Brain Disorders Research Articles

Electrochemical Sensing of Dopamine with an Implantable Microelectrode Array Microprobe Including an On-Probe Iridium Oxide Reference Electrode.

Inclusion of an on-probe iridium oxide (IrOx) reference electrode on an implantable microelectrode array (MEA) microprobe enabled dopamine (DA) sensing with high sensitivity, an ultralow limit of detection, and high selectivity against common electroactive interferents. The monitoring of DA signaling in vivo is important for the study of brain disorders such as Parkinson's disease and substance abuse. A postfabrication method for electrochemical deposition of an IrOx film onto a targeted microelectrode enabled integration of an IrOx reference electrode (RE) onto the same MEA as the DA sensing, working electrode (WE). The on-probe IrOx RE is an attractive alternative to commonly used external Ag/AgCl wire REs, which can be unstable and can cause inflammatory responses in vivo. The on-probe IrOx RE was tested for support of DA sensing performance in two-electrode (i.e., WE and RE) and three-electrode (i.e., WE, RE and counter electrode) configurations. The sensitivities of the integrated and externally referenced DA sensing microprobes were comparable at ∼2500 nA/(μM·cm2), however the integrated three-electrode configuration exhibited a 6-fold lower limit of detection of ∼9 nM due to an 82% reduction in baseline noise. In addition, excellent 1000:1 selectivity against common electroactive interferents makes these DA sensing microprobes attractive for implementation in vivo.

Alterations of Adult Prefrontal Circuits Induced by Early Postnatal Fluoxetine Treatment Mediated by 5-HT7 Receptors.

The prefrontal cortex (PFC) plays a key role in high-level cognitive functions and emotional behaviors, and PFC alterations correlate with different brain disorders including major depression and anxiety. In mice, the first two postnatal weeks represent a critical period of high sensitivity to environmental changes. In this temporal window, serotonin (5-HT) levels regulate the wiring of PFC cortical neurons. Early-life insults and postnatal exposure to the selective serotonin reuptake inhibitor fluoxetine (FLX) affect PFC development leading to depressive and anxiety-like phenotypes in adult mice. However, the mechanisms responsible for these dysfunctions remain obscure. We found that early postnatal FLX exposure (PNFLX) results in reduced overall firing and high-frequency bursting of putative pyramidal neurons (PNs) of deep layers of the medial PFC of adult mice of both sexes in vivo. Ex vivo, patch-clamp recordings revealed that PNFLX abolished high-frequency firing in a distinct subpopulation of deep-layer mPFC PNs, which transiently express the serotonin transporter SERT during the first 2 postnatal weeks. SERT+ and SERT- PNs exhibit distinct morphofunctional properties. Genetic deletion of 5-HT7Rs and pharmacological 5-HT7R blockade partially rescued both the PNFLX-induced reduction of PN firing in vivo and the altered firing of SERT+ PNs in vitro. This indicates a pivotal role of this 5-HTR subtype in mediating 5-HT-dependent maturation of PFC circuits that are susceptible to early-life insults. Overall, our results suggest potential novel neurobiological mechanisms, underlying detrimental neurodevelopmental consequences induced by early-life alterations of 5-HT levels.

Transcriptomic Regulation by Astrocytic m6A Methylation in the mPFC.

Astrocytes, the most prevalent type of glial cells, have been found to play a crucial part in numerous physiological functions. By offering metabolic and structural support, astrocytes are vital for the proper functioning of the brain and regulating information processing and synaptic transmission. Astrocytes located in the medial prefrontal cortex (mPFC) are highly responsive to environmental changes and have been associated with the development of brain disorders. One of the primary mechanisms through which the brain responds to environmental factors is epitranscriptome modification. M6-methyladenosine methylation is the most prevalent internal modification of eukaryotic messenger RNA (mRNA), and it significantly impacts transcript processing and protein synthesis. However, the effects of m6A on astrocyte transcription and function are still not well understood. Our research demonstrates that ALKBH5, an RNA demethylase of m6A found in astrocytes, affects gene expression in the mPFC. These findings suggest that further investigation into the potential role of astrocyte-mediated m6A methylation in the mPFC is warranted.

