Linda Bierer - Academia.edu (original) (raw)

Papers by Linda Bierer

Differential brain expression oftheAlzheimer's amyloid

European Neuropsychopharmacology, Nov 1, 2020

War veterans are at increased risk of suicide that may be related to deployment and/or postdeploy... more War veterans are at increased risk of suicide that may be related to deployment and/or postdeployment stressors and to adjustment-related factors. The aim of this study was to examine whether levels of plasma neuropeptide Y (NPY) might distinguish combat veterans who have made a post-deployment suicide attempt from those who have never made a suicide attempt. We focused on NPY because of prior findings linking NPY with the neurobiology of resilience, stress-related and other disorders, and suicidal behavior. Demographic and clinical parameters of suicide attempters and non-attempters were assessed and plasma NPY was determined by radioimmunoassay. NPY levels were higher among attempters in comparison to non-attempters, controlling for sex and body-mass index. Suicide attempters had higher Scale for Suicidal Ideation (SSI) scores than non-attempters. There was a positive correlation between NPY levels and SSI scores among non-attempters but not among attempters. Likewise, NPY levels positively correlated with Brown-Goodwin Aggression Scale scores among suicide attempters but not among non-attempters. This is the first demonstration of altered plasma NPY levels in association with suicide attempt history and suicidal ideation in veterans. Our findings suggest that clinical differences between combat veterans with or without a history of suicide attempt may have a neurobiological origin.

bioRxiv (Cold Spring Harbor Laboratory), Mar 2, 2021

Post-traumatic stress disorder (PTSD) results from severe trauma exposure, but the extent to whic... more Post-traumatic stress disorder (PTSD) results from severe trauma exposure, but the extent to which genetic and epigenetic risk factors impact individual clinical outcomes is unknown. We assessed the impact of genomic differences following glucocorticoid administration by examining the transcriptional profile of human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and live cultured peripheral blood mononuclear cells from combat veterans with PTSD (n=5) and without PTSD (n=5). This parallel examination in baseline and glucocorticoid-treated conditions resolves cell-type specific and diagnosis-dependent elements of stress response, and permits discrimination of gene expression signals associated with PTSD risk from those induced by stress. Computational analyses revealed neuron-specific glucocorticoid-response expression patterns that were enriched for transcriptomic patterns observed in clinical PTSD samples. PTSD-specific signatures, albeit underpowered, accurately stratify veterans with PTSD relative to combat-exposed controls. Overall, in vitro PTSD and glucocorticoid response signatures in blood and brain cells represent exciting new platforms with which to test the genetic and epigenetic mechanisms underlying PTSD, identify biomarkers of PTSD risk and onset, and conduct drug-screening to identify novel therapeutics to prevent or ameliorate clinical phenotypes. .

Translational Psychiatry, Aug 21, 2019

Post-traumatic stress disorder (PTSD) is a condition of stress reactivity, whose clinical manifes... more Post-traumatic stress disorder (PTSD) is a condition of stress reactivity, whose clinical manifestations are evident when patients are triggered following exposure to a traumatic event. While baseline differences in gene expression of glucocorticoid signaling and inflammatory cytokines in peripheral blood mononuclear cells (PBMCs) have been associated with PTSD, these alterations do not fully recapitulate the molecular response to physiological triggers, such as stress hormones. Therefore, it is critical to develop new techniques that will capture the dynamic transcriptional response associated with stress-activated conditions relative to baseline conditions. To achieve this goal, cultured PBMCs from combat-exposed veterans with PTSD(+) (n = 10) and without PTSD(−) (n = 10) were incubated with increasing concentrations (vehicle, 2.5 nM, 5 nM, 50 nM) of dexamethasone (DEX). Across diagnosis and dosage, several genes and gene networks were reliable markers of glucocorticoid stimulation (FDR < 5%), including enhanced expression of FKPB5, VIPR1, NR1I3, and apoptosis-related pathways, and reduced expression of NR3C1, STAT1, IRF1, and related inflammatory and cellular stress-responsive pathways. Dose-dependent differential transcriptional changes in several genes were also identified between PTSD+ and PTSD−. Robust changes in expression were observed at 2.5 nM DEX in PTSD− but not PTSD+ participants; whereas, with increasing concentrations (5 nM and 50 nM), several genes were identified to be uniquely up-regulated in PTSD+ but not PTSD− participants. Collectively, these preliminary findings suggest that genome-wide gene expression profiling of DEX-stimulated PBMCs is a promising method for the exploration of the dynamic differential molecular responses to stress hormones in PTSD, and may identify novel markers of altered glucocorticoid signaling and responsivity in PTSD.

