Long-term mortality of critically ill patients with cancer and delirium who survived to discharge: a retrospective cohort study.

PURPOSE: Delirium is common in critically ill patients and has been associated with lower short-term survival; however, its association with long-term survival has been scarcely evaluated and few studies have shown divergent results. METHODS: We conducted a retrospective cohort study of adult patients with cancer admitted to the intensive care unit (ICU) and discharged from hospital from January 2015 to December 2018. We considered delirium present if the Confusion Assessment Method for Intensive Care Unit (CAM-ICU) result was positive. We assessed the association between delirium during ICU stay and long-term mortality (up to three years after discharge). We also assessed the association between delirium type (hypoactive, hyperactive, and mixed) with long-term mortality. RESULTS: We included 3,079 patients. Of these, 430 (14%) were considered delirious at some point during their ICU stay. Delirium was associated with one-year mortality after hospital discharge (hazard ratio [HR], 1.58; 95% confidence interval [CI], 1.36 to 1.83) after adjustment for potential confounders, but not with one to three year-mortality (HR, 0.92; 95% CI, 0.61 to 1.39). Hypoactive and mixed delirium were associated with one-year mortality (HR, 1.77; 95% CI, 1.46 to 2.14 and HR, 1.56; 95% CI, 1.21 to 2.00, respectively), but none of the delirium motor types was associated with one to three-year mortality. CONCLUSIONS: We observed that delirium during ICU stay was associated with increased one-year mortality, but was not with mortality after one year. This association was observed in hypoactive and mixed delirium types but not with hyperactive delirium.

RéSUMé: OBJECTIF: Le delirium est fréquent chez la patientèle gravement malade et a été associé à une survie réduite à court terme; son association avec la survie à long terme n'a cependant que très peu été évaluée et les rares études ont affiché des résultats divergents. MéTHODE: Nous avons mené une étude de cohorte rétrospective de patient·es adultes atteint·es de cancer admis·es à l'unité de soins intensifs (USI) et ayant reçu leur congé de l'hôpital entre janvier 2015 et décembre 2018. Nous avons considéré qu'un delirium était présent si le résultat de la Méthode d'évaluation de la confusion pour l'unité de soins intensifs (CAM-USI) était positif. Nous avons évalué l'association entre le delirium pendant le séjour aux soins intensifs et la mortalité à long terme (jusqu'à trois ans après le congé). Nous avons également évalué l'association entre le type de delirium (hypoactif, hyperactif et mixte) et la mortalité à long terme. RéSULTATS: Nous avons inclus 3079 patient·es. De ce nombre, 430 (14 %) personnes ont été considérées comme en delirium à un moment donné pendant leur séjour à l'USI. Le delirium était associé à la mortalité à un an après le congé de l'hôpital (rapport de risque [RR], 1,58; intervalle de confiance [IC] à 95%, 1,36 à 1,83) et après ajustement des données pour tenir compte des facteurs de confusion potentiels, mais pas à la mortalité d'un à trois ans après le congé (RR, 0,92; IC 95%, 0,61 à 1,39). Les deliriums hypoactif et mixte étaient associés à la mortalité à un an (RR, 1,77; IC 95 %, 1,46 à 2,14 et RR, 1,56; IC 95 %, 1,21 à 2,00, respectivement), mais aucun des types moteurs de delirium n'était associé à la mortalité d'un à trois ans. CONCLUSION: Nous avons observé qu'un delirium pendant le séjour à l'USI était associé à une augmentation de la mortalité à un an, mais pas à la mortalité après un an. Cette association a été observée dans les types de delirium hypoactif et mixte, mais pas avec le type hyperactif.

In Utero Exposure to Zika Virus Results in sex-Specific Memory Deficits and Neurological Alterations in Adult Mice.

SUMMARY STATEMENT: In utero exposure to ZIKV leads to decreased number of neurons in adult mice. Female mice exposed to ZIKV in utero exhibit lower levels of BDNF, a decrease in synaptic markers, memory deficits, and risk-taking behavior during adulthood.

mGluR5 ablation leads to age-related synaptic plasticity impairments and does not improve Huntington's disease phenotype.

