Search

Disturbances in T-cells, specifically the Th17/Treg balance, have been implicated in adverse pregnancy outcomes. We investigated these two T-cell populations following pre-pregnancy and pregnancy SARS-CoV-2 infection and COVID-19 vaccination in 351 participants from a pregnancy cohort in New York City (Generation C; 2020-2022). SARS-CoV-2 infection status was determined via laboratory or medical diagnosis and COVID-19 vaccination status via survey and electronic medical records data. Peripheral blood mononuclear cells (PBMCs) were collected at routine prenatal visits throughout gestation (median 108 days; IQR 67-191 days) with repeated measures for 104 participants (29.6%). T-cell populations CD4+/CD3+, Th17/CD4+, Treg/CD4+ and the Th17/Treg ratio were quantified using flow cytometry. Results showed that inter-individual differences are a main influencing factor in Th17 and Treg variance, however total variance explained remained small (R2 = 15-39%). Overall, Th17 and Treg populations were not significantly affected by SARS-CoV-2 infection during pregnancy in adjusted linear mixed models (p>0.05), however comparison of repeated measures among SARS-CoV-2 infected participants and non-infected controls suggests a relative increase of the Th17/Treg ratio following infection. In addition, the Th17/Treg ratio was significantly higher after SARS-CoV-2 infection prior to pregnancy (10-138 weeks) compared to controls (b=0.48, p=0.003). COVID-19 vaccination was not associated with Th17 and Treg cells. Our findings suggest an impact of SARS-CoV-2 infection on the Th17/Treg ratio, likely depending on severity of infection, yet the observed trends and their potential consequences for pregnancy outcomes require further investigation. Our study contributes to growing evidence that COVID-19 vaccination during pregnancy does not lead to an exacerbated immune response. [ABSTRACT FROM AUTHOR]

• Tetracyclines have been proposed as candidate drugs for schizophrenia. • Potential long-term effects of doxycycline were explored using Danish Registry data. • 11,157 schizophrenia patients were analyzed, of which 718 redeemed a prescription of doxycycline. • The incidence of disability pension was selected as proxy measure of functioning. • Doxycycline prescription was associated with a lower incidence rate of disability pension. The brain-penetrant tetracycline antibiotics, minocycline and doxycycline, have been proposed as potential candidate drugs for treatment of schizophrenia, based on preclinical studies and clinical trials. A potential long-term beneficial effect of these antibiotics for schizophrenia patients has not been investigated. This study was designed to determine if redemption of doxycycline prescription in schizophrenia is associated with decreased incidence of disability pension, a proxy for long-term functioning. We performed a population-based cohort study with data from schizophrenia patients available through the Danish registers. Survival analysis models with time-varying covariates were constructed to assess incidence rate ratios (IRR) of disability pension after exposure to doxycycline or a non-brain penetrant tetracycline, defined as at least one filled prescription. The analysis was adjusted for age, sex, calendar year, parental psychiatric status and educational level. We used data from 11,157 individuals with schizophrenia (4,945 female and 6,212 male; average age 22.4 years old, standard deviation (std) 4.50). 718 of these were exposed to brain-penetrant doxycycline, and 1,498 individuals redeemed a prescription of one or more of the non-brain-penetrant tetracyclines. The average years at risk per person in this cohort was 4.9, and 2,901 individuals received disability pension in the follow-up period. There was a significantly lower incidence rate of disability pension in schizophrenia patients who had redeemed doxycycline compared to patients who did not redeem a prescription of any tetracycline antibiotics (Incidence rate ratio (IRR) 0.68; 95 % CI 0.56, 0.83). There was also a significant lower rate of disability pension in schizophrenia patients who redeemed doxycycline compared to individuals who redeemed a prescription of one of the non-brain penetrant tetracycline antibiotics (IRR 0.69 95 % CI 0.55, 0.87). In this observational study, doxycycline exposure is associated with a reduced incidence of disability pension. These data support further studies on the potential long term neuroprotective effects of doxycycline and level of functioning in schizophrenia patients. [ABSTRACT FROM AUTHOR]

