Associations between COVID-19 and putative markers of neuroinflammation: A diffusion basis spectrum imaging study.

COVID-19 remains a significant international public health concern. Yet, the mechanisms through which symptomatology emerges remain poorly understood. While SARS-CoV-2 infection may induce prolonged inflammation within the central nervous system, the evidence primarily stems from limited small-scale case investigations. To address this gap, our study capitalized on longitudinal UK Biobank neuroimaging data acquired prior to and following COVID-19 testing (N = 416 including n = 224 COVID-19 cases; Mage = 58.6). Putative neuroinflammation was assessed in gray matter structures and white matter tracts using non-invasive Diffusion Basis Spectrum Imaging (DBSI), which estimates inflammation-related cellularity (DBSI-restricted fraction; DBSI-RF) and vasogenic edema (DBSI-hindered fraction; DBSI-HF). We hypothesized that COVID-19 case status would be associated with increases in DBSI markers after accounting for potential confound (age, sex, race, body mass index, smoking frequency, and data acquisition interval) and multiple testing. COVID-19 case status was not significantly associated with DBSI-RF (|ß|'s < 0.28, pFDR >0.05), but with greater DBSI-HF in left pre- and post-central gyri and right middle frontal gyrus (ß's > 0.3, all pFDR = 0.03). Intriguingly, the brain areas exhibiting increased putative vasogenic edema had previously been linked to COVID-19-related functional and structural alterations, whereas brain regions displaying subtle differences in cellularity between COVID-19 cases and controls included regions within or functionally connected to the olfactory network, which has been implicated in COVID-19 psychopathology. Nevertheless, our study might not have captured acute and transitory neuroinflammatory effects linked to SARS-CoV-2 infection, possibly due to symptom resolution before the imaging scan. Future research is warranted to explore the potential time- and symptom-dependent neuroinflammatory relationship with COVID-19.

Personality traits moderate associations between word recall and subjective memory.

Cognitive gerontology research requires consideration of performance as well as perceptions of performance. While subjective memory is positively associated with memory performance, these correlations typically are modest in magnitude, leading to the need to consider whether certain people may show weaker or stronger linkages between performance and perceptions. The current study leveraged personality (NEO Big Five), memory performance (i.e., word recall), and perceptions of memory ability (i.e., metamemory in adulthood and memory decline) data from the St. Louis Personality and Aging Network (SPAN) study (n = 774, mean age: 71.52 years). Extraversion and conscientiousness held the most consistent associations with the cognitive variables of interest, as both traits were positively associated with metamemory and word recall, but negatively associated with subjective decline. Moreover, extraversion moderated associations between word recall and both memory capacity and complaints, insofar that objective-subjective associations were weaker for those adults higher in extraversion. These findings highlight the need to understand how personality influences the sources of information employed for subjective cognitive beliefs.

Reliability of diurnal salivary cortisol metrics: A meta-analysis and investigation in two independent samples.

Stress-induced dysregulation of diurnal cortisol is a cornerstone of stress-disease theories; however, observed associations between cortisol, stress, and health have been inconsistent. The reliability of diurnal cortisol features may contribute to these equivocal findings. Our meta-analysis (5 diurnal features from 11 studies; total participant n = 3307) and investigation (15 diurnal cortisol features) in 2 independent studies (St. Louis Personality and Aging Network [SPAN] Study, n = 147, ages 61-73; Minnesota Longitudinal Study of Risk and Adaptation [MLSRA] Study, n = 90, age 37) revealed large variability in the day-to-day test-retest reliability of diurnal features derived from salivary cortisol data (i.e., ICC = 0.00-0.75). Collectively, these data indicate that some commonly used diurnal cortisol features have poor reliability that is insufficient for individual differences research (e.g., cortisol awakening response) while others (e.g., area under the curve with respect to ground) have fair-to-good reliability that could support reliable identification of associations in well-powered studies.

Associations between COVID-19 and putative markers of neuroinflammation: A diffusion basis spectrum imaging study.

