice. Several lines of evidence demonstrate that Shank3 expression is regulated by Homer1a in competition with crosslinking forms of Homer, and consistent with this model, Shank3 expression and function that are reduced in Shank3ΔC/+ mice are rescued in Shank3ΔC/+;Homer1a−/− mice. Studies highlight the interaction between stress and genetics and focus attention on activity-dependent changes that may contribute to pathogenesis.

Despite the importance of experimental confirmation, the ability of wide range of brain mapping methods to discover brain cognitive architectures in most studies can’t be evaluated directly. Only in rare cases, when due to medical need, it is possible to conduct experiments during neurosurgical operations, is it possible to assess the accuracy of certain approaches. In this paper we evaluate, how well we can reveal brain cognitive architectures structure by established and novel approaches based on fMRI data, with special focus on resting-state fMRI, and how well these findings match Direct Cortical Stimulation mapping data, which is a gold standard in neurosurgery. We illustrate our approach on three representative examples with different motor and cognitive architectures mapping. We found a significant correspondence between predicted maps and intraoperative data for both brain networks. This indicates that resting-state fMRI could be used as an additional source of information for neurosurgical planning, though its applicability to exploring and describing the whole variety of brain architectures for research purposes should be investigated in future.

The epoxy resins are widely used in nuclear and aerospace industries. The certain properties of epoxy resins as well as the resistance to radiation can be improved by the incorporation of different fillers. This study examines the effect of electron beam irradiation on the thermal and mechanical properties of the epoxy composites filled with aluminum nanoparticles at percentage of 0.35 wt%. The epoxy composites were exposed to the irradiation doses of 30, 100 and 300 kGy using electron beam generated by the linear electron accelerator ELU-4. The effects of the doses on thermal and mechanical properties of the aluminum based epoxy composites were investigated by the methods of thermal gravimetric analysis, tensile test, and dynamic mechanical analysis. The results revealed that the studied epoxy composites showed good radiation resistance. The thermal and mechanical properties of the aluminum based epoxy composites increased with increasing the irradiation dose up to 100 kGy and decreased with further increasing the dose.

Objective Recently, in modern neurosurgery, a tendency toward low-traumatic surgical approaches has become clear. To provide a minimal degree of injury to the brain tissue, we have offered microsurgical approaches through a burr hole. Methods From February 2016 to November 2017, 200 microsurgical interventions through a single burr hole with a diameter of 14 mm were performed. The age of the patients varied from 16 to 79 years. The female/male ratio was 1.6:1. In 176 cases, the procedure was performed on an intracranial mass lesion in various locations. In the remaining 24 cases, selective amygdalohippocampectomy was performed in patients with hippocampal sclerosis. Results Various surgical approaches were used, including transcortical in 81 (40.5%), retrosigmoid in 38 (19%), subtemporal in 32 (16%), infratentorial supracerebellar in 25 (12.5%), interhemispheric in 17 (8.5%), telovelar in 5 (2.5%), and eyebrow in 2. The extent of lesion removal was evaluated in 167 patients for whom maximal tumor resection had been planned before surgery. Gross total and near total removal was achieved in 145 patients (87%), subtotal in 15 patients (9%), and partial in 7 patients (4%). The operative time ranged from 35 to 300 minutes (median, 80). The interval to extubation postoperatively varied from 5 minutes to 5 days (median, 70 minutes). Of the 200 patients, 195 (97.5%) were mobilized during the first 3 postoperative days. Conclusions Burr hole microsurgery provides the ability to perform successful surgery on patients with the most diverse intracranial pathological features through a smaller opening than that used for keyhole surgery.

In current work we propose a three-step approach to automatic and efficient functional brain areas mapping as well demonstrate in case studies on three patients with gliomas the potential applicability of constrained source separation technique (semiblind Independent Component Analysis, ICA) to brain networks discovery and the similarity of task-based-fMRI (t-fMRI) and resting state-fMRI (rs-fMRI) results. Blind and semiblind ICA-analysis was applied for both methods t-fMRI and rs-fMRI. To measure similarity between spatial maps we used Dice coefficient, which shows the ratio of overlapping voxels and all active voxels in two compared maps for each patient Based on the analysis of Dice coefficients, there was a fairly high degree of overlap between the t-fMRI active areas, Broca and Wernicke and the language network obtained from rs-fMRI. The degree of motor areas overlap with sensorimotor network is less pronounced, but the activation sites correspond to anatomical landmarks - a complex of central gyri and supplementary motor area. In general, in comparisons of the functional brain areas obtained with t-fMRI and rs-fMRI, there is a greater specificity of semiblind ICA compared to blind ICA. RSNs of interest (motor and language) discovered by rs-fMRI highly correlate with t-fMRI reference and are located in anticipated anatomical regions. As a result, rs-fMRI maps seem as a good approximation of t-fMRI maps, especially in case of semiblind ICA decomposition. We hope that further our research of individual changes in sensorimotor and language networks based on functional rs-MRI will allow predicting the activity of neural network architectures and non-invasive mapping of functional areas for preoperative planning.