Brain Behavior and Immunity, Oct 1, 2015

Nervous System in coordination with an other systems as endocrine and immune. Several studies hav... more Nervous System in coordination with an other systems as endocrine and immune. Several studies have shown that conditions of e34 Abstracts / Brain, Behavior, and Immunity 49 (2015) e1-e50

Journal of Psychiatric Research, Nov 1, 2021

Combat exposure has been linked to increased risk of suicidal ideation, suicide attempts, and dea... more Combat exposure has been linked to increased risk of suicidal ideation, suicide attempts, and death by suicide, and suicidality has been linked with altered testosterone levels. In this study, we examined morning baseline free and total testosterone levels and the effect of dexamethasone administration on testosterone levels in male combat veterans with or without a history of suicide attempt. Demographic and clinical parameters of the study participants were assessed and recorded. Blood samples were collected between 8:00 and 8:30 a.m. on the day prior to and following dexamethasone (0.5 mg) ingestion. Suicide attempters had higher schedule for suicidal ideation (SSI) scores in comparison to non-attempters. Baseline free and total testosterone levels were lower in suicide attempters compared to non-attempters. In the whole sample, both baseline free and total testosterone levels negatively correlated with SSI scores. Free testosterone levels decreased after dexamethasone administration among non-attempters but not among attempters. Free testosterone post-dexamethasone levels positively correlated with aggression scores among non-attempters but not among suicide attempters. Our findings indicate that there are substantial differences in the testosterone regulation between combat veterans with or without a history of suicide attempt. Studies of the relation between the testosterone function and suicidal behavior among combat veterans may lead to improvement in detection of suicidality and finding new pharmacological targets for prevention of suicide among veterans.

medRxiv (Cold Spring Harbor Laboratory), Dec 8, 2020

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by pee... more doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Biological Psychiatry, May 1, 2020

Background: Schizophrenia (SCZ) is associated with an increased risk of violence compared to the ... more Background: Schizophrenia (SCZ) is associated with an increased risk of violence compared to the general population. Previous studies have indicated smaller hippocampal and amygdala volumes in violent than non-violent psychotic patients. However, little is known about volumetric differences at the subdivision level of these structures. Methods: In the present study, hippocampal subfields and amygdala nuclei volumes were estimated with FreeSurfer from 3T MRI of SCZ patients with (SCZ-V, n¼24) and without (SCZ-NV, n¼51) a history of severe violence and 90 healthy controls (HC). Volumetric differences between groups were explored with a general linear model covarying for confounders, in addition to follow-up analyses in patient groups controlling for clinical characteristics such as antipsychotic medication, duration of illness and illicit substance use. Results: SCZ-V had smaller total hippocampal volume and smaller CA1, HATA, fimbria and molecular layer of DG volumes compared to HC. Total amygdala volume together with basal nucleus, accessory basal nucleus, CTA and paralaminar nucleus volumes were smaller in SCZ-V compared to HC. In SCZ-NV, compared to HC, the observed smaller volumes were limited to basal and paralaminar nucleus. There were no significant differences in hippocampal subfield and amygdala nuclei volumes between SCZ-V and SCZ-NV. Follow-up analyses showed that the results in patient groups were not affected by clinical characteristics. Conclusions: The results suggest that smaller hippocampal subfield and amygdala nuclei volumes may be relevant to violence risk in SCZ. However, the neurobiological signature of violence in SCZ should be further investigated in larger cohorts.