Intranasal Delivery of Paclitaxel-Loaded Ligand Conjugated Polymeric Nanoparticles for Targeted Brain Delivery.

Compared to the conventional blood-brain barrier crossing over, nose-to-brain delivery provides a potentially effective substitution, particularly when large molecules of drugs need to be delivered. The majority of macromolecules degrade quickly in a physiological environment. Therefore, drug molecules can be protected against early breakdown by using nanocarrier systems. Targeting nanocarrier system with ligand potential of enhancing bioavailability due to tailored binding affinity to targeting site. In the current study, we prepared paclitaxel (PTX)loaded ascorbic acid (AA) conjugated polycaprolactone (PCL) nanoparticles (NPs) for intranasal administration. Polymeric nanoparticles (PNPs) were prepared using the solvent evaporation method, which was further analyzed for particle size, polydispersity index (PDI), surface charge, encapsulation-efficiency (EE), drug loading (DL), surface morphology, in-vitro drug release, and in-vivo pharmacokinetic evaluation. Results showed the optimized PTX-PNPs showed particle size 114.7 ± 2.96nm, zeta potential -27.6 ± 1.63mV, with entrapment efficiency 97.3 ± 0.41%, and drug loading 35.3 ± 0.38%. In-vitro PTX release showed a biphasic release pattern, primary burst release followed by sustained release was observed. An in-vivo pharmacokinetic study showed a 5.6-fold increase in the PTX concentration reaching to the brain. Histopathological results of the nasal mucosa showed minimal alteration after 72h of administering surface-modified paclitaxel loaded polymeric nanoparticles (AA-PTX-PNPs). Thus, this study highlighted the suitability of a AA-PTX-PNPs as a promising strategy for intranasal administration therapy for various brain disorders.

Suppressing astrocytic GABA transaminase enhances tonic inhibition and weakens hippocampal spatial memory.

Pharmacological suppression of γ-aminobutyric acid (GABA) transaminase (GABA-T), the sole GABA-degrading enzyme and a potential therapeutic target for treating brain disorders such as epilepsy, increases not only phasic inhibition but also tonic inhibition. However, the specific cellular source, neuromodulatory effects and potential therapeutic benefits of this enhanced tonic inhibition remain unexplored due to the lack of cell-type-specific gene manipulation studies. Here we report that the increase in tonic GABA currents observed after GABA-T suppression is predominantly due to increased tonic GABA release from astrocytes rather than action-potential-dependent synaptic GABA spillover. General GABA-T knockdown (KD) by a short hairpin RNA considerably increased tonic GABA currents in dentate granule cells, thereby enhancing tonic inhibition. An astrocyte-specific rescue of GABA-T following general GABA-T KD normalized the elevated tonic GABA currents to near control levels. Tetrodotoxin-insensitive tonic GABA currents were significantly increased after general GABA-T KD, whereas tetrodotoxin-sensitive tonic GABA currents showed no significant increase, suggesting that this enhanced tonic inhibition is primarily action-potential independent. General GABA-T KD reduced the spike probability of granule cells and impaired dorsal hippocampus-dependent spatial memory, which were fully reversed by astrocyte-specific GABA-T rescue. These findings suggest that suppressing astrocytic GABA-T may be sufficient to influence the excitatory/inhibitory balance in the brain and associated behaviors. Our study implies that the therapeutic benefits of pharmacological GABA-T suppression may be largely attributed to the modulation of astrocytic GABA-T and its impact on tonic GABA release from astrocytes. Here, we report distinct effects of GABA-T suppression depending on cell type; suppressing GABA-T in astrocytes enhances tonic inhibition, while its suppression in GABAergic neurons augments phasic inhibition. Our findings demonstrate that targeted suppression of astrocytic GABA-T not only enhances tonic GABA release from astrocytes but also significantly influences the excitation/inhibition balance in the brain, with consequential effects on behavior. This suggests that astrocytic GABA-T modulation holds promising potential for developing novel therapeutic strategies aimed at treating cognitive and neurological disorders through the regulation of astrocytic GABA metabolism. GAD glutamate decarboxylase, MAO-B monoamine oxidase B, BEST1 bestrophin 1, GABA-T GABA transaminase, GAT GABA transporter, DG dentate gyrus, SSA succinic semialdehyde.