A pseudomeningocele and an incisional cerebrospinal fluid leak are considered frequent complications following neurosurgical operations. The rate of these complications especially increases following neurosurgical procedures on the posterior cranial fossae. According to some publications, the rate of pseudomeningoceles has been reported as high as 40%, whereas that of incisional cerebrospinal fluid leaks is up to 17%. For the purposes of reducing the risk of these complications after a midline suboccipital craniotomy, we propose suturing the arachnoid membrane of the cisterna magna. In this paper, we present a retrospective analysis of arachnoid membrane suturing. Seventy patients underwent midline suboccipital craniotomy by the first author between 2012 and 2016 at Burdenko Neurosurgery Institute. In this group was included a consecutive group of patients with posterior fossae tumors where the approach was performed through the cisterna magna arachnoid membrane following midline suboccipital craniotomy and dural opening. The patients were divided into two groups. Group 1 included 38 patients to whom cisterna magna arachnoid membrane suturing was performed with monofilament nonabsorbable suture 7.0., and additionally, the suture was sealed with fibrin adhesive sealant TachoComb®. Group 2 included 32 patients without arachnoid membrane suturing. There was no other significant difference in terms of clinical signs and surgical procedures between these groups. In the postoperative period, the frequency of developing a pseudomeningocele and an incisional cerebrospinal fluid leak was assessed in these two groups. The results were evaluated on the basis of clinical, CT, and MRI data performed in the postoperative period. In the patients who underwent arachnoid membrane suturing (group I), pseudomeningocele formation was observed in one (2.6%) and CSF leak in one (2.6%) of the 38 patients. In group II, in which patients had no arachnoid membrane suturing, we observed pseudomeningocele formation in 11 (34.4%) patients and a CSF leak in 7 (25.0%) out of 28 patients with known follow-up. Statistical analysis of the data indicates a significantly higher risk of postoperative pseudomeningocele formation and/or an incisional cerebrospinal fluid leak in a group of patients who did not undergo arachnoid membrane suturing (p

The epoxy polymers are characterized by low thermal stability and high flammability. Nanoparticles are considered to be effective fillers of polymer composites for improving their thermal and functional properties. In this work, the epoxy composites were prepared using epoxy resin ED-20, polyethylene polyamine as a hardener, aluminum nanopowder and boric acid fine powder as flame-retardant filler. The thermal characteristics of the obtained samples were studied using thermogravimetric analysis and differential scanning calorimetry. The mechanical characteristics of epoxy composites were also studied. It was found that an addition of all fillers enhances the thermal stability and mechanical characteristics of the epoxy composites. The best thermal stability showed the epoxy composite filled with boric acid. The highest flexural properties showed the epoxy composite based on the combination of boric acid and aluminum nanopowder.

Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer's disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a revision of our theoretical views and questions every stage of translation—from how we model the disease to how we run clinical trials. In the following sections, we will use some specific examples of the therapeutics from acetylcholinesterase inhibitors to recent anti-Aβ immunization and γ-secretase inhibition to discuss whether preclinical studies could predict the limitations in efficacy and side effects that we were so disappointed to observe in recent clinical trials. We discuss ways to improve both the predictive validity of mouse models and the translation of knowledge between preclinical and clinical stages of drug development.