Glutamate receptors, including mGluR5, are involved in learning and memory impairments triggered by aging and neurological diseases. However, each condition involves distinct molecular mechanisms. It is still unclear whether the mGluR5 cell signaling pathways involved in normal brain aging differ from those altered due to neurodegenerative disorders. Here, we employed wild type (WT), mGluR5-/-, BACHD, which is a mouse model of Huntington's Disease (HD), and mGluR5-/-/BACHD mice, at the ages of 2, 6 and 12 months, to distinguish the mGluR5-dependent cell signaling pathways involved in aging and neurodegenerative diseases. We demonstrated that the memory impairment exhibited by mGluR5-/- mice is accompanied by massive neuronal loss and decreased dendritic spine density in the hippocampus, similarly to BACHD and BACHD/mGluR5-/- mice. Moreover, mGluR5 ablation worsens some of the HD-related alterations. We also show that mGluR5-/- and BACHD/mGluR5-/- mice have decreased levels of PSD95, BDNF, and Arc/Arg3.1, whereas BACHD mice are mostly spared. PSD95 expression was affected exclusively by mGluR5 ablation in the aging context, making it a potential target to treat age-related alterations. Taken together, we reaffirm the relevance of mGluR5 for memory and distinguish the mGluR5 cell signaling pathways involved in normal brain aging from those implicated in HD.

Metabotropic glutamate receptor 5 knockout rescues obesity phenotype in a mouse model of Huntington's disease.

Obesity represents a global health problem and is characterized by metabolic dysfunctions and a low-grade chronic inflammatory state, which can increase the risk of comorbidities, such as atherosclerosis, diabetes and insulin resistance. Here we tested the hypothesis that the genetic deletion of metabotropic glutamate receptor 5 (mGluR5) may rescue metabolic and inflammatory features present in BACHD mice, a mouse model of Huntington's disease (HD) with an obese phenotype. For that, we crossed BACHD and mGluR5 knockout mice (mGluR5-/-) in order to obtain the following groups: Wild type (WT), mGluR5-/-, BACHD and BACHD/mGluR5-/- (double mutant mice). Our results showed that the double mutant mice present decreased body weight as compared to BACHD mice in all tested ages and reduced visceral adiposity as compared to BACHD at 6 months of age. Additionally, 12-month-old double mutant mice present increased adipose tissue levels of adiponectin, decreased leptin levels, and increased IL-10/TNF ratio as compared to BACHD mice. Taken together, our preliminary data propose that the absence of mGluR5 reduce weight gain and visceral adiposity in BACHD mice, along with a decrease in the inflammatory state in the visceral adipose tissue (VAT), which may indicate that mGluR5 may play a role in adiposity modulation.

Aß oligomers induce pathophysiological mGluR5 signaling in Alzheimer's disease model mice in a sex-selective manner.

The prevalence, presentation, and progression of Alzheimer's disease (AD) differ between men and women, although ß-amyloid (Aß) deposition is a pathological hallmark of AD in both sexes. Aß-induced activation of the neuronal glutamate receptor mGluR5 is linked to AD progression. However, we found that mGluR5 exhibits distinct sex-dependent profiles. Specifically, mGluR5 isolated from male mouse cortical and hippocampal tissues bound with high affinity to Aß oligomers, whereas mGluR5 from female mice exhibited no such affinity. This sex-selective Aß-mGluR5 interaction did not appear to depend on estrogen, but rather Aß interaction with cellular prion protein (PrPC), which was detected only in male mouse brain homogenates. The ternary complex between mGluR5, Aß oligomers, and PrPC was essential to elicit mGluR5-dependent pathological suppression of autophagy in primary neuronal cultures. Pharmacological inhibition of mGluR5 reactivated autophagy, mitigated Aß pathology, and reversed cognitive decline in male APPswe/PS1ΔE9 mice, but not in their female counterparts. Aß oligomers also bound with high affinity to human mGluR5 isolated from postmortem donor male cortical brain tissue, but not that from female samples, suggesting that this mechanism may be relevant to patients. Our findings indicate that mGluR5 does not contribute to Aß pathology in females, highlighting the complexity of mGluR5 pharmacology and Aß signaling that supports the need for sex-specific stratification in clinical trials assessing AD therapeutics.

mGluR5 regulates REST/NRSF signaling through N-cadherin/ß-catenin complex in Huntington's disease.

