Neurocognitive Dysfunction Research Articles

Stimulating olfactory epithelium mitigates mechanical ventilation-induced hippocampal inflammation and apoptosis.

Mechanical ventilation (MV), as a life-saving procedure in critical patients, is a risk factor to develop of neurocognitive dysfunction and triggers of inflammation and apoptosis in the brain. Since diversion of breathing route to the tracheal tube diminishes brain activity entrained by physiological nasal breathing, we hypothesized that simulating nasal breathing using rhythmic air-puff (AP) into the nasal cavity of mechanically ventilated rats can reduce hippocampal inflammation and apoptosis in association with restoring respiration-coupled oscillations. We found that stimulating olfactory epithelium through applying rhythmic nasal AP, in association with reviving respiration-coupled brain rhythm, mitigates MV-induced hippocampal apoptosis and inflammation involving microglia and astrocytes. The current translational study opens a window for a novel therapeutic approach to reduce neurological complications induced by MV.

Comment on the Need to Fill a Gap in the Assessment of Neurological Status Before Elective Surgery.

Comment on the Need to Fill a Gap in the Assessment of Neurological Status Before Elective Surgery.

Sleep Disturbances in Children With Atopic Dermatitis: A Scoping Review.

Atopic dermatitis (AD) is associated with various quality of life concerns including poor sleep. Sleep impairments in children with AD are associated with increased risk of short stature, metabolic syndrome, mental illness and neurocognitive dysfunction. Although the association between AD and sleep disturbance is well established, the specific types of sleep disturbance in pediatric AD patients and their underlying mechanisms are not fully understood. A scoping literature review was performed to characterize and summarize the types of sleep disturbance in children (less than 18 years of age) with AD. 31 papers met inclusion criteria and extracted data were analyzed in an iterative manner. Two types of sleep disturbances were found to be more prevalent in pediatric AD patients in comparison to controls. One category was related to loss of sleep (increased frequency or duration of awakenings, increased sleep fragmentation, delayed sleep onset, decreased total sleep duration, and decreased sleep efficiency). Another category was associated with unusual behaviors during sleep (restlessness/limb movement/scratching, sleep-disordered breathing including obstructive sleep apnea and snoring, nightmares, nocturnal enuresis and nocturnal hyperhidrosis). Some mechanisms underlying these sleep disturbances include pruritus and induced scratching and increased proinflammatory markers induced by sleep loss. Sleep disturbance appears to be associated with AD. We recommend clinicians to consider interventions that may reduce sleep disturbances in children with AD. Further investigation of these sleep disturbances is needed to elucidate pathophysiology, develop additional treatments, and reduce negative impacts on the health outcomes and quality of life in pediatric AD patients.

The Role of The Predominant Polarity on Neurocognitive and Social Cognitive Dysfunctions in Patients with Bipolar Disorder

IntroductionBipolar disorder (BD) is characterized by significant inter-individual variation in terms of course and outcome. The most important factors associated with the outcome are subsyndromal depression and cognitive disability. Predominant polarity (PP), which is a proposed course specifier for BD, can be associated with various clinical differences such as psychotic feature, suicidality, hospitalization, while it is thought to be associated with the severity of cognitive impairment.ObjectivesTo elucidate the role of the predominant polarity on cognitive dysfunction in patients with BD.MethodsPatients with BD in remission (n=84) and healthy control volunteers (HC, n=27) participated in the study. Patients were divided into 3 subgroups according to their PP characteristics: manic (MPP, n=31), depressive (DPP, n=25), and undetermined (UPP, n=28). Structured Clinical Interview for DSM-5 Disorders-Clinician Version (SCID-5/CV), WAIS-R-Vocabulary Subtest, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Young Mania Rating Scale, Rey’s Auditory Verbal Learning Test (RAVLT), Trail Making Test (TMT), Stroop Test (ST), WMS-R Visual Reproduction Subtest, Controlled Oral Word Association Test (COWAT), Auditory Consonant Trigrams Test (ACT), Reading the Mind in the Eyes Test (RMET), Hinting Test (HT), Wisconsin Card Sorting Test (WCST), and Conners Continuous Performance Test (CCPT) were administered. Scores that do not show normal distribution were transformed using the two-step normalization method. Principal component analysis (PCA) with direct oblimin rotation was applied as a dimension reduction technique to identify different neurocognitive domains. Single-factorial PCA was also applied to calculate global cognition scores.ResultsIn MPP group compared to HC, worse performance was observed in ACT (d=1.24), COWAT (d=1.16), RMET (d=1.03), HT (d=1.78), WCST correct answers (d=0.99), CCPT correct target section (d=0.99) and a prolongation in TMT-A (d=1.00). Compared to DPP, MPP had a weak performance in COWAT (d=0.89), RMET (d=0.86) and HT (d=1.00). MPP (d=1.18) and UPP (d=1.03) groups showed deterioration in processing speed compared to HC. MPP group showed impairment in working memory (d=1.17) and attention (d=0.70) compared to HC. In problem-solving and reasoning, deterioration was found in MPP compared to HC (d=1.16) and UPP (d=0.67), also in DPP compared to HC (d=0.74).ConclusionsThe MPP group yielded more severe cognitive impairment in verbal fluency and social cognition tests compared to DPP. Predominant polarity may also be related to cognitive impairment patterns seen in BD.Disclosure of InterestNone Declared

