Doctor of Medicine and Doctor of Philosophy (MDPhD)
Community Brain Art
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
Neuroimaging and postmortem findings indicate loss and dysfunction of presynaptic terminals contribute to cognitive deterioration and depression in the elderly. However, the molecular mechanisms remain unclear. The contributions of presynaptic cannabinoid receptor 1 (CB1R) and calcium-sensing synaptotagmin- 1 (STG) isoforms to the pathologic burden, cognitive performance, and likelihood of depressive symptoms were investigated in older individuals from a community-based prospective study. Levels of CB1R and STG isoforms were quantified in middle frontal gyrus (n = 308) and hippocampus (n = 294) by immunoblotting. A possible link between CB1R and presynaptic proteins was investigated using coimmunoprecipitation assays and confocal microscopy. The role of calpain activity in cleavage of the 25 kDa synaptosomal-associated protein (SNAP-25) was studied in prefrontal cortical synaptosomes (n = 66). Findings indicated CB1R level was unchanged in both brain regions across pathologically and cognitively diagnosed groups. Linear regression models adjusting for demographics and age-related neuropathologies revealed that prefrontal cortical and hippocampal levels of CB1R were not associated with global cognitive function. Each unit increase of hippocampal CB1R level was associated with a lower likelihood of depressive symptoms. Presynaptic proteins were immunoprecipitated and colocalized with the CB1R. Immunoblotting detected full-length STG (65 kDa) and two fragments (47 kDa and 35 kDa). More severe tau pathology and poorer global cognitive function were associated with lower levels of hippocampal 35 kDa STG but not 65 kDa or 47 kDa STG. Greater amounts of 65 kDa STG only were associated with lower odds of depressive symptoms. No associations between pathology, cognition, or depression were observed for STG in prefrontal cortex. Higher synaptosomal calpain activity was not associated with SNAP-25 cleavage but demonstrated a complex relationship with the odds of clinical dementia. These findings suggest a role for the CB1R in altered presynaptic function in the elderly, isoform-specific effects of STG on cognition and depression in aging, and a possible link between calpain activity and dementia.
People living in marginal or inadequate housing experience increased risk for premature mortality and face accumulating health challenges associated with poverty, substance use, and physical and mental illness. In particular, psychotic disorders, such as schizophrenia or schizoaffective disorder, may be more common. Psychosis, or grossly impaired reality testing, is a key feature of these disorders, but remains poorly understood, due to the heterogeneous course, multifaceted etiology, and complex clinical presentation. As part of a five-year longitudinal study of adults living in urban marginalized housing in Vancouver, Canada, we sought to characterize the consequences, risk factors, and dynamics of psychosis over time. First, we demonstrated that psychotic disorders were a significant risk factor for premature mortality over the study period, beyond other potentially treatable illnesses. Second, through direct clinical interviews each month, we observed a high prevalence of psychosis and psychosis risk factors. Among those without schizophrenia or schizoaffective disorder, the number of days of methamphetamine, powder cocaine, cannabis, or alcohol use predicted dose-related increases in odds of psychosis, without evidence of interaction or reverse causation. Recent trauma, and histories of early-life trauma or brain injury, also had independent effects on psychosis. No relationships with risk factors were demonstrated in the schizophrenia/schizoaffective group. Lastly, we examined how psychosis may evolve over time through the interplay between psychotic symptoms themselves. By assessing symptoms monthly and applying a multilevel dynamic network analytic approach, we disentangled the within-individual temporal dynamics of psychotic symptoms from the stable between-individual differences. Psychotic symptoms fluctuated and were positively reinforcing over time. Delusions had a central role in the symptom network, at both the between-individual and within-individual levels. Delusions were associated with more severe unusual thought content or suspiciousness, but not conceptual disorganization. In the dynamic symptom network, suspiciousness was upstream and hallucinations were downstream in the symptom activation cascade. Dynamic network connectivity was greatest in the group with schizophrenia or schizoaffective disorder. Overall, these studies identify multiple risk factors and psychopathological processes that contribute to the longitudinal characteristics of psychosis and suggest potential targets for intervention and prevention strategies among adults at risk for psychosis.