The most studied HIV eradication approach is the "shock and kill" strategy, which aims to reactivate the latent reservoir by latency reversing agents (LRAs) and allowing elimination of these cells by immune‐mediated clearance or viral cytopathic effects. The CNS is an anatomic compartment in which (persistent) HIV plays an important role in HIV‐associated neurocognitive disorder. Restriction of the CNS by the blood–brain barrier is important for maintenance of homeostasis of the CNS microenvironment, which includes CNS‐specific cell types, expression of transcription factors, and altered immune surveillance. Within the CNS predominantly myeloid cells such as microglia and perivascular macrophages are thought to be a reservoir of persistent HIV infection. Nevertheless, infection of T cells and astrocytes might also impact HIV infection in the CNS. Genetic adaptation to this microenvironment results in genetically distinct, compartmentalized viral populations with differences in transcription profiles. Because of these differences in transcription profiles, LRAs might have different effects within the CNS as compared with the periphery. Moreover, reactivation of HIV in the brain and elimination of cells within the CNS might be complex and could have detrimental consequences. Finally, independent of activity on latent HIV, LRAs themselves can have adverse neurologic effects. We provide an extensive overview of the current knowledge on compartmentalized (persistent) HIV infection in the CNS and on the "shock and kill" strategy. Subsequently, we reflect on the impact and promise of the "shock and kill" strategy on the elimination of persistent HIV in the CNS. [ABSTRACT FROM AUTHOR]

Evidence of the impact of nutrition on human brain development is compelling. Previous in vitro and in vivo results show that three specific amino acids, histidine, lysine, and threonine, synergistically inhibit mTOR activity and behavior. Therefore, the prenatal availability of these amino acids could be important for human neurodevelopment. However, methods to study the underlying mechanisms in a human model of neurodevelopment are limited. Here, we pioneer the use of human cerebral organoids to investigate the impact of amino acid supplementation on neurodevelopment. In this study, cerebral organoids were exposed to 10 mM and 50 mM of the amino acids threonine, histidine, and lysine. The impact was determined by measuring mTOR activity using Western blots, general cerebral organoid size, and gene expression by RNA sequencing. Exposure to threonine, histidine, and lysine led to decreased mTOR activity and markedly reduced organoid size, supporting findings in rodent studies. RNA sequencing identified comprehensive changes in gene expression, with enrichment in genes related to specific biological processes (among which are mTOR signaling and immune function) and to specific cell types, including proliferative precursor cells, microglia, and astrocytes. Altogether, cerebral organoids are responsive to nutritional exposure by increasing specific amino acid concentrations and reflect findings from previous rodent studies. Threonine, histidine, and lysine exposure impacts the early development of human cerebral organoids, illustrated by the inhibition of mTOR activity, reduced size, and altered gene expression. [ABSTRACT FROM AUTHOR]

The achievement of an HIV cure is dependent on the eradication or permanent silencing of HIV-latent viral reservoirs, including the understudied central nervous system (CNS) reservoir. This requires a deep understanding of the molecular mechanisms of HIV's entry into the CNS, latency establishment, persistence, and reversal. Therefore, representative CNS culture models that reflect the intercellular dynamics and pathophysiology of the human brain are urgently needed in order to study the CNS viral reservoir and HIV-induced neuropathogenesis. In this study, we characterized a human cerebral organoid model in which microglia grow intrinsically as a CNS culture model to study HIV infection in the CNS. We demonstrated that both cerebral organoids and isolated organoid-derived microglia (oMG), infected with replication-competent HIVbal reporter viruses, support productive HIV infection via the CCR5 co-receptor. Productive HIV infection was only observed in microglial cells. Fluorescence analysis revealed microglia as the only HIV target cell. Susceptibility to HIV infection was dependent on the co-expression of microglia-specific markers and the CD4 and CCR5 HIV receptors. Altogether, this model will be a valuable tool within the HIV research community to study HIV–CNS interactions, the underlying mechanisms of HIV-associated neurological disorders (HAND), and the efficacy of new therapeutic and curative strategies on the CNS viral reservoir. [ABSTRACT FROM AUTHOR]

Transcriptome studies have revealed age-, disease-, and region-associated microglial phenotypes reflecting changes in microglial function during development, aging, central nervous system homeostasis, and pathology. The molecular mechanisms that contribute to these transcriptomic changes are largely unknown. The aim of this study was to characterize the DNA methylation landscape of human microglia and the factors that contribute to variations in the microglia methylome. We hypothesized that both age and brain region would have a large impact on DNA methylation in microglia. Microglia from postmortem brain tissue of four different brain regions of 22 donors, encompassing 1 patient with schizophrenia, 13 patients with mood disorder pathology, and 8 control subjects, were isolated and assayed using a genome-wide methylation array. We found that human microglial cells have a methylation profile distinct from bulk brain tissue and neurons, and age explained a considerable part of the variation. Additionally, we showed that interindividual factors had a much larger effect on the methylation landscape of microglia than brain region, which was also seen at the transcriptome level. In our exploratory analysis, we found various differentially methylated regions that were related to disease status (mood disorder vs. control). This included differentially methylated regions that are linked to gene expression in microglia, as well as to myeloid cell function or neuropsychiatric disorders. Although based on relatively small samples, these findings suggest that the methylation profile of microglia is responsive to interindividual variations and thereby plays an important role in the heterogeneity of microglia observed at the transcriptome level. [ABSTRACT FROM AUTHOR]