Abstract Number: LBA11 CADASIL revealed by COVID‐19: A case report and systematic review

Introduction Cerebral Autosomal Dominant Arteriopathy with subcortical Infarcts and leuko‐encephalopathy (CADASIL) is a genetic condition characterized by migraine, ischemic strokes, mood disturbances, and cognitive impairment. Since COVID‐19 pandemic started in late 2019, six patients (including our case) were reported to present with neurological symptoms associated with CADASIL mutation and four of them were diagnosed while hospitalized for COVID‐19 illness. Methods A case report anda systematic literature review done via PubMed search that was performed up to Oct 15, 2022. Studies reporting on CADASIL and COVID‐19 infection were included. Results In addition to our case report, 5 case‐reports were identified, and full articles were reviewed and summarized. Including our case, the mean age of patients was 45.44 years, and all of them were females. The diagnosis of CADASIL was established after COVID‐19 infection in four of the cases including ours, while the diagnosis of CADASIL was established in the other two patients after neurological symptoms and prior strokes warranting investigations and stroke workup. CADASIL diagnosis was confirmed with genetic testing in all of them. Two cases had history of migraines with aura, three cases had hypertension, and two patients had unremarkable past medical history. Four cases reported dysarthria as one of the initial symptoms at presentation. The initial MRI brain reported involvement of corona radiata in two cases, centrum semiovale in two cases, cerebellum in one case. All cases reported bilateral changes on imaging. Aspirin, clopidogrel, statins, intravenous immunoglobulins, and steroids were the medical treatment modalities used amongst those patients. Four cases had mild‐complete recovery of symptoms, one case was reported to have partial resolution of deficits, and one patient had complete resolution of motor deficit and persistent mild neurocognitive dysfunction. Conclusions COVID‐19 infection might be a triggering factor forCADASIL flare. Although it is unclear whether CADASIL mutations would be the only etiology behind the neurological deficits in these patients, as COVID‐19 infection has been reported to be associated with many neurological manifestations, the reported imaging findings along with the genetic confirmation weighs more towards COVID‐19 infection acting as a trigger for CADASIL flare.

The Conners Continuous Performance Test CPT3™: Is it a reliable marker to predict neurocognitive dysfunction in Myalgic encephalomyelitis/chronic fatigue syndrome?

The main objective is to delimit the cognitive dysfunction associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in adult patients by applying the Continuous Performance Test (CPT3™). Additionally, provide empirical evidence on the usefulness of this computerized neuropsychological test to assess ME/CFS. The final sample (n = 225; 158 Patients/67 Healthy controls) were recruited in a Central Sensitization Syndromes (CSS) specialized unit in a tertiary hospital. All participants were administered this neuropsychological test. There were significant differences between ME/CFS and healthy controls in all the main measures of CPT3™. Mainly, patients had a worse indicator of inattentiveness, sustained attention, vigilance, impulsivity, slow reaction time, and more atypical T-scores, which is associated with a likelihood of having a disorder characterized by attention deficits, such as Attention Deficit Hyperactivity Disorder (ADHD). In addition, relevant correlations were obtained between the CPT3™ variables in the patient's group. The most discriminative indicators of ME/CFS patients were Variability and Hit Reaction Time, both measures of response speed. The CPT3™ is a helpful tool to discriminate neurocognitive impairments from attention and response speed in ME/CFS patients, and it could be used as a marker of ME/CFS severity for diagnosing or monitoring this disease.