Biological Psychiatry, May 1, 2017

Dementia in elderly schizophrenics

Schizophrenia Research, 1992

Acta Psychiatrica Scandinavica, May 22, 2018

The goal of this study was to determine whether combat veterans who have made a suicide attempt p... more The goal of this study was to determine whether combat veterans who have made a suicide attempt postdeployment can be distinguished from combat veterans who have never made a suicide attempt based on differences in psychological and biological variables. Methods: Demographic and clinical parameters of suicide attempters and non-attempters were assessed. Blood samples were assayed for dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS). Results: Suicide attempters had higher Scale for Suicidal Ideation and Montgomery-Asberg Depression Rating Scale (MADRS)-suicidal thoughts item scores in comparison with non-attempters. There was a trend toward higher MADRS scores in the suicide attempter group compared with non-attempters. Suicide attempters had significantly lower levels of DHEA and DHEAS compared with non-attempters. Scale for Suicidal Ideation scores in all study participants combined negatively correlate with DHEA and DHEAS levels. DHEAS levels negatively correlate with Scale for Suicidal Ideation scores in suicide non-attempters but not in suicide attempters. DHEA/DHEAS ratios positively correlate with total adolescence aggression scores, total adulthood aggression scores, and total aggression scale scores in suicide attempters but not in suicide non-attempters. Conclusion: There are psychobiological differences between combat veterans with or without a history of suicidal behaviour.

Neuropsychopharmacology, Nov 10, 2020

Offspring of trauma survivors are more likely to develop PTSD, mood, and anxiety disorders and de... more Offspring of trauma survivors are more likely to develop PTSD, mood, and anxiety disorders and demonstrate endocrine and molecular alterations compared to controls. This study reports the association between parental Holocaust exposure and genomewide gene expression in peripheral blood mononuclear cells (PBMC) from 77 Holocaust survivor offspring and 15 comparison subjects. Forty-two differentially expressed genes (DEGs) were identified in association with parental Holocaust exposure (FDRadjusted p < 0.05); most of these genes were downregulated and co-expressed in a gene network related to immune cell functions. When both parental Holocaust exposure and maternal age at Holocaust exposure shared DEGs, fold changes were in the opposite direction. Similarly, fold changes of shared DEGs associated with maternal PTSD and paternal PTSD were in opposite directions, while fold changes of shared DEGs associated with both maternal and paternal Holocaust exposure or associated with both maternal and paternal age at Holocaust exposure were in the same direction. Moreover, the DEGs associated with parental Holocaust exposure were enriched for glucocorticoid-regulated genes and immune pathways with some of these genes mediating the effects of parental Holocaust exposure on C-reactive protein. The top gene across all analyses was MMP8, encoding the matrix metalloproteinase 8, which is a regulator of innate immunity. To conclude, this study identified a set of glucocorticoid and immunerelated genes in association with parental Holocaust exposure with differential effects based on parental exposure-related factors.

American Journal of Psychiatry, Aug 1, 2020

The EMBO Journal, Dec 1, 1989

The expression of the Alzheimer amyloid protein precursor (AAPP) was examined in human, monkey, d... more The expression of the Alzheimer amyloid protein precursor (AAPP) was examined in human, monkey, dog and rat brains. Two proteins, one identified as AAPP695 and the other as AAPP751, were immunoprecipitated from the in vitro translation of human, dog and rat brain polysomes. The AAPP75, to AAPP695 ratio was highest in human, intermediate in dog and lowest in rat brain polysomes. Human cerebral cortex contained higher levels of the AAPP751 mRNA than either dog or rat cortex. AAPP695 was detected in both cerebral cortex and cerebellum of all species examined. In contrast, AAPP751 was detected predominantly in the cortex of human, monkey and to a lesser extent dog brains while it was not detected in rat brain. These findings indicate that the amyloid precursors are differentially expressed in different mammalian brains and suggest that AAPP751 is mainly expressed in the brain regions involved in plaque formation. Key words: Alzheimer's disease/amyloid precursor protein/ immunoblotting/in vitro translation/protein expression Dayan, 1971; Vaughn and Peters, 1981; Selkoe et al., 1987). The absence of AP amyloid depositions in rat could be related to their shorter lifespan or to differences in the expression and/or processing of the AAPP in the rat brain compared to mammals with longer lifespans. In the present study we used anti-AAPP antisera to study the expression of the AP precursors in the cortex and cerebellum of human, monkey, dog and rat brains.