COVID-19 remains a significant international public health concern. Yet, the mechanisms through which symptomatology emerges remain poorly understood. While SARS-CoV-2 infection may induce prolonged inflammation within the central nervous system, the evidence primarily stems from limited small-scale case investigations. To address this gap, our study capitalized on longitudinal UK Biobank neuroimaging data acquired prior to and following COVID-19 testing (N=416 including n=224 COVID-19 cases; Mage=58.6). Putative neuroinflammation was assessed in gray matter structures and white matter tracts using non-invasive Diffusion Basis Spectrum Imaging (DBSI), which estimates inflammation-related cellularity (DBSI-restricted fraction; DBSI-RF) and vasogenic edema (DBSI-hindered fraction; DBSI-HF).We hypothesized that COVID-19 case status would be associated with increases in DBSI markers after accounting for potential confound (age, sex, race, body mass index, smoking frequency, and data acquisition interval) and multiple testing. COVID-19 case status was not significantly associated with DBSI-RF (|ß|'s<0.28, pFDR >0.05), but with greater DBSI-HF in left pre- and post-central gyri and right middle frontal gyrus (ß's>0.3, all pFDR=0.03). Intriguingly, the brain areas exhibiting increased putative vasogenic edema had previously been linked to COVID-19-related functional and structural alterations, whereas brain regions displaying subtle differences in cellularity between COVID-19 cases and controls included regions within or functionally connected to the olfactory network, which has been implicated in COVID-19 psychopathology. Nevertheless, our study might not have captured acute and transitory neuroinflammatory effects linked to SARS-CoV-2 infection, possibly due to symptom resolution before the imaging scan. Future research is warranted to explore the potential time- and symptom-dependent neuroinflammatory relationship with COVID-19.

A Phenome-Wide Association Study (PheWAS) of Late Onset Alzheimer Disease Genetic Risk in Children of European Ancestry at Middle Childhood: Results from the ABCD Study.

Genetic risk for Late Onset Alzheimer Disease (AD) has been associated with lower cognition and smaller hippocampal volume in healthy young adults. However, whether these and other associations are present during childhood remains unclear. Using data from 5556 genomically-confirmed European ancestry youth who completed the baseline session of the ongoing the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®), our phenome-wide association study estimating associations between four indices of genetic risk for late-onset AD (i.e., AD polygenic risk scores (PRS), APOE rs429358 genotype, AD PRS with the APOE region removed (ADPRS-APOE), and an interaction between ADPRS-APOE and APOE genotype) and 1687 psychosocial, behavioral, and neural phenotypes revealed no significant associations after correction for multiple testing (all ps > 0.0002; all pfdr > 0.07). These data suggest that AD genetic risk may not phenotypically manifest during middle-childhood or that effects are smaller than this sample is powered to detect.

Sense of purpose as a potential buffer between mental health and subjective cognitive decline.

OBJECTIVES: Purposeful adults may experience greater cognitive resilience because sense of purpose may help buffer against the effects of depressive symptoms and loneliness. We also evaluated whether these associations differed by race. DESIGN: This study uses a wave of self-report data from the SPAN study of psychosocial aging. SETTING: Participants come from a representative sample of older adults in St. Louis. PARTICIPANTS: Participants (N = 595) ages range from 65 to 78 (Mage = 71.46), with 18.3% of participants identifying as Black/African-American. MEASURES: Sense of purpose was assessed with the Life Engagement Test, depressive symptoms with the Beck Depression Inventory-II, loneliness with the UCLA Loneliness Scale, and subjective cognitive decline with the AD-8. RESULTS: Correlational analyses supported predictions that sense of purpose was negatively related to subjective cognitive decline, whereas depressive symptoms and loneliness were positively related (|r|s > .30, ps < .001). For loneliness, but not depression, this association was moderated by sense of purpose (b = -0.43, p < .001). A relatively high sense of purpose attenuated associations between loneliness and subjective cognitive decline. A three-way race × purpose × loneliness interaction (b = -0.25, p = .021) revealed that the buffering effects of sense of purpose on subjective cognitive decline were stronger for Black adults. DISCUSSION: This study provided partial support for the buffering hypothesis, showing that sense of purpose may help mitigate the cognitive decrements associated with loneliness. Future research needs to consider how purpose-promoting programs may support healthy cognitive aging, particularly among Black older adults and those who experience greater social isolation.

Prospective self- and informant-personality associations with inflammation, health behaviors, and health indicators.