Repressor element 1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a transcription repressor and its expression is regulated by the Wnt pathway through ß-catenin. Metabotropic glutamate receptor 5 (mGluR5) signaling plays a key role in controlling neuronal gene expression. Interestingly, REST/NRSF nuclear translocation and signaling, as well as mGluR5 signaling are altered in the presence of mutant huntingtin. It remains unclear whether mGluR5 can modulate Wnt and REST/NRSF signaling under physiological conditions and whether this modulation is altered in Huntington's disease (HD). Using primary corticostriatal neurons derived from wild type mouse embryos, we find that targeting mGluR5 using the agonist, DHPG, or the negative allosteric modulator, CTEP, modulates REST/NRSF expression by regulating the assembly of N-cadherin/ ß-catenin complex in a Src kinase-dependent manner. We have validated our in vitro findings in vivo using two HD mouse models. Specifically, we show that pharmacological inhibition of mGluR5 in zQ175 mice and genetic ablation of mGluR5 in BACHD mice corrected the pathological activation of Src and rescued REST/NRSF-dependent signaling. Together, our data provide evidence that mGluR5 regulates REST/NRSF expression via the Wnt pathway and highlight the contribution of impaired REST/ NRSF signaling to HD pathology.

Metabotropic glutamate receptor 5 ablation accelerates age-related neurodegeneration and neuroinflammation.

The growing elderly population world widely prompts the need for studies regarding aged brain and its susceptibility to neurodegenerative diseases. It has been shown that aged brain exhibits several alterations, including neuroinflammation, which prone this organ to neurodegenerative processes. Metabotropic glutamate receptor 5 (mGlu5 receptor) has a role in neuronal cell loss and inflammation. Although the relevance of mGlu5 receptor in different diseases has been investigated, its involvement in normal brain aging remains unclear. In the present study, we used the mGlu5 receptor knockout (mGluR5-/-) mice, a model of Huntington's Disease (BACHD), and the double mutant mice (mGluR5-/-/BACHD), at the ages of 2, 6 and 12 months, to investigate whether mGlu5 receptor has a role in brain aging. We demonstrated that mGluR5-/- mice exhibit diminished number of neurons at 12 months of age in the cortex and striatum, similarly to what was observed in the case of BACHD and mGluR5-/-/BACHD mice. In addition, ablation of mGlu5 receptor increased the number of astrocytes and microglia in BACHD and wild type (WT) mice in an age-dependent manner in the cortical region, but not in the striatum. Interestingly, 12-month-old mGluR5-/- mice induced microglia activation, evidenced by increased CD68 expression and diminished number of microglia ramifications in skeleton analyses. Importantly, the presence of mutant huntingtin and the absence of mGlu5 receptor promoted decreased levels of fractalkine expression in aged mice, which could account for the decreased levels of microglia activation in these mice. Together, our data provide evidence that mGlu5 receptor plays a role in brain aging by modulating different cell types in the central nervous system (CNS).

The mGluR5 positive allosteric modulator VU0409551 improves synaptic plasticity and memory of a mouse model of Huntington's disease.

Huntington's Disease (HD) is an autosomal-dominant neurodegenerative disorder, characterized by involuntary body movements, cognitive impairment, and psychiatric disorder. The metabotropic glutamate receptor 5 (mGluR5) plays an important role in HD and we have recently demonstrated that mGluR5-positive allosteric modulators (PAMs) can ameliorate pathology and the phenotypic signs of a mouse model of HD. In this study, we investigated the molecular mechanisms involved in mGluR5 PAMs effect on memory. Our results demonstrate that subchronic treatment with the mGluR5 PAM VU0409551 was effective in reversing the memory deficits exhibited by BACHD mice, a mouse model for HD. Moreover, VU0409551 treatment stabilized mGluR5 at the cellular plasma membrane of BACHD mice, increasing the expression of several genes important for synaptic plasticity, including c-Fos, brain-derived neurotrophic factor, Arc/Arg3.1, syntaxin 1A, and post-synaptic density-95. In addition, VU0409551 treatment also increased dendritic spine density and maturation and augmented the number of pre-synaptic sites. In conclusion, our results demonstrate that VU0409551 triggered the activation of cell signaling pathways important for synaptic plasticity, enhancing the level of dendritic spine maturation and rescuing BACHD memory impairment. OPEN PRACTICES: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/.