Identifying major depressive disorder based on cerebral blood flow and brain structure: An explainable multimodal learning study.

Magnetic resonance imaging (MRI) offers non-invasive assessments of brain structure and function for analyzing brain disorders. With the increasing accumulation of multimodal MRI data in recent years, integrating information from various modalities has become an effective strategy for improving the detection of brain disorders. This study focuses on identifying major depressive disorder (MDD) by using arterial spin labeling (ASL) perfusion MRI in conjunction with structural MRI data. We collected ASL and structural MRI data from 260 participants, including 169 MDD patients and 91 healthy controls. We developed an explainable fusion method to identify MDD, utilizing cerebral blood flow (CBF) data from ASL perfusion MRI and brain tissue volumes from structural MRI. The fusion model, which integrates multimodal data, demonstrated superior predictive performance for MDD. By combining MRI regional volumes with CBF data, we achieved more effective results than using each modality independently. Additionally, we analyzed feature importance and interactions to explain the fusion model. We identified fourteen important features, comprising eight regional volumes and six regional CBF measures, that played a crucial role in the identification of MDD. Furthermore, we found three feature interactions among the important features and seven interactions between structural and functional features, which were particularly prominent in the model. The results of this study suggest that the fusion learning approach, which integrates ASL and structural MRI data, is effective in detecting MDD. Moreover, the study demonstrates that the model explanation method can reveal key features that influence the decisions of models, as well as potential interactions among these key features or between functional and structural features in identifying MDD.

Circulating microRNAs and physical activity: Impact in diabetes.

The term "ci-miRNAs," or "circulating microRNAs," refers to extracellular microRNAs (miRNAs) that exist outside of cells and can be detected in various bodily fluids, including blood, saliva, urine, and breast milk. These ci-miRNAs play a role in regulating gene expression and are mainly recognized for their functions beyond the cell, serving as signaling molecules in the blood. Researchers have thoroughly investigated the roles of these circulating miRNAs in various diseases. The capacity to detect and quantify ci-miRNAs in bodily fluids suggests their potential as biomarkers for monitoring several health conditions, including cancer, heart disease, brain disorders, and metabolic disorders, where fluctuations in miRNA levels may correlate with different physiological and pathological states. Current methods enable researchers to identify and measure miRNAs in these fluids, facilitating the exploration of their roles in health maintenance and disease resistance. Although research on ci-miRNAs is ongoing, recent studies focus on uncovering their significance, assessing their viability as biomarkers, and clarifying their functions. However, our understanding of how various types, intensities, and durations of exercise influence the levels of these miRNAs in the bloodstream is still limited. This section seeks to provide an overview of the changes in ci-miRNAs in response to exercise.

Characterizing the microstructural transition at the gray matter-white matter interface: Implementation and demonstration of age-associated differences.