OBJECTIVE: Personality influences many aspects of the health process. It is unclear to what extent self- and informant-reports of the Big Five offer incremental validity for the prediction of inflammatory biomarkers and whether inflammation provides a unique pathway between personality and indicators of physical health, independent of health behaviors. METHOD: Using data from older adults (N = 1,630) enrolled in the St. Louis Personality and Aging Network study, we tested whether self- and informant-reported Big Five traits show unique associations with inflammation (IL-6, CRP, TNF-α). Further, we tested whether inflammation and health behaviors indirectly link personality to health-related quality of life, body mass index, and chronic disease burden using longitudinal mediation in a structural equation modeling framework. RESULTS: Self-reports, informant-reports, and general trait factors of personality predicted future inflammatory biomarker levels (unstandardized regression coefficients ranged -.08 to .07 for self, -.13 to -.10 for informants, and -.16 to -.11 for general). Additionally, all assessment methods of personality were associated with the indicators of physical health through biomarker and health behavior pathways. Effects were primarily found for conscientiousness and neuroticism; IL-6 and CRP were the biomarkers with the most indirect effects; and indirect paths overall emerged more frequently through health behaviors, but this varied by outcome. CONCLUSIONS: Self- and informant-reports provided unique predictive validity of inflammatory biomarkers. Findings highlight the benefits of using of multiple assessments of personality and the importance of examining multiple, distinct pathways by which personality might influence health to understand the mechanisms underlying this relationship more fully. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Using an Environmentally Friendly Disposal Bag to Discard Leftover Opioids After Gynecologic Surgery.

OBJECTIVE: To evaluate the effects of an environmentally friendly drug deactivation bag on opioid disposal among patients undergoing gynecologic surgery. METHODS: This prospective cohort study included patients undergoing gynecologic procedures requiring an opioid prescription from March 2020 to December 2020. Patients were managed on a restrictive opioid prescribing algorithm and given an opioid disposal bag. The carbon drug deactivation bag neutralizes the opioid medication and can be discarded safely in the trash. Patients were educated about pain management goals and the disposal bag. Patients were surveyed at their postoperative visit to evaluate satisfaction, number of leftover pills, and disposal methods. Statistical analysis was performed using SPSS Statistics 26. RESULTS: Two hundred patients were asked to complete the survey, with a response rate of 78%. The most common procedures were exploratory laparotomy (50%) and minimally invasive hysterectomy (41%). Most patients (91%, 95% CI 91-97) filled their opioid prescription and 64 (41%, 95% CI 34-48) had leftover opioid pills. Most patients with leftover opioid pills (73%, 95% CI 67-79) discarded them; 78%, 95% CI 69-80 used the disposal bag. Patients undergoing an exploratory laparotomy most commonly used the disposal bag. All patients who used the disposal bag stated they would use it again. CONCLUSION: Despite a restrictive opioid prescribing algorithm, 41% of gynecologic surgical patients had leftover opioid pills. This study demonstrated that leftover opioid pills were safely discarded 73% of the time when patients were provided an opioid disposal bag and preoperative education.

Inflammation is associated with future depressive symptoms among older adults.

Inflammation has been reliably associated with depression. However, the directionality of this association is poorly understood, with evidence that elevated inflammation may promote and precede the development of depression, as well as arise following its expression. Using data from older adults (N â€‹= â€‹1,072, ages 60-73) who participated in the ongoing longitudinal St. Louis Personality and Aging Network (SPAN) study, we examined whether inflammatory markers (interleukin-6: IL-6, C-reactive protein: CRP, and tumor necrosis factor α: TNFα) and depression were prospectively predictive of one another. Fasting serum samples and self-reports of depressive symptoms (Beck Depression Inventory-II) were obtained from participants at 2 sessions approximately 2 years apart. Structural equation models as well as regressions that accounted for a host of potentially confounding covariates and depression at baseline revealed that baseline IL-6 and CRP, but not baseline TNFα were associated with elevated depressive symptoms at the follow-up session (IL-6: ߠ​= â€‹0.080, p â€‹= â€‹0.036; CRP: ߠ​= â€‹0.083, p â€‹= â€‹0.03; TNFα: ߠ​= â€‹0.039, p â€‹= â€‹0.314). However, there was no association between baseline depressive symptoms and follow-up inflammatory markers (ßs â€‹= â€‹-0.12 to -0.006, all ps â€‹> â€‹0.05). Collectively, these data suggest that inflammation prospectively predicts depression, but depression does not predict inflammation in older age. These data add to a growing literature suggesting that inflammatory signaling may plausibly promote the development of depression.

Long-lasting Behavioral and Neuroanatomical Effects of Postnatal Valproic Acid Treatment.