We have created a mouse genetic model that mimics a human mutation of Shank3 that deletes the C terminus and is associated with autism. Expressed as a single copy [Shank3(+/ΔC) mice], Shank3ΔC protein interacts with the wild-type (WT) gene product and results in >90% reduction of Shank3 at synapses. This "gain-of-function" phenotype is linked to increased polyubiquitination of WT Shank3 and its redistribution into proteasomes. Similarly, the NR1 subunit of the NMDA receptor is reduced at synapses with increased polyubiquitination. Assays of postsynaptic density proteins, spine morphology, and synapse number are unchanged in Shank3(+/ΔC) mice, but the amplitude of NMDAR responses is reduced together with reduced NMDAR-dependent LTP and LTD. Reciprocally, mGluR-dependent LTD is markedly enhanced. Shank3(+/ΔC) mice show behavioral deficits suggestive of autism and reduced NMDA receptor function. These studies reveal a mechanism distinct from haploinsufficiency by which mutations of Shank3 can evoke an autism-like disorder.

The increased use of explosives in recent wars has increased the number of veterans with blast injuries. Of particular interest is blast injury to the brain, and a key question is whether the primary overpressure wave of the blast is injurious or whether brain injury from blast is mostly due to secondary and tertiary effects. Using a shock tube generating shock waves comparable to open-field blast waves, we explored the effects of blast on parenchymatous organs of mice with emphasis on the brain. The main injuries in nonbrain organs were hemorrhages in the lung interstitium and alveolar spaces and hemorrhagic infarcts in liver, spleen, and kidney. Neuropathological and behavioral outcomes of blast were studied at mild blast intensity, that is, 68 ± 8 kPag (9.9 ±1.2 psig) static pressure, 103 kPag (14.9 psig) total pressure and 183 ± 14 kPag (26.5 ± 2.1 psig) membrane rupturepressure. Under these conditions, we observed multifocal axonal injury, primarily in the cerebellum/brainstem, the corticospinal system, and the optic tract. We also found prolonged behavioral and motor abnormalities, including deficits in social recognition and spatial memory and in motor coordination. Shielding of the torso ameliorated axonal injury and behavioral deficits. These findings indicate that long CNS axon tracts are particularly vulnerable to the effects of blast, even at mild intensities that match the exposure of most veterans in recent wars. Prevention of some of these neurological effects by torso shielding may generate new ideas as to how to protect military and civilian populations in blast scenarios. Language: en

β-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-β precursor protein (APP) leading to the generation of amyloid-β peptides that is central to the pathogenesis of Alzheimer's disease. In addition to its role in endoproteolysis of APP, BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) and influences the myelination of central and peripheral axons. Although NRG1 has been genetically linked to schizophrenia and NRG1 +/− mice exhibit a number of schizophrenia-like behavioral traits, it is not known whether altered BACE1-dependent NRG1 signaling can cause similar behavioral abnormalities. To test this hypothesis, we analyze the behaviors considered to be rodent analogs of clinical features of schizophrenia in BACE1 −/− mice with impaired processing of NRG1. We demonstrate that BACE1 −/− mice exhibit deficits in prepulse inhibition, novelty-induced hyperactivity, hypersensitivity to a glutamatergic psychostimulant (MK-801), cognitive impairments, and deficits in social recognition. Importantly, some of these manifestations were responsive to treatment with clozapine, an atypical antipsychotic drug. Moreover, although the total amount of ErbB4, a receptor for NRG1 was not changed, binding of ErbB4 with postsynaptic density protein 95 (PSD95) was significantly reduced in the brains of BACE1 −/− mice. Consistent with the role of ErbB4 in spine morphology and synaptic function, BACE1 −/− mice displayed reduced spine density in hippocampal pyramidal neurons. Collectively, our findings suggest that alterations in BACE1-dependent NRG1/ErbB4 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders.

Significant progress has been made since the 1980s in understanding the neurobiology of Alzheimer disease (AD). The clinical syndrome of AD results from synaptic dysfunction and death of neurons in specific brain regions and circuits, particularly populations of nerve cells subserving memory and cognition. The pathological hallmarks are the extracellular deposition of β-pleated assemblies of Aβ-peptide (amyloid plaques) and intracellular aggregates of hyperphosphorylated tau protein (neurofibrillary tangles). Utilization of transgenic models of AD has advanced understanding of the pathogenesis of this disease and resulted in the discovery of therapeutic targets. The first attempts to implement novel antiamyloid treatments in mild to moderate AD had disappointing results, suggesting that therapy should be given much earlier in the course of the disease. Recognition that pathophysiological processes of AD begin decades before clinical symptoms appear calls for the development of tools for early diagnosis (imaging and biomarkers) and early treatment.