The cortical gray matter-white matter interface (GWI) is a natural transition zone where the composition of brain tissue abruptly changes and is a location for pathologic change in brain disorders. While diffusion magnetic resonance imaging (dMRI) is a reliable and well-established technique to characterize brain microstructure, the GWI is difficult to assess with dMRI due to partial volume effects and is normally excluded from such studies. In this study, we introduce an approach to characterize the dMRI microstructural profile across the GWI and to assess the sharpness of the microstructural transition from cortical gray matter (GM) to white matter (WM). This analysis includes cross-sectional data from a total of 146 participants (18-91 years; mean age: 52.4 (SD 21.4); 83 (57 %) female) enrolled in two normative lifespan cohorts at Albert Einstein College of Medicine from 2019 to 2023. We compute the aggregate GWI slope for each parameter, across each of 6 brain regions (cingulate, frontal, occipital, orbitofrontal, parietal, and temporal) for each participant. The association of GWI slope in each region with age was assessed using a linear model, with biological sex as a covariate. We demonstrate this method captures an inherent change in fractional anisotropy (FA), axial diffusivity (AD), orientation dispersion index (ODI) and intracellular volume fraction (ICVF) across the GWI that is characterized by small variance. We identified statistically significant associations of FA slope with age in all regions (p < 0.002 for all analyses), with FA slope magnitude inversely associated with higher age. Similar statistically significant age-related associations were found for AD slope in cingulate, occipital, and temporal regions, for ODI slope in parietal and occipital regions, and for ICVF slope in frontal, orbitofrontal, parietal, and temporal regions. The inverse association of slope magnitude with age indicates loss of the sharp GWI transition in aging, which is consistent with processes such as dendritic pruning, axonal degeneration, and inflammation. This method overcomes techniques issues related to interrogating the GWI. Beyond characterizing normal aging, it could be applied to explore pathological effects at this crucial, yet under-researched region.

Effects of Nickel Bioaccumulation on Hematological, Biochemical, Immune Responses, Neuroinflammatory, Oxidative Stress Parameters, and Neurotoxicity in Rats.

Nickel (Ni) exposure is linked to numerous health issues, including dermatitis, immunotoxicity, and cancer. Emerging evidence suggests Ni may cross the blood-brain barrier, accumulating in the brain and causing neuroinflammation, oxidative stress, and neuronal apoptosis. Herein, we investigated the effect of Ni exposure through the intraperitoneal route, studying the Ni effect in subacute and chronic toxicity, on various health parameters in Wistar rats. Rats were randomly divided into four groups (n = 10 per group): two groups received a daily intraperitoneal injection of NiCl₂ at a dose of 0.25mg/kg for subacute (21days) or chronic (60days) exposure periods, while the other two groups were treated with NaCl solution (0.9%) as a control for equivalent durations. The study assessed behavioral, biochemical, hematological, immunological, neurobiochemical, and histopathological effects over 21 and 60days. Neurobehavioral tests, blood and tissue analyses, and organ examinations were conducted. This study demonstrates that Ni bioaccumulation in subacute and chronic exposure has significant health impacts in Wistar rats, including hematological, immunological, biochemical, AchE activity, neuroinflammatory, oxidative stress, and neurobehavioral changes. Chronic exposure results in higher Ni accumulation, particularly in the brain, causing neurotoxicity, inflammation, and behavioral disorders such as anxiety, depression, and memory impairment. The findings highlight the importance of limiting Ni exposure to prevent adverse health effects.

Plexins: Navigating through the neural regulation and brain pathology.

Plexins are a family of transmembrane receptors known for their diverse roles in neural development, axon guidance, neuronal migration, synaptogenesis, and circuit formation. Semaphorins are a class of secreted and membrane proteins that act as primary ligands for plexin receptors. Semaphorins play a crucial role in central nervous system (CNS) development by regulating processes such as axonal growth, neuronal positioning, and synaptic connectivity. Various types of semaphorins like sema3A, sema4A, sema4C, sema4D, and many more have a crucial role in developing brain diseases. Likewise, various evidence suggests that plexin receptors are of four types: plexin A, plexin B, plexin C, and plexin D. Plexins have emerged as crucial regulators of neurogenesis and neuronal development and connectivity. When bound to semaphorins, these receptors trigger two major networking cascades, namely Rho and Ras GTPase networks. Dysregulation of plexin networking has been implicated in a myriad of brain disorders, including autism spectrum disorder (ASD), Schizophrenia, Alzheimer's disease (AD), Parkinson's disease (PD), and many more. This review synthesizes findings from molecular, cellular, and animal model studies to elucidate the mechanisms by which plexins contribute to the pathogenesis of various brain diseases.