Background: Childhood adversity increases the risk of a range of mental disorders including bipolar disorder, but the underlying mechanisms are still unknown. Previous studies identified DNA methylation levels at the cg27512205 locus on the KIT Ligand (KITLG) gene as a mediator between childhood adversity and stress responsivity. This raises the question whether this locus also plays a role in stress related disorders such as bipolar disorder. Therefore, the current study aims to compare the level of KITLG (cg27512205) methylation between bipolar patients and healthy individuals and its relation to childhood adversity. Methods: KITLG (cg27512205) methylation was measured in 50 bipolar disorder patients and 91 healthy control participants using the HumanMethylation450K BeadChip platform. Childhood adversity in each individual was assessed using the Childhood Trauma Questionnaire. Analyses of the association of KITLG methylation with bipolar disorder, the association of childhood adversity with bipolar disorder as well as the association of KITLG methylation with childhood adversity in bipolar patients and controls were conducted using linear regression with age, gender, childhood adversity, smoking, and cell-type composition estimates as covariates. Results: KITLG (cg27512205) methylation level was significantly lower in bipolar disorder patients (β = −0.351, t = −6.316 p < 0.001). Childhood adversity levels were significantly higher in the bipolar disorder group (β = 4.903, t = 2.99, p = 0.003). In the bipolar disorder patients KITLG methylation was not associated with childhood adversity (β = 0.004, t = 1.039, p = 0.304) in contrast to the healthy controls (β = 0.012, t = 3.15, p = 0.002). Conclusions: KITLG methylation was lower in bipolar disorder despite high levels of childhood adversity, whereas childhood adversity was associated with higher KITLG methylation in healthy controls. In addition to lower methylation at this locus there is an indication that failure to adjust KITLG methylation to high levels of childhood adversity is a risk factor for bipolar disorder. [ABSTRACT FROM AUTHOR]

Background: Since postpartum psychosis has been linked to activation of the immune system, it has been hypothesized that infectious agents may be involved in the pathogenesis of this disorder. We therefore investigated whether exposure to pathogens that can infect the central nervous system is increased in patients with postpartum psychosis.Methods: We measured the prevalence and titers of immunoglobulin G (IgG) and M (IgM) to herpes simplex virus type 1 (HSV-1) and 2 (HSV-2), Epstein-Barr virus (EBV), cytomegalovirus (CMV) and Toxoplasma Gondii (TG) in a cohort of patients with postpartum psychosis (n = 81) and compared these to matched postpartum controls.Results: We did not find significant differences in seroprevalence or antibody titers for any of these pathogens.Limitations: Limitations of this study include the indirect measurement of infectious disease and the cross-sectional design.Conclusion: Our results do not support the hypothesis that exposure to these neurotropic pathogens is involved in postpartum psychosis. [ABSTRACT FROM AUTHOR]

There is a consensus in the field that microglia play a prominent role in neurodevelopmental processes like synaptic pruning and neuronal network maturation. Thus, a current momentum of associating microglia deficits with neurodevelopmental disorders (NDDs) emerged. This concept is challenged by rodent studies and clinical data. Intriguingly, reduced numbers of microglia or altered microglial functions do not necessarily lead to overt NDD phenotypes, and neuropsychiatric symptoms seem to develop primarily in adulthood. Hence, it remains open for discussion whether microglia are truly indispensable for healthy neurodevelopment. Here, we critically discuss the role of microglia in synaptic pruning and highlight area- and age dependency. We propose an updated model of microglia-mediated synaptic pruning in the context of NDDs and discuss the potential of targeting microglia for treatment of these disorders. [ABSTRACT FROM AUTHOR]