The thermal properties of epoxy composites filled with boric acid fine powder at different percentage were studied. Epoxy composites were prepared using epoxy resin ED-20, boric acid as flame-retardant filler, hexamethylenediamine as a curing agent. The prepared samples and starting materials were examined using methods of thermal analysis, scanning electron microscopy and infrared spectroscopy. It was found that the incorporation of boric acid fine powder enhances the thermal stability of epoxy composites.

In Alzheimer’s disease (AD), one of the early responses to Aβ amyloidosis is recruitment of microglia to areas of new plaque. Microglial receptors such as cannabinoid receptor 2 (CB2) might be a suitable target for development of PET radiotracers that could serve as imaging biomarkers of Aβ-induced neuroinflammation. Mouse models of amyloidosis (J20APPswe/ind and APPswe/PS1ΔE9) were used to investigate the cellular distribution of CB2 receptors. Specificity of CB2 antibody (H60) was confirmed using J20APPswe/ind mice lacking CB2 receptors. APPswe/PS1ΔE9 mice were used in small animal PET with a CB2-targeting radiotracer, [11C]A836339. These studies revealed increased binding of [11C]A836339 in amyloid-bearing mice. Specificity of the PET signal was confirmed in a blockade study with a specific CB2 antagonist, AM630. Confocal microscopy revealed that CB2-receptor immunoreactivity was associated with astroglial (GFAP) and, predominantly, microglial (CD68) markers. CB2 receptors were observed, in particular, in microglial processes forming engulfment synapses with Aβ plaques. In contrast to glial cells, neuron (NeuN)-derived CB2 signal was equal between amyloid-bearing and control mice. The pattern of neuronal CB2 staining in amyloid-bearing mice was similar to that in human cases of AD. The data collected in this study indicate that Aβ amyloidosis without concomitant tau pathology is sufficient to activate CB2 receptors that are suitable as an imaging biomarker of neuroinflammation. The main source of enhanced CB2 PET binding in amyloid-bearing mice is increased CB2 immunoreactivity in activated microglia. The presence of CB2 immunoreactivity in neurons does not likely contribute to the enhanced CB2 PET signal in amyloid-bearing mice due to a lack of significant neuronal loss in this model. However, significant loss of neurons as seen at late stages of AD might decrease the CB2 PET signal due to loss of neuronally-derived CB2. Thus this study in mouse models of AD indicates that a CB2-specific radiotracer can be used as a biomarker of neuroinflammation in the early preclinical stages of AD, when no significant neuronal loss has yet developed.

Transgenic mice that express mutant amyloid precursor protein (APPsi) using tet-Off vector systems provide an alternative model for assessing short- and long-term effects of Aβ-targeting therapies on phenotypes related to the deposition of Alzheimer-type amyloid. Here we use such a model, termed APPsi:tTA, to determine what phenotypes persist in mice with high amyloid burden after new production of APP/Aβ has been suppressed. We find that 12- to 13-month-old APPsi:tTA mice are impaired in cognitive tasks that assess short- and long-term memories. Acutely suppressing new APPsi/Aβ production produced highly significant improvements in performing short-term spatial memory tasks, which upon continued suppression translated to superior performance in more demanding tasks that assess long-term spatial memory and working memory. Deficits in episodic-like memory and cognitive flexibility, however, were more persistent. Arresting mutant APPsi production caused a rapid decline in the brain levels of soluble APP ectodomains, full-length APP, and APP C-terminal fragments. As expected, amyloid deposits persisted after new APP/Aβ production was inhibited, whereas, unexpectedly, we detected persistent pools of solubilizable, relatively mobile, Aβ42. Additionally, we observed persistent levels of Aβ-immunoreactive entities that were of a size consistent with SDS-resistant oligomeric assemblies. Thus, in this model with significant amyloid pathology, a rapid amelioration of cognitive deficits was observed despite persistent levels of oligomeric Aβ assemblies and low, but detectable solubilizable Aβ42 peptides. These findings implicate complex relationships between accumulating Aβ and activities of APP, soluble APP ectodomains, and/or APP C-terminal fragments in mediating cognitive deficits in this model of amyloidosis.