Valproic acid (VPA) administered to mice during the early postnatal period causes social, cognitive, and motor deficits similar to those observed in humans with autism spectrum disorder (ASD). However, previous studies on the effects of early exposure to VPA have largely focused on behavioral deficits occurring before or during the juvenile period of life. Given that ASD is a life-long condition, the present study ought to extend our understanding of the behavioral profile following early postnatal VPA into adulthood. Male mice treated with VPA on postnatal day 14 (P14) displayed increased aggression, decreased avoidance of the open arms in the elevated plus maze, and impaired reversal learning in the Y maze. This may indicate a disinhibited or impulsive phenotype in male, but not female, mice treated with VPA during the second week of postnatal life. Decreased dendritic spine density and dendritic spine morphological abnormalities in the mPFC of VPA-treated mice may be indicative of PFC hypofunction, consistent with the observed behavioral differences. Since these types of long-lasting deficits are not exclusively found in ASD, early life exposure to VPA may reflect dysfunction of a neurobiological domain common to several developmental disorders, including ASD, ADHD, and conduct disorder.

Valproic acid induces nuclear factor erythroid 2-related factor 2 expression in fetal and neonatal brains but not in adult brain: evidence of the gamma-aminobutyric acid-shift hypothesis.

The gamma-aminobutyric acid (GABA)-shift hypothesis proposes that GABA agonist action is excitatory early in development and transitions to an inhibitory role later in life. In experiment 1, the nonspecific GABA agonist, valproic acid (VPA), was administered to pregnant C57BL/6 mice on embryonic day 13. Fetal and maternal brains were harvested 2 h post-VPA exposure and assayed for nuclear factor erythroid 2-related factor 2 (NRF2) and H3 expression through western blot analysis. In experiment 2, VPA was administered to neonatal pups on P14 and adult mice on P60. In both experiments, it was observed that NRF2 expression was increased in fetal and neonatal brains, but not in the adult brain. Because NRF2 expression is activated by oxidative stress, these results imply support of the GABA-shift hypothesis in that VPA may exert its developmental damage in the fetal and neonatal periods through excitotoxicity.

Maternal immune activation with staphylococcal enterotoxin A produces unique behavioral changes in C57BL/6 mouse offspring.

Stimulation of the immune system during pregnancy, known as maternal immune activation (MIA), can cause long-lasting neurobiological and behavioral changes in the offspring. This phenomenon has been implicated in the etiology of developmental psychiatric disorders, such as autism and schizophrenia. Much of this evidence is predicated on animal models using bacterial agents such as LPS and/or viral mimics such as Poly I:C, both of which act through toll-like receptors. However, fewer studies have examined the role of direct activation of maternal T-cells during pregnancy using microbial agents. Bacterial superantigens, such as Staphylococcal Enterotoxin A and B (SEA; SEB), are microbial proteins that activate CD4+ T-cells and cause prominent T-cell proliferation and cytokine production. We injected pregnant and non-pregnant adult female C57BL/6 mice with 200 µg/Kg of SEA, SEB, or 0.9% saline, and measured splenic T-cell-derived cytokine concentrations (viz., IL-2, IFN-γ, IL-6, and IL-4) 2 h later; animals injected with SEA were also measured for splenic concentrations of TNF-α and IL-17A. Half of the injected pregnant animals were brought to term, and their offspring were tested on a series of behavioral tasks starting at six weeks of age (postnatal day 42 [P42]). These tasks included social interaction, the elevated plus maze (EPM), an open field and object recognition (OR) task, prepulse inhibition (PPI) of sensorimotor gating, and the Morris water maze (MWM). Results showed that SEA and SEB induced significant concentrations of all measured cytokines, and in particular IFN-γ, although cytokine responses were greater following SEA exposure. In addition, pregnancy induced an inhibitory effect on cytokine production. Behavioral results showed distinct phenotypes among offspring from SEA- or SEB-injected mothers, very likely due to differences in the magnitude of cytokines generated in response to each toxin. Offspring from SEA-injected mothers displayed modest decreases in social behavior, but increased anxiety, locomotion, interest in a novel object, and short-term spatial memory, while offspring of SEB-injected mothers only exhibited increased anxiety and locomotion. There were no deficits in PPI, which was actually pronounced in SEA and SEB offspring. Overall, the novel use of SEA and SEB as prenatal immune challenges elicited distinct behavioral profiles in the offspring that both mirrors and diverges from previous models of maternal immune activation in important ways. We conclude that superantigen-induced T-cell-mediated maternal immune activation is a valid and valuable model for studying and expanding our understanding of the effects of prenatal immune challenge on neurodevelopmental and behavioral alterations in offspring.

