Psychiatry - Theses

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    Striatal morphology, frontostriatal circuits and functional correlates in neurodegenerative disease
    Looi, Jeffrey Chee Leong ( 2017)
    This thesis comprises five major sections, based on research work that I have led via an international network of collaborators that I established. The studies in this thesis are targeted at characterising quantitative measures of the structural integrity of recurrent fronto-striato-pallido-thalamo-cortical neural circuits and the relationship of such measures to clinical manifestations of neurodegenerative disease. Section 1 presents the foundational basis of my conceptualisation of quantitative measurement of human brain neuroanatomical structures (shape and volume – morphology), specifically, the striatum, as a means of developing in vivo biomarkers that correlate to clinical intermediate phenotypic manifestations (endophenotypes) of neurodegenerative disease. I describe here the international collaborative research network I established to conduct the research program embodied in this thesis. Section 2 involves the results of studies of the in vivo morphology of the striatum in neurodegenerative diseases in which neuropathology of the striatum has been implicated, comparing relative differences in striatal morphology between disease groups. In Section 3, I extend the work in Section 2 by examining whether quantitative morphology (morphometry) of the striatum correlates to endophenotypic cognitive, emotional, behavioural and motoric manifestations of the specific neurodegenerative diseases. In Section 4, the theoretical underpinning of the conceptualisation of the thalamus as another target for quantitative morphology and correlation to endophenotype, as well as the development of an innovative quantitative manual measurement method for the thalamus, is described. Through the works in Sections 1-4, I had come to conceptualise a subcortical connectome (Section 5): a quantitative mapping of the hubs and spokes of recurrent neuroanatomical circuits, as well as potentially the spaces between the structures underlying and connecting to the cortex. In Section 5, I also describe the development of a further vision for my collaborative research program. Section 1: The first two chapters describe the theory and hypotheses underpinning my research on the quantitative morphometry (measurement of shape and volume) of fronto-striato-pallido-thalamo-cortical (frontostriatal) circuit hubs in neurodegenerative disease. Chapter 1 describes the conceptual background for the study of striatal morphology, a key hub of frontostriatal circuits, as a potential biomarker in neurodegenerative disease. Chapter 2 extends the striatal morphology biomarker model to the frontotemporal dementias towards establishing potential intermediate phenotypes (endophenotypes). Chapter 3 describes the Australian, US, Scandinavian Imaging Exchange (AUSSIE) research network I established to conduct the research program and to expand our knowledge of the role of the subcortical connectome as a potential biomarker in neurodegenerative disease. Section 2: Chapters 4-7 describe the application of the theory and methods outlined in section 1, initially in differentiating between neurodegenerative disease groups that have striatal morphologic change implicated as part of disease progression. Chapters 3 and 4 describe cross-sectional studies of differential striatal morphometry in frontotemporal dementia subtypes and Alzheimer’s disease (AD). Chapter 5 describes the application of striatal morphometry to progressive supranuclear palsy (PSP), whilst Chapter 6 describes cross-sectional studies of differential striatal morphometry in Huntington’s disease (HD), frontotemporal dementia (FTD) and Alzheimer’s disease. Section 3: Chapters 8-10 describe the extension of the striatal morphometric work to investigate functional correlations of morphology with clinical manifestations of the cognitive, emotional and motor circuits subserved by frontostriatal circuits, i.e. towards establishing an endophenotype. Chapters 7 and 8 describe correlations of striatal morphometry with executive dysfunction and gait disturbance in a cohort of persons with age-related white matter change respectively. Chapter 9 describes correlations of striatal morphometry with measures of behavioural change in frontotemporal dementia. Section 4: Chapters 11-12 describe development of methods for further research into another hub in fronto-striatal circuits (Chapter 10). Chapter 10 describes the characterisation of another crucial hub in frontostriatal circuits, the thalamus, and the rationale for further investigation. Chapter 11 describes the development of a method for manual neuroanatomical measurement of the thalamus for quantification of its shape and volume, i.e. morphology, in neurodegenerative disease. Section 5: Chapter 13 describes the conceptualisation of the overarching concept of the subcortical connectome to direct further research extending to other key subcortical structures and spaces in neurodegenerative disease. This thesis describes the development of quantitative measures of the shape and volume of crucial brain neurocircuit hubs (quantified morphology = morphometry) in human neurodegenerative disease that correlate to clinical cognitive, emotional, behavioural and motoric manifestations of disease aimed towards developing endophenotypes.  