The Effect of Central Sensitization on Postoperative Neurocognitive Dysfunction in Hospitalized Elderly Patients: A Prospective Cohort Clinical Trial

ABSTRACT Objective To investigate whether central sensitization (CS) in elderly patients was a predictive risk factor for postoperative neurocognitive dysfunction (PNCD). Methods One hundred and thirty-three aged patients undergoing total knee arthroplasty (TKA) who received femoral nerve block and general anesthesia were recruited in this research and prospectively assigned into two groups according to the Central Sensitization Inventory (CSI) score: group C (n = 106, CSI score less than 40) and group CS (n = 27, CSI score higher than 40). Scores of Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Confusion Assessment Method (CAM), Numerical Rating Scale (NRS) and Quality of recovery-40 (QoR-40) questionnaires were assessed. Basic information and clinical records of all participants were also collected. Results PNCD occurred in 24 (22.6%) of patients in group C and 16 (59.3%) in group CS (p < .05). Multivariate logistic regression analysis revealed that patients with CSI score ≥40 before surgery exhibited higher risk of PNCD after adjustment for other risk factors (p < .05). Compared to group C, the pre- and post-operative NRS scores, pain duration, the WOMAC score, and propofol consumptions for anesthesia induction were significantly increased in group CS (p < .05). Conclusion Hospitalized elderly patients with clinical symptoms of CS scores may have increased risk of PNCD following TKA.

Autophagy impairment in patients with obstructive sleep apnea modulates intermittent hypoxia-induced oxidative stress and cell apoptosis via hypermethylation of the ATG5 gene promoter region

BackgroundAutophagy is a catabolic process that recycles damaged organelles and acts as a pro-survival mechanism, but little is known about autophagy dysfunction and epigenetic regulation in patients with obstructive sleep apnea (OSA).MethodsProtein/gene expressions and DNA methylation levels of the autophagy-related genes (ATG) were examined in blood leukocytes from 64 patients with treatment-naïve OSA and 24 subjects with primary snoring (PS).ResultsLC3B protein expression of blood monocytes, and ATG5 protein expression of blood neutrophils were decreased in OSA patients versus PS subjects, while p62 protein expression of cytotoxic T cell was increased, particularly in those with nocturia. ATG5, ULK1, and BECN1 gene expressions of peripheral blood mononuclear cells were decreased in OSA patients versus PS subjects. LC3B gene promoter regions were hypermethylated in OSA patients, particularly in those with excessive daytime sleepiness, while ATG5 gene promoter regions were hypermethylated in those with morning headache or memory impairment. LC3B protein expression of blood monocytes and DNA methylation levels of the LC3B gene promoter region were negatively and positively correlated with apnea hyponea index, respectively. In vitro intermittent hypoxia with re-oxygenation exposure to human THP-1/HUVEC cell lines resulted in LC3B/ATG5/ULK1/BECN1 down-regulations and p62 up-regulation along with increased apoptosis and oxidative stress, while rapamycin and umbilical cord-mesenchymal stem cell treatment reversed these abnormalities through de-methylation of the ATG5 gene promoter.ConclusionsImpaired autophagy activity in OSA patients was regulated by aberrant DNA methylation, correlated with clinical phenotypes, and contributed to increased cell apoptosis and oxidative stress. Autophagy enhancers may be novel therapeutics for OSA-related neurocognitive dysfunction.

Contribution of preoperative gut microbiota in postoperative neurocognitive dysfunction in elderly patients undergoing orthopedic surgery.