Design, synthesis and biological evaluation of galantamine analogues for cognitive improvement in Alzheimer's disease.

Galantamine plays a crucial role in the management of brain disorders. In this study, a series of galantamine analogues were designed, synthesized and evaluated as potential therapeutic agents for Alzheimer's disease (AD). Compound C2, a dual inhibitor of cholinesterase, was obtained by introducing a benzylpyridine ring to the hydroxyl group of galantamine. Compared to galantamine (hAChE, IC50=1529±6nM), C2 exhibited excellent inhibitory activities against hAChE (IC50=513.90±9.60nM) and hBuChE (IC50=357.77±10.24nM). Further studies revealed that C2 possessed significant abilities to protect PC12cells from H2O2-induced apoptosis and reactive oxygen species (ROS) production. The acute toxicity test in vivo indicated that C2 exhibited a remarkable safety profile. Whether in the acute memory impairment induced by the Aβ1-42 model or in the amnesia induced by the scopolamine model, oral administration of C2 demonstrated superior improvement on cognition and spatial memory. In summary, both in vitro and in vivo results suggest that C2 deserves to be further explored as an anti-AD agent.

The Utility of Prolonged Chronic Unpredictable Stress to Study the Effects of Chronic Fluoxetine, Eicosapentaenoic Acid, and Lipopolysaccharide on Anxiety-Like Behavior and Hippocampal Transcriptomic Responses in Male Rats.

Chronic stress is a common trigger of multiple neuropsychiatric illnesses. Animal models are widely used to study stress-induced brain disorders and their interplay with neuroinflammation and other neuroimmune processes. Here, we apply the prolonged 12-week chronic unpredictable stress (PCUS) model to examine rat behavioral and hippocampal transcriptomic responses to stress and to chronic 4-week treatment with a classical antidepressant fluoxetine, an anti-inflammatory agent eicosapentaenoic acid (EPA), a pro-inflammatory agent lipopolysaccharide and their combinations. Overall, PCUS evoked anxiety-like behavioral phenotype in rats, corrected by chronic fluoxetine (alone or combined with other drugs), and EPA. PCUS also evoked pronounced transcriptomic responses in rat hippocampi, involving > 200 differentially expressed genes. While pharmacological manipulations did not affect hippocampal gene expression markedly, Gpr6, Drd2 and Adora2a were downregulated in stressed rats treated with fluoxetine, EPA and fluoxetine + EPA, suggesting their respective protein products (G protein-coupled receptor 6, dopamine D2 receptor and adenosine A2A receptor) as potential evolutionarily conserved targets under chronic stress. Overall, these findings support the validity of rat PCUS paradigm as a useful model to study stress-related anxiety pathogenesis, and call for further research probing how various conventional and novel drugs may (co)modulate behavioral and neurotranscriptomic biomarkers of chronic stress.

Transcriptional signature of a hypersensitive glucocorticoid receptor variant in the neuroendocrine system suggests enhanced vulnerability to brain disorders.