As only symptomatic treatments are now available for Alzheimer's disease (AD), safe and effective mechanism-based therapies remain a great unmet need for patients with this neurodegenerative disease. Although gamma-secretase and BACE1 [beta-site beta-amyloid (Abeta) precursor protein (APP) cleaving enzyme 1] are well-recognized therapeutic targets for AD, untoward side effects associated with strong inhibition or reductions in amounts of these aspartyl proteases have raised concerns regarding their therapeutic potential. Although moderate decreases of either gamma-secretase or BACE1 are not associated with mechanism-based toxicities, they provide only modest benefits in reducing Abeta in the brains of APPswe/PS1DeltaE9 mice. Because the processing of APP to generate Abeta requires both gamma-secretase and BACE1, it is possible that moderate reductions of both enzymes would provide additive and significant protection against Abeta amyloidosis. Here, we test this hypothesis and assess the value of this novel anti-amyloid combination therapy in mutant mice. We demonstrate that genetic reductions of both BACE1 and gamma-secretase additively attenuate the amyloid burden and ameliorate cognitive deficits occurring in aged APPswe/PS1DeltaE9 animals. No evidence of mechanism-based toxicities was associated with such decreases in amounts of both enzymes. Thus, we propose that targeting both gamma-secretase and BACE1 may be an effective and safe treatment strategy for AD.

Cyclooxygenase-2 (COX-2) is a neuronal immediate early gene that is regulated by N-methyl d aspartate (NMDA) receptor activity. COX-2 enzymatic activity catalyzes the first committed step in prostaglandin synthesis. Recent studies demonstrate an emerging role for the downstream PGE2 EP2 receptor in diverse models of activity-dependent synaptic plasticity and a significant function in models of neurological disease including cerebral ischemia, Familial Alzheimer's disease, and Familial amyotrophic lateral sclerosis. Little is known, however, about the normal function of the EP2 receptor in behavior and cognition. Here we report that deletion of the EP2 receptor leads to significant cognitive deficits in standard tests of fear and social memory. EP2−/− mice also demonstrated impaired prepulse inhibition (PPI) and heightened anxiety, but normal startle reactivity, exploratory behavior, and spatial reference memory. This complex behavioral phenotype of EP2−/− mice was associated with a deficit in long-term depression (LTD) in hippocampus. Our findings suggest that PGE2 signaling via the EP2 receptors plays an important role in cognitive and emotional behaviors that recapitulate some aspects of human psychopathology related to schizophrenia.

Administration of non-steroidal anti-inflammatory agents reduces the risk of developing Alzheimer's disease in normal aging populations, an effect that may occur from inhibition of the cyclooxygenases, the rate-limiting enzymes in the formation of prostaglandins. In this study, we investigated whether increased activity of cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, potentiates disease progression in a transgenic mouse model of Alzheimer's disease. To study the functional effects of COX-2 activity, male and female bigenic mice (amyloid precursor protein with Swedish mutation [APPswe]-presenilin-1 protein with deletion of exon 9 [PS1dE9] and trigenic COX-2/APPswe-PS1dE9) were behaviorally tested +/-administration of the selective COX-2 inhibitor celecoxib. Behavioral testing included a three-trial Y maze that measures spatial working and recognition memories and an open field task that tested levels of hyperactivity. Overexpression of COX-2 in APPswe-PS1dE9 mice resulted in specific deficits in spatial working memory in female but not male mice. These sex-specific deficits were abolished by pharmacological inhibition of COX-2 activity. Importantly, COX-2-associated deficits were dependent on co-expression of all three transgenes since COX-2 single transgenic and APPswe-PS1dE9 bigenic mice showed normal memory. Quantification of amyloid plaque load and total Abeta 40 and 42 peptides did not reveal significant differences in trigenic versus bigenic mice treated with either vehicle or celecoxib. Taken together, these data indicate an interaction between the effects of COX-2 and Abeta peptides on cognition that occurs in a sex-specific manner in the absence of significant changes in amyloid burden. These findings suggest that pathological activation of COX-2 may potentiate the toxicity of Abeta peptides, particularly in females, without significantly affecting Abeta accumulation.