To investigate the role of gut microbiota and metabolites in POCD in elderly orthopedic patients, and screen the preoperative diagnostic indicators of gut microbiota in elderly POCD. 40 elderly patients undergoing orthopedic surgery were enrolled and divided into Control group and POCD group following neuropsychological assessments. Gut microbiota was determined by 16S rRNA MiSeq sequencing, and metabolomics of GC-MS and LC-MS was used to screen the differential metabolites. We then analyzed the pathways enriched by metabolites. There was no difference in alpha or beta diversity between Control group and POCD group. There were significant differences in 39 ASV and 20 genera bacterium in the relative abundance. Significant diagnostic efficiency analyzed by the ROC curves were found in 6 genera bacterium. Differential metabolites in the two groups including acetic acid, arachidic acid, pyrophosphate etc. were screened out and enriched to certain metabolic pathways which impacted the cognition function profoundly. Gut microbiota disorders exist preoperatively in the elderly POCD patients, by which there could be a chance to predict the susceptible population. [http://www.chictr.org.cn/edit.aspx?pid=133843&htm=4], identifier [ChiCTR2100051162].

Delirium among people aging with and without HIV: Role of alcohol and Neurocognitively active medications.

People aging with and without HIV (PWH and PWoH) want to avoid neurocognitive dysfunction, especially delirium. Continued use of alcohol in conjunction with neurocognitively active medications (NCAMs) may be a largely underappreciated cause, especially for PWH who experience polypharmacy a decade earlier than PWoH. We compare absolute and relative risk of delirium among PWH and PWoH by age, level of alcohol use, and exposure to NCAMs. Using the VACS cohort, we compare absolute and relative risk of inpatient delirium among PWH and PWoH by age, level of alcohol use, and exposure to NCAMs between 2007 and 2019. We matched each case based on age, race/ethnicity, sex, HIV, baseline year, and observation time with up to 5 controls. The case/control date was defined as date of admission for cases and the date corresponding to the same length of time on study for controls. Level of alcohol use was defined using Alcohol Use Disorder Identification Test-Consumption (AUDIT-C). Medication exposure was measured from 45 to 3 days prior to index date; medications were classified as anticholinergic NCAM, non-anticholinergic NCAM, or non NCAM and counts generated. We used logistic regression to determine odds ratios (ORs) for delirium associated with medication counts stratified by HIV status and adjusted for demographics, severity of illness, and related diagnoses. PWH experienced a higher incidence of delirium (5.6, [95% CI 5.3-5.9/1000 PY]) than PWoH (5.0, [95% CI 4.8-5.1/1000 PY]). In multivariable analysis, anticholinergic and non-anticholinergic NCAM counts and level of alcohol use demonstrated strong independent dose-response associations with delirium. Decreasing alcohol use and limiting the use of neurocognitively active medications may help decrease excess rates of delirium, especially among PWH.

Microglial pyroptosis in hippocampus mediates sevolfurane-induced cognitive impairment in aged mice via ROS-NLRP3 inflammasome pathway

BackgroundPostoperative cognitive dysfunction (POCD) is a common complication with its pathophysiological mechanisms not been fully elucidated. Pyroptosis is a novel type of pro-inflammatory cell death and considered to be associated with cognitive dysfunction. Therefore, our study aimed to examine the effect of pyroptosis on sevoflurane-induced cognitive impairment in aged mice as well as its underlying mechanism. MethodsA mice model of cognitive impairment was established by sevoflurane exposure and the levels of reactive oxygen species (ROS), N-GSDMD, cleaved caspase-1, ASC, IL-1β and IL-18, and NLRP3 in hippocampus was determined. To explore the underlying mechanism, a pyroptosis inhibitor, necrosulfonamide (NSA), and a ROS scavenger, N-acetylcysteine (NAC), were administrated before sevoflurane exposure both in vitro and in vivo. Neurobehavioral tests, western blot, transmission electron microscope (TEM) observation, and immunofluorescence staining were performed. ResultsSevoflurane induced hippocampal pyroptosis in the cognitive impairment model. NSA effectively inhibited the pyroptosis and improved cognitive function. Co-labeled immunofluorescence staining suggested sevoflurane induces microglial pyroptosis. Sevoflurane induced pyroptosis accompanied with ROS accumulation in a dose-independent manner in BV2 cells, and NAC effectively reduce the levels of ROS and pyroptosis through NLRP3 inflammasome pathway in both vitro and vivo. Furthermore, NAC could also alleviate sevoflurane-induced cognitive dysfunction. ConclusionsMicroglial pyroptosis in hippocampus mediates sevolfurane-induced cognitive impairment in aged mice via ROS-NLRP3 inflammasome pathway. Both pyroptosis inhibition and ROS scavenging might be potential approaches to ameliorate sevoflurane-induced neurocognitive dysfunction.