Schizophrenia (SCZ) is a severe and complex disorder that presents in young adults and evolves to chronicity causing pervasive deterioration in personal, social, and professional functioning. SCZ is better conceptualized as a syndrome as the concrete underlying etiopathological mechanisms have not been identified. Nonetheless, there are reports of subtle abnormal post-mortem findings, moderate brain deficits, and severe neurocognitive impairments. Although the etiology of SCZ is unknown, evidence suggests a strong genetic contribution to the disorder. The apolipoprotein E gene (APOE) codifies for the apoE protein, which is involved in a wide range of functions from cholesterol metabolism to synaptic plasticity. One of the three main allele polymorphisms of APOE, APOE-ε4, is associated with increased risk of Alzheimer’s disease, decreased hippocampal volume, and neuropathological findings. However, data in youth indicates that it may also be associated with cognitive performance or brain development. Samples of post-mortem brain tissue from SCZ patients and healthy controls from Brodmann area 9 were used to quantify the amount of apoE, cholesterol, methylation of the promoter region of reelin, reelin mRNA, apoE receptor 2 (apoER2), and very-low density lipoprotein receptor (VLDLR). In addition, a sample of first-episode psychosis patients and healthy controls was recruited. Subjects underwent neurocognitive testing as well as brain imaging at baseline and 9 to 12 months after. Our data demonstrated higher levels of methylation of the reelin promoter region and decreased expression of apoER2 in SCZ samples, but there were no differences in apoE, cholesterol, reelin or VLDLR. In SCZ data suggested dysregulation of apoE and cholesterol in both grey and white matter. In FEP, there was severe impairment in verbal memory, but APOE-ε4 was associated with improved verbal memory over time in SCZ. APOE-ε4 status, but not memory capacity was associated with smaller hippocampal volume.APOE-ε4 is associated with different phenotypes of opposing effects in SCZ and may be associated with the syndromic expression of the disorder.
Synaptic dysfunction likely contributes to abnormal brain function in schizophrenia. Patient symptoms indicate that the striatum is involved in this disease. The three neuronal soluble-NSF-attachment receptor (SNARE) proteins (SNAP-25, syntaxin-1 and VAMP) interact at the presynaptic neuronal membrane to facilitate neurotransmission, and are thus key players in synaptic function. SNARE abnormalities have already been reported in cortical and hippocampal brain regions in schizophrenia. Their involvement in striatal dysfunction has not been investigated. Normal synaptic function requires the SNAREs to physically interact with each other, but little is known about how altered SNARE protein levels in schizophrenia relate to SNARE protein interactions. Multiple isoforms of each SNARE exist in the brain, may affect SNARE protein interactions and synaptic transmission differently, and may diverge functionally. SNARE isoform expression in schizophrenia is unknown. Thus, abnormalities in SNARE protein expression or function may underlie or contribute to brain dysfunction and disease. In this thesis, SNARE protein levels were measured in human post mortem brain samples of schizophrenia subjects for the first time in the striatum. The functional consequences of SNARE alterations were investigated by developing a novel ELISA assay to measure SNARE protein interactions. The possible confounding effects of medications were addressed in several ways, including the use of striatal tissue from animals exposed to antipsychotic medications. Alterations in SNAP-25 and syntaxin-1 protein levels were further dissected by measuring protein isoforms. Syntaxin-1 isoforms were assayed by quantitative immunoblotting. A mass-spectrometry based assay was developed and used to measure SNAP-25 protein isoform levels. The results of these investigations suggest that SNARE protein alterations in schizophrenia are restricted to distinct functional regions of the striatum, perturb SNARE protein interactions, involve specific protein isoforms, and may occur independent of patient treatment with antipsychotic medications. Furthermore, these studies contribute a new, high-throughput method for measuring SNARE protein interactions, and for the first time, a means of detecting and quantifying SNAP-25 isoforms in brain tissue.