The natural substitution Ala610Val in the porcine glucocorticoid receptor (GRAla610Val) leads to a profound compensatory downregulation of the hypothalamic-pituitary-adrenal (HPA) axis in early ontogeny. In this study, we leveraged this unique animal model to explore mechanisms of HPA axis regulation and consequences of its genetically-based persistent hypoactivity. To this end, we examined transcriptional signature of GRAla610Val in the hypothalamus, hippocampus, amygdala and adrenal gland in resting conditions (i.e. baseline glucocorticoid level) using mRNA sequencing. In addition, we studied transcriptome responses to two different doses of dexamethasone in the hypothalamus and hippocampus, depending on GRAla610Val. Across tissues, GRAla610Val consistently influenced the expression of several clustered protocadherins, particularly PCDHB7. Clustered protocadherins play an important role in neuronal connectivity and are implicated in different neurobiological disorders. Moreover, in line with our previous findings in blood immune cells, we found higher expression of pro-inflammatory genes, including canonical members of the TLR4 signaling pathway, in the brain of Val carriers. While the pro-inflammatory priming occurs already at resting conditions in the amygdala, in hypothalamus and hippocampus this seems to be associated with a stronger downregulation of several marker genes of homeostatic microglia, such as SALL1, by dexamethasone in Val carriers. Regarding the regulation of the HPA axis, GRAla610Val showed a dose-dependent effect on the central regulator of the axis, CRH, suggesting a dynamic adaptation to the glucocorticoid hypersensitivity of the Val variant. In the adrenal gland, GRAla610Val appears to downregulate cortisol production by impairing mitochondrial function. Overall, the transcriptional signature of GRAla610Val provides strong evidence that GR hypersensitivity leads to increased susceptibility to brain disorders.

Neuroimmunometabolism: how metabolism orchestrates immune response in healthy and diseased brain.

Neuroimmunometabolism describes how neuroimmune cells, such as microglia, adapt their intracellular metabolic pathways to alter their immune functions in the central nervous system (CNS). Emerging evidence indicates that neurons also orchestrate the microglia-mediated immune response through neuro-immune cross talk, perhaps through metabolic signaling. However, little is known about how the brain's metabolic microenvironment and microglial intracellular metabolism orchestrate the neuroimmune response in healthy and diseased brains. This review addresses the balance of immunometabolic substrates in healthy and diseased brains, their metabolism by brain-resident microglia, and the potential impact of metabolic dysregulation of these substrates on the neuroimmune response and pathophysiology of psychiatric disorders. This review also suggests metabolic reprogramming of microglia as a preventive strategy for the management of neuroinflammation-related brain disorders, including psychiatric diseases.

Monoaminergic neurotransmitters are bimodal effectors of tau aggregation.

Neurotransmitters (NTs) mediate trans-synaptic signaling, and disturbances in their levels are linked to aging and brain disorders. Here, we ascribe an additional function for NTs in mediating intracellular protein aggregation by interaction with cytosolic protein fibrils. Cell-based seeding experiments revealed monoaminergic NTs as inhibitors of tau. Seeding is a disease-relevant mechanism involving catalysis by fibrils, leading to the aggregation of proteins in Alzheimer's disease and other neurodegenerative diseases. Chemotyping small molecules with varied backbone structures revealed determinants of aggregation inhibitors and catalysts. Among those identified were monoaminergic NTs. Dose titrations revealed bimodal effects indicative of fibril disaggregation, with aggregation catalysis occurring at low ratios of NTs and inhibited seeding ensuing at higher concentrations. Bimodal effects by NTs extend from in vitro systems to dopaminergic neurons, suggesting that pharmacotherapies that modify intracellular NT levels could shape the neuronal protein aggregation environment.

Characterizing the Spatial Patterns and Determinants of Cerebrospinal Fluid Pseudorandom Flow in the Human Brain with Low b-value Diffusion MRI