Single-nucleus Atlas of Sevoflurane-induced Hippocampal Cell Type- and Sex-specific Effects during Development in Mice.

Multiple neonatal exposures to sevoflurane induce neurocognitive dysfunctions in rodents. The lack of cell type-specific information after sevoflurane exposure limits the mechanistic understanding of these effects. In this study, the authors tested the hypothesis that sevoflurane exposures alter the atlas of hippocampal cell clusters and have neuronal and nonneuronal cell type-specific effects in mice of both sexes. Neonatal mice were exposed to 3% sevoflurane for 2 h at postnatal days 6, 8, and 10 and analyzed for the exposure effects at postnatal day 37. Single-nucleus RNA sequencing was performed in the hippocampus followed by in situ hybridization to validate the results of RNA sequencing. The Morris Water Maze test was performed to test neurocognitive function. The authors found sex-specific distribution of hippocampal cell types in control mice alongside cell type- and sex-specific effects of sevoflurane exposure on distinct hippocampal cell populations. There were important changes in male but not in female mice after sevoflurane exposure regarding the proportions of cornu ammonis 1 neurons (control vs. sevoflurane, males: 79.9% vs. 32.3%; females: 27.3% vs. 24.3%), dentate gyrus (males: 4.2% vs. 23.4%; females: 36.2% vs. 35.8%), and oligodendrocytes (males: 0.6% vs. 6.9%; females: 5.9% vs. 7.8%). In male but not in female mice, sevoflurane altered the number of significantly enriched ligand-receptor pairs in the cornu ammonis 1, cornu ammonis 3, and dente gyrus trisynaptic circuit (control vs. sevoflurane, cornu ammonis 1-cornu ammonis 3: 18 vs. 42 in males and 15 vs. 21 in females; cornu ammonis 1-dentate gyrus: 21 vs. 35 in males and 12 vs. 20 in females; cornu ammonis 3-dentate gyrus: 25 vs. 45 in males and 17 vs. 20 in females), interfered with dentate gyrus granule cell neurogenesis, hampered microglia differentiation, and decreased cornu ammonis 1 pyramidal cell diversity. Oligodendrocyte differentiation was specifically altered in females with increased expressions of Mbp and Mag. In situ hybridization validated the increased expression of common differentially expressed genes. This single-nucleus RNA sequencing study reveals the hippocampal atlas of mice, providing a comprehensive resource for the neuronal and nonneuronal cell type- and sex-specific effects of sevoflurane during development.

Chronic viral coinfections differentially affect the likelihood of developing long COVID.

BACKGROUNDThe presence and reactivation of chronic viral infections, such as EBV, CMV, and HIV, have been proposed as potential contributors to long COVID (LC), but studies in well-characterized postacute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited.METHODSIn a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status) and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms.RESULTSWe observed that LC symptoms, such as fatigue and neurocognitive dysfunction, at a median of 4 months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen-diffuse IgG positivity) or high nuclear antigen (EBNA) IgG levels but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (early antigen-diffuse IgG positivity) was most strongly associated with fatigue (OR = 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR = 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR = 0.52).CONCLUSIONOverall, these findings suggest differential effects of chronic viral coinfections on the likelihood of developing LC and association with distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.TRIAL REGISTRATIONLong-term Impact of Infection with Novel Coronavirus; ClinicalTrials.gov NCT04362150.FUNDINGThis work was supported by NIH/National Institute of Allergy and Infectious Diseases grants (3R01AI141003-03S1, R01AI158013, and K24AI145806); the Zuckerberg San Francisco General Hospital Department of Medicine and Division of HIV, Infectious Diseases, and Global Medicine; and the UCSF-Bay Area Center for AIDS Research (P30-AI027763).