American Journal of Psychiatry, Nov 1, 2003

The authors examined the relationship of borderline personality disorder to posttraumatic stress ... more The authors examined the relationship of borderline personality disorder to posttraumatic stress disorder (PTSD) with respect to the role of trauma and its timing. Method: The Trauma History Questionnaire and the PTSD module of the Structured Clinical Interview for DSM-III-R were administered to 180 male and female outpatients with a diagnosis of one or more DSM-III-R personality disorders. Path analysis was used to evaluate the relationship between borderline personality disorder and PTSD.

Transcriptional Perturbations to Glucocorticoids Across Blood and Brain Cells Derived From Individuals With Post-Traumatic Stress Disorder

Biological Psychiatry, May 1, 2021

World Journal of Biological Psychiatry, Mar 13, 2023

Objective: Endothelial dysfunction assessed by brachial artery flow-mediated dilation (FMD) is a ... more Objective: Endothelial dysfunction assessed by brachial artery flow-mediated dilation (FMD) is a marker of early atherosclerosis. Glucocorticoid receptor gene (NR3C1) regulates many biological processes, including stress response, behavioral, cardiometabolic and immunologic functions. Genetic variants in NR3C1 have been associated with atherosclerosis and related risk factors. This study investigated the association of NR3C1 promoter methylation with FMD, independent of genetic and family-level environmental factors. Methods: We studied 84 middle-aged, maleemale monozygotic twin pairs recruited from the Vietnam Era Twin Registry. Brachial artery FMD was measured by ultrasound. DNA methylation levels at 22 CpG residues in the NR3C1 exon 1F promoter region were quantified by bisulfite pyrosequencing in genomic DNA isolated from peripheral blood leukocytes. Co-twin control analyses were conducted to examine the association of methylation variation with FMD, adjusting for smoking, physical activity, body mass index, lipids, blood pressure, fasting glucose, and depressive symptoms. Multiple testing was corrected using the false discovery rate. Results: Mean methylation level across the 22 studied CpG sites was 2.02%. Methylation alterations at 12 out of the 22 CpG residues were significantly associated with FMD. On average, a 1% increase in the intrapair difference in mean DNA methylation was associated with 2.83% increase in the intra-pair difference in FMD (95% CI: 1.46e4.20; P < 0.0001) after adjusting for risk factors and multiple testing. Conclusion: Methylation variation in NR3C1 exon 1F promoter significantly influences subclinical atherosclerosis, independent of genetic, early family environmental and other risk factors.

Psychiatry Research-neuroimaging, May 1, 2020

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service... more This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Highlights  Suicide attempters had higher suicidal ideation in comparison to non-attempters  2-AG levels were higher among suicide attempters in comparison to non-attempters  Clinically observed differences between the groups may have a neurobiological basis

Cingulate and hippocampal subregion abnormalities in combat-exposed veterans with PTSD

Journal of Affective Disorders, Aug 1, 2022

Translational Psychiatry, Jul 13, 2021

Epigenetic changes are currently invoked as explanations for both the chronicity and tenacity of ... more Epigenetic changes are currently invoked as explanations for both the chronicity and tenacity of post-traumatic stress disorder (PTSD), a heterogeneous condition showing varying, sometimes idiosyncratic responses to treatment. This study evaluated epigenetic markers in the context of a randomized clinical trial of PTSD patients undergoing prolonged-exposure psychotherapy with and without a hydrocortisone augmentation prior to each session. The purpose of the longitudinal epigenome-wide analyses was to identify predictors of recovery (from pretreatment data) or markers associated with symptom change (based on differences between pre-and post-therapy epigenetic changes). The results of these analyses identified the CREB-BDNF signaling pathway, previously linked to startle reaction and fear learning and memory processes, as a convergent marker predicting both symptom change and severity. Several previous-reported resilience markers were also identified (FKBP5, NR3C1, SDK1, and MAD1L1) to associate with PTSD recovery in this study. Especially, the methylation levels of FKBP5 in the gene body region decreased significantly as CAPS score decreased in responders, while no changes occurred in nonresponders. These biomarkers may have future utility in understanding clinical recovery in PTSD and potential applications in predicting treatment effects.