Psychiatry - Theses
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ItemInflammation in psychosis: Impact on brain structure and symptoms in animal models and humans( 2019)Schizophrenia is a severe neuropsychiatric disorder, arising in adolescence and early adulthood and characterised by hallucinations, delusions, blunted affect and disorganised thought patterns. One of the most enduring features of schizophrenia and psychosis are structural brain deficits, whose pathophysiological mechanism is unknown. Accumulating evidence indicates that inflammation both peripherally and centrally in the form of increased activation of the brain’s immune cells, microglia, may be a potential cause of structural deficits in psychosis. The evidence is multi-faceted ranging from mouse models that demonstrate increased numbers of microglia, to clinical studies of patients with schizophrenia showing increased pro- inflammatory molecules within peripheral blood. However, there are still many questions that remain unanswered, including whether inflammation varies across stages of psychosis, whether it is related to structural brain deficits and symptomatology and how inflammation identified in schizophrenia relates to other candidate pathways implicated in psychosis. In this thesis a multi-disciplinary approach was adopted, considered appropriate to tackling the complexity of these questions. Firstly, to determine whether inflammation was associated with other candidate pathways implicated in psychosis, we conducted an animal study, utilising an mGluR5 KO mouse model of psychosis. Glutamate has been shown to influence neuroinflammation, with cellular studies demonstrating that mGluR5 can regulate microglial numbers and activation. At the time of conducting the study, there were no satisfactory mGluR5 PET ligands that enabled in vivo monitoring within the clinical population. The mGluR5 KO mouse had been shown to display neuropsychiatric endophenotypes related to schizophrenia and thereby offered an alternative approach to gaining further insight into the role of mGluR5 in neuroinflammation and how this may impact symptoms associated with psychosis. Our aim was to determine whether neuroinflammation, in the form of increased microglial numbers and activation was present in the mGluR5 KO mouse model thereby giving further insight as to the potential interaction of the glutamatergic system and in particular, mGluR5, with microglial homeostasis. Secondly, we aimed to determine whether peripheral inflammation was related to brain structure and clinical symptomatology. This was executed by conducting two clinical studies, that examined peripheral pro- and anti-inflammatory cytokines and complement proteins in relation to brain regional thickness and volume measurements. We used a multiplex enzyme linked immune-absorbent assays (ELISA) in serum to quantify peripheral cytokines and complement proteins across various stages of psychosis ranging from those at ultra-high risk of psychosis (UHR), to individuals experiencing their first episode (FEP) and subjects with chronic schizophrenia. We sought to determine whether circulating cytokine and complement protein levels were associated with clinical symptomatology and measurements of thickness and brain volume detected using structural magnetic resonance imaging (MRI). This thesis aimed to investigate: 1) whether mGluR5 KO mice, which demonstrate phenotypic features of schizophrenia displayed neuroinflammation in the form of increased microglial numbers when compared to their wildtype littermates 2) whether there was a relationship between cytokine or complement proteins and structural brain measurements across UHR, FEP and chronic schizophrenia 3) whether peripheral inflammatory markers (cytokine or complement proteins) were increased or decreased across stages of psychosis and examine their relationship with clinical symptoms. We found that mGluR5 KO mice have increased microglial numbers compared to WT. This agreed with our hypothesis that animals lacking mGluR5, would show higher rates of inflammation in the brain, in accordance with an anti-inflammatory effect of increased mGluR5 signalling and the psychotic endophenotype of these mice. Our findings indicate that mGluR5 may affect microglial homeostasis in the context of neurodevelopment and may impact on psychosis related behaviours exhibited by mGluR5 KO mice. Secondly, our clinical studies showed that cytokines and complement proteins were related to several brain structures implicated in psychosis, including the frontal cortex and ventricles. We revealed a positive correlation between several anti-inflammatory cytokines such as IL4 and IL13 and increases in frontal cortical thickness, which was absent in patients with psychosis. Conversely, increases in pro-inflammatory cytokine IL5 were associated with decreases in whole brain volume in FEP individuals. Thirdly, we found that while peripheral cytokines did not differ significantly between patients and controls, complement proteins were elevated in UHR and chronic schizophrenia patients. While there were no associations between cytokine proteins and clinical symptoms, we identified a molecular pattern of increased C4 and decreased C3 protein, which was associated with increases in positive and negative symptoms. Taken together, the work of this thesis suggests that inflammation is present in psychosis both in the brain and peripherally but that this depends on the proteins and stage of illness examined. Moreover, we revealed that complement proteins C3 and C4 were associated with alterations in brain structure across the combined cohort; in the case of cytokines however, the positive association between elevated anti-inflammatory cytokines and increased frontal thickness was not preserved or reversed in patient groups, indicating a potential imbalance of pro- and anti- inflammatory cytokines may influence brain structure in psychosis. Finally, we have shown that peripheral inflammation in the form of cytokine and complement proteins, may influence both brain structure and clinical symptomatology, which provides fertile ground for future longitudinal exploration of neuroinflammation in schizophrenia and psychosis.
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ItemEffects of childhood adversity and glutamatergic polygenic risk score on brain structure and cognition in schizophrenia( 2019)Schizophrenia is a chronic disabling disorder with complex multifactorial aetiology. It is associated with childhood adversity and glutamatergic genes, both of which contribute to brain development and cognition. However, the relationships between these factors are not fully understood and must still be elucidated. This thesis addresses gaps in understanding of this complex link. These findings will be informative for early identification and treatment of those with schizophrenia. Chapter one provides a conceptual framework for the models used in this thesis. A literature review on schizophrenia, childhood adversity, glutamatergic genes, brain development, and cognition is included. The links between these factors are described and the aims of the thesis are justified. Chapter two aimed to identify the association between metabotropic glutamate receptor 3 genetic variation and schizophrenia and explored potential population stratification. This meta-analysis study consisted of 14 single nucleotide polymorphisms of metabotropic glutamate receptor 3 from a total of 11318 schizophrenia cases, 13820 controls, and 486 parent proband trios. We found significant associations for three single nucleotide polymorphisms. We also found evidence for population stratification in that the risk allele was dependent on the population under study. These findings support the genome wide-implicated link between metabotropic glutamate receptor 3 genetic variation and schizophrenia risk, and further support the notion that alleles conferring this risk may be population specific. Chapter three aimed to examine the extent to which the association between childhood adversity and cognition is mediated by structural brain volumes and moderated by glutamatergic polygenic risk score in the context of brain volumes as a mediator. A total of 176 schizophrenia patients and 118 healthy controls participants were assessed for a history of childhood adversity and underwent cognitive testing and structural neuroimaging. Six glutamatergic genes were genotyped, and a weighted glutamatergic polygenic risk score was calculated. Mediation and moderated-mediation models were tested. We found that that there were significant mediation effects of intracranial and total brain volumes on the association between childhood adversity and delayed memory in the overall sample, as well as in the schizophrenia patients. There was also a significant mediation effect of subcortical volume on the association between childhood adversity and working memory in the schizophrenia patients, but not healthy controls. However, there was no significant moderation effect of glutamatergic polygenic risk score on the association between childhood adversity and cognition in the context of brain volume as a mediator. This study demonstrated that childhood adversity exerts a negative impact on intracranial, total brain, and subcortical volumes in schizophrenia. Adversity encountered during childhood may pre-program the brain for subsequent memory performance in adulthood. The effect of glutamatergic polygenic on the association between childhood adversity, brain volume, and cognition in schizophrenia could be related to illness stage or severity. Chapter four aimed to examine interrelationships between childhood adversity, glutamatergic polygenic risk score, frontal lobe volume, and spatial working memory in 51 treatment-resistant schizophrenia patients and 40 healthy controls from the Cooperative Research Centre for Mental Health psychosis study cohort. We found that treatment-resistant schizophrenia patients displayed impairment in spatial working memory between search errors, spatial working memory strategy, and spatial span relative to healthy controls. A significant moderation effect of glutamatergic polygenic risk score was found on the association between childhood adversity and the spatial working memory factor which comprising spatial working memory between search errors, spatial working memory strategy, and spatial span in the treatment-resistant schizophrenia group, but not in the healthy controls. The conditional effects on the association between childhood adversity and spatial working memory indicated that, in the presence of higher childhood adversity, treatment-resistant schizophrenia patients with higher glutamatergic polygenic risk score demonstrated poorer spatial working memory, while those with lower glutamatergic polygenic risk score showed better spatial working memory. Synergistic effects between childhood adversity and glutamatergic polygenic risk score on spatial working memory performance in treatment-resistant schizophrenia patients suggests that lower glutamatergic polygenic risk score may, in part, protect patients from the detrimental effects of childhood adversity on spatial working memory performance, while higher glutamatergic polygenic risk score increases the risk. Chapter five summarises the main findings of each study and highlights the clinical implications and future directions of this critical research area so as to improve mental health for children subjected to adversity.