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    Understanding the role of frontotemporal brain structures in schizophrenia through magnetic resonance imaging and neuropathological studies
    Section 1: The first two chapters describe my initial hippocampal volumetric work in patients with first-episode psychosis and chronic schizophrenia that identified hippocampal changes early in the course of psychosis. Chapter 3 explores in detail the theoretical basis for hippocampal involvement in schizophrenia and introduces for the first time the concept that the hippocampal volume changes observed in patients with first episode psychosis and chronic schizophrenia may not be present in patients at high risk of psychosis. Chapters 4 to 6 describe a series of cross sectional studies showing that hippocampal volumes are normal in high risk patients who later develop psychosis (Chapter 4 and 6), normal in patients with schizophreniform psychosis (Chapter 6), reduced on the left side in patients with first-episode schizophrenia (Chapter 6) and bilaterally reduced in patients with chronic schizophrenia (Chapter 6). These findings suggest that right hippocampal volume reduction occurs with increased illness duration, a finding supported by a voxel based morphometry study of patients with chronic schizophrenia (Chapter 5). Finally in contrast to our original findings (Chapter 1) that hippocampal volumes were equally reduced in patients with first-episode schizophrenic and non schizophrenic psychoses, our study of a much larger first-episode cohort (Chapter 6) showed that hippocampal volume reduction was specific to schizophrenic psychoses while amygdala enlargement was specific to non schizophrenic first-episode psychoses. These findings suggested either that (i) patients who make the transition from high-risk to first-episode or first-episode to chronic schizophrenia already have hippocampal changes and/or (ii) that hippocampal volume changes occurred progressively over the course of the illness. Section 2: Chapters 7 and 8 describe follow-up longitudinal imaging studies in a first-episode cohort and a high-risk cohort respectively. We did not identify hippocampal volume change over a two-year period (Chapter 7) but observed whole brain changes over time in first-episode and chronic schizophrenia cohorts. We hypothesised that structural changes may have occurred prior to or over the transition to active psychotic illness. Chapter 8 describes parahippocampal and frontal changes in high-risk patients who developed a psychotic illness and not in those who did not develop a psychotic illness. These findings provided support for the concept that some patients with a psychotic illness exhibit progressive structural brain changes. Section 3: Chapters 1 to 8 describe evidence for the presence of structural brain changes in the hippocampi of patients with schizophrenia. Structural MRI cannot determine the neurobiological correlates of such brain changes i.e what is causing the changes or which elements of brain tissue are involved. The neurobiology of diseases that mimic schizophrenia (‘secondary schizophrenias’) has provided insights into schizophrenia. Chapter 9 describes a previously unrecognised association between young onset frontotemporal dementia and schizophrenia-like psychosis and specific hippocampal pathology in these cases. Chapter 10 describes similar pathological abnormalities in the hippocampus of patients with schizophrenia and bipolar disorder, who had never been suspected of having dementia earlier in life. The identification of clinical and neuropathological associations between FTD and schizophrenia / bipolar disorder is of significant clinical relevance and provide new avenues for research into the underlying neurobiology of major mental disorders. Section 4: The concluding section discusses how the work in this thesis can be understood within the context of neuroimaging work that has emanated from this large dataset and the current schizophrenia literature. The association between schizophrenia and FTD identified in Chapters 9 and 10 is explored further in this final section with reference to the literature and some illustrative case reports.