Abstract The circulation of cerebrospinal fluid (CSF) is essential for maintaining brain homeostasis and clearance, and impairments in its flow can lead to various brain disorders. Recent studies have shown that CSF effective motility can be interrogated using low b-value diffusion magnetic resonance imaging (low-b dMRI). Nevertheless, the spatial organization of intracranial CSF flow dynamics remains largely elusive. Here, we developed a whole-brain voxel-based analysis framework, termed CSF pseudo-diffusion spatial statistics (CΨSS), to examine CSF mean pseudo-diffusivity (MΨ), a measure of CSF flow magnitude derived from low-b dMRI. We showed that intracranial CSF MΨ demonstrates characteristic covariance patterns by employing seed-based correlation analysis. Next, we applied non-negative matrix factorization analysis to further elucidate the covariance patterns of CSF MΨ in a hypothesis-free, data-driven way. We identified ten distinct CSF compartments with high reproducibility and reliability, reflected by a high mean adjusted Rand index with a low standard deviation (0.82 [SD: 0.018]) in split-half analyses of the discovery multimodal aging dataset (n = 187). The identified patterns displayed similar MΨ across three replication datasets. In discovery and replication multimodal aging cohorts (unique n = 264), our study revealed that age, sex, brain atrophy, ventricular anatomy, and cerebral perfusion differentially influence MΨ across these CSF spaces. Notably, of the 35 individuals exhibited anomalous CSF flow patterns, five displayed clinically consequential incidental findings on multimodal neuroradiological examinations, which were not observed in other participants (p = 3.04×10-5). Our work sets forth a new paradigm to study CSF flow, with potential applications in clinical settings.

Beagles kept as companion animals in the UK – demography, disorders and mortality

BackgroundBeagles are a popular companion animal dog breed and are generally stated to be a healthy breed. This VetCompass study aimed to report the demography, common disorders and mortality of Beagles under primary veterinary care in the UK. Anonymised clinical records within VetCompass were followed over time to extract disorder and mortality data during 2019 on Beagles under primary veterinary care in the UK.ResultsBeagles comprised 19,906 (0.88%) of the 2,250,417 dogs in the study population. Annual proportional birth rates showed an increasing breed popularity from 0.41% of all dogs born in 2005 and peaking at 1.06% in 2012, followed by a decrease to 0.90% in 2019. The median adult bodyweight was 18.19 kg (IQR 15.68–21.07). From a random sample of Beagles (3,729/19,906, 18.73%), the most diagnosed disorders were obesity (24.27%, 95% CI: 22.89–25.65), periodontal disease (17.78%, 95% CI: 16.55–19.01), overgrown nail(s) (11.61%, 95% CI: 10.58–12.64), otitis externa (11.18%, 95% CI: 10.17–12.19) and anal sac impaction (10.59%, 95% CI 9.60-11.58). Once disorders were grouped by pathology, the most common group-level disorders were obesity (24.27%, 95% CI: 22.89–25.65), dental disorders (21.48%, 95% CI: 20.16–22.80), ear disorders (13.62%, 95% CI: 12.52–14.72), claw/nail disorders (13.14%, 95% CI: 12.06–14.22) and anal sac disorders (11.10%, 95% CI: 10.09–12.11). The median age at death was 11.28 years (IQR 9.32–13.08) for 322 deaths recorded during the study period. The most common causes of death at group level were neoplasia (19.26%, 95% CI: 14.76–23.75), mass (13.18%, 95% CI: 9.32–17.03), poor quality of life (12.84%, 95% CI: 9.03–16.65), and brain disorders (6.76%, 95% CI: 3.90–9.62).ConclusionsTheir disorder profile suggests the Beagle breed should not be considered to have an extreme conformation. Owners and veterinary teams should put special emphasis on care related to bodyweight control and dental hygiene in Beagles. Their median age at death of 11.70 years suggests reasonable overall health but neoplasia is a common biomedical cause of death in Beagles.

Exploring the role of Tcells in Alzheimer's and other neurodegenerative diseases: Emerging therapeutic insights from the T Cells in the Brain symposium.