Epidemiological studies suggest that individuals with greater education or more cognitively demanding occupations have diminished risk of developing dementia. We wanted to test whether this effect could be recapitulated in rodents using environmental enrichment, a paradigm well documented to attenuate behavioral deficits induced by various pathological insults. Here, we demonstrate that learning and memory deficits observed in a transgenic mouse model of Alzheimer's disease can be ameliorated by enrichment. Female transgenic mice overexpressing amyloid precursor protein and/or presenilin-1 and nontransgenic controls were placed into enriched or standard cages at 2 months of age and tested for cognitive behavior after 6 months of differential housing. Enrichment significantly improved performance of all genotypes in the radial water maze and in the classic and repeated-reversal versions of the Morris water maze. However, enrichment did not benefit all genotypes equally. Mice overproducing amyloid-β (Aβ), particularly those with amyloid deposits, showed weaker memory for the platform location in the classic Morris water maze and learned new platform positions in the repeated-reversals task less quickly than their nontransgenic cagemates. Nonetheless, enrichment normalized the performance of Aβ-overproducing mice to the level of standard-housed nontransgenic mice. Moreover, this functional preservation occurred despite increased neuritic plaque burden in the hippocampus of double-transgenic animals and elevated steady-state Aβ levels, because both endogenous and transgene-derived Aβ are increased in enriched animals. These results demonstrate that the generation of Aβin vivoand its impact on the function of the nervous system can be strongly modulated by environmental factors.

Transgenic mice made by crossing animals expressing mutant amyloid precursor protein (APPswe) to mutant presenilin 1 (PS1dE9) allow for incremental increases in Abeta42 production and provide a model of Alzheimer-type amyloidosis. Here, we examine cognition in 6- and 18-month old transgenic mice expressing APPswe and PS1dE9, alone and in combination. Spatial reference memory was assessed in a standard Morris Water Maze task followed by assessment of episodic-like memory in Repeated Reversal and Radial Water maze tasks. We then used factor analysis to relate changes in performance in these tasks with cholinergic markers, somatostatin levels, and amyloid burden. At 6 months of age, APPswe/PS1dE9 double-transgenic mice showed visible plaque deposition; however, all genotypes, including double-transgenic mice, were indistinguishable from nontransgenic animals in all cognitive measures. In the 18-month-old cohorts, amyloid burdens were much higher in APPswe/PS1dE9 mice with statistically significant but mild decreases in cholinergic markers (cortex and hippocampus) and somatostatin levels (cortex). APPswe/PS1dE9 mice performed all cognitive tasks less well than mice from all other genotypes. Factor and correlation analyses defined the strongest correlation as between deficits in episodic-like memory tasks and total Abeta loads in the brain. Collectively, we find that, in the APPswe/PS1dE9 mouse model, some form of Abeta associated with amyloid deposition can disrupt cognitive circuits when the cholinergic and somatostatinergic systems remain relatively intact; and that episodic-like memory seems to be more sensitive to the toxic effects of Abeta.

Objective Microsurgical fenestration of the third ventricular floor performed in one session with resection of deep seated tumors has been recently demonstrated as an approach to specifically address the concomitant obstructive hydrocephalus. As with endoscopic third ventriculostomy, occlusion of the stoma may result in progression of the obstructive hydrocephalus. In order to provide reliable communication between the basal cisterns and ventricles, we propose stenting of the stoma in cases of direct surgical approach to deep seated tumors. Methods After performing tumor resection through the anterior transcallosal approach, premamillar and Liliequist's membranes were identified and fenestrated. A silicon stent was inserted into the prepontine cistern through the fenestrated floor of the third ventricle; the stent connected the third and lateral ventricles with the basal cisterns. Results Microsurgical ventriculostomy of the third ventricle and stenting of the stoma was performed in 9 patients simultaneously with tumor resection (5 cases), open biopsy (3 cases), or microsurgical dissection of severe adhesions at the level of Monro foramina (1 case). In 7 cases, the third ventricular floor was infiltrated with the tumor and obstruction of the aqueduct persisted after tumor surgery; in 2 patients, high risk of reocclusion at the level of Monro foramen was expected. Stenting of the ventricular system provided patency of the stoma and Monro foramen. None of the patients required a shunt postoperatively. The follow-up time ranged from 3 to 22 months. Conclusion Microsurgical fenestration of the third ventricle floor combined with stoma stenting can be a viable option for hydrocephalus control.

Our paper reported an analysis of a mouse genetic model that deletes the C terminus of Shank3 to mimic human mutations that cause autism spectrum disorder. Figure panels for several polyubiquitination assays were improperly assembled, leading to multiple repetitions of bands in western blots of the lysates. These errors did not affect the quantitative analysis of polyubiquitination because this analysis was performed as described and was not dependent on representative western blot images. In light of the figure preparation issues, we feel that the most responsible course of action is to retract the paper. We sincerely apologize to the scientific community for any misunderstanding that these errors may have caused.