Animal Toxins as Therapeutic Tools to Treat Neurodegenerative Diseases.

Neurodegenerative diseases affect millions of individuals worldwide. So far, no disease-modifying drug is available to treat patients, making the search for effective drugs an urgent need. Neurodegeneration is triggered by the activation of several cellular processes, including oxidative stress, mitochondrial impairment, neuroinflammation, aging, aggregate formation, glutamatergic excitotoxicity, and apoptosis. Therefore, many research groups aim to identify drugs that may inhibit one or more of these events leading to neuronal cell death. Venoms are fruitful natural sources of new molecules, which have been relentlessly enhanced by evolution through natural selection. Several studies indicate that venom components can exhibit selectivity and affinity for a wide variety of targets in mammalian systems. For instance, an expressive number of natural peptides identified in venoms from animals, such as snakes, scorpions, bees, and spiders, were shown to lessen inflammation, regulate glutamate release, modify neurotransmitter levels, block ion channel activation, decrease the number of protein aggregates, and increase the levels of neuroprotective factors. Thus, these venom components hold potential as therapeutic tools to slow or even halt neurodegeneration. However, there are many technological issues to overcome, as venom peptides are hard to obtain and characterize and the amount obtained from natural sources is insufficient to perform all the necessary experiments and tests. Fortunately, technological improvements regarding heterologous protein expression, as well as peptide chemical synthesis will help to provide enough quantities and allow chemical and pharmacological enhancements of these natural occurring compounds. Thus, the main focus of this review is to highlight the most promising studies evaluating animal toxins as therapeutic tools to treat a wide variety of neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, brain ischemia, glaucoma, amyotrophic lateral sclerosis, and multiple sclerosis.

Estradiol enhances object recognition memory in Swiss female mice by activating hippocampal estrogen receptor α.

In rodents, 17ß-estradiol (E2) enhances hippocampal function and improves performance in several memory tasks. Regarding the object recognition paradigm, E2 commonly act as a cognitive enhancer. However, the types of estrogen receptor (ER) involved, as well as the underlying molecular mechanisms are still under investigation. In the present study, we asked whether E2 enhances object recognition memory by activating ERα and/or ERß in the hippocampus of Swiss female mice. First, we showed that immediately post-training intraperitoneal (i.p.) injection of E2 (0.2 mg/kg) allowed object recognition memory to persist 48 h in ovariectomized (OVX) Swiss female mice. This result indicates that Swiss female mice are sensitive to the promnesic effects of E2 and is in accordance with other studies, which used C57/BL6 female mice. To verify if the activation of hippocampal ERα or ERß would be sufficient to improve object memory, we used PPT and DPN, which are selective ERα and ERß agonists, respectively. We found that PPT, but not DPN, improved object memory in Swiss female mice. However, DPN was able to improve memory in C57/BL6 female mice, which is in accordance with other studies. Next, we tested if the E2 effect on improving object memory depends on ER activation in the hippocampus. Thus, we tested if the infusion of intra-hippocampal TPBM and PHTPP, selective antagonists of ERα and ERß, respectively, would block the memory enhancement effect of E2. Our results showed that TPBM, but not PHTPP, blunted the promnesic effect of E2, strongly suggesting that in Swiss female mice, the ERα and not the ERß is the receptor involved in the promnesic effect of E2. It was already demonstrated that E2, as well as PPT and DPN, increase the phospho-ERK2 level in the dorsal hippocampus of C57/BL6 mice. Here we observed that PPT increased phospho-ERK1, while DPN decreased phospho-ERK2 in the dorsal hippocampus of Swiss female mice subjected to the object recognition sample phase. Taken together, our results suggest that the type of receptor as well as the molecular mechanism used by E2 to improve object memory may differ in Swiss female mice.