Background: Microglia are tissue‐resident macrophages of the central nervous system that are essential for homeostasis, immune response, neurogenesis, and neuronal plasticity. Genetic studies have strongly implicated microglial dysfunction in multiple neurodegenerative diseases. However, investigating genetically‐driven changes in gene expression in microglia has been limited by lack of access to these cells from the number of subjects required to perform well‐powered genomic analysis. Method: Here we describe the transcriptome analysis of 255 primary human CD11b+ microglia samples isolated at autopsy from multiple brain regions of 100 human subjects with neurodegenerative and neuropsychiatric disorders. We performed systematic analyses to investigate various aspects of microglial heterogeneities including brain region, age, sex, and disease. By intersecting transcriptomics and genetics, we performed expression and splicing QTL analyses and by combining microglia from four different brain regions using a multivariate meta‐analysis method (mashR). Result: We observed widespread transcriptome variation associated with microglia, suggesting that these genes may play important role in diversified responses to pathological stimuli of microglia at different locations. We also observed 1,693 genes (FDR < 0.05) whose expression is associated with age including many genes in Alzheimer's (AD) (MS4A6A, FCER1G, and CR1) or Parkinson's disease (PD) (BST1 and FCGR2A) GWAS loci. We identified 3,611 eQTLs (mashR local false sign rate < 0.05), of which 50% (1,791) show region‐specific effects. We identified over 300 eQTLs that colocalize with a known risk locus for a neurodegenerative or neuropsychiatric disease, nearly half of which are not found in prefrontal cortex or in peripheral monocytes. We prioritized 7 and 13 putative causal genes for AD and PD, respectively, many of which are novel genes (ITGAX, USP6NL, TSPOAP1, P2RY12, FCGR2C, and FGF20). Fine‐mapping of these colocalized loci with CNS chromatin accessibility (ATAC‐seq) and histone modification (H3K27ac) data nominates candidate causal variants that are within microglia‐specific enhancers and are likely to modify disease susceptibility by regulating gene expression and/or splicing in microglia. Conclusion: In summary, we have built the most comprehensive catalog to date of genetic effects on the microglia transcriptome and propose molecular mechanisms of action of candidate functional variants in several neurological and neuropsychiatric diseases. [ABSTRACT FROM AUTHOR]

The article focuses on the absence of N-Methyl-D-aspartate receptor Immunoglobulin G (IgG) auto antibodies in schizophrenia and the importance of cross-validation studies. Topics discussed include mental disorders associated with autoimmune encephalitis, assessments of neurological symptoms, and s investigation of cerebrospinal fluid and serum of acutely ill patients with first-episode psychosis.

Despite antiretroviral therapy (ART), HIV persistence in the central nervous system (CNS) continues to cause a range of cognitive impairments in people living with HIV (PLWH). Upon disease progression, transmigrating CCR5-using T-cell tropic viruses are hypothesized to evolve into macrophage-tropic viruses in the CNS that can efficiently infect low CD4-expressing cells, such as microglia. We examined HIV-1 RNA concentration, co-receptor usage, and CSF compartmentalization in paired CSF and blood samples from 19 adults not on treatment. Full-length envelope CSF- and plasma-derived reporter viruses were generated from 3 subjects and phenotypically characterized in human primary CD4+ T-cells and primary microglia. Median HIV RNA levels were higher in plasma than in CSF (5.01 vs. 4.12 log10 cp/mL; p = 0.004), and coreceptor usage was mostly concordant for CCR5 across the paired samples (n = 17). Genetically compartmentalized CSF viral populations were detected in 2 subjects, one with and one without neurological symptoms. All viral clones could replicate in T-cells (R5 T cell-tropic). In addition, 3 CSF and 1 plasma patient-derived viral clones also had the capacity to replicate in microglia/macrophages and, therefore have an intermediate macrophage tropic phenotype. Overall, with this study, we demonstrate that in a subset of PLWH, plasma-derived viruses undergo genetic and phenotypic evolution within the CNS, indicating viral infection and replication in CNS cells. It remains to be studied whether the intermediate macrophage-tropic phenotype observed in primary microglia represents a midpoint in the evolution towards a macrophage-tropic phenotype that can efficiently replicate in microglial cells and propagate viral infection in the CNS. [ABSTRACT FROM AUTHOR]

Recent imaging studies have suggested that accelerated aging occurs in schizophrenia. However, the exact cause of these findings is still unclear. In this study we measured telomere length, a marker for cell senescence, in gray and white matter brain tissue from the medial frontal gyrus (MFG) and superior temporal gyrus (STG) of 9 patients with schizophrenia and 11 controls. No alterations in telomere length were found in MFG gray and white matter and in STG gray matter. A significant reduction in telomere length was observed in STG white matter of patients with schizophrenia as compared to controls (fold change of −0.42, U = 5, P = 0.008). Our results support previous findings that telomere length in gray matter is not affected, whereas they suggest that increased cell senescence may affect white matter temporal brain tissue. [ABSTRACT FROM AUTHOR]

A subpopulation of patients with bipolar disorder type I (BD-I) might suffer from undiagnosed autoimmune encephalitis. We tested plasma of 104 BD-I patients with a current or recent manic episode in the past 2 years for the presence of neuronal autoantibodies using immunohistochemistry, immunocytochemistry and cell-based assay (CBA). Neuronal antibodies were not detected in any of the BD type I. This finding suggests that the frequency of an undiagnosed autoimmune encephalitis in patients with BD I is less than 1%. However, these findings need to be confirmed in cerebrospinal fluid and/or blood of acutely ill manic patients. [ABSTRACT FROM AUTHOR]