Rozprawy doktorskie na temat „Psychotic disease”

Psychiatry stands at a pivotal point of development. With the advent of brain imaging modalities, descriptive diagnostic criteria have been called into question. Psychotic disorders, historically dichotomized into “schizophrenia” and “bipolar disorder,” and the intermediate “schizoaffective disorder,” have been shown to overlap in clinical symptomatology, familial inheritance, and genetic association studies. Scientific investigation of disease pathogenesis provides an opportunity to develop biological diagnostic criteria from the ground upwards – correlating anatomy, pathophysiology, genetics, and symptomatology. In this context, structural MRI studies have the capacity to shed light on structural abnormalities underlying psychotic disorders (schizophrenia, schizoaffective disorder, and psychotic bipolar disorder) and contribute to the development of a comprehensive mechanistic model of disease. Neuropathological and in vivo neuroimaging studies have identified the temporal lobe as a key area of alteration in schizophrenia, but large-scale studies examining the hippocampal volumes of patients across the psychotic spectrum have not yet been performed. Further, until recently, the manual labor and error involved in parcellating hippocampal subfield volumes made the task unfeasible. New automatic parcellation techniques enable the analysis of hippocampal subfield volumes among patients with schizophrenia, schizoaffective disorder, and bipolar disorder. The objectives of our study were to: (1) investigate using magnetic resonance imaging hippocampal volume in addition to entorhinal cortex volume, parahippocampal gyrus volume, and hippocampal subfield volumes in patients with schizophrenia, schizoaffective disorder, and bipolar disorder; and, to (2) correlate volumetric alterations with clinical metrics of psychosis and cognition. We utilized a case-control cross- sectional design to collect data from patients with schizophrenia (n=219), patients with schizoaffective disorder (n=142), patients with psychotic bipolar disorder (n=188), and healthy controls (n=337). Freesurfer image analysis software was utilized to automatically parcellate and quantify hippocampal, hippocampal subfield, entorhinal cortex, and parahippocampal gyrus volumes. Clinical ratings and neuropsychological tests were administered as well to assess positive symptoms and cognition. Bilateral hippocampal volume alterations were noted among patients with all three psychotic disorders, while alterations in the surrounding medial temporal lobe regions were noted only in schizoaffective disorder and schizophrenia, but not in patients with bipolar disorder. While widespread hippocampal subfield volume alterations were noted in schizophrenia and schizoaffective disorder, only the cornu ammonis 2/3, dentate gyrus, and subicular regions were noted to be altered across all three psychotic disorders. The most prominent alterations were noted in the cornu ammonis 2/3. Hippocampal volumes were negatively correlated with psychosis and positively correlated with measures of declarative memory. Findings suggest that alterations in the hippocampus are present across psychotic disorders and may contribute to the pathogenesis of psychosis. In particular, alterations in the cornu ammonis, an area which supports memory pattern completion, and in the dentate gyrus, an area which supports memory separation may play a role in the pathophysiology of psychosis.

Delusions in AD have been poorly investigated and research focusing on identifying the neurobiological substrates of delusions in degenerative dementia has shown lack of consistent findings among studies. By using a cognitive and neuroimaging approach, we studied content specific delusions in AD with the aim to identify their neurological and cognitive correlates. Our data indicate that delusions in AD may be associated with areas of hypoperfusion in the right anterior hemisphere. Further, by selecting AD patients presenting delusions of similar content we have demonstrated that the locus of the brain dysfunction is crucial in determining the content of the delusion. Different delusions result from discrete foci of dysfunction within the right hemisphere. A substantial part of this project focused on a detailed study of a new form of delusion that we have termed autobiographical delusions. Findings showed that this form of delusion results from discrete dysfunction in the right frontal lobe. The patients with autobiographical delusions appear to share also a similar neuropsychological profile. When compared with patients not showing delusions, a difference in performance was detected in episodic memory and executive function tests.

Background: Psychotic symptoms occur in approximately 40% of patients with Alzheimer's disease (AD) and have been linked with striatal dopamine (D2/3) receptor function. The first component of the thesis aims to investigate the neuropsychological profile accompanying psychotic symptoms in AD, and establish whether cognitive and motor tasks which have a documented association with dopaminergic function might be markers of psychotic symptoms and delusional subtypes in AD. Dopamine D2/3 receptor occupancy studies have been instrumental in guiding antipsychotic prescribing in schizophrenia. The second part of the thesis aims to adapt [18F]fallypride imaging for use in healthy older people and in dopamine (D2/3) receptor occupancy studies in AD. Methods: Neuropsychology: 70 AD subjects aged between 65 and 95 years were categorised into psychotic (n=34) and non-psychotic (n=36) groups, based on carer-rated scales, and then compared using a hypothesis-driven test battery. Imaging: Eight healthy older (>65 years) adults were scanned twice, 4-6 weeks apart. [18F]fallypride binding potential (BPND) was determined and test-retest variability and intraclass correlation coefficient (ICC) values were calculated. A further six subjects with AD were recruited prior to commencing amisulpride treatment. [18F]fallypride BPND pre/post 2-8 weeks of amisulpride treatment and D2/3 occupancy was measured. Results: Neuropsychology: Subjects with psychotic symptoms, in particular misidentification phenomena, had significantly poorer sustained attentional and visuoperceptual function. Imaging: The adapted [18F]fallypride scanning protocol showed high reproducibility and reliability in all but the prefrontal regions and was generally well tolerated in AD subjects. Conclusion: Neuropsychology: Sustained attention deficits may act as a marker of psychotic symptoms in AD due to associations with dopaminergic function in the associative striatum. Visuoperceptual deficits may indicate additional pathology in the ventral visual stream, which could characterize the misidentification subgroup. Imaging: The feasibility of an adapted scanning protocol was demonstrated in AD subjects and represents the first step towards defining a 'therapeutic window' of D2/3 occupancy to guide antipsychotic prescribing in AD.

Bakgrund: Patienter med psykossjukdom lider ofta av somatisk ohälsa som uttrycker sig i metabolt syndrom. Dåliga levnadsvanor som till exempel dålig kosthållning, inaktivitet, droger etcetera, samt den nödvändiga läkemedelsbehandling är faktorer som bidrar till utvecklandet av metabolt syndrom. Dessa faktorer leder till att denna patientgrupp riskerar att dö upp till 25 år tidigare än den övriga populationen. Syfte: Syftet med studien var att belysa preventiva och lindrande omvårdnadsinterventioner mot metabolt syndrom hos personer som behandlas för psykossjukdomar. Metod: Studien är utformad och genomförd som en allmän litteraturstