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ItemEffects of childhood adversity and glutamatergic polygenic risk score on brain structure and cognition in schizophreniaMohamed Saini, Suriati ( 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.
ItemSpecialization and integration in brain networks underlying cognitive control in healthy individuals and patients with schizophreniaHarding, Ian Herbert ( 2013)Cognitive control lies at the foundation of dynamic and adaptive human behaviour. Through the flexible top-down regulation of lower-order processes, cognitive control operations serve to direct the perceptual, motor, and other cognitive resources of the brain in response to ever changing environmental demands and behavioural goals. These abilities, including cognitive interference resolution and working memory operations, rely on a common set of brain regions located within the prefrontal and parietal association cortices, together forming the frontoparietal control network. The component regions of this network are variously responsible for encoding and updating goal and context representations, signalling motivational salience, monitoring action-outcomes, and discriminating amongst ambiguous perceptual information and behavioural contingencies. Meaningful and coherent behaviour is dependent both on information processing within each of these regions (specialization) and the amalgamation of function across the network (integration). Although the frontoparietal control network is well defined and has been widely investigated, little is yet known about how it operates when faced with multiple concurrent control demands, as would be expected in real-world environments. Moreover, the shared and unique nature of connectivity patterns within this common brain network across different cognitive control processes is currently unknown. In schizophrenia patients, dysfunction in cognitive control abilities is endemic and is thought to lie at the core of the significant disability faced by patients suffering from the illness. Current theories variously propose that abnormalities in the integrity and efficiency of neural functioning, as well as in the normal integration of activity within the frontoparietal control network may underlie these deficits. This thesis presents a series of experiments exploring the activation and connectivity patterns defining the frontoparietal network as a function of distinct cognitive control demands. Functional magnetic resonance imaging (fMRI) data was acquired during performance of a novel cognitive paradigm in which cognitive interference and working memory demands were manipulated in a factorial manner. Functional activations and effective connectivity were assessed using statistical parametric mapping (SPM) and dynamic causal modelling (DCM) techniques, respectively. Investigations were first undertaken in a group of healthy adults, and followed thereafter by a characterization of differences evident in a cohort of patients suffering from schizophrenia. Taken together, the frontoparietal system was found to be highly adaptable, widely interconnected, and characterized by both common and unique dynamics in response to different cognitive control demands. These characteristics were generally shared in patients with schizophrenia, although distinct decrements in inter-regional interactions within the prefrontal cortex were observed. The outcomes of this work serve to build upon, and in some cases challenge, current mechanistic models of cognitive functioning and pathophysiological processes, and inform compelling future research directions in the fields of cognitive neuroscience and psychiatry.
ItemMemory decline and Aβ amyloid as markers of neurodegeneration in preclinical Alzheimer's diseaseLim, Yen Ying ( 2013)Alzheimer’s disease (AD) is pathologically characterised by neurofibrillary tangles and beta-amyloid (Aβ) plaques. Clinically, it is characterised by a gradual decline in cognitive function, particularly in episodic memory. Current neuropsychological models emphasise the measurement of cognitive impairment to determine cognitive abnormality. However, as AD is a neurodegenerative disease, it has been suggested that the repeated assessment of cognitive function could provide important information about an individual’s performance over time, particularly as any changes in cognitive function in the very early stages of the disease are likely to be subtle. The overarching aim of this thesis was to investigate the relationship between a known marker of AD, Aβ amyloid, as determined by positron emission tomography (PET) neuroimaging using 11C-Pittsburgh Compound B, and decline in cognitive function as potential markers of neurodegeneration in the preclinical stages of AD. Additionally, the role of genetic polymorphisms in modifying the relationship between Aβ amyloid and cognitive decline were explored. First, the nature and magnitude of Aβ amyloid-related impairment in cognitive function was characterised cross-sectionally in both healthy older adults and adults with mild cognitive impairment (MCI). The data suggested that there were very small differences between healthy older adults with high and low levels of Aβ amyloid. Further, in adults with MCI, high Aβ amyloid was associated with a more focal impairment in episodic memory, but low Aβ amyloid was associated with additional impairments in executive function, attention and language, suggesting the presence of other underlying neurological or psychiatric processes. The relationship between Aβ amyloid and cognitive function in both healthy older adults and adults with MCI became clearer when studied prospectively. High levels of Aβ amyloid were associated with increased rates of cognitive decline, particularly in episodic memory, and this decline occurred at the same rate in both healthy older adults and in adults with MCI. High Aβ amyloid levels were also associated with higher risk of disease progression in both healthy older adults and adults with MCI. Carriage of the apolipoprotein E (APOE) ε4 allele did not moderate this relationship between Aβ amyloid and cognitive decline; although carriage of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism Met allele did. Low levels of Aβ amyloid were associated with stable cognitive function in both healthy older adults and adults with MCI, lending strength to the hypothesis that the underlying pathological process in adults with MCI and low Aβ amyloid is non-AD in nature. These findings have important implications for future clinical trials in AD as the data strongly suggest that healthy older adults with high levels of Aβ amyloid and objectively defined decline in memory are in the preclinical stages of AD, and are promising candidates for anti-amyloid therapies aimed at halting or modifying the neurodegenerative disease process in the early stages of the disease.
ItemCognitive impairment and vitamin B12Moore, Eileen Mary ( 2013)Vitamin B12 is an essential enzyme co-factor that is required for neuronal health. Vitamin B12 participates in two reactions in man, specifically; (i) the regeneration of methionine from homocysteine (Hcy), which supports cellular methylation reactions, and (ii) the re-arrangement of methylmalonic acid (MMA) to succinyl-CoA for metabolising odd-numbered fatty acids. Hcy and MMA levels are elevated in vitamin B12 deficiency (serum vitamin B12 levels <150ρmol/L). Elevated Hcy (serum level >12µmol/L) is a risk factor for cardiovascular disease (CVD) and Alzheimer’s disease (AD). Elevated MMA has been associated with a faster rate of brain volume loss and cognitive impairment. The prevalence of vitamin B12 deficiency increases in older age, and is associated with gastritis, achlorhydria, pernicious anaemia, terminal ileal resection, and use of medications that interfere with absorption. International studies have reported that deficiency amongst older adults is common; and, in over-50 year olds the prevalence is between 6.1% and 24.6%. A recent survey of over-50 year olds in Australia reported that vitamin B12 deficiency and subclinical low-normal levels (~150-250ρmol/L) were 6.3% and 29.0%, respectively. I studied vitamin B12 levels in 1,085 men and 1,125 women aged 20 to 97 years, of whom 176 (8.0%) were on vitamin B12 supplements. The age-adjusted prevalence of vitamin B12 deficiency was 3.6% amongst those who were not on vitamin B12 supplements. The prevalence of vitamin B12 deficiency rose to 5.2% in over-50 year olds, and 8.5% in over-65 year olds. The age-adjusted prevalence of subclinical low-normal vitamin B12 levels was 25.8% amongst those who were not on vitamin B12 supplements. The prevalence of subclinical low-normal vitamin B12 levels was 27.5% in over-50 year olds, and 28.7% in over-65 year olds. Vitamin B12 levels below 250ρmol/L are therefore common in a random sample of the Australian population and this is therefore likely to be the case with the population as a whole. The next objective of this study was therefore to investigate any association between serum vitamin B12 levels and neurological health. In the literature, vitamin B12 deficiency is associated with cognitive impairment. Also, subclinical low-normal serum vitamin B12 levels are reported to be associated with AD, vascular dementia, and Parkinson’s disease. In clinical trials, vitamin B12 therapy improved cognition in those who were already deficient. The lower limit of the reference range for serum vitamin B12 was originally statistically derived from a random sample of the haematologically normal adult population. The level chosen (~150ρmol/L) may not be adequate for maintaining neuronal health in later life, as AD, Parkinson’s disease, and vascular dementia have each been associated with serum vitamin B12 levels in the subclinical low-normal range. This study included 1,354 participants who had cognitive performance assessed within six months of having blood tests for serum vitamin B12 and red cell folate (RCF). Participants were recruited from four sources, namely; (i) the Prospective Research in Memory (PRIME) clinics study, (ii) the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing, (iii) patients who attended a geriatric specialist clinic in the Barwon region, or (iv) who were a patient of the Cognitive, Dementia and Memory Services (CDAMS) of the McKellar Centre between 2001 and 2011. The study group included 480 AD patients, 187 participants with mild cognitive impairment (MCI), 372 cognitively-intact participants with memory complaints, and 315 cognitively-intact participants without memory complaints. Cognitive performance was assessed by the Mini-Mental State Examination (MMSE). Participant’s cognitive performance was rated in one of four categories, namely; (i) most-impaired (MMSE <18, n=137), (ii) mildly-impaired (MMSE 18-23, n=240), (iii) minimally-impaired (MMSE 24-28, n=295), and (iv) not-impaired (MMSE >28, n=682). Annualised change in MMSE scores (ACMS) was calculated arithmetically for a sub-group of 1,307 participants who had at least two MMSE measurements taken at least six months apart. Four categories for the rate of cognitive decline were formed; (i) fast-decliners (ACMS <-3, n=119), (ii) moderate-decliners (ACMS <-1 to -3, n=233), (iii) slow-decliners (ACMS <0 to -1, n=197), and (iv) stable or improving (ACMS ≥ 0, n=758). In this study, models that were formed met the model assumptions of ordinal logistic regression (OLR). Serum vitamin B12 levels above 253ρmol/L were associated with better cognitive performance (odds ratio 1.63, 95% CI: 1.01-2.65, p-value 0.046). Very high RCF levels (>1,594nmol/L) were associated with a worse cognitive performance (odds ratio 0.57, 95% CI: 0.35-0.92, p-value 0.022). Also, each micromole per litre (µmol/L) increase in serum Hcy level was associated with a 5% increased likelihood of having a worse cognitive performance (odds ratio 0.95, 95% CI: 0.90-1.00, p-value 0.034). Serum Hcy levels >7.7µmol/L were associated with a faster rate of cognitive decline (odds ratio 0.48, 95% CI: 0.24-0.95, p-value 0.034). My findings indicate that better neurological health in later life is associated with serum vitamin B12 levels >253ρmol/L, RCF <1,594nmol/L, and serum Hcy <8.0µmol/L. Consideration should be given to revising the current reference ranges for these biochemical markers. The databases also allowed me to study the effects of other supplements. Calcium regulates neurotransmitter secretion at the synapse between neurons, so being on calcium supplements could be beneficial to cognition. Omega-3 fish oil is comprised of fatty acids that are a component of the lipid membranes in the brain. Supplementing omega-3 fatty acid levels may aid in the correct formation and repair of neuronal structures. In this study, better cognitive performance was associated with being on calcium supplements (odds ratio 1.90, 95% CI: 1.51-2.40, p-value <0.001) or omega-3 supplements (odds ratio 1.74, 95% CI: 1.26-2.41, p-value 0.001). Cognitive performance was not associated with being on vitamin E, diuretics, or proton pump inhibitors (PPI), or with having CVD, hypertension, anxiety, fractures, diverticular disease, gastro-oesophageal reflux disease (GORD), or resection of the distal ileum. A prospective, well-resourced, and sufficiently-powered intervention trial would provide further evidence for the need to revise the current reference ranges for serum vitamin B12, and to prove the efficacy of calcium and omega-3 supplements for improving cognition in later life. The rate of conversion to AD in the normal population is around 1-2%, therefore such a trial would need to recruit very large numbers (>1000) to show prevention. The latent period of effect of vitamin B12 on cognition is currently unknown. It is possible that, to be effective in preventing cognitive decline, intervention would need to commence early, in 50-60 year olds, and continue for years longer than has been studied previously. Previous studies have reported that patients with diabetes are at a greater risk for AD. In this study, cognitive performance was worse in 126 participants with diabetes compared to those without diabetes. An objective of this study was to assess whether being on metformin, or the levels of serum vitamin B12, and RCF, were associated with cognition in participants with diabetes. Metformin improves sensitivity to insulin, so is prescribed as a first line monotherapy for treating type II diabetes. In cell culture, metformin induces over-secretion of Aβ peptides, which form amyloid plaques that are in the brains of people with AD at autopsy. Also, metformin use induces vitamin B12 deficiency in up to 30% of its users via a drug interaction at the distal ileum that impedes absorption. In the literature, vitamin B12 and calcium supplements have been shown to reverse vitamin B12 deficiency induced by metformin. Better cognitive performance in participants with diabetes was associated with increasing vitamin B12 levels (p-value 0.043), decreasing RCF levels (p-value 0.025), and being on vitamin B12 supplements (odds ratio 3.40, 95% CI: 1.01-11.46, p-value 0.048). Participants with diabetes who were on calcium supplements showed a trend towards better cognitive performance, but the association did not reach significance (odds ratio 2.12, 95% CI: 0.98-4.58, p-value 0.056). Participants with diabetes who were on metformin had a worse cognitive performance than participants with diabetes who were not on metformin (odds ratio 0.45, 95% CI: 0.21-0.95, p-value 0.037). My findings indicate that worse cognition in patients with diabetes is associated with having a low serum vitamin B12 level or being on metformin. Vitamin B12 and calcium supplements are inexpensive, safe and effective; so should be considered for routine and adjunct therapy for improving the cognitive outcomes of patients with diabetes. Vitamin B12 deficiency is common; also subclinical low-normal vitamin B12 levels affect over one-quarter of adults, but are associated with cognitive impairment and a faster rate of cognitive decline. Patients with diabetes are a group with worse cognitive impairment; those on metformin may be in particular need of supplements.