This proceedings article summarizes the inaugural "T Cells in the Brain" symposium held at Columbia University. Experts gathered to explore the role of Tcells in neurodegenerative diseases. Key topics included characterization of antigen-specific immune responses, Tcell receptor (TCR) repertoire, microbial etiology in Alzheimer's disease (AD), and microglia-Tcell crosstalk, with a focus on how Tcells affect neuroinflammation and AD biomarkers like amyloid beta and tau. The symposium also examined immunotherapies for AD, including the Valacyclovir Treatment of Alzheimer's Disease (VALAD) trial, and two clinical trials leveraging regulatory Tcell approaches for multiple sclerosis and amyotrophic lateral sclerosis therapy. Additionally, single-cell RNA/TCR sequencing of Tcells and other immune cells provided insights into immune dynamics in neurodegenerative diseases. This article highlights key findings from the symposium and outlines future research directions to further understand the role of Tcells in neurodegeneration, offering innovative therapeutic approaches for AD and other neurodegenerative diseases. HIGHLIGHTS: Researchers gathered to discuss approaches to study Tcells in brain disorders. New technologies allow high-throughput screening of antigen-specific Tcells. Microbial infections can precede several serious and chronic neurological diseases. Central and peripheral Tcell responses shape neurological disease pathology. Immunotherapy can induce regulatory Tcell responses in neuroinflammatory disorders.

White matter connections within the central sulcus subserving the somato-cognitive action network.

The somato-cognitive action network (SCAN) consists of three nodes interspersed within Penfield's motor effector regions. The configuration of the somato-cognitive action network nodes resembles the one of the 'plis de passage' of the central sulcus: small gyri bridging the precentral and postcentral gyri. Thus, we hypothesize that these may provide a structural substrate of the somato-cognitive action network. Here, using microdissections of sixteen human hemispheres, we consistently identified a chain of three distinct plis de passage with increased underlying white matter, in locations analogous to the somato-cognitive action network nodes. We mapped localizations of plis de passage into standard stereotactic space to seed fMRI connectivity across 9,000 resting-state fMRI scans, which demonstrated the connectivity of these sites with the somato-cognitive action network. Intraoperative recordings during direct electrical central sulcus stimulation further identified inter-effector regions corresponding to plis de passage locations. This work provides a critical step towards improved understanding of the somato-cognitive action network in both structural and functional terms. Further, our work has the potential to guide the development of refined motor cortex stimulation techniques for treating brain disorders, and operative resective techniques for complex surgery of the motor cortex.

Exploring Drug-Drug Interactions between Losartan and Carbamazepine: A Pharmacokinetic and Pharmacodynamic Study.

Hypertension, which affects 1.28 billion people globally aged 30 to 79, is characterized by continuously high blood pressure (140/90 or more) and raises the risk of premature death. Losartan, an angiotensin receptor blocker (ARB), is suggested for patients under the age of 55 who cannot take ACE inhibitors as a first treatment option. Epilepsy, a chronic neurological illness marked by repeated seizures, affects more than 50 million individuals worldwide and is the third most common chronic brain disorder. Both hypertension and epilepsy are frequent chronic illnesses, with increased blood pressure greatly raising the risk of epilepsy due to its relationship with cerebrovascular disease, doubling the risk when compared to people with normal blood pressure. The effect on pharmacokinetic and pharmacodynamics of losartan on concomitant administration with carbamazepine was investigated. Wistar rats of either sex, with a minimum of six animals per group, were used in the investigation. The rats were treated with Losartan and Losartan-Carbamazepine for 30 days. Blood samples were taken via retro-orbital plexus at 0, 1, 2, 4, 6, and 12 hours after treatment concluded, and they were subjected to high-performance liquid chromatography for plasma analysis to calculate AUC, t1/2, and Clearance. A pharmacodynamic evaluation was done by inducing hypertension in rats using a 10% fructose solution and the effect of pretreated Losartan and Losartan-Carbamazepine on blood pressure was determined. In the Losartan and Carbamazepine treated group, there was a reduction in the AUC and t1/2 and a reported increase in the clearance value compared to Losartan alone treated rats. In fructose-induced hypertension model to evaluate the effect of losartan and carbamazepine on BP showed an increase in mean arterial pressure, plasma glucose, and a reduction in triglycerides level was noted in comparison to Losartan alone treated rats indicating therapeutic failure of Losartan. Based on these studies, it is concluded that CBZ has reduced the effectiveness of losartan and therefore, co-administration of these drugs should be avoided.