151 results on '"Cynthia Shannon Weickert"'
Search Results
2. Correction: Obesity and brain structure in schizophrenia – ENIGMA study in 3021 individuals
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Sean R. McWhinney, Katharina Brosch, Vince D. Calhoun, Benedicto Crespo-Facorro, Nicolas A. Crossley, Udo Dannlowski, Erin Dickie, Lorielle M. F. Dietze, Gary Donohoe, Stefan Du Plessis, Stefan Ehrlich, Robin Emsley, Petra Furstova, David C. Glahn, Alfonso Gonzalez- Valderrama, Dominik Grotegerd, Laurena Holleran, Tilo T. J. Kircher, Pavel Knytl, Marian Kolenic, Rebekka Lencer, Igor Nenadić, Nils Opel, Julia-Katharina Pfarr, Amanda L. Rodrigue, Kelly Rootes-Murdy, Alex J. Ross, Kang Sim, Antonín Škoch, Filip Spaniel, Frederike Stein, Patrik Švancer, Diana Tordesillas-Gutiérrez, Juan Undurraga, Javier Vázquez-Bourgon, Aristotle Voineskos, Esther Walton, Thomas W. Weickert, Cynthia Shannon Weickert, Paul M. Thompson, Theo G. M. van Erp, Jessica A. Turner, and Tomas Hajek
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Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Molecular Biology - Published
- 2023
3. Perturbed iron biology in the prefrontal cortex of people with schizophrenia
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Amit Lotan, Sandra Luza, Carlos M. Opazo, Scott Ayton, Darius J. R. Lane, Serafino Mancuso, Avril Pereira, Suresh Sundram, Cynthia Shannon Weickert, Chad Bousman, Christos Pantelis, Ian P. Everall, and Ashley I. Bush
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Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Molecular Biology - Abstract
Despite loss of grey matter volume and emergence of distinct cognitive deficits in young adults diagnosed with schizophrenia, current treatments for schizophrenia do not target disruptions in late maturational reshaping of the prefrontal cortex. Iron, the most abundant transition metal in the brain, is essential to brain development and function, but in excess, it can impair major neurotransmission systems and lead to lipid peroxidation, neuroinflammation and accelerated aging. However, analysis of cortical iron biology in schizophrenia has not been reported in modern literature. Using a combination of inductively coupled plasma-mass spectrometry and western blots, we quantified iron and its major-storage protein, ferritin, in post-mortem prefrontal cortex specimens obtained from three independent, well-characterised brain tissue resources. Compared to matched controls (n = 85), among schizophrenia cases (n = 86) we found elevated tissue iron, unlikely to be confounded by demographic and lifestyle variables, by duration, dose and type of antipsychotic medications used or by copper and zinc levels. We further observed a loss of physiologic age-dependent iron accumulation among people with schizophrenia, in that the iron level among cases was already high in young adulthood. Ferritin, which stores iron in a redox-inactive form, was paradoxically decreased in individuals with the disorder. Such iron-ferritin uncoupling could alter free, chemically reactive, tissue iron in key reasoning and planning areas of the young-adult schizophrenia cortex. Using a prediction model based on iron and ferritin, our data provide a pathophysiologic link between perturbed cortical iron biology and schizophrenia and indicate that achievement of optimal cortical iron homeostasis could offer a new therapeutic target.
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- 2023
4. Neuroinflammation in schizophrenia: the role of nuclear factor kappa B
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Caitlin E. Murphy, Adam K. Walker, and Cynthia Shannon Weickert
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Regulator ,Prefrontal Cortex ,Inflammation ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Review Article ,Molecular neuroscience ,Cellular and Molecular Neuroscience ,Immune system ,Medicine ,Humans ,Transcription factor ,Biological Psychiatry ,Neuroinflammation ,business.industry ,Effector ,NF-kappa B ,medicine.disease ,Dorsolateral prefrontal cortex ,Psychiatry and Mental health ,medicine.anatomical_structure ,Schizophrenia ,Cytokines ,medicine.symptom ,business ,Neuroscience ,Transcription Factors ,RC321-571 - Abstract
Neuroinflammation, particularly in the dorsolateral prefrontal cortex, is well-established in a subset of people with schizophrenia, with significant increases in inflammatory markers including several cytokines. Yet the cause(s) of cortical inflammation in schizophrenia remains unknown. Clues as to potential microenvironmental triggers and/or intracellular deficits in immunoregulation may be gleaned from looking further upstream of effector immune molecules to transcription factors that control inflammatory gene expression. Here, we focus on the ‘master immune regulator’ nuclear factor kappa B (NF-κB) and review evidence in support of NF-κB dysregulation causing or contributing to neuroinflammation in patients. We discuss the utility of ‘immune biotyping’ as a tool to analyse immune-related transcripts and proteins in patient tissue, and the insights into cortical NF-κB in schizophrenia revealed by immune biotyping compared to studies treating patients as a single, homogenous group. Though the ubiquitous nature of NF-κB presents several hurdles for drug development, targeting this key immunoregulator with novel or repurposed therapeutics in schizophrenia is a relatively underexplored area that could aid in reducing symptoms of patients with active neuroinflammation.
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- 2021
5. Single-nucleus RNA sequencing of midbrain blood-brain barrier cells in schizophrenia reveals subtle transcriptional changes with overall preservation of cellular proportions and phenotypes
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Sofía Puvogel, Astrid Alsema, Laura Kracht, Maree J. Webster, Cynthia Shannon Weickert, Iris E. C. Sommer, Bart J. L. Eggen, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Movement Disorder (MD), Molecular Neuroscience and Ageing Research (MOLAR), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
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Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,WIDE ASSOCIATION ANALYSIS ,CORTEX ,MOLECULES ,ADULT ,IDENTIFICATION ,PROTEINS ,FOXP2 ,PROTOPLASMIC ASTROCYTES ,Molecular Biology ,ENDOTHELIAL-CELLS ,METAANALYSIS - Abstract
The midbrain is an extensively studied brain region in schizophrenia, in view of its reported dopamine pathophysiology and neuroimmune changes associated with this disease. Besides the dopaminergic system, the midbrain contains other cell types that may be involved in schizophrenia pathophysiology. The neurovascular hypothesis of schizophrenia postulates that both the neurovasculature structure and the functioning of the blood-brain barrier (BBB) are compromised in schizophrenia. In the present study, potential alteration in the BBB of patients with schizophrenia was investigated by single-nucleus RNA sequencing of post-mortem midbrain tissue (15 schizophrenia cases and 14 matched controls). We did not identify changes in the relative abundance of the major BBB cell types, nor in the sub-populations, associated with schizophrenia. However, we identified 14 differentially expressed genes in the cells of the BBB in schizophrenia as compared to controls, including genes that have previously been related to schizophrenia, such as FOXP2 and PDE4D. These transcriptional changes were limited to the ependymal cells and pericytes, suggesting that the cells of the BBB are not broadly affected in schizophrenia.
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- 2022
6. Reduced adult neurogenesis is associated with increased macrophages in the subependymal zone in schizophrenia
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Glenda M. Halliday, Michael Piper, Maree J. Webster, Guy Barry, Hayley F. North, Janice M. Fullerton, Christin Weissleder, Mainá Bitar, Rachel Sager, and Cynthia Shannon Weickert
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Adult ,0301 basic medicine ,Neurogenesis ,Biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Neural Stem Cells ,mental disorders ,medicine ,Subependymal zone ,Humans ,Bipolar disorder ,Progenitor cell ,Child ,Molecular Biology ,Progenitor ,Neurons ,Macrophages ,medicine.disease ,Neural stem cell ,Psychiatry and Mental health ,030104 developmental biology ,Schizophrenia ,CD163 ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Neural stem cells in the human subependymal zone (SEZ) generate neuronal progenitor cells that can differentiate and integrate as inhibitory interneurons into cortical and subcortical brain regions; yet the extent of adult neurogenesis remains unexplored in schizophrenia and bipolar disorder. We verified the existence of neurogenesis across the lifespan by chartering transcriptional alterations (2 days-103 years, n = 70) and identifying cells indicative of different stages of neurogenesis in the human SEZ. Expression of most neural stem and neuronal progenitor cell markers decreased during the first postnatal years and remained stable from childhood into ageing. We next discovered reduced neural stem and neuronal progenitor cell marker expression in the adult SEZ in schizophrenia and bipolar disorder compared to controls (n = 29-32 per group). RNA sequencing identified increased expression of the macrophage marker CD163 as the most significant molecular change in schizophrenia. CD163+ macrophages, which were localised along blood vessels and in the parenchyma within 10 µm of neural stem and progenitor cells, had increased density in schizophrenia but not in bipolar disorder. Macrophage marker expression negatively correlated with neuronal progenitor marker expression in schizophrenia but not in controls or bipolar disorder. Reduced neurogenesis and increased macrophage marker expression were also associated with polygenic risk for schizophrenia. Our results support that the human SEZ retains the capacity to generate neuronal progenitor cells throughout life, although this capacity is limited in schizophrenia and bipolar disorder. The increase in macrophages in schizophrenia but not in bipolar disorder indicates that immune cells may impair neurogenesis in the adult SEZ in a disease-specific manner.
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- 2021
7. Obesity and brain structure in schizophrenia - ENIGMA study in 3021 individuals
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Sean R. McWhinney, Katharina Brosch, Vince D. Calhoun, Benedicto Crespo-Facorro, Nicolas A. Crossley, Udo Dannlowski, Erin Dickie, Lorielle M. F. Dietze, Gary Donohoe, Stefan Du Plessis, Stefan Ehrlich, Robin Emsley, Petra Furstova, David C. Glahn, Alfonso Gonzalez- Valderrama, Dominik Grotegerd, Laurena Holleran, Tilo T. J. Kircher, Pavel Knytl, Marian Kolenic, Rebekka Lencer, Igor Nenadić, Nils Opel, Julia-Katharina Pfarr, Amanda L. Rodrigue, Kelly Rootes-Murdy, Alex J. Ross, Kang Sim, Antonín Škoch, Filip Spaniel, Frederike Stein, Patrik Švancer, Diana Tordesillas-Gutiérrez, Juan Undurraga, Javier Vázquez-Bourgon, Aristotle Voineskos, Esther Walton, Thomas W. Weickert, Cynthia Shannon Weickert, Paul M. Thompson, Theo G. M. van Erp, Jessica A. Turner, Tomas Hajek, European Commission, European Research Council, German Research Foundation, Agencia Nacional de Investigación y Desarrollo (Chile), Fondo Nacional de Desarrollo Científico y Tecnológico (Chile), and Alexander von Humboldt Foundation
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Medical and Health Sciences ,Cellular and Molecular Neuroscience ,SDG 3 - Good Health and Well-being ,Clinical Research ,2.1 Biological and endogenous factors ,Humans ,Obesity ,Aetiology ,Molecular Biology ,Nutrition ,Psychiatry ,Depressive Disorder ,Depressive Disorder, Major ,Psychology and Cognitive Sciences ,Neurosciences ,Major ,Brain ,Biological Sciences ,Serious Mental Illness ,Magnetic Resonance Imaging ,Brain Disorders ,Psychiatry and Mental health ,Mental Health ,Schizophrenia ,Biomedical Imaging - Abstract
Hajek, Tomas: et al., Schizophrenia is frequently associated with obesity, which is linked with neurostructural alterations. Yet, we do not understand how the brain correlates of obesity map onto the brain changes in schizophrenia. We obtained MRI-derived brain cortical and subcortical measures and body mass index (BMI) from 1260 individuals with schizophrenia and 1761 controls from 12 independent research sites within the ENIGMA-Schizophrenia Working Group. We jointly modeled the statistical effects of schizophrenia and BMI using mixed effects. BMI was additively associated with structure of many of the same brain regions as schizophrenia, but the cortical and subcortical alterations in schizophrenia were more widespread and pronounced. Both BMI and schizophrenia were primarily associated with changes in cortical thickness, with fewer correlates in surface area. While, BMI was negatively associated with cortical thickness, the significant associations between BMI and surface area or subcortical volumes were positive. Lastly, the brain correlates of obesity were replicated among large studies and closely resembled neurostructural changes in major depressive disorders. We confirmed widespread associations between BMI and brain structure in individuals with schizophrenia. People with both obesity and schizophrenia showed more pronounced brain alterations than people with only one of these conditions. Obesity appears to be a relevant factor which could account for heterogeneity of brain imaging findings and for differences in brain imaging outcomes among people with schizophrenia., NAC et al. were supported by the Agencia Nacional de Investigación y Desarrollo, Chile, through its grants PIA ACT1414, ANID-PIA-ACT 192064, and FONDECYT regular 1200601. This work was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD; SFB-TRR58, Projects C09 and Z02 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). The NUDZ and IKEM sites were supported by funding from the Ministry of Health of the Czech Republic (16-32791A, NU20-04-00393) and conceptual development of research organization (Institute for Clinical and Experimental Medicine – IKEM, IN 00023001). This work was also funded by the German Research Foundation (DFG grant FOR2107, KI588/14-1 and FOR2107, KI588/14-2 to TTJK, Marburg, Germany), as well as, the Alexander von Humboldt Foundation, EU and Deutsche Forschungsgemeinschaft (DFG), grants NE2254/1-2, NE2254/3-1, NE2254/4-1. Additional support provided by research grants from the National Healthcare Group, Singapore (SIG/05004; SIG/05028), and the Singapore Bioimaging Consortium (RP C009/2006) research grants awarded to KS. EW was supported by the European Union’s Horizon 2020 research and innovation programme (Early Cause, grant n° 848158). Funding for TWW was provided by the National Health and Medical Research Council Australia Project Grant 568807; New South Wales Health, University of New South Wales, Neuroscience Research Australia and the Schizophrenia Research Institute. GD’s research was funded by the European Research Council 677467 and Science Foundation Ireland 16/ERCS/3787. VDC was supported by NIH R01MH118695. PMT was supported by NIMH grant R01MH116147. Lastly, TH was supported by funding from the Canadian Institutes of Health Research (103703, 106469 and 142255), Nova Scotia Health Research Foundation, Dalhousie Clinical Research Scholarship to TH, Brain & Behavior Research Foundation (formerly NARSAD); 2007 Young Investigator and 2015 Independent Investigator Awards to TH.
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- 2022
8. Cancer activates microglia to the same extent as chronic stress throughout stress neurocircuitry in a mouse model of breast cancer
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Delyse McCaffrey, Adam J. Lawther, Cynthia Shannon Weickert, and Adam K. Walker
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Psychiatry and Mental health ,Endocrinology ,Endocrine and Autonomic Systems ,Endocrinology, Diabetes and Metabolism ,Biological Psychiatry - Abstract
The prevalence of stress-related comorbidities is increased approximately 3-fold in cancer patients compared to the general population. There is a scarcity of research focusing on the biological brain changes caused by the cancer due to the assumption that psychological symptoms are solely caused by the stress of a cancer diagnosis. Recent clinical evidence indicates that declines in cognition and increases in mood symptoms occur prior to an individual receiving a cancer diagnosis, suggesting that the cancer itself may play a role in mediating biological brain change. Furthermore, the presence of a tumour may change the brain response to environmental stressors unrelated to a cancer diagnosis. Using a syngeneic, orthotopic mouse model of breast cancer, we compared the impact of mammary tumours and chronic restraint stress on microglial and astrocytic activation throughout stress-relevant neurocircuitry. We also examined whether changes in microglial and astrocytic activation overlapped with changes in chronic neuronal activity. We show that cancer and chronic restraint stress activates microglia to the same magnitude in the same subcortical brain regions, and that this activation correlates with stress coping behaviours. The findings suggest that in some cancer patients, microglia may be activated in brain regions involved in interpreting and responding to psychological distress before they are aware of their diagnosis. In contrast, cancer reduced astrocyte reactivity in two cortical brain regions where there were no clear changes in response to chronic restraint stress. Taken together, it is likely that interventions that aim to improve anxiety and stress in cancer patients by targeting glial responses to cancer would need to be cell-specific; reducing microglial activation and/or stimulating astrocytic activation.
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- 2022
9. Increased peripheral inflammation in schizophrenia is associated with worse cognitive performance and related cortical thickness reductions
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Jason M. Bruggemann, Chad A. Bousman, Vaidy Swaminathan, Rhoshel K. Lenroot, Christos Pantelis, Cynthia Shannon Weickert, Vanessa Cropley, Hayley F. North, Avril Pereira, Suresh Sundram, Andrew Zalesky, and Thomas W. Weickert
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Oncology ,medicine.medical_specialty ,Psychosis ,business.industry ,Cognition ,General Medicine ,Neuropathology ,medicine.disease ,030227 psychiatry ,03 medical and health sciences ,Psychiatry and Mental health ,0302 clinical medicine ,Schizophrenia ,Internal medicine ,Diabetes mellitus ,Cohort ,medicine ,Biomarker (medicine) ,Pharmacology (medical) ,Effects of sleep deprivation on cognitive performance ,business ,030217 neurology & neurosurgery ,Biological Psychiatry - Abstract
While the biological substrates of brain and behavioural changes in persons with schizophrenia remain unclear, increasing evidence implicates that inflammation is involved. In schizophrenia, including first-episode psychosis and anti-psychotic naive patients, there are numerous reports of increased peripheral inflammation, cognitive deficits and neuropathologies such as cortical thinning. Research defining the relationship between inflammation and schizophrenia symptomatology and neuropathology is needed. Therefore, we analysed the level of C-reactive protein (CRP), a peripheral inflammation marker, and its relationship with cognitive functioning in a cohort of 644 controls and 499 schizophrenia patients. In a subset of individuals who underwent MRI scanning (99 controls and 194 schizophrenia cases), we tested if serum CRP was associated with cortical thickness. CRP was significantly increased in schizophrenia patients compared to controls, co-varying for age, sex, overweight/obesity and diabetes (p
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- 2021
10. The impact of smoking status on cognition and brain morphology in schizophrenia spectrum disorders
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Cynthia Shannon Weickert, Suresh Sundram, Jason M. Bruggemann, Andrew Zalesky, Christos Pantelis, Tamsyn E Van Rheenen, Thomas W. Weickert, Vanessa Cropley, Elysha Ringin, and Chad A. Bousman
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Cigarette Smoker ,business.industry ,Smoking ,Brain morphometry ,Australia ,Brain ,Cognition ,Moderation ,Magnetic Resonance Imaging ,030227 psychiatry ,03 medical and health sciences ,Psychiatry and Mental health ,0302 clinical medicine ,Schizophrenia ,Humans ,Medicine ,Cognitive skill ,Effects of sleep deprivation on cognitive performance ,Cognitive decline ,business ,030217 neurology & neurosurgery ,Applied Psychology ,Clinical psychology ,Schizophrenia spectrum - Abstract
BackgroundCigarette smoking is associated with worse cognition and decreased cortical volume and thickness in healthy cohorts. Chronic cigarette smoking is prevalent in schizophrenia spectrum disorders (SSD), but the effects of smoking status on the brain and cognition in SSD are not clear. This study aimed to understand whether cognitive performance and brain morphology differed between smoking and non-smoking individuals with SSD compared to healthy controls.MethodsData were obtained from the Australian Schizophrenia Research Bank. Cognitive functioning was measured in 299 controls and 455 SSD patients. Cortical volume, thickness and surface area data were analysed from T1-weighted structural scans obtained in a subset of the sample (n = 82 controls, n = 201 SSD). Associations between smoking status (cigarette smoker/non-smoker), cognition and brain morphology were tested using analyses of covariance, including diagnosis as a moderator.ResultsNo smoking by diagnosis interactions were evident, and no significant differences were revealed between smokers and non-smokers across any of the variables measured, with the exception of a significantly thinner left posterior cingulate in smokers compared to non-smokers. Several main effects of smoking in the cognitive, volume and thickness analyses were initially significant but did not survive false discovery rate (FDR) correction.ConclusionsDespite the general absence of significant FDR-corrected findings, trend-level effects suggest the possibility that subtle smoking-related effects exist but were not uncovered due to low statistical power. An investigation of this topic is encouraged to confirm and expand on our findings.
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- 2021
11. Reduced Insulin-Like Growth Factor Family Member Expression Predicts Neurogenesis Marker Expression in the Subependymal Zone in Schizophrenia and Bipolar Disorder
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Christin Weissleder, Guy Barry, Cynthia Shannon Weickert, and Maree J. Webster
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Adult ,Male ,medicine.medical_specialty ,Bipolar Disorder ,Neurogenesis ,medicine.medical_treatment ,Subventricular zone ,Biology ,Receptor, IGF Type 1 ,03 medical and health sciences ,Insulin-like growth factor ,0302 clinical medicine ,Epidermal growth factor ,Neurotrophic factors ,Ependyma ,Internal medicine ,medicine ,Subependymal zone ,Humans ,RNA, Messenger ,Insulin-Like Growth Factor I ,030304 developmental biology ,0303 health sciences ,Brain-Derived Neurotrophic Factor ,Middle Aged ,medicine.disease ,Neural stem cell ,Insulin-Like Growth Factor Binding Protein 2 ,Psychiatry and Mental health ,medicine.anatomical_structure ,Endocrinology ,Schizophrenia ,Female ,Biomarkers ,030217 neurology & neurosurgery ,Regular Articles - Abstract
The generation of inhibitory interneurons from neural stem cells in the subependymal zone is regulated by trophic factors. Reduced levels of trophic factors are associated with inhibitory interneuron dysfunction in the prefrontal cortex and hippocampus in psychiatric disorders, yet the extent to which altered trophic support may underpin deficits in inhibitory interneuron generation in the neurogenic niche remains unexplored in schizophrenia and bipolar disorder. We determined whether the expression of ligands, bioavailability-regulating binding proteins, and cognate receptors of 4 major trophic factor families (insulin-like growth factor [IGF], epidermal growth factor [EGF], fibroblast growth factor [FGF], and brain-derived neurotrophic factor [BDNF]) are changed in schizophrenia and bipolar disorder compared to controls. We used robust linear regression analyses to determine whether altered expression of trophic factor family members predicts neurogenesis marker expression across diagnostic groups. We found that IGF1 mRNA was decreased in schizophrenia and bipolar disorder compared with controls (P ≤ .006), whereas both IGF1 receptor (IGF1R) and IGF binding protein 2 (IGFBP2) mRNAs were reduced in schizophrenia compared with controls (P ≤ .02). EGF, FGF, and BDNF family member expression were all unchanged in both psychiatric disorders compared with controls. IGF1 expression positively predicted neuronal progenitor and immature neuron marker mRNAs (P ≤ .01). IGFBP2 expression positively predicted neural stem cell and neuronal progenitor marker mRNAs (P ≤ .001). These findings provide the first molecular evidence of decreased IGF1, IGF1R, and IGFBP2 mRNA expression in the subependymal zone in psychiatric disorders, which may potentially impact neurogenesis in schizophrenia and bipolar disorder.
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- 2020
12. Increased immune cell and altered microglia and neurogenesis transcripts in an Australian schizophrenia subgroup with elevated inflammation
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Hayley F. North, Christin Weissleder, Janice M. Fullerton, Maree J. Webster, and Cynthia Shannon Weickert
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Inflammation ,metabolism [Inflammation] ,Subventricular zone ,Neurogenesis ,Macrophages ,Post-mortem ,Australia ,Subtype ,metabolism [Microglia] ,physiology [Neurogenesis] ,Psychosis ,metabolism [RNA, Messenger] ,Psychiatry and Mental health ,Glia ,Schizophrenia ,Humans ,RNA ,genetics [Schizophrenia] ,metabolism [Schizophrenia] ,Microglia ,RNA, Messenger ,ddc:610 ,Biological Psychiatry ,Follow-Up Studies - Abstract
We previously identified a subgroup of schizophrenia cases (~40 %) with heightened inflammation in the neurogenic subependymal zone (SEZ) (North et al., 2021b). This schizophrenia subgroup had changes indicating reduced microglial activity, increased peripheral immune cells, increased stem cell dormancy/quiescence and reduced neuronal precursor cells. The present follow-up study aimed to replicate and extend those novel findings in an independent post-mortem cohort of schizophrenia cases and controls from Australia. RNA was extracted from SEZ tissue from 20 controls and 22 schizophrenia cases from the New South Wales Brain Tissue Resource Centre, and gene expression analysis was performed. Cluster analysis of inflammation markers (IL1B, IL1R1, SERPINA3 and CXCL8) revealed a high-inflammation schizophrenia subgroup comprising 52 % of cases, which was a significantly greater proportion than the 17 % of high-inflammation controls. Consistent with our previous report (North et al., 2021b), those with high-inflammation and schizophrenia had unchanged mRNA expression of markers for steady-state and activated microglia (IBA1, HEXB, CD68), decreased expression of phagocytic microglia markers (P2RY12, P2RY13), but increased expression of markers for macrophages (CD163), monocytes (CD14), natural killer cells (FCGR3A), and the adhesion molecule ICAM1. Similarly, the high-inflammation schizophrenia subgroup emulated increased quiescent stem cell marker (GFAPD) and decreased neuronal progenitor (DLX6-AS1) and immature neuron marker (DCX) mRNA expression; but also revealed a novel increase in a marker of immature astrocytes (VIM). Replicating primary results in an independent cohort demonstrates that inflammatory subgroups in the SEZ in schizophrenia are reliable, robust and enhance understanding of neuropathological heterogeneity when studying schizophrenia.
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- 2022
13. Transcriptional changes in the stress pathway are related to symptoms in schizophrenia and to mood in schizoaffective disorder
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D Sinclair, Cynthia Shannon Weickert, Maryanne O'Donnell, Thomas W. Weickert, Dennis Liu, Cynthia H. Lee, and Cherrie Galletly
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Adult ,Male ,medicine.medical_specialty ,Transcription, Genetic ,Schizoaffective disorder ,BAG1 ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,RNA, Messenger ,Biological Psychiatry ,Depression (differential diagnoses) ,Positive and Negative Syndrome Scale ,business.industry ,Middle Aged ,medicine.disease ,030227 psychiatry ,Affect ,Psychiatry and Mental health ,Endocrinology ,Mood ,Psychotic Disorders ,Schizophrenia ,Anxiety ,Female ,FKBP5 ,medicine.symptom ,business ,Stress, Psychological ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Altered levels of stress-signalling transcripts have been identified in post-mortem brains of people with schizophrenia, and since stress effects may be expressed throughout the body, there should be similar changes in peripheral cells. However, the extent to which these markers are altered in peripheral white blood cells of people with schizophrenia is not known. Furthermore, how peripheral cortisol and stress-related mRNA are associated with negative symptom severity and emotional states in people with schizophrenia versus schizoaffective disorder has not been determined. Whole blood samples were collected from 86 patients with either schizophrenia or schizoaffective disorder (56 people with schizophrenia and 30 people with schizoaffective disorder), and 77 healthy controls. Total RNA was isolated, cDNA was synthesized, and stress-signalling mRNA levels (for NR3C1, FKBP5, FKBP4, PTGES3 and BAG1) were determined. Stress and symptom severity scores were measured by the Depression, Anxiety and Stress Scale, and the Positive and Negative Syndrome Scale, respectively. We found increased FKBP5 mRNA, Z(156) = 2.5, p = 0.01, decreased FKBP4 mRNA, t(155) = 3.5, p ≤ 0.001, and decreased PTGES3 mRNA, t(153) = 3.0, p ≤ 0.01, in schizophrenia and schizoaffective disorder cohorts combined compared to healthy controls. Stress-related peripheral mRNA levels were differentially correlated with negative emotional states and symptom severity in schizoaffective disorder (β's = –0.45–0.56, p's = 0.05–0.001) and schizophrenia (β's = −0.34–0.38, p's = 0.04–0.03), respectively. Therefore, molecules of the stress-signalling pathway appear to differentially contribute to clinical features of schizophrenia versus schizoaffective disorder.
- Published
- 2019
14. A schizophrenia subgroup with elevated inflammation displays reduced microglia, increased peripheral immune cell and altered neurogenesis marker gene expression in the subependymal zone
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Hayley F. North, Christin Weissleder, Janice M. Fullerton, Rachel Sager, Maree J. Webster, and Cynthia Shannon Weickert
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Inflammation ,Bipolar disorder ,Neurogenesis ,Receptors, IgG ,Gene Expression ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Molecular neuroscience ,Article ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,mental disorders ,Schizophrenia ,Humans ,Microglia ,Biological Psychiatry ,RC321-571 - Abstract
Inflammation regulates neurogenesis, and the brains of patients with schizophrenia and bipolar disorder have reduced expression of neurogenesis markers in the subependymal zone (SEZ), the birthplace of inhibitory interneurons. Inflammation is associated with cortical interneuron deficits, but the relationship between inflammation and reduced neurogenesis in schizophrenia and bipolar disorder remains unexplored. Therefore, we investigated inflammation in the SEZ by defining those with low and high levels of inflammation using cluster analysis of IL6, IL6R, IL1R1 and SERPINA3 gene expression in 32 controls, 32 schizophrenia and 29 bipolar disorder cases. We then determined whether mRNAs for markers of glia, immune cells and neurogenesis varied with inflammation. A significantly greater proportion of schizophrenia (37%) and bipolar disorder cases (32%) were in high inflammation subgroups compared to controls (10%, p P2RY12, P2RY13), while mRNAs of markers for perivascular macrophages (CD163), pro-inflammatory macrophages (CD64), monocytes (CD14), natural killer cells (FCGR3A) and adhesion molecules (ICAM1) were increased. Specific to high inflammation schizophrenia, quiescent stem cell marker mRNA (GFAPD) was reduced, whereas neuronal progenitor (ASCL1) and immature neuron marker mRNAs (DCX) were decreased compared to low inflammation control and schizophrenia subgroups. Thus, a heightened state of inflammation may dampen microglial response and recruit peripheral immune cells in psychiatric disorders. The findings elucidate differential neurogenic responses to inflammation within psychiatric disorders and highlight that inflammation may impair neuronal differentiation in the SEZ in schizophrenia.
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- 2021
15. White Matter Disruptions in Schizophrenia Are Spatially Widespread and Topologically Converge on Brain Network Hubs
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Stanley V. Catts, Chad A. Bousman, Alex Fornito, Paul Klauser, Simon T.E. Baker, Patricia T. Michie, Rhoshel K. Lenroot, Bryan J. Mowry, Carmel M. Loughland, Andrew Zalesky, Cynthia Shannon Weickert, Luca Cocchi, Vaughan J. Carr, Thomas W. Weickert, Janice M. Fullerton, Christos Pantelis, Ulrich Schall, Frans Henskens, Paul E. Rasser, and Vanessa Cropley
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Adult ,Male ,Adolescent ,Schizoaffective disorder ,Corpus callosum ,Gyrus Cinguli ,Corpus Callosum ,White matter ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Thalamus ,Neural Pathways ,Fractional anisotropy ,mental disorders ,Connectome ,medicine ,Humans ,Cingulum (brain) ,Aged ,Cerebral Cortex ,Regular Article ,Middle Aged ,medicine.disease ,White Matter ,030227 psychiatry ,Psychiatry and Mental health ,Diffusion Tensor Imaging ,medicine.anatomical_structure ,Psychotic Disorders ,Schizophrenia ,Female ,Nerve Net ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,Diffusion MRI - Abstract
White matter abnormalities associated with schizophrenia have been widely reported, although the consistency of findings across studies is moderate. In this study, neuroimaging was used to investigate white matter pathology and its impact on whole-brain white matter connectivity in one of the largest samples of patients with schizophrenia. Fractional anisotropy (FA) and mean diffusivity (MD) were compared between patients with schizophrenia or schizoaffective disorder (n = 326) and age-matched healthy controls (n = 197). Between-group differences in FA and MD were assessed using voxel-based analysis and permutation testing. Automated whole-brain white matter fiber tracking and the network-based statistic were used to characterize the impact of white matter pathology on the connectome and its rich club. Significant reductions in FA associated with schizophrenia were widespread, encompassing more than 40% (234ml) of cerebral white matter by volume and involving all cerebral lobes. Significant increases in MD were also widespread and distributed similarly. The corpus callosum, cingulum, and thalamic radiations exhibited the most extensive pathology according to effect size. More than 50% of cortico-cortical and cortico-subcortical white matter fiber bundles comprising the connectome were disrupted in schizophrenia. Connections between hub regions comprising the rich club were disproportionately affected. Pathology did not differ between patients with schizophrenia and schizoaffective disorder and was not mediated by medication. In conclusion, although connectivity between cerebral hubs is most extensively disturbed in schizophrenia, white matter pathology is widespread, affecting all cerebral lobes and the cerebellum, leading to disruptions in the majority of the brain's fiber bundles.
- Published
- 2021
16. Alterations in the kynurenine pathway and excitatory amino acid transporter-2 in depression with and without psychosis: Evidence of a potential astrocyte pathology
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Samara J. Brown, Amelia M. Brown, Tertia D. Purves-Tyson, Xu-Feng Huang, Cynthia Shannon Weickert, and Kelly A. Newell
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Psychiatry and Mental health ,Depressive Disorder, Major ,Psychotic Disorders ,Depression ,Astrocytes ,Humans ,Kynurenic Acid ,Biological Psychiatry ,Kynurenine - Abstract
Evidence, largely obtained from peripheral studies, suggests that alterations in the kynurenine pathway contribute to the aetiology of depression and disorders involving psychosis. Stimulation of the kynurenine pathway leads to the formation of neuroactive metabolites, including kynurenic acid (predominantly in astrocytes) and quinolinic acid (predominantly in microglia), which are antagonists and agonists of the glutamate NMDA receptor, respectively. In this study, we measured gene expression via qRT-PCR of the main kynurenine pathway enzymes in the anterior cingulate cortex (ACC) in people with major depressive disorder and matched controls. In parallel, we tested for diagnostic differences in gene expression of relevant glial markers. We used total RNA isolated from the ACC from depression subjects with psychosis (n = 12) and without psychosis (n = 12), and non-psychiatric controls (n = 12) provided by the Stanley Medical Research Institute. In the ACC, KYAT1 (KAT I), AADAT (KAT II), and the astrocytic SLC1A2 (EAAT2) mRNAs, were significantly increased in depression, when combining those with and without psychosis. The increased KYAT1 and AADAT mRNA indicates that depression is associated with increased activation of the kynurenic acid arm of the kynurenine pathway in the ACC, suggesting an astrocyte response in depression. Considering EAAT2 and KATs increase astrocytic glutamate uptake and production of the NMDA receptor antagonist kynurenic acid, the observed increases of these markers may relate to changes in glutamatergic signalling in depression. These results suggest dysfunction of the kynurenine pathway in the brain in depression and point to the kynurenine pathway as a possible driver of glutamate dysfunction in depression.
- Published
- 2021
17. Cell type-specific manifestations of cortical thickness heterogeneity in schizophrenia
- Author
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Maria A. Di Biase, Michael P. Geaghan, William R. Reay, Jakob Seidlitz, Cynthia Shannon Weickert, Alice Pébay, Melissa J. Green, Yann Quidé, Joshua R. Atkins, Michael J. Coleman, Sylvain Bouix, Evdokiya E. Knyazhanskaya, Amanda E. Lyall, Ofer Pasternak, Marek Kubicki, Yogesh Rathi, Andrew Visco, Megan Gaunnac, Jinglei Lv, Raquelle I. Mesholam-Gately, Kathryn E. Lewandowski, Daphne J. Holt, Matcheri S. Keshavan, Christos Pantelis, Dost Öngür, Alan Breier, Murray J. Cairns, Martha E. Shenton, and Andrew Zalesky
- Subjects
Cerebral Cortex ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Multifactorial Inheritance ,Schizophrenia ,Brain ,Endothelial Cells ,Humans ,Molecular Biology ,Magnetic Resonance Imaging - Abstract
Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor cells (OPCs); (4) excitatory neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells (r = −0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes (r = −0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.
- Published
- 2021
18. N-Methyl-d-Aspartate receptor and inflammation in dorsolateral prefrontal cortex in schizophrenia
- Author
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Tasnim Rahman, Tertia Purves-Tyson, Amy E. Geddes, Xu-Feng Huang, Kelly A. Newell, and Cynthia Shannon Weickert
- Subjects
Cerebral Cortex ,Inflammation ,Psychiatry and Mental health ,Dorsolateral Prefrontal Cortex ,Schizophrenia ,Humans ,Prefrontal Cortex ,Receptors, N-Methyl-D-Aspartate ,Biological Psychiatry - Abstract
Lower N-methyl-d-aspartate receptor (NMDAR) GluN1 subunit levels and heightened neuroinflammation are found in the cortex in schizophrenia. Since neuroinflammation can lead to changes in NMDAR function, it is possible that these observations are linked in schizophrenia. We aimed to extend our previous studies by measuring molecular indices of NMDARs that define key functional properties of this receptor - particularly the ratio of GluN2A and GluN2B subunits - in dorsolateral prefrontal cortex (DLPFC) from schizophrenia and control cases (37/37). We sought to test whether changes in these measures are specific to the subset of schizophrenia cases with high levels of inflammation-related mRNAs, defined as a high inflammatory subgroup. Quantitative autoradiography was used to detect 'functional' NMDARs ([
- Published
- 2021
19. Evidence for Network-Based Cortical Thickness Reductions in Schizophrenia
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Ian P. Everall, Cynthia Shannon Weickert, Eleni P. Ganella, Stephen J. Wood, Cassandra Wannan, Thomas W. Weickert, Cali F. Bartholomeusz, M. Mallar Chakravarty, Vanessa Cropley, Patrick D. McGorry, Jason M. Bruggemann, Christos Pantelis, Dennis Velakoulis, Andrew Zalesky, and Chad A. Bousman
- Subjects
Adult ,Male ,structural covariance ,Psychosis ,Nerve net ,Neuroimaging ,Biology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Cerebral Cortex ,structural neuroimaging ,brain connectivity ,cortical thickness ,medicine.disease ,Magnetic Resonance Imaging ,030227 psychiatry ,schizophrenia ,Psychiatry and Mental health ,Cross-Sectional Studies ,medicine.anatomical_structure ,Schizophrenia ,Structural covariance ,Cerebral cortex ,Case-Control Studies ,network ,Female ,Nerve Net ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Objective: Cortical thickness reductions in schizophrenia are irregularly distributed across multiple loci. The authors hypothesized that cortical connectivity networks would explain the distribution of cortical thickness reductions across the cortex, and, specifically, that cortico-cortical connectivity between loci with these reductions would be exceptionally strong and form an interconnected network. This hypothesis was tested in three cross-sectional schizophrenia cohorts: first-episode psychosis, chronic schizophrenia, and treatment-resistant schizophrenia. Methods: Structural brain images were acquired for 70 patients with first-episode psychosis, 153 patients with chronic schizophrenia, and 47 patients with treatment-resistant schizophrenia and in matching healthy control groups (N=57, N=168, and N=54, respectively). Cortical thickness was compared between the patient and respective control groups at 148 regions spanning the cortex. Structural connectivity strength between pairs of cortical regions was quantified with structural covariance analysis. Connectivity strength between regions with cortical thickness reductions was compared with connectivity strength between 5,000 sets of randomly chosen regions to establish whether regions with reductions were interconnected more strongly than would be expected by chance. Results: Significant (false discovery rate corrected) and widespread cortical thickness reductions were found in the chronic schizophrenia (79 regions) and treatment-resistant schizophrenia (106 regions) groups, with more circumscribed reductions in the first-episode psychosis group (34 regions). Cortical thickness reductions with the largest effect sizes were found in frontal, temporal, cingulate, and insular regions. In all cohorts, both the patient and healthy control groups showed significantly increased structural covariance between regions with cortical thickness reductions compared with randomly selected regions. Conclusions: Brain network architecture can explain the irregular topographic distribution of cortical thickness reductions in schizophrenia. This finding, replicated in three distinct schizophrenia cohorts, suggests that the effect is robust and independent of illness stage.
- Published
- 2019
20. Blood and brain protein levels of ubiquitin-conjugating enzyme E2K (UBE2K) are elevated in individuals with schizophrenia
- Author
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Cynthia Shannon Weickert, Hannah Meiklejohn, Ian P. Everall, Christos Pantelis, Shaki Mostaid, Sandra Luza, Debora A. Rothmond, Sonny Atherton, Chad A. Bousman, Ashley I. Bush, Serafino G. Mancuso, Dali Kang, and Carlos Opazo
- Subjects
Adult ,Male ,medicine.medical_specialty ,Psychosis ,behavioral disciplines and activities ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Cortex (anatomy) ,mental disorders ,medicine ,Humans ,Biological Psychiatry ,Clozapine ,Whole blood ,business.industry ,Australia ,Brain ,Middle Aged ,medicine.disease ,Pathophysiology ,030227 psychiatry ,Dorsolateral prefrontal cortex ,Psychiatry and Mental health ,Endocrinology ,medicine.anatomical_structure ,Schizophrenia ,Ubiquitin-Conjugating Enzymes ,Female ,Orbitofrontal cortex ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
A number of recent studies have suggested the ubiquitin proteasome system (UPS) in schizophrenia is dysfunctional. The purpose of this study was to investigate UBE2K, a ubiquitin-conjugating (E2) enzyme within the UPS that has been associated with psychosis symptom severity, in the blood and brain of individuals with schizophrenia. Whole blood and erythrocytes from 128 (71 treatment-resistant schizophrenia, 57 healthy controls) individuals as well as frozen dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) post-mortem samples from 74 (37 schizophrenia, 37 controls) individuals were obtained. UBE2K gene expression was assayed in whole blood and DLPFC samples, whereas protein levels were assayed in erythrocytes and OFC samples. Elevated levels of UBE2K mRNA were observed in whole blood of individuals with schizophrenia (p = 0.03) but not in the DLPFC, while protein levels were raised in erythrocytes and the OFC (p
- Published
- 2019
21. Important unanswered questions about adult neurogenesis in schizophrenia
- Author
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Cynthia Shannon Weickert, Hayley F. North, and Christin Weissleder
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Neurons ,business.industry ,Neurogenesis ,Schizophrenia (object-oriented programming) ,Hippocampus ,behavioral disciplines and activities ,030227 psychiatry ,03 medical and health sciences ,Psychiatry and Mental health ,0302 clinical medicine ,Cellular Microenvironment ,mental disorders ,Schizophrenia ,Animals ,Humans ,Medicine ,business ,Neuroscience ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Aberrant neurogenesis may contribute to the pathogenesis, pathophysiology and symptoms of schizophrenia. This review summarizes the state of knowledge of adult neurogenesis in schizophrenia and raises important unanswered questions. We highlight how alterations in signalling molecules in the local and peripheral environments in schizophrenia may regulate adult neurogenesis in the human subgranular zone of the hippocampus and the subependymal zone (SEZ).Cell proliferation and density of mature neurons are reduced in the hippocampus, yet the extent of adult neurogenesis remains unexplored in the SEZ in schizophrenia. The human SEZ is a major source of postnatally migrating cortical and striatal inhibitory interneurons, indicating that aberrant neurogenesis may extend to the SEZ and contribute to inhibitory interneuron deficits in schizophrenia. Trophic factors and inflammatory cytokines regulate the generation of new neurons in rodents, suggesting that altered expression of these signalling molecules in the brain, peripheral vasculature and cerebrospinal fluid in schizophrenia may impact adult neurogenesis in both the hippocampus and the SEZ.Knowledge about adult neurogenesis remains scant in schizophrenia. We propose that a more rigorous examination of adult neurogenesis in relation to regulatory signalling molecules will allow us to identify how abnormalities may contribute to the pathophysiology of schizophrenia.
- Published
- 2019
22. Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia
- Author
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Cynthia Shannon Weickert, Ryan P. Balzan, Maryanne O'Donnell, Gilles J. Guillemin, Jochen Kindler, Rhoshel K. Lenroot, Thomas W. Weickert, Chai K. Lim, Cherrie Galletly, Danny Boerrigter, Jason M. Bruggemann, Dennis Liu, and Kelly R. Jacobs
- Subjects
Adult ,Male ,medicine.medical_specialty ,Kynurenine pathway ,medicine.medical_treatment ,Prefrontal Cortex ,610 Medicine & health ,Kynurenic Acid ,Article ,Proinflammatory cytokine ,Young Adult ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Kynurenic acid ,Internal medicine ,mental disorders ,medicine ,Humans ,Attention ,Neurotransmitter ,Prefrontal cortex ,Molecular Biology ,Kynurenine ,Chemistry ,Middle Aged ,Dorsolateral prefrontal cortex ,Psychiatry and Mental health ,medicine.anatomical_structure ,Endocrinology ,Cytokine ,Schizophrenia ,Cytokines ,Female ,Inflammation Mediators - Abstract
The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-d-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes, leading to DLPFC volume loss, and attention impairment in schizophrenia.
- Published
- 2019
23. An Interleukin-1 beta (IL1B) haplotype linked with psychosis transition is associated with IL1B gene expression and brain structure
- Author
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Christos Pantelis, Shaki Mostaid, Ian P. Everall, Cynthia Shannon Weickert, Chad A. Bousman, Vanessa Cropley, Cassandra Wannan, and Stefanos Dimitrakopoulos
- Subjects
Adult ,Male ,medicine.medical_specialty ,Psychosis ,Interleukin-1beta ,Gene Expression ,Prefrontal Cortex ,Biology ,Grey matter ,behavioral disciplines and activities ,03 medical and health sciences ,Lateral ventricles ,0302 clinical medicine ,Lateral Ventricles ,Internal medicine ,Genetic variation ,Gene expression ,medicine ,Humans ,Gray Matter ,Prefrontal cortex ,Biological Psychiatry ,Haplotype ,Middle Aged ,medicine.disease ,Up-Regulation ,030227 psychiatry ,Dorsolateral prefrontal cortex ,Psychiatry and Mental health ,medicine.anatomical_structure ,Endocrinology ,Haplotypes ,Schizophrenia ,Female ,030217 neurology & neurosurgery - Abstract
We investigated IL1B genetic variation previously associated with risk for transition to psychosis for its association with gene expression in human post-mortem dorsolateral prefrontal cortex (DLPFC) from 74 (37 schizophrenia, 37 control) individuals and brain structure in 92 (44 schizophrenia, 48 control) living individuals. The IL1B A-G-T 'risk for psychosis transition' haplotype (rs16944|rs4848306|rs12621220) was associated with upregulation of IL1B mRNA expression in the DLPFC as well as reduced total grey matter and left middle frontal volumes and enlarged left lateral ventricular volume. Our results suggest IL1B genetic variation may confer psychosis risk via elevated mRNA expression and/or brain structure abnormalities.
- Published
- 2019
24. Investigation of peripheral complement factors across stages of psychosis
- Author
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Patrick D. McGorry, Vanessa Cropley, Christos Pantelis, Ian P. Everall, Cynthia Shannon Weickert, Liliana Laskaris, Barnaby Nelson, Gursharan Chana, Bernhard T. Baune, Chad A. Bousman, Maria A Di Biase, and Andrew Zalesky
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Psychosis ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Humans ,Medicine ,Young adult ,Complement C1q ,Biological Psychiatry ,business.industry ,Acute-phase protein ,Complement C4 ,Complement C3 ,Middle Aged ,medicine.disease ,030227 psychiatry ,Complement (complexity) ,Complement system ,Psychiatry and Mental health ,Clinical research ,Psychotic Disorders ,Schizophrenia ,Chronic Disease ,Female ,business ,030217 neurology & neurosurgery - Abstract
The complement cascade has been proposed to contribute to the pathogenesis of schizophrenia. However, it remains unclear whether peripheral complement levels differ in cases compared to controls, change over the course of illness and whether they are associated with current symptomatology. This study aimed to: i) investigate whether peripheral complement protein levels are altered at different stages of illness, and ii) identify patterns among complement protein levels that predict clinical symptoms. Complement factors C1q, C3 and C4 were quantified in 183 participants [n = 83 Healthy Controls (HC), n = 10 Ultra-High Risk (UHR) for psychosis, n = 40 First Episode Psychosis (FEP), n = 50 Chronic schizophrenia] using Multiplex ELISA. Permutation-based t-tests were used to assess between-group differences in complement protein levels at each of the three illness stages, relative to age- and gender-matched healthy controls. Canonical correlation analysis was used to identify patterns of complement protein levels that correlated with clinical symptoms. C4 was significantly increased in chronic schizophrenia patients, while C3 and C4 were significantly increased in UHR patients. There were no differences in C1q, C3 and C4 in FEP patients when adjusting for BMI. A molecular pattern of increased C4 and decreased C3 was associated with positive and negative symptom severity in the pooled patient sample. Our findings indicate that peripheral complement concentration is increased across specific stages of psychosis and its imbalance may be associated with symptom severity. Given the small sample size of the UHR group, these findings should be regarded as exploratory, requiring replication.
- Published
- 2019
25. Exploring the moderating effects of dopaminergic polymorphisms and childhood adversity on brain morphology in schizophrenia-spectrum disorders
- Author
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Suresh Sundram, Thomas W. Weickert, Rhoshel K. Lenroot, Tamsyn E Van Rheenen, Jason M. Bruggemann, Cynthia Shannon Weickert, Christos Pantelis, Serafino G. Mancuso, Vanessa Cropley, Cassandra R. Hoffmann, Chad A. Bousman, and Andrew Zalesky
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Genotype ,Dopamine ,Neuroscience (miscellaneous) ,Hippocampus ,Schizoaffective disorder ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,mental disorders ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Bipolar disorder ,Polymorphism, Genetic ,business.industry ,Putamen ,Dopaminergic ,Brain morphometry ,Brain ,medicine.disease ,Magnetic Resonance Imaging ,030227 psychiatry ,Dorsolateral prefrontal cortex ,Psychiatry and Mental health ,medicine.anatomical_structure ,Adult Survivors of Child Adverse Events ,Schizophrenia ,Regression Analysis ,Female ,Gene-Environment Interaction ,Schizophrenic Psychology ,business ,030217 neurology & neurosurgery - Abstract
Genetic and environmental etiologies may contribute to schizophrenia and its associated neurobiological profile. We examined the interaction between dopaminergic polymorphisms, childhood adversity and diagnosis (schizophrenia/schizoaffective disorder) on dopamine-related brain structures. Childhood adversity histories and structural MRI data were obtained from 249 (153 schizophrenia/schizoaffective, 96 controls) participants registered in the Australian Schizophrenia Research Bank. Polymorphisms in DRD2 and COMT were genotyped and a dopaminergic risk allelic load (RAL) was calculated. Regression analysis was used to test the main and interaction effects of RAL, childhood adversity and diagnosis on volumes of dopamine-related brain structures (caudate, putamen, nucleus accumbens, dorsolateral prefrontal cortex and hippocampus). A schizophrenia/schizoaffective diagnosis showed significant main effects on bilateral hippocampus, left dorsolateral prefrontal cortex and bilateral putamen volumes. RAL showed a significant main effect on left putamen volumes. Furthermore, across the whole sample, a significant two-way interaction between dopaminergic RAL and childhood adversity was found for left putamen volumes. No brain structure volumes were predicted by a three-way interaction that included diagnosis. Our finding suggests the left putamen may be particularly sensitive to dopaminergic gene-environment interactions regardless of diagnosis. However, larger studies are needed to assess whether these interactions are more or less pronounced in those with schizophrenia/schizoaffective disorders.
- Published
- 2018
26. Cortisol-dehydroepiandrosterone ratios are inversely associated with hippocampal and prefrontal brain volume in schizophrenia
- Author
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David J. Handelsman, Ellen Ji, Cynthia Shannon Weickert, Maryanne O'Donnell, Reena Desai, Cherrie Galletly, Thomas W. Weickert, Tertia D. Purves-Tyson, Rhoshel K. Lenroot, Dennis Liu, Christopher J. White, University of Zurich, and Ji, Ellen
- Subjects
endocrine system ,medicine.medical_specialty ,Hydrocortisone ,Endocrinology, Diabetes and Metabolism ,Dehydroepiandrosterone ,Hippocampus ,610 Medicine & health ,Neuropathology ,Hippocampal formation ,03 medical and health sciences ,2738 Psychiatry and Mental Health ,0302 clinical medicine ,Dorsolateral Prefrontal Cortex ,Endocrinology ,Internal medicine ,polycyclic compounds ,medicine ,Humans ,skin and connective tissue diseases ,Biological Psychiatry ,business.industry ,Endocrine and Autonomic Systems ,Organ Size ,medicine.disease ,Pathophysiology ,030227 psychiatry ,1310 Endocrinology ,Dorsolateral prefrontal cortex ,Diabetes and Metabolism ,2712 Endocrinology, Diabetes and Metabolism ,2807 Endocrine and Autonomic Systems ,Psychiatry and Mental health ,medicine.anatomical_structure ,Schizophrenia ,Case-Control Studies ,10054 Clinic for Psychiatry, Psychotherapy, and Psychosomatics ,Brain size ,business ,human activities ,2803 Biological Psychiatry ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery - Abstract
While high levels of glucocorticoids are generally neuro-damaging, a related adrenal steroid, dehydroepiandrosterone (DHEA), has anti-glucocorticoid and neuroprotective properties. Previous work has shown increased circulating levels of DHEA and abnormal cortisol/DHEA ratios in people with schizophrenia, however reports are limited and their relationship to neuropathology is unclear. We performed the largest study to date to compare levels of serum DHEA and cortisol/DHEA ratios in people with schizophrenia and healthy controls, and investigated the extent to which cortisol/DHEA ratios predict brain volume. Serum cortisol and DHEA were assayed in 94 people with schizophrenia and 81 healthy controls. T1-weighted high-resolution anatomical scans were obtained using a 3 T Achieva scanner on a subset of 59 people with schizophrenia and 60 healthy controls. Imaging data were preprocessed and analyzed using SPM12. People with schizophrenia had significantly increased serum DHEA levels (p = 0.002), decreased cortisol/DHEA ratios (p = 0.02) and no difference in cortisol levels compared to healthy controls. Cortisol/DHEA ratios were inversely correlated with hippocampal (r = -0.33 p = 0.01) and dorsolateral prefrontal cortex (r = -0.30, p = 0.02) volumes in patients. Our findings suggest that the cortisol/DHEA ratio may be a molecular blood signature of hippocampal and cortical damage. These results further implicate the role of DHEA and hypothalamic-pituitary-adrenal axis dysfunction in the pathophysiology of schizophrenia.
- Published
- 2021
27. A new suspect in the unsolved case of neuroinflammation in schizophrenia
- Author
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Cynthia Shannon Weickert and Caitlin E. Murphy
- Subjects
Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,business.industry ,Schizophrenia (object-oriented programming) ,MEDLINE ,Medicine ,Suspect ,business ,Molecular Biology ,Neuroscience ,Neuroinflammation - Published
- 2021
28. Impact of Gonadectomy on Maturational Changes in Brain Volume in Adolescent Macaques
- Author
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Jeffrey T. Young, Debora A. Rothmond, Rebecca C. Knickmeyer, Martin Styner, Anne Haunton, Pamela L. Noble, Cynthia Shannon Weickert, Crystal T. Nguyen, Rhoshel K. Lenroot, John H. Gilmore, and Michael R. Kosorok
- Subjects
Male ,Brain development ,Endocrinology, Diabetes and Metabolism ,Physiology ,Brain tissue ,Article ,White matter ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,medicine ,Animals ,Castration ,Sexual Maturation ,Gray Matter ,Prefrontal cortex ,Biological Psychiatry ,medicine.diagnostic_test ,Endocrine and Autonomic Systems ,business.industry ,Brain ,Magnetic resonance imaging ,Macaca mulatta ,Magnetic Resonance Imaging ,030227 psychiatry ,Psychiatry and Mental health ,Developmental trajectory ,medicine.anatomical_structure ,Brain size ,business ,030217 neurology & neurosurgery - Abstract
Adolescence is a transitional period between childhood and adulthood characterized by significant changes in global and regional brain tissue volumes. It is also a period of increasing vulnerability to psychiatric illness. The relationship between these patterns and increased levels of circulating sex steroids during adolescence remains unclear. The objective of the current study was to determine whether gonadectomy, prior to puberty, alters adolescent brain development in male rhesus macaques. Ninety-six structural MRI scans were acquired from 12 male rhesus macaques (8 time points per animal over a two-year period). Six animals underwent gonadectomy and 6 animals underwent a sham operation at 29 months of age. Mixed-effects models were used to determine whether gonadectomy altered developmental trajectories of global and regional brain tissue volumes. We observed a significant effect of gonadectomy on the developmental trajectory of prefrontal gray matter (GM), with intact males showing peak volumes around 3.5 years of age with a subsequent decline. In contrast, prefrontal GM volumes continued to increase in gonadectomized males until the end of the study. We did not observe a significant effect of gonadectomy on prefrontal white matter or on any other global or regional brain tissue volumes, though we cannot rule out that effects might be detected in a larger sample. Results suggest that the prefrontal cortex is more vulnerable to gonadectomy than other brain regions.
- Published
- 2020
29. Large-Scale Evidence for an Association Between Peripheral Inflammation and White Matter Free Water in Schizophrenia and Healthy Individuals
- Author
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Suheyla Cetin-Karayumak, Ofer Pasternak, Hayley F. North, Vanessa Cropley, Paul A. Tooney, Andrew Zalesky, Danny Boerrigter, Yogesh Rathi, Jinglei Lv, Maria A Di Biase, Christos Pantelis, and Cynthia Shannon Weickert
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Corpus callosum ,Proinflammatory cytokine ,White matter ,03 medical and health sciences ,0302 clinical medicine ,Body Water ,Internal medicine ,Fractional anisotropy ,medicine ,Humans ,Neuroinflammation ,Inflammation ,business.industry ,Australia ,Middle Aged ,medicine.disease ,White Matter ,030227 psychiatry ,Psychiatry and Mental health ,medicine.anatomical_structure ,Cytokine ,Endocrinology ,Cross-Sectional Studies ,Diffusion Magnetic Resonance Imaging ,Diffusion Tensor Imaging ,Schizophrenia ,Cytokines ,Female ,business ,030217 neurology & neurosurgery ,Diffusion MRI ,Regular Articles - Abstract
Introduction Clarifying the role of neuroinflammation in schizophrenia is subject to its detection in the living brain. Free-water (FW) imaging is an in vivo diffusion-weighted magnetic resonance imaging (dMRI) technique that measures water molecules freely diffusing in the brain and is hypothesized to detect inflammatory processes. Here, we aimed to establish a link between peripheral markers of inflammation and FW in brain white matter. Methods All data were obtained from the Australian Schizophrenia Research Bank (ASRB) across 5 Australian states and territories. We first tested for the presence of peripheral cytokine deregulation in schizophrenia, using a large sample (N = 1143) comprising the ASRB. We next determined the extent to which individual variation in 8 circulating pro-/anti-inflammatory cytokines related to FW in brain white matter, imaged in a subset (n = 308) of patients and controls. Results Patients with schizophrenia showed reduced interleukin-2 (IL-2) (t = −3.56, P = .0004) and IL-12(p70) (t = −2.84, P = .005) and increased IL-6 (t = 3.56, P = .0004), IL-8 (t = 3.8, P = .0002), and TNFα (t = 4.30, P < .0001). Higher proinflammatory signaling of IL-6 (t = 3.4, P = .0007) and TNFα (t = 2.7, P = .0007) was associated with higher FW levels in white matter. The reciprocal increases in serum cytokines and FW were spatially widespread in patients encompassing most major fibers; conversely, in controls, the relationship was confined to the anterior corpus callosum and thalamic radiations. No relationships were observed with alternative dMRI measures, including the fractional anisotropy and tissue-related FA. Conclusions We report widespread deregulation of cytokines in schizophrenia and identify inflammation as a putative mechanism underlying increases in brain FW levels.
- Published
- 2020
30. Neutrophil-lymphocyte ratio - a simple, accessible measure of inflammation, morbidity and prognosis in psychiatric disorders?
- Author
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Dennis Liu, Thomas W. Weickert, Cherrie Galletly, Cynthia Shannon Weickert, Nicholas Myles, and Zlatan Zulfic
- Subjects
Inflammation ,medicine.medical_specialty ,business.industry ,Neutrophils ,Lymphocyte ,Mental Disorders ,fungi ,Measure (physics) ,Prognosis ,Psychiatry and Mental health ,Leukocyte Count ,medicine.anatomical_structure ,Inflammatory marker ,Medicine ,Humans ,Narrative review ,Lymphocytes ,medicine.symptom ,Morbidity ,business ,Psychiatry ,Biomarkers - Abstract
Objective: A narrative review to describe the utility of the neutrophil-lymphocyte ratio (NLR) as an inflammatory marker in psychiatric and non-psychiatric disorders and to discuss the potential role of NLR in psychiatric research. Conclusions: NLR is inexpensive and readily available using division of two measures obtained on routine blood testing. NLR is elevated in a number of psychiatric disorders. It can predict morbidity and mortality in a wide range of non-psychiatric conditions, but this has not been confirmed in psychiatric conditions. It can be calculated in large, pre-existing datasets to investigate clinical correlates of inflammatory processes. NLR may have a future role in identifying patients with an inflammatory phenotype who could benefit from adjunctive anti-inflammatory medications.
- Published
- 2020
31. Increased macrophages and changed brain endothelial cell gene expression in the frontal cortex of people with schizophrenia displaying inflammation
- Author
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Thomas W. Weickert, Cynthia Shannon Weickert, Vibeke S. Catts, Cherrie Galletly, Helen Q Cai, Maree J. Webster, Dennis Liu, and Maryanne O'Donnell
- Subjects
0301 basic medicine ,Male ,Molecular biology ,Gene Expression ,Occludin ,0302 clinical medicine ,Prefrontal cortex ,Microglia ,Brain ,Middle Aged ,Intercellular Adhesion Molecule-1 ,Frontal Lobe ,Psychiatry and Mental health ,medicine.anatomical_structure ,Frontal lobe ,Schizophrenia ,Blood-Brain Barrier ,Encephalitis ,Female ,medicine.symptom ,Adult ,medicine.medical_specialty ,Prefrontal Cortex ,Inflammation ,Blood–brain barrier ,behavioral disciplines and activities ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Immune system ,Internal medicine ,mental disorders ,medicine ,Humans ,Endothelium ,business.industry ,Macrophages ,Endothelial Cells ,medicine.disease ,030104 developmental biology ,Endocrinology ,Psychotic Disorders ,Astrocytes ,business ,030217 neurology & neurosurgery ,Biomarkers ,Neuroscience - Abstract
Elevated pro-inflammatory cytokines exist in both blood and brain of people with schizophrenia but how this affects molecular indices of the blood–brain barrier (BBB) is unclear. Eight mRNAs relating to BBB function, a microglia and three immune cell markers were measured by qPCR in the prefrontal cortex from 37 people with schizophrenia/schizoaffective disorder and 37 matched controls. This cohort was previously grouped into “high inflammation” and “low inflammation” subgroups based on cortical inflammatory-related transcripts. Soluble intercellular adhesion molecule-1 (sICAM1) was measured in the plasma of 78 patients with schizophrenia/schizoaffective disorder and 73 healthy controls. We found that sICAM1 was significantly elevated in schizophrenia. An efflux transporter, ABCG2, was lower, while mRNAs encoding VE-cadherin and ICAM1 were higher in schizophrenia brain. The “high inflammation” schizophrenia subgroup had lower ABCG2 and higher ICAM1, VE-cadherin, occludin and interferon-induced transmembrane protein mRNAs compared to both “low inflammation” schizophrenia and “low inflammation” control subgroups. ICAM1 immunohistochemistry showed enrichment in brain endothelium regardless of diagnosis and was localised to astrocytes in some brains. Microglia mRNA was not altered in schizophrenia nor did it correlate with ICAM1 expression. Immune cell mRNAs were elevated in “high inflammation” schizophrenia compared to both “low inflammation” schizophrenia and controls. CD163+ perivascular macrophages were identified by immunohistochemistry in brain parenchyma in over 40% of “high inflammation” schizophrenia brains. People with high levels of cytokine expression and schizophrenia display changes consistent with greater immune cell transmigration into brain via increased ICAM1, which could contribute to other neuropathological changes found in this subgroup of people.
- Published
- 2018
32. Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders
- Author
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Kuo Ping Huang, Keiichi I. Nakayama, Isabella A. Graef, Akito Nakao, Hirotaka Shoji, Yuta Katayama, Cynthia Shannon Weickert, Vibeke S. Catts, Freesia L. Huang, Tsuyoshi Miyakawa, Hideo Hagihara, Yasuo Mori, Tsuyoshi Takagi, and Shunsuke Ishii
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Endophenotypes ,medicine.medical_treatment ,Mice ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,medicine ,Animals ,Humans ,Lactic Acid ,Bipolar disorder ,Antipsychotic ,Psychiatry ,Brain Chemistry ,Mice, Knockout ,Pharmacology ,Mice, Inbred BALB C ,Mental Disorders ,Confounding ,Brain ,Hydrogen-Ion Concentration ,medicine.disease ,3. Good health ,Mice, Inbred C57BL ,Disease Models, Animal ,Psychiatry and Mental health ,Drug-naïve ,030104 developmental biology ,Autism spectrum disorder ,Schizophrenia ,Endophenotype ,Meta-analysis ,Original Article ,Female ,Psychology ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Although the brains of patients with schizophrenia and bipolar disorder exhibit decreased brain pH relative to those of healthy controls upon postmortem examination, it remains controversial whether this finding reflects a primary feature of the diseases or is a result of confounding factors such as medication and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models that can be studied without confounds inherent in human studies. In the present study, we first reevaluated the pH of the postmortem brains of patients with schizophrenia and bipolar disorder by conducting a meta-analysis of existing data sets from 10 studies. We then measured pH, lactate levels, and related metabolite levels in brain homogenates from five neurodevelopmental mouse models of psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder. All mice were drug naive with the same agonal state, postmortem interval, and age within each strain. Our meta-analysis revealed that brain pH was significantly lower in patients with schizophrenia and bipolar disorder than in control participants, even when a few potential confounding factors (postmortem interval, age, and history of antipsychotic use) were considered. In animal experiments, we observed significantly lower pH and higher lactate levels in the brains of model mice relative to controls, as well as a significant negative correlation between pH and lactate levels. Our findings suggest that lower pH associated with increased lactate levels is not a mere artifact, but rather implicated in the underlying pathophysiology of schizophrenia and bipolar disorder.
- Published
- 2018
33. Lower antioxidant capacity in the prefrontal cortex of individuals with schizophrenia
- Author
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Vibeke S. Catts, Cynthia Shannon Weickert, and Yiru Zhang
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Antioxidant ,Glutamate-Cysteine Ligase ,medicine.medical_treatment ,Prefrontal Cortex ,Tissue Banks ,medicine.disease_cause ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Humans ,Medicine ,Prefrontal cortex ,Glutathione Peroxidase ,business.industry ,General Medicine ,Human brain ,Glutathione ,Middle Aged ,medicine.disease ,Oxidative Stress ,Psychiatry and Mental health ,Antioxidant capacity ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Schizophrenia ,Female ,business ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
Objective: The glutathione (GSH) pathway is the main antioxidant system to protect against oxidative stress in the human brain. In this study, we tested whether molecular components of the GSH antioxidant system are changed in dorsolateral prefrontal cortex tissue from people with schizophrenia compared to controls. Method: The levels of total glutathione and reduced GSH were determined by fluorometric assay via quantifying thiols in extracts from frontal cortex of 68 people. Immunoblotting was used to measure levels of enzymes responsible for maintaining GSH, the glutamyl-cysteine ligase (GCL) catalytic subunit (GCLC) and the GSH peroxidase (GPx)-like protein ( n = 74). Quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to measure GCLC messenger RNA (mRNA) expression. Results: Both total glutathione ( t(66) = 2.467, p = 0.016) and reduced GSH ( t(66) = 3.001, p = 0.004) levels were significantly less in people with schizophrenia than in controls. However, there were no significant differences in either GCLC-like protein ( t(72) = −1.077, p = 0.285) or GCLC mRNA expression ( t(71) = −0.376, p = 0.708) between people with schizophrenia and control subjects. There was also no significant difference of GPx-like protein levels between schizophrenia and controls ( t(72) = −0.060, p = 0.952). Moreover, no significant correlations of putative confounding factors with GSH changes were detected. Discussion: These results suggest that people with schizophrenia have impaired GSH antioxidant capacity, alongside normal levels of key regulatory proteins.
- Published
- 2017
34. Overexpression of Neuregulin 1 Type III Confers Hippocampal mRNA Alterations and Schizophrenia-Like Behaviors in Mice
- Author
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Cynthia Shannon Weickert, D Sinclair, Carrie L. Heusner, Juan C Olaya, Mari Kondo, Mitsuyuki Matsumoto, and Tim Karl
- Subjects
Male ,0301 basic medicine ,Genetically modified mouse ,type III ,Neuregulin-1 ,Transgene ,Mice, Transgenic ,Biology ,Hippocampal formation ,Hippocampus ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Ca2+/calmodulin-dependent protein kinase ,mental disorders ,Animals ,Neuregulin 1 ,mouse ,Prepulse inhibition ,transgenic ,neuregulin 1 ,Behavior, Animal ,behavior ,Cell biology ,schizophrenia ,Disease Models, Animal ,Psychiatry and Mental health ,030104 developmental biology ,Synaptic plasticity ,Forebrain ,biology.protein ,Neuroscience ,030217 neurology & neurosurgery ,Regular Articles - Abstract
Neuregulin 1 (NRG1) is a schizophrenia candidate gene whose protein product is involved in neuronal migration, survival, and synaptic plasticity via production of specific isoforms. Importantly, NRG1 type III (NRG1 III) mRNA is increased in humans inheriting a schizophrenia risk haplotype for the NRG1 gene (HapICE), and NRG1 protein levels can be elevated in schizophrenia. The nature by which NRG1 type III overexpression results in schizophrenia-like behavior and brain pathology remains unclear, therefore we constructed a transgenic mouse with Nrg1 III overexpression in forebrain neurons (CamKII kinase+). Here, we demonstrate construct validity for this mouse model, as juvenile and adult Nrg1 III transgenic mice exhibit an overexpression of Nrg1 III mRNA and Nrg1 protein in multiple brain regions. Furthermore, Nrg1 III transgenic mice have face validity as they exhibit schizophrenia-relevant behavioral phenotypes including deficits in social preference, impaired fear-associated memory, and reduced prepulse inhibition. Additionally, microarray assay of hippocampal mRNA uncovered transcriptional alterations downstream of Nrg1 III overexpression, including changes in serotonin receptor 2C and angiotensin-converting enzyme. Transgenic mice did not exhibit other schizophrenia-relevant behaviors including hyperactivity, social withdrawal, or an increased vulnerability to the effects of MK-801 malate. Our results indicate that this novel Nrg1 III mouse is valid for modeling potential pathological mechanisms of some schizophrenia-like behaviors, for determining what other neurobiological changes may be downstream of elevated NRG1 III levels and for preclinically testing therapeutic strategies that may be specifically efficacious in patients with the NRG1 (HapICE) risk genotype.
- Published
- 2017
35. Widespread Volumetric Reductions in Schizophrenia and Schizoaffective Patients Displaying Compromised Cognitive Abilities
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Avril Pereira, Suresh Sundram, Chad A. Bousman, Tamsyn E Van Rheenen, Thomas W. Weickert, Andrew Zalesky, Jason M. Bruggemann, Roshel K Lenroot, Christos Pantelis, Danielle Weinberg, Vanessa Cropley, Ruth Wells, and Cynthia Shannon Weickert
- Subjects
Adult ,Male ,medicine.medical_specialty ,Psychosis ,Schizoaffective disorder ,Audiology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Neurodevelopmental disorder ,medicine ,Humans ,Cognitive Dysfunction ,Bipolar disorder ,Cerebral Cortex ,business.industry ,Neuropsychology ,Middle Aged ,medicine.disease ,030227 psychiatry ,Psychiatry and Mental health ,Psychotic Disorders ,Schizophrenia ,Brain size ,Female ,Occipital lobe ,business ,030217 neurology & neurosurgery ,Regular Articles - Abstract
Objective Progress toward understanding brain mechanisms in psychosis is hampered by failures to account for within-group heterogeneity that exists across neuropsychological domains. We recently identified distinct cognitive subgroups that might assist in identifying more biologically meaningful subtypes of psychosis. In the present study, we examined whether underlying structural brain abnormalities differentiate these cognitively derived subgroups. Method 1.5T T1 weighted structural scans were acquired for 168 healthy controls and 220 patients with schizophrenia/schizoaffective disorder. Based on previous work, 47 patients were categorized as being cognitively compromised (impaired premorbid and current IQ), 100 as cognitively deteriorated (normal premorbid IQ, impaired current IQ), and 73 as putatively cognitively preserved (premorbid and current IQ within 1 SD of controls). Global, subcortical and cortical volume, thickness, and surface area measures were compared among groups. Results Whole cortex, subcortical, and regional volume and thickness reductions were evident in all subgroups compared to controls, with the largest effect sizes in the compromised group. This subgroup also showed abnormalities in regions not seen in the other patient groups, including smaller left superior and middle frontal areas, left anterior and inferior temporal areas and right lateral medial and inferior frontal, occipital lobe and superior temporal areas. Conclusions This pattern of more prominent brain structural abnormalities in the group with the most marked cognitive impairments-both currently and putatively prior to illness onset, is consistent with the concept of schizophrenia as a progressive neurodevelopmental disorder. In this group, neurodevelopmental and neurodegenerative factors may be important for cognitive function.
- Published
- 2017
36. Accelerated Gray and White Matter Deterioration With Age in Schizophrenia
- Author
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Rhoshel K. Lenroot, Cynthia Shannon Weickert, Maria A Di Biase, Andrew Zalesky, Avril Pereira, Suresh Sundram, Jason M. Bruggemann, Paul Klauser, Chad A. Bousman, Vanessa Cropley, Christos Pantelis, and Thomas W. Weickert
- Subjects
Adult ,Male ,medicine.medical_specialty ,Psychosis ,Schizoaffective disorder ,Audiology ,computer.software_genre ,Brain mapping ,White matter ,Young Adult ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,Reference Values ,Voxel ,Fractional anisotropy ,medicine ,Humans ,Gray Matter ,Psychiatry ,Aged ,Brain Mapping ,medicine.diagnostic_test ,Age Factors ,Neurodegenerative Diseases ,Magnetic resonance imaging ,Organ Size ,Middle Aged ,medicine.disease ,White Matter ,030227 psychiatry ,Psychiatry and Mental health ,medicine.anatomical_structure ,Psychotic Disorders ,Disease Progression ,Schizophrenia ,Anisotropy ,Female ,Schizophrenic Psychology ,Psychology ,computer ,Gray (horse) ,030217 neurology & neurosurgery - Abstract
Although brain changes in schizophrenia have been proposed to mirror those found with advancing age, the trajectory of gray matter and white matter changes during the disease course remains unclear. The authors sought to measure whether these changes in individuals with schizophrenia remain stable, are accelerated, or are diminished with age.Gray matter volume and fractional anisotropy were mapped in 326 individuals diagnosed with schizophrenia or schizoaffective disorder and in 197 healthy comparison subjects aged 20-65 years. Polynomial regression was used to model the influence of age on gray matter volume and fractional anisotropy at a whole-brain and voxel level. Between-group differences in gray matter volume and fractional anisotropy were regionally localized across the lifespan using permutation testing and cluster-based inference.Significant loss of gray matter volume was evident in schizophrenia, progressively worsening with age to a maximal loss of 8% in the seventh decade of life. The inferred rate of gray matter volume loss was significantly accelerated in schizophrenia up to middle age and plateaued thereafter. In contrast, significant reductions in fractional anisotropy emerged in schizophrenia only after age 35, and the rate of fractional anisotropy deterioration with age was constant and best modeled with a straight line. The slope of this line was 60% steeper in schizophrenia relative to comparison subjects, indicating a significantly faster rate of white matter deterioration with age. The rates of reduction of gray matter volume and fractional anisotropy were significantly faster in males than in females, but an interaction between sex and diagnosis was not evident.The findings suggest that schizophrenia is characterized by an initial, rapid rate of gray matter loss that slows in middle life, followed by the emergence of a deficit in white matter that progressively worsens with age at a constant rate.
- Published
- 2017
37. M174. REDUCED CHEMOKINE SIGNALLING CAPACITY IS ASSOCIATED WITH INHIBITORY INTERNEURON DYSFUNCTION IN SUBCORTICAL BRAIN REGIONS IN SCHIZOPHRENIA AND BIPOLAR DISORDER
- Author
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Christin Weissleder, Maree J. Webster, and Cynthia Shannon Weickert
- Subjects
Chemokine ,Poster Session II ,biology ,business.industry ,AcademicSubjects/MED00810 ,medicine.disease ,Psychiatry and Mental health ,Signalling ,Schizophrenia ,mental disorders ,biology.protein ,medicine ,Inhibitory interneuron ,Bipolar disorder ,business ,Neuroscience - Abstract
Background The subependymal zone (SEZ) adjacent to the lateral ventricles represents the largest reservoir of postnatally-generated cortical and striatal inhibitory interneurons in the human brain. Expression of markers representing the generation of neuronal progenitors from neural stem cells is reduced in the adult SEZ in schizophrenia and bipolar disorder; however, underlying mechanisms and relationships to inhibitory interneuron dysfunction remain unknown. Stem cell maintenance, neuronal migration and cell survival are regulated by signaling of the CXC motif chemokine 12 (CXCL12) through CXC motif chemokine receptors 4 (CXCR4) and 7 (CXCR7), which are increasingly implicated in the pathophysiology of psychiatric disorders. Methods Post-mortem tissue was obtained from 33 schizophrenia, 32 bipolar disorder and 33 control cases from the Stanley Medical Research Institute. SEZ and caudate nucleus tissue was dissected from 60 µm sections for RNA isolation and cDNA synthesis. Gene expression of CXCL12, CXCR4 and CXCR7 were determined by quantitative polymerase chain reactions. Semi-partial correlations were performed to assess whether CXC chemokine family member mRNAs may correlate with markers of neural stem cells (PROM1, GFAPD), neuronal progenitors (SOX2, ASCL1) and inhibitory interneurons (CALB2, NPY) in the SEZ and caudate nucleus. Results In the SEZ, CXCL12 mRNA was decreased in schizophrenia compared to controls and bipolar disorder (14–24%, all p≤0.03). CXCR4 and CXCR7 mRNAs were both decreased in schizophrenia and bipolar disorder compared to controls (9–33%, all p≤0.05). CXCL12, CXCR4 and CXCR7 expression positively correlated with PROM1, GFAPD, SOX2 and ASCL1 mRNAs (0.28≥sr≤0.61). In the caudate nucleus, CXCL12 mRNA was decreased in schizophrenia and bipolar disorder compared to controls (19–26%, all p≤0.05). CXCR4 mRNA was decreased in schizophrenia compared to controls (20%, p=0.01), while CXCR7 expression did not significantly differ across diagnostic groups. CALB2 and NPY mRNAs were increased in bipolar disorder compared to controls (13–27%, all p≤0.05). CXCR4 expression positively correlated with CALB2 mRNA (sr=0.26), while CXCR7 expression negatively correlated with NPY mRNA (sr=0.26). Discussion These findings provide the first molecular evidence of decreased CXC chemokine family member expression in the SEZ and caudate nucleus in psychiatric disorders, with exacerbated deficits in schizophrenia compared to bipolar disorder. Dysregulated CXC chemokine family member expression may hamper neural stem cell maintenance and neuronal differentiation, which may contribute to inhibitory interneuron dysfunction in psychiatric disorders. Future work will determine the cellular localisation of CXCR4 and CXCR7 expression in the SEZ and caudate nucleus to disentangle the regulatory role of CXCL12 signalling in the generation, migration and survival of inhibitory interneurons in the human brain.
- Published
- 2020
38. O11.5. INCREASED INFLAMMATION AND MACROPHAGE INFILTRATION IS ASSOCIATED WITH ALTERED SUBEPENDYMAL ZONE NEUROGENESIS IN SCHIZOPHRENIA BUT NOT BIPOLAR DISORDER
- Author
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Janice M. Fullerton, Guy Barry, Rachel Sager, Christin Weissleder, Maree J. Webster, Hayley F. North, Cynthia Shannon Weickert, and Mainá Bitar
- Subjects
Pathology ,medicine.medical_specialty ,Oral Session: Digital Health/Methods ,business.industry ,AcademicSubjects/MED00810 ,Macrophage infiltration ,Neurogenesis ,Inflammation ,medicine.disease ,O11. Oral Session: Genes/ Inflammation/ Peripheral ,Psychiatry and Mental health ,Schizophrenia ,mental disorders ,Subependymal zone ,Medicine ,Bipolar disorder ,medicine.symptom ,business - Abstract
Background Inflammation is implicated in the pathogenesis of schizophrenia and bipolar disorder. Inflammation regulates neurogenesis, and markers for stem cells and neuronal progenitors are reduced in schizophrenia and bipolar disorder in the subependymal zone (SEZ) – the brain’s largest region of neurogenesis. This research aimed to discover core differences in gene expression and cellular composition in the SEZ in psychiatric disorders that may contribute to dysregulated neurogenesis. Methods We performed total RNA sequencing in the SEZ of 20 post-mortem schizophrenia and 21 control brains. Quantitative PCR (qPCR) and immunohistochemistry were performed in 32 schizophrenia and 32 control overlapping cases and 29 bipolar disorder cases. Immunohistochemistry was used for quantification and localisation of CD163+ macrophages. Cluster-analysis of IL6, IL6R, IL1R1 and SERPINA3 expression defined low and high inflammation subgroups, which were used to compare neurogenesis marker expression. Results Out of >60,000 genes, the most significantly differentially expressed gene in schizophrenia was CD163, a macrophage marker, which was increased 3.3 times compared to controls and confirmed by qPCR. Abundant CD163+ macrophages were located surrounding blood vessels, in the parenchyma and seem to infiltrate throughout the SEZ where neural stem and progenitor cells typically reside. Macrophage cell density was increased in schizophrenia compared to controls and bipolar disorder (by 29% and 61%; p = 0.017 and p = 0.002 respectively). CD163 expression positively correlated with the quiescent neural stem cell marker GFAPδ (r = 0.56, p = 0.001), and negatively correlated with neuronal progenitor marker ASCL1 (r = - 0.40, p = 0.032) in schizophrenia but not bipolar disorder. Cluster analysis of inflammatory gene expression revealed 40% of schizophrenia but only 10% of control cases were highly inflamed. The high inflammation schizophrenia subgroup had increased CD163 and GFAPδ expression but decreased ASCL1 expression (all p < 0.026). Discussion Increased macrophages in the SEZ is a key difference in schizophrenia pathology and potentially drives heightened inflammation in a subgroup. Inflammation has varied effects on different stages of neurogenesis in schizophrenia but not bipolar disorder, implicating divergent mechanisms leading to reduced neurogenesis in each psychiatric condition. In schizophrenia, macrophages and high inflammation seem to reduce neuronal differentiation and sustain neural stem cell quiescence, likely blunting stem cell proliferation. Therefore, reduced SEZ neurogenesis across the lifespan in schizophrenia may contribute to the widely reported inhibitory interneuron deficits.
- Published
- 2020
39. O11.2. ELEVATION OF MACROPHAGE-RELATED TRANSCRIPTS IN THE MIDBRAIN IN SCHIZOPHRENIA
- Author
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Debora A. Rothmond, Danny Boerrigter, Tertia D. Purves-Tyson, Helen Q Cai, and Cynthia Shannon Weickert
- Subjects
Oral Session: Digital Health/Methods ,business.industry ,AcademicSubjects/MED00810 ,Biology ,medicine.disease ,O11. Oral Session: Genes/ Inflammation/ Peripheral ,Midbrain ,Psychiatry and Mental health ,Elevation (emotion) ,Text mining ,Schizophrenia ,Immunology ,medicine ,Macrophage ,business - Abstract
Background Neuroinflammation and dopamine dysregulation contribute to psychosis and cognitive deficits in schizophrenia. Approximately 50% of people with schizophrenia have elevated gene expression of proinflammatory cytokines in the postmortem midbrain, the location of the dopamine neurons. Infiltration of macrophages into the cortex was identified in a subset of high inflammatory schizophrenia cases. It is not known whether molecular measures of macrophages and cell adhesion molecules are increased in the midbrain in schizophrenia. We hypothesised that gene expression of macrophage markers CD163 (cluster of differentiation 163; perivascular macrophages), Fn1 (fibronectin 1; expressed by peripheral macrophages, not brain microglia), CD64 (pro-inflammatory macrophage), MRC1 (anti-inflammatory macrophage) and intracellular cell adhesion molecule 1 (ICAM1; enabling recruitment of peripheral macrophages into the brain), will be elevated in the midbrain of schizophrenia cases compared to controls. Methods Gene expression was examined by qRT-PCR in the midbrain from 28 schizophrenia cases (13 high inflammation, 15 low inflammation) and 29 healthy controls (low inflammation). ANCOVA, with age, PMI and RIN as covariates when correlations detected, were used to detect differences between diagnostic or diagnostic/inflammatory groups. For schizophrenia cases, antipsychotic doses were converted to chlorpromazine (CPZ) equivalents. Correlations were used to determine relationships between illness duration, antipsychotics and gene expression. CD163+ cells were identified in fresh frozen midbrain (14µm) from schizophrenia and control cases by immunohistochemistry to qualitatively assess their location relative to dopamine neurons. Results We found abundant macrophages (CD163+ cells) in and around blood vessels and in the schizophrenia midbrain parenchyma in close proximity to dopamine neurons. CD163, Fn1 and ICAM mRNAs were increased 237.6%, 39.67% and 137.7% respectively, in schizophrenia cases compared to control cases [all F(1,50 >5.045, p0.5, p0.05, n=28). Fn1 mRNA did not correlate with illness duration or antipsychotics. Discussion Increased ICAM1 may lead to increased transmigration of monocytes into the midbrain parenchyma. The increase in CD64 and the positive relationship between Fn1, expressed by peripheral monocytes/macrophages but not brain microglia, and CD163 expression in schizophrenia cases provides support that there is an increase in pro-inflammatory bone marrow-derived immune cells in the psychotic midbrain. These peripheral immune cells may be a source of increased cytokines identified in the midbrain schizophrenia cases and thus may contribute to dopamine neuron pathophysiology. Although the role of antipsychotics in increased macrophage marker expression in the midbrain is suggested, increased antipsychotics in patients displaying higher expression of inflammatory transcripts may indicate a more symptomatic patient requiring higher treatment doses.
- Published
- 2020
40. M62. PERIPHERAL INFLAMMATION MARKERS IDENTIFY SUBSET OF PATIENTS WITH SCHIZOPHRENIA AND RELATED PSYCHOSES WHO HAVE INTELLECTUAL DECLINE FROM PREMORBID LEVELS
- Author
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Cynthia Shannon Weickert, Dennis Liu, Ryan P. Balzan, Seetha Ramanathan, Rhoshel K. Lenroot, Cherrie Galletly, and Thomas W. Weickert
- Subjects
Psychiatry and Mental health ,Poster Session II ,AcademicSubjects/MED00810 ,business.industry ,Schizophrenia (object-oriented programming) ,Immunology ,Medicine ,Inflammation ,medicine.symptom ,business ,Peripheral - Abstract
Background Higher inflammation has been identified in a substantial subset of both high-risk and chronically ill patients with schizophrenia and related psychoses and this may account for some of the heterogeneity of the schizophrenia. There is also much heterogeneity in cognitive deficits related to schizophrenia with some patients showing a marked decline from premorbid intellectual levels while others show little change from either normal or low intellect. However, the relationship between intellectual change with the illness onset and inflammation in schizophrenia has not been established. Methods Here, we report the assessment of two common markers of inflammation from two independent samples of generally chronically ill patients with schizophrenia and related psychoses (one sample of 73 patients versus 70 healthy controls from Sydney, NSW, Australia and one sample of 297 patients from Syracuse, NY, USA). Peripheral venous blood samples were collected from all patients and blood markers of inflammation (C-Reactive Protein, CRP, and Neutrophil to Lymphocyte Ratio, NLR) were assayed using standard procedures. Assessment of premorbid and current intellectual abilities were obtained from the Sydney cohort of patients. Results Grouping the patients and controls from the Sydney sample into those with elevated (> 3 mg/L) versus normal (< 3 mg/L) CRP levels revealed 42% of the patients versus 20% of the healthy controls had elevated CRP (Chi Square = 9.16, p = .002) and further evidence of inflammation with an elevated mean NLR of 2.5. The frequency of peripheral inflammation was confirmed by the independent sample from Syracuse in which 39% of the patients (n= 115) had an elevated NLR above a cutoff score for normal of 2.2 which was consistent with the Sydney sample. Patients from the Sydney sample who had an elevated CRP also had a significant mean 15-point IQ decline from premorbid IQ levels, whereas the patients with CRP levels within normal limits did not show a statistically significant drop in IQ from premorbid levels (mean IQ decline 7.6 points). Healthy controls with normal CRP had no IQ change (0.0 points) and healthy controls with elevated CRP has a slight, non-significant IQ decline (mean 2.3 points). Discussion Thus, our study showed supportive evidence of elevated peripheral inflammation markers in subgroups of chronically ill patients with schizophrenia from two independent samples and a link between marked intellectual decline from premorbid levels and current peripheral inflammation in one chronically ill subgroup of patients with schizophrenia suggesting a role for inflammation in the cognitive impairment of a substantial proportion (40%) of patients with schizophrenia.
- Published
- 2020
41. Raloxifene increases prefrontal activity during emotional inhibition in schizophrenia based on estrogen receptor genotype
- Author
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Jochen Kindler, Cynthia Shannon Weickert, Peter R. Schofield, Thomas W. Weickert, and Rhoshel K. Lenroot
- Subjects
Adult ,Male ,Selective Estrogen Receptor Modulators ,medicine.medical_specialty ,Adolescent ,Genotype ,Emotions ,Clinical Neurology ,Prefrontal Cortex ,Estrogen receptor ,610 Medicine & health ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Raloxifene ,Prefrontal cortex ,Biological Psychiatry ,Pharmacology ,Cross-Over Studies ,Raloxifene Hydrochloride ,Estrogen Receptor alpha ,Genetic Variation ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,030227 psychiatry ,3. Good health ,Inhibition, Psychological ,Psychiatry and Mental health ,Endocrinology ,Neurology ,Selective estrogen receptor modulator ,Schizophrenia ,Adjunctive treatment ,Female ,Schizophrenic Psychology ,Neurology (clinical) ,Psychology ,Estrogen receptor alpha ,030217 neurology & neurosurgery ,medicine.drug - Abstract
People with schizophrenia show decreased prefrontal cortex (PFC) activity during emotional response inhibition, a cognitive process sensitive to hormonal influences. Raloxifene, a selective estrogen receptor modulator, binds estrogen receptor alpha (ESR-α), improves memory, attention and normalizes cortical and hippocampal activity during learning and emotional face recognition in schizophrenia. Here, we tested the extent to which raloxifene restores neuronal activity during emotional response inhibition in schizophrenia. Since genetic variation in estrogen receptor alpha (ESR-1) determines cortical ESR-α production and correlates with cognition, we also predicted that genetic ESR-1 variation would differentially relate to increased cortical activity by raloxifene administration. Thirty people with schizophrenia participated in a thirteen-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of raloxifene administered at 120mg/day. Effects of raloxifene on brain activation were assessed based on ESR-1 genotype using functional magnetic resonance imaging during emotional word inhibition. Raloxifene increased PFC activity during inhibition of response to negative words and the raloxifene related increased PFC activity was greater in patients homozygous for ESR-1 rs9340799 AA relative to G carriers. Comparison to 23 healthy controls demonstrated that PFC activity of people with schizophrenia receiving raloxifene was more similar to controls than to their own brain activity during placebo. Estrogen receptor modulation by raloxifene restores PFC activity during emotional response inhibition in schizophrenia and ESR-1 genotype predicts degree of increased neural activity in response to raloxifene. While these preliminary results require replication, they suggest the potential for personalized pharmacotherapy using ESR-1 and estrogen receptor targeting compounds in schizophrenia.
- Published
- 2016
42. In Vivo Imaging of Translocator Protein in Long-term Cannabis Users
- Author
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Cynthia Shannon Weickert, Jeremy J. Watts, Pablo Rusjan, Jeffrey H. Meyer, Sina Hafizi, Romina Mizrahi, Sylvain Houle, and Tania Da Silva
- Subjects
Adult ,Male ,medicine.medical_specialty ,Fluorine Radioisotopes ,Marijuana Abuse ,Cross-sectional study ,Young Adult ,Neuroimaging ,Receptors, GABA ,Internal medicine ,medicine ,Translocator protein ,Humans ,Young adult ,biology ,business.industry ,Case-control study ,Brain ,biology.organism_classification ,Psychiatry and Mental health ,C-Reactive Protein ,Cross-Sectional Studies ,Blood biomarkers ,Case-Control Studies ,Positron-Emission Tomography ,biology.protein ,Anxiety ,Cytokines ,Female ,Marijuana Use ,Cannabis ,medicine.symptom ,business - Abstract
Cannabis is the most commonly used illicit drug in the world. Cannabinoids have been shown to modulate immune responses; however, the association of cannabis with neuroimmune function has never been investigated in vivo in the human brain.To investigate neuroimmune activation or 18-kDa translocator protein (TSPO) levels in long-term cannabis users, and to evaluate the association of brain TSPO levels with behavioral measures and inflammatory blood biomarkers.This cross-sectional study based in Toronto, Ontario, recruited individuals from January 1, 2015, to October 30, 2018. Participants included long-term cannabis users (n = 24) and non-cannabis-using controls (n = 27). Cannabis users were included if they had a positive urine drug screen for only cannabis and if they used cannabis at least 4 times per week for the past 12 months and/or met the criteria for cannabis use disorder. All participants underwent a positron emission tomography scan with [18F]FEPPA, or fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide.Total distribution volume was quantified across regions of interest. Stress and anxiety as well as peripheral measures of inflammatory cytokines and C-reactive protein levels were also measured.In total, 24 long-term cannabis users (mean [SD] age, 23.1 [3.8] years; 15 men [63%]) and 27 non-cannabis-using controls (mean [SD] age, 23.6 [4.2] years; 18 women [67%]) were included and completed all study procedures. Compared with the controls, cannabis users had higher [18F]FEPPA total distribution volume (main group effect: F1,48 = 6.5 [P = .01]; ROI effect: F1,200 = 28.4 [P .001]; Cohen d = 0.6; 23.3% higher), with a more prominent implication for the cannabis use disorder subgroup (n = 15; main group effect: F1,39 = 8.5 [P = .006]; ROI effect: F1,164 = 19.3 [P .001]; Cohen d = 0.8; 31.5% higher). Greater TSPO levels in the brain were associated with stress and anxiety and with higher circulating C-reactive protein levels in cannabis users.The results of this study suggest that TSPO levels in cannabis users, particularly in those with cannabis use disorder, are higher than those in non-cannabis-using controls. The findings emphasize the need for more complementary preclinical systems for a better understanding of the role of cannabinoids and TSPO in neuroimmune signaling.
- Published
- 2019
43. White matter neuron biology and neuropathology in schizophrenia
- Author
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Cynthia Shannon Weickert, Paul A. Tooney, and Ryan J. Duchatel
- Subjects
lcsh:RC435-571 ,Population ,Review Article ,Grey matter ,White matter ,03 medical and health sciences ,0302 clinical medicine ,lcsh:Psychiatry ,Cortex (anatomy) ,mental disorders ,medicine ,education ,education.field_of_study ,biology ,medicine.disease ,Cellular neuroscience ,030227 psychiatry ,Dorsolateral prefrontal cortex ,Psychiatry and Mental health ,medicine.anatomical_structure ,nervous system ,Schizophrenia ,biology.protein ,Neuron ,NeuN ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Schizophrenia is considered a neurodevelopmental disorder as it often manifests before full brain maturation and is also a cerebral cortical disorder where deficits in GABAergic interneurons are prominent. Whilst most neurons are located in cortical and subcortical grey matter regions, a smaller population of neurons reside in white matter tracts of the primate and to a lesser extent, the rodent brain, subjacent to the cortex. These interstitial white matter neurons (IWMNs) have been identified with general markers for neurons [e.g., neuronal nuclear antigen (NeuN)] and with specific markers for neuronal subtypes such as GABAergic neurons. Studies of IWMNs in schizophrenia have primarily focused on their density underneath cortical areas known to be affected in schizophrenia such as the dorsolateral prefrontal cortex. Most of these studies of postmortem brains have identified increased NeuN+ and GABAergic IWMN density in people with schizophrenia compared to healthy controls. Whether IWMNs are involved in the pathogenesis of schizophrenia or if they are increased because of the cortical pathology in schizophrenia is unknown. We also do not understand how increased IWMN might contribute to brain dysfunction in the disorder. Here we review the literature on IWMN pathology in schizophrenia. We provide insight into the postulated functional significance of these neurons including how they may contribute to the pathophysiology of schizophrenia.
- Published
- 2019
44. The Impact of Childhood Adversity on Cognitive Development in Schizophrenia
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Cynthia Shannon Weickert, Ruth Wells, Thomas W. Weickert, Vaidy Swaminathan, Vanessa Cropley, Christos Pantelis, Danielle Weinberg, Rhoshel K. Lenroot, Avril Pereira, Jason M. Bruggemann, Suresh Sundram, Andrew Zalesky, Chad A. Bousman, and Isabella Jacomb
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Adult ,Male ,Psychosis ,media_common.quotation_subject ,Human Development ,Verbal abuse ,behavioral disciplines and activities ,Neglect ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Adverse Childhood Experiences ,mental disorders ,medicine ,Cognitive development ,Humans ,Cognitive Dysfunction ,Functional ability ,Family history ,media_common ,Australia ,Cognition ,Middle Aged ,medicine.disease ,030227 psychiatry ,Psychiatry and Mental health ,Adult Survivors of Child Adverse Events ,Psychotic Disorders ,Schizophrenia ,Female ,Psychology ,030217 neurology & neurosurgery ,Clinical psychology ,Regular Articles - Abstract
Childhood adversity, such as physical, sexual, and verbal abuse, as well as neglect and family conflict, is a risk factor for schizophrenia. Such adversity can lead to disruptions of cognitive function during development, undermining intellectual capabilities and academic achievement. Schizophrenia is a neurodevelopmental disorder that is associated with cognitive impairments that may become evident during childhood. The Australian Schizophrenia Research Bank database comprises a large community cohort (N = 1169) in which we previously identified 3 distinct cognitive groups among people with schizophrenia: (1) Compromised, current, and estimated premorbid cognitive impairment; (2) Deteriorated, substantial decline from estimated premorbid function; and (3) Preserved, performing in the normal cognitive range without decline. The compromised group displayed the worst functional and symptom outcomes. Here, we extend our previous work by assessing the relationship among these categories of cognitive abilities and reported childhood adversity in 836 patients and healthy controls. Exploratory factor analysis of the Childhood Adversity Questionnaire revealed 3 factors (lack of parental involvement; overt abuse; family breakdown and hardship). People with schizophrenia reported significantly more childhood adversity than healthy controls on all items and factors. People with schizophrenia in the compromised group reported significantly more lack of parental involvement and family breakdown and hardship and lower socioeconomic status than those in the deteriorated group. The cognitive groups were not related to family history of psychosis. These findings identify specific social and family factors that impact cognition, highlighting the important role of these factors in the development of cognitive and functional abilities in schizophrenia.
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- 2019
45. Evidence for enhanced androgen action in the prefrontal cortex of people with bipolar disorder but not schizophrenia or major depressive disorder
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Samantha J Owens, Tertia D. Purves-Tyson, Cynthia Shannon Weickert, and Maree J. Webster
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Adult ,Male ,medicine.medical_specialty ,Bipolar Disorder ,Prefrontal Cortex ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,mental disorders ,Medicine ,Humans ,Testosterone ,Bipolar disorder ,Prefrontal cortex ,Biological Psychiatry ,Aged ,Depressive Disorder, Major ,business.industry ,Middle Aged ,medicine.disease ,030227 psychiatry ,Androgen receptor ,Dorsolateral prefrontal cortex ,Psychiatry and Mental health ,Endocrinology ,medicine.anatomical_structure ,Schizophrenia ,Receptors, Androgen ,Case-Control Studies ,Androgens ,Major depressive disorder ,Anxiety ,Female ,Schizophrenic Psychology ,medicine.symptom ,business ,Trinucleotide repeat expansion ,030217 neurology & neurosurgery - Abstract
Anxiety and depressive disorders are more prevalent in hypogonadal men. Low testosterone levels are associated with greater negative symptoms and impaired cognition in men with schizophrenia. Thus, androgens may contribute to brain pathophysiology in psychiatric disorders. We investigated androgen-related mRNAs in post-mortem dorsolateral prefrontal cortex of psychiatric disorders. We also assessed androgen receptor (AR) CAG trinucleotide repeat length, a functional AR gene variant associated with AR gene expression, receptor activity, and circulating testosterone. AR CAG repeat length was determined from genomic DNA and AR and 5α-reductase mRNAs measured using quantitative PCR in schizophrenia, bipolar disorder and control cases [n = 35/group; Stanley Medical Research Institute (SMRI) Array collection]. Layer-specific AR gene expression was determined using in situ hybridisation in schizophrenia, bipolar disorder, major depressive disorder and control cases (n = 15/group; SMRI Neuropathology Consortium). AR mRNA was increased in bipolar disorder, but was unchanged in schizophrenia, relative to controls. AR and 5α-reductase mRNAs were significantly positively correlated in bipolar disorder. AR CAG repeat length was significantly shorter in bipolar disorder relative to schizophrenia. AR mRNA expression was highest in cortical layers IV and V, but no layer-specific diagnostic differences were detected. Together, our results suggest enhanced cortical androgen action in people with bipolar disorder.
- Published
- 2019
46. S33. REDUCTION IN PERIPHERAL C-REACTIVE PROTEIN LEVELS WITH CANAKINUMAB ADMINISTRATION IS RELATED TO REDUCED POSITIVE SYMPTOM SEVERITY IN PATIENTS WITH SCHIZOPHRENIA AND INFLAMMATION
- Author
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Adith Mohan, Rhoshel K. Lenroot, Thomas W. Weickert, Andrew R. Lloyd, Maryanne O'Donnell, Isabella Jacomb, David Brown, Denis Wakefield, Dennis Liu, Clive Stanton, Julia Lappin, Danielle Weinberg, William S. Brooks, D Pellen, Jochen Kindler, Cynthia Shannon Weickert, and Cherrie Galletly
- Subjects
medicine.medical_specialty ,Poster Session III ,biology ,business.industry ,C-reactive protein ,Symptom severity ,Inflammation ,medicine.disease ,Gastroenterology ,Peripheral ,Psychiatry and Mental health ,Canakinumab ,Schizophrenia ,Internal medicine ,biology.protein ,Medicine ,In patient ,medicine.symptom ,business ,medicine.drug - Abstract
BACKGROUND: Schizophrenia is characterized by positive and negative symptoms and cognitive deficits related to functional disability. Approved treatments targeting small molecule neurotransmitter receptors are limited in their effectiveness and often leave residual symptoms and debilitating side effects. Psychotic symptoms, cognitive deficits, and treatment response are variable in schizophrenia, highlighting heterogeneity in the etiology and presentation of the illness. There is a critical need for novel treatments targeting subgroups related to underlying biology that can be identified by biomarkers. A substantial subgroup (40%) of people with schizophrenia can be distinguished by cytokines in both peripheral blood and in brain. The cytokine interleukin 1-beta (IL-1β) mRNA and protein levels are significantly increased in serum, plasma, white blood cells, cerebrospinal fluid and brain in chronically ill patients and in first episode psychosis. Canakinumab is an approved human anti-IL-1β monoclonal antibody that interferes with the bioactivity of IL-1β and interrupts excessive immune response. However, the extent to which IL-1β blockade by canakinumab can reduce peripheral markers of an overactive immune system (e.g., high sensitivity C-reactive protein: hsCRP) and reduce psychotic symptom severity in schizophrenia is unknown. METHODS: We conducted a randomized, placebo-controlled, double-blind, parallel group trial of the monoclonal antibody canakinumab to block IL-1β in schizophrenia. Twenty-seven chronically ill patients with schizophrenia or schizoaffective disorder who had elevated peripheral inflammation markers (IL-1β, IL-6, hsCRP and/or neutrophil to lymphocyte ratio) at baseline were randomized to a one-time subcutaneous injection of canakinumab (150 mg) or placebo (normal saline) as an adjunctive treatment to antipsychotics. Peripheral hsCRP levels were measured at baseline (prior to injection) and at 1, 4- and 8-weeks post treatment. Positive and Negative Syndrome Scale scores were assessed at baseline and at 4- and 8-weeks post treatment. RESULTS: Separate t-tests comparing canakinumab or placebo at weeks 1, 4, and 8 to baseline showed significant reductions in peripheral hsCRP levels at all time points (all p’s < .02) for canakinumab only. Separate t-tests also showed a significant reduction in positive symptom severity scores at week 8 (p = 0.05) for canakinumab and at week 4 (p = 0.02) for placebo. There was a trend for low peripheral hsCRP levels to be strongly correlated with low positive symptom severity scores (r = .57, p = .07) only at week 8 in the canakinumab group. There were no significant reductions in negative or general psychopathology symptom severity scores in either group. DISCUSSION: Blockade of the cytokine IL-1β by the monoclonal antibody canakinumab significantly reduces peripheral hsCRP serum levels and these reductions may be related to a reduction in positive symptom severity in chronically ill patients with schizophrenia. Importantly, only those patients who initially displayed elevated peripheral markers of inflammation were recruited. The effects of canakinumab on the reduction of peripheral hsCRP is potentially beneficial to general health. The relatively strong relationship between the effects of canakinumab on the biological marker hsCRP and positive symptom severity after 8 weeks of treatment supports the effect of canakinumab on positive symptom severity. Given that treatment with a monoclonal antibody is a novel and substantial advance in the potential treatment of psychotic symptom severity in schizophrenia, future studies should consider increased or top-up doses with longer follow-up to confirm the benefit of adjunctive canakinumab treatment in schizophrenia.
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- 2019
47. Neurocognitive effects of transcranial direct current stimulation (tDCS) in unipolar and bipolar depression: Findings from an international randomized controlled trial
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Adith Mohan, Donel Martin, Cynthia Shannon Weickert, John P. O'Reardon, Colleen Loo, Shawn M. McClintock, Sarah H. Lisanby, Angelo Alonzo, Mustafa M. Husain, William M. McDonald, and Scott Aaronson
- Subjects
medicine.medical_specialty ,Bipolar Disorder ,medicine.medical_treatment ,Prefrontal Cortex ,Audiology ,Verbal learning ,Catechol O-Methyltransferase ,Transcranial Direct Current Stimulation ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Double-Blind Method ,law ,medicine ,Verbal fluency test ,Humans ,Bipolar disorder ,Depressive Disorder, Major ,Transcranial direct-current stimulation ,business.industry ,medicine.disease ,030227 psychiatry ,Psychiatry and Mental health ,Clinical Psychology ,Treatment Outcome ,Major depressive disorder ,Verbal memory ,business ,Neurocognitive ,030217 neurology & neurosurgery - Abstract
OBJECTIVE Transcranial direct current stimulation (tDCS) has been found to have antidepressant effects and may have beneficial neurocognitive effects. However, prior research has produced an unclear understanding of the neurocognitive effects of repeated exposure to tDCS. The study's aim was to determine the neurocognitive effects following tDCS treatment in participants with unipolar or bipolar depression. METHOD The study was a triple-masked, randomized, controlled clinical trial across six international academic medical centers. Participants were randomized to high dose (2.5 mA for 30 min) or low dose (0.034 mA, for 30 min) tDCS for 20 sessions over 4 weeks, followed by an optional 4 weeks of open-label high dose treatment. The tDCS anode was centered over the left dorsolateral prefrontal cortex at F3 (10/20 EEG system) and the cathode over F8. Participants completed clinical and neurocognitive assessments before and after tDCS. Genotype (BDNF Val66Met and catechol-o-methyltransferase [COMT] Val158Met polymorphisms) were explored as potential moderators of neurocognitive effects. RESULTS The study randomized 130 participants. Across the participants, tDCS treatment (high and low dose) resulted in improvements in verbal learning and recall, selective attention, information processing speed, and working memory, which were independent of mood effects. Similar improvements were observed in the subsample of participants with bipolar disorder. There was no observed significant effect of tDCS dose. However, BDNF Val66Met and COMT Val158Met polymorphisms interacted with tDCS dose and affected verbal memory and verbal fluency outcomes, respectively. CONCLUSIONS These findings suggest that tDCS could have positive neurocognitive effects in unipolar and bipolar depression. Thus, tDCS stimulation parameters may interact with interindividual differences in BDNF and COMT polymorphisms to affect neurocognitive outcomes, which warrants further investigation.
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- 2019
48. Temporal proteomic profiling of postnatal human cortical development
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Avi Ma'ayan, Zichen Wang, Sabine Bahn, Michael S. Breen, Maree J. Webster, Nitin Rustogi, Cynthia Shannon Weickert, Michael G. Gottschalk, Jordan M. Ramsey, Joseph D. Buxbaum, Sureyya Ozcan, Breen, Michael S [0000-0002-6739-939X], Wang, Zichen [0000-0002-1415-1286], Ma'ayan, Avi [0000-0002-6904-1017], Weickert, Cynthia Shannon [0000-0002-4560-0259], Buxbaum, Joseph D [0000-0001-8898-8313], Bahn, Sabine [0000-0003-4690-6302], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Adult ,Male ,Proteomics ,Cytoskeleton organization ,Adolescent ,Proteome ,Prefrontal Cortex ,Computational biology ,Biology ,Article ,lcsh:RC321-571 ,Transcriptome ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Young Adult ,0302 clinical medicine ,Transcription (biology) ,medicine ,Humans ,Protein Interaction Maps ,Child ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Biological Psychiatry ,030304 developmental biology ,Gliogenesis ,Postnatal human ,0303 health sciences ,Proteomic Profiling ,RNA ,Infant ,Middle Aged ,Dorsolateral prefrontal cortex ,Postnatal age ,Psychiatry and Mental health ,medicine.anatomical_structure ,030104 developmental biology ,Child, Preschool ,Female ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Healthy cortical development depends on precise regulation of transcription and translation. However, the dynamics of how proteins are expressed, function and interact across postnatal human cortical development remain poorly understood. We surveyed the proteomic landscape of 69 dorsolateral prefrontal cortex samples across seven stages of postnatal life and integrated these data with paired transcriptome data. We detected 911 proteins by liquid chromatography-mass spectrometry, and 83 were significantly associated with postnatal age (FDR p < 0.05). Network analysis identified three modules of co-regulated proteins correlated with age, including two modules with increasing expression involved in gliogenesis and NADH-metabolism and one neurogenesis-related module with decreasing expression throughout development. Integration with paired transcriptome data revealed that these age-related protein modules overlapped with RNA modules and displayed collinear developmental trajectories. Importantly, RNA expression profiles that are dynamically regulated throughout cortical development display tighter correlations with their respective translated protein expression compared to those RNA profiles that are not. Moreover, the correspondence between RNA and protein expression significantly decreases as a function of cortical aging, especially for genes involved in myelination and cytoskeleton organization. Finally, we used this data resource to elucidate the functional impact of genetic risk loci for intellectual disability, converging on gliogenesis, myelination and ATP-metabolism modules in the proteome and transcriptome. We share all data in an interactive, searchable companion website. Collectively, our findings reveal dynamic aspects of protein regulation and provide new insights into brain development, maturation and disease.
- Published
- 2018
49. Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression
- Author
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John Leyden, E. O'Keefe, Cynthia Shannon Weickert, Dusan Hadzi-Pavlovic, Paul Glue, Simon Harper, Philip B. Mitchell, Colleen Loo, R. Lai, Verònica Gálvez, and Andrew A. Somogyi
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Adult ,Male ,Injections, Subcutaneous ,Pilot Projects ,Placebo ,Injections, Intramuscular ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Randomized controlled trial ,law ,medicine ,Humans ,Ketamine ,Adverse effect ,Psychiatric Status Rating Scales ,Depressive Disorder ,Cross-Over Studies ,Dose-Response Relationship, Drug ,business.industry ,Middle Aged ,Psychotomimetic ,Antidepressive Agents ,030227 psychiatry ,Psychiatry and Mental health ,Treatment Outcome ,Anesthesia ,Feasibility Studies ,Midazolam ,Antidepressant ,Administration, Intravenous ,Female ,Nasal administration ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Objective This pilot study assessed the feasibility, efficacy and safety of an individual dose-titration approach, and of the intravenous (IV), intramuscular (IM) and subcutaneous (SC) routes for treating depression with ketamine. Method Fifteen treatment-refractory depressed participants received ketamine or midazolam (control treatment) in a multiple crossover, double-blind study. Ketamine was administered by IV (n = 4), IM (n = 5) or SC (n = 6) injection. Dose titration commenced at 0.1 mg/kg, increasing by 0.1 mg/kg up to 0.5 mg/kg, given in separate treatment sessions separated by ≥1 week, with one placebo control treatment randomly inserted. Mood, psychotomimetic and hemodynamic effects were assessed and plasma ketamine concentrations assayed. Results Twelve participants achieved response and remission criteria, achieved at doses as low as 0.1 mg/kg. All three routes of administration resulted in comparable antidepressant effects. Fewest adverse effects were noted with the SC route. Antidepressant response, adverse effects and ketamine concentrations were dose-related. Conclusion Antidepressant response occurred at a range of doses and at
- Published
- 2016
50. Differential Response to Risperidone in Schizophrenia Patients byKCNH2Genotype and Drug Metabolizer Status
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Vaughan J. Carr, Juliane Heide, Daniel R. Weinberger, Fengyu Zhang, Jamie I. Vandenberg, Kristin L. Bigos, Cynthia Shannon Weickert, Melissa J. Green, and Stefan A. Mann
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Drug ,medicine.medical_specialty ,Risperidone ,business.industry ,media_common.quotation_subject ,medicine.medical_treatment ,Pharmacology ,medicine.disease ,Psychiatry and Mental health ,Schizophrenia ,Dopamine ,medicine ,Paliperidone ,business ,Antipsychotic ,Psychiatry ,5-HT receptor ,Drug metabolism ,medicine.drug ,media_common - Abstract
Objective:Antipsychotic drugs target dopamine and serotonin receptors as well as Kv11.1 potassium channels encoded by KCNH2. Variable patient responses and a wide range of side effects, however, limit their efficacy. Slow metabolizer status and gene variants in KCNH2 associated with increased expression of Kv11.1-3.1, an alternatively spliced isoform of Kv11.1, are correlated with improved responses to antipsychotic medications. Here, the authors test the hypothesis that these effects may be influenced by differential drug binding to Kv11.1 channel isoforms.Method:Drug block of Kv11.1 isoforms was tested in cellular electrophysiology assays. The effects of drug metabolism and KCNH2 genotypes on clinical responses were assessed in patients enrolled in the multicenter Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).Results:Risperidone caused greater in vitro block of the alternatively spliced Kv11.1-3.1 isoform than full-length Kv11.1-1A channels, whereas its metabolite paliperidone and ...
- Published
- 2016
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