Theory-driven computational models of drug addiction in humans: Fruitful or futile?

Maladaptive behavior in drug addiction is widely regarded as a result of neurocognitive dysfunctions. Recently, there has been a growing trend to adopt computational methods to study these dysfunctions in drug-addicted patients, not least because it provides a quantitative framework to infer the psychological mechanisms that may have gone awry in addiction. We therefore sought to evaluate the extent to which these theory-driven computational models have fulfilled this purpose in addiction research. We discuss several learning and decision-making theories proposed to explain symptoms that characterize impaired control and the intense urge to use drugs in addiction, and outline the computational algorithms frequently used to model these processes. Specifically, impaired behavioral control over drugs have been explained by aberrant reinforcement learning algorithms and an imbalance between model-based and model-free control, whereas the strong desire for drugs might be explained by a neurocomputational model of incentive sensitization and behavioral economic theory. We argue that while theory-driven computational models may appear to be useful tools that generate novel mechanistic insights into drug addiction, their use should be informed by psychological theory, experimental data, and clinical observations.

Clinical and developmental characteristics of cognitive subgroups in a transdiagnostic sample of schizophrenia spectrum disorders and bipolar disorder

Evidence suggests that neurocognitive dysfunction is a transdiagnostic feature of individuals across the continuum between schizophrenia and bipolar disorder. However, there is significant heterogeneity of neuropsychological and social-cognitive abilities in schizophrenia, schizoaffective disorder, and bipolar disorder. The current study aimed to investigate the clinical and developmental characteristics of cognitive subgroups within the schizo-bipolar spectrum. 147 clinically stable patients with schizophrenia, schizoaffective or bipolar disorder were assessed using clinical rating scales for current psychotic and affective symptoms, and a comprehensive neuropsychological battery including measures of social cognition (Hinting and Reading the mind from the Eyes (RMET) task)). Developmental history and premorbid academic functioning were also evaluated. The study also included 36 healthy controls. Neurocognitive subgroups were investigated using latent class analysis (LCA). The optimal number of clusters was determined based on the Bayesian information criterion. A logistic regression analysis was conducted to investigate the predictors of membership to the globally impaired subgroup. LCA revealed two neurocognitive clusters including globally impaired (n = 89, 60.5%) and near-normal cognitive functioning (n = 58, 39.5%) subgroups. The near-normal cognitive functioning subgroup was not significantly different from healthy controls. The globally impaired subgroup had a higher score of developmental abnormalities (p<0.001), poorer premorbid academic functioning, mothers who were less educated and more severe disorganized speech (p = 0.001) and negative symptoms (p = 0.004) compared to the near-normal cognitive functioning group. History of developmental abnormalities and persistent disorganization rather than diagnosis are significant predictors of the subgroup of individuals with global cognitive impairment in the schizophrenia-bipolar disorder continuum.

Cancer treatment induces neuroinflammation and behavioral deficits in mice.

Introduction: Cancer survivors are increasingly diagnosed with a syndrome of neurocognitive dysfunction termed cancer-related cognitive impairment (CRCI). Chemotherapy and radiation therapy have been implicated in CRCI; however, its underlying pathogenesis remains unclear, hindering effective prevention or treatment. Methods: We used the hairless strain SKH1 (11-12-week-old) and treated the mice with radiation to the right hindlimb, doxorubicin (a chemotherapy agent), concurrent radiation, and doxorubicin, or no treatment (control). Neurocognition was evaluated via standardized behavioral testing following treatment. Mice were subsequently humanely euthanized, and plasma and brains were collected to identify inflammatory changes. Results: Mice treated with radiation, doxorubicin, or both radiation and doxorubicin demonstrated equivalent hippocampal dependent memory deficits and significant increases in activated microglia and astrocytes compared to control mice. Doxorubicin-treated mice had significantly increased plasma IL-6 and failed to gain weight compared to control mice over the study period. Discussion: This study demonstrates that non-brain directed radiation induces both gliosis and neurocognitive deficits. Moreover, this work presents the first characterization of SKH1 mice as a relevant and facile animal model of CRCI. This study provides a platform from which to build further studies to identify potential key targets that contribute to CRCI such that strategies can be developed to mitigate unintended neuropathologic consequences associated with anticancer treatment.