Disruption of a conserved region of Xist exon 1 impairs Xist RNA localisation and X-linked gene silencing during random and imprinted X chromosome inactivation.

In XX female mammals a single X chromosome is inactivated early in embryonic development, a process that is required to equalise X-linked gene dosage relative to XY males. X inactivation is regulated by a cis-acting master switch, the Xist locus, the product of which is a large non-coding RNA that coats the chromosome from which it is transcribed, triggering recruitment of chromatin modifying factors that establish and maintain gene silencing chromosome wide. Chromosome coating and Xist RNA-mediated silencing remain poorly understood, both at the level of RNA sequence determinants and interacting factors. Here, we describe analysis of a novel targeted mutation, Xist(INV), designed to test the function of a conserved region located in exon 1 of Xist RNA during X inactivation in mouse. We show that Xist(INV) is a strong hypomorphic allele that is appropriately regulated but compromised in its ability to silence X-linked loci in cis. Inheritance of Xist(INV) on the paternal X chromosome results in embryonic lethality due to failure of imprinted X inactivation in extra-embryonic lineages. Female embryos inheriting Xist(INV) on the maternal X chromosome undergo extreme secondary non-random X inactivation, eliminating the majority of cells that express the Xist(INV) allele. Analysis of cells that express Xist(INV) RNA demonstrates reduced association of the mutant RNA to the X chromosome, suggesting that conserved sequences in the inverted region are important for Xist RNA localisation.

Dicer regulates Xist promoter methylation in ES cells indirectly through transcriptional control of Dnmt3a.

BACKGROUND: X chromosome inactivation is the mechanism used in mammals to achieve dosage compensation of X-linked genes in XX females relative to XY males. Chromosome silencing is triggered in cis by expression of the non-coding RNA Xist. As such, correct regulation of the Xist gene promoter is required to establish appropriate X chromosome activity both in males and females. Studies to date have demonstrated co-transcription of an antisense RNA Tsix and low-level sense transcription prior to onset of X inactivation. The balance of sense and antisense RNA is important in determining the probability that a given Xist allele will be expressed, termed the X inactivation choice, when X inactivation commences. RESULTS: Here we investigate further the mechanism of Xist promoter regulation. We demonstrate that both sense and antisense transcription modulate Xist promoter DNA methylation in undifferentiated embryonic stem (ES) cells, suggesting a possible mechanistic basis for influencing X chromosome choice. Given the involvement of sense and antisense RNAs in promoter methylation, we investigate a possible role for the RNA interference (RNAi) pathway. We show that the Xist promoter is hypomethylated in ES cells deficient for the essential RNAi enzyme Dicer, but that this effect is probably a secondary consequence of reduced levels of de novo DNA methyltransferases in these cells. Consistent with this we find that Dicer-deficient XY and XX embryos show appropriate Xist expression patterns, indicating that Xist gene regulation has not been perturbed. CONCLUSION: We conclude that Xist promoter methylation prior to the onset of random X chromosome inactivation is influenced by relative levels of sense and antisense transcription but that this probably occurs independent of the RNAi pathway. We discuss the implications for this data in terms of understanding Xist gene regulation and X chromosome choice in random X chromosome inactivation.

Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation.

Checkpoints that control Myc-mediated proliferation and apoptosis are bypassed during tumorigenesis. Genes encoding polyamine biosynthetic enzymes are overexpressed in B cells from E mu-Myc transgenic mice. Here, we report that disabling one of these Myc targets, Ornithine decarboxylase (Odc), abolishes Myc-induced suppression of the Cdk inhibitors p21(Cip1) and p27(Kip1), thereby impairing Myc's proliferative, but not apoptotic, response. Moreover, lymphoma development was markedly delayed in E mu-Myc;Odc(+/-) transgenic mice and in E mu-Myc mice treated with the Odc inhibitor difluoromethylornithine (DFMO). Strikingly, tumors ultimately arising in E mu-Myc;Odc(+/-) transgenics lacked deletions of Arf, suggesting that targeting Odc forces other routes of transformation. Therefore, Odc is a critical Myc transcription target that regulates checkpoints that guard against tumorigenesis and is an effective target for cancer chemoprevention.