Prolonged anesthesia induces neuroinflammation and complement-mediated microglial synaptic elimination involved in neurocognitive dysfunction and anxiety-like behaviors

BackgroundPerioperative neurocognitive disorders (PND) with a high incidence frequently occur in elderly surgical patients closely associated with prolonged anesthesia-induced neurotoxicity. The neuromorphopathological underpinnings of anesthesia-induced neurotoxicity have remained elusive.MethodsProlonged anesthesia with sevoflurane was used to establish the sevoflurane-induced neurotoxicity (SIN) animal model. Morris water maze, elevated plus maze, and open field test were employed to track SIN rats’ cognitive behavior and anxiety-like behaviors. We investigated the neuropathological basis of SIN through techniques such as transcriptomic, electrophysiology, molecular biology, scanning electron microscope, Golgi staining, TUNEL assay, and morphological analysis. Our work further clarifies the pathological mechanism of SIN by depleting microglia, inhibiting neuroinflammation, and C1q neutralization.ResultsThis study shows that prolonged anesthesia triggers activation of the NF-κB inflammatory pathway, neuroinflammation, inhibition of neuronal excitability, cognitive dysfunction, and anxiety-like behaviors. RNA sequencing found that genes of different types of synapses were downregulated after prolonged anesthesia. Microglial migration, activation, and phagocytosis were enhanced. Microglial morphological alterations were also observed. C1qa, the initiator of the complement cascade, and C3 were increased, and C1qa tagging synapses were also elevated. Then, we found that the “Eat Me” complement pathway mediated microglial synaptic engulfment in the hippocampus after prolonged anesthesia. Afterward, synapses were remarkably lost in the hippocampus. Furthermore, dendritic spines were reduced, and their genes were also downregulated. Depleting microglia ameliorated the activation of neuroinflammation and complement and rescued synaptic loss, cognitive dysfunction, and anxiety-like behaviors. When neuroinflammatory inhibition or C1q neutralization occurred, complement was also decreased, and synaptic elimination was interrupted.ConclusionsThese findings illustrated that prolonged anesthesia triggered neuroinflammation and complement-mediated microglial synaptic engulfment that pathologically caused synaptic elimination in SIN. We have demonstrated the neuromorphopathological underpinnings of SIN, which have direct therapeutic relevance for PND patients.

The gut microbiota-astrocyte axis: Implications for type 2 diabetic cognitive dysfunction.

Diabetic cognitive dysfunction (DCD) is one of the most insidious complications of type 2 diabetes mellitus, which can seriously affect the ability to self-monitoring of blood glucose and the quality of life in the elderly. Previous pathological studies of cognitive dysfunction have focused on neuronal dysfunction, characterized by extracellular beta-amyloid deposition and intracellular tau hyperphosphorylation. In recent years, astrocytes have been recognized as a potential therapeutic target for cognitive dysfunction and important participants in the central control of metabolism. The disorder of gut microbiota and their metabolites have been linked to a series of metabolic diseases such as diabetes mellitus. The imbalance of intestinal flora has the effect of promoting the occurrence and deterioration of several diabetes-related complications. Gut microbes and their metabolites can drive astrocyte activation. We reviewed the pathological progress of DCD related to the "gut microbiota-astrocyte" axis in terms of peripheral and central inflammation, intestinal and blood-brain barrier (BBB) dysfunction, systemic and brain energy metabolism disorders to deepen the pathological research progress of DCD and explore the potential therapeutic targets. "Gut microbiota-astrocyte" axis, unique bidirectional crosstalk in the brain-gut axis, mediates the intermediate pathological process of neurocognitive dysfunction secondary to metabolic disorders in diabetes mellitus.

Comparison of Cognitive Functions Between Patients with Alzheimer Disease, Patients with Mild Cognitive Impairment, and Healthy People

Background: There is a growing need for predicting Alzheimer disease (AD) based on emerging neurocognitive dysfunction before the onset of the disease. Objectives: According to neuropathological changes in the mesial temporal lobe (MTL) before the onset of clinical symptoms and the relationship between the function of these structures and cognitive functions (such as visual memory, working memory, and new learning), we aimed to investigate the possibility of these cognitive functions as markers of transition from mild cognitive impairment (MCI) to AD. Methods: In this case-control study, 15 patients with AD, 18 patients with MCI (from memory clinics of Tehran University of Medical Sciences), and 15 healthy people were compared using the 3 subtests of the Cambridge Neuropsychological Test Automated Battery (CANTAB), including spatial working memory (SWM), pattern recognition memory (PRM), and paired-associate learning (PAL). The tests were performed between 9 AM and 12 noon. The scores were compared by a 1-way analysis of variance (ANOVA). Results: The mean ages of AD, MCI, and healthy groups were 68.66, 68.22, and 64.26 years, respectively. In terms of the SWM test, in 2 of 3 variables, there were significant differences between the 3 groups (P = 0.000 and P = 0.001). Regarding the PRM test, there were significant differences between the 3 groups in accuracy and response time (P = 0.000 and P = 0.004, respectively). Regarding PAL, there were significant differences between the 3 groups in all 3 variables (P = 0.000). The Mini-mental State Examination (MMSE) scores were associated with almost all variable scores (P = 0.000). Conclusions: Dysfunction in new learning and recognition memory can be indicators of MCI and its progression to AD, whereas the assessment of SWM can only be used to assess the progression of MCI to AD.

A "Seed-and-Soil" Radiomics Model Predicts Brain Metastasis Development in Lung Cancer: Implications for Risk-Stratified Prophylactic Cranial Irradiation.

Introduction: Brain is a major site of metastasis for lung cancer, and effective therapy for developed brain metastasis (BM) is limited. Prophylactic cranial irradiation (PCI) has been shown to reduce BM rate and improve survival in small cell lung cancer, but this result was not replicated in unselected non-small cell lung cancer (NSCLC) and had the risk of inducing neurocognitive dysfunctions. We aimed to develop a radiomics BM prediction model for BM risk stratification in NSCLC patients. Methods: 256 NSCLC patients with no BM at baseline brain magnetic resonance imaging (MRI) were selected; 128 patients developed BM within three years after diagnosis and 128 remained BM-free. For radiomics analysis, both the BM and non-BM groups were randomly distributed into training and testing datasets at an 70%:30% ratio. Both brain MRI (representing the soil) and chest computed tomography (CT, representing the seed) radiomic features were extracted to develop the BM prediction models. We first developed the radiomic models using the training dataset (89 non-BM and 90 BM cases) and subsequently validated the models in the testing dataset (39 non-BM and 38 BM cases). A radiomics BM score (RadBM score) was generated, and BM-free survival were compared between RadBM score-high and RadBM score-low groups. Results: The radiomics model developed from baseline brain MRI features alone can predict BM development in NSCLC patients. A fusion model integrating brain MRI features with primary tumor CT features (seed-and-soil model) provided synergetic effect and was more efficient in predicting BM (areas under the receiver operating characteristic curve 0.84 (95% confidence interval: 0.80−0.89) and 0.80 (95% confidence interval: 0.71−0.88) in the training and testing datasets, respectively). BM-free survival was significantly shorter in the RadBM score-high group versus the RadBM score-low group (Log-rank, p < 0.001). Hazard ratios for BM were 1.056 (95% confidence interval: 1.044−1.068) per 0.01 increment in RadBM score. Cumulative BM rates at three years were 75.8% and 24.2% for the RadBM score-high and RadBM score-low groups, respectively. Only 1.2% (7/565) of the BM lesions were located within the hippocampal avoidance region. Conclusion: The results demonstrated that intrinsic features of a non-metastatic brain exert a significant impact on BM development, which is first-in-class in metastasis prediction studies. A radiomics BM prediction model utilizing both primary tumor and pre-metastatic brain features might provide a useful tool for individualized PCI administration in NSCLC patients more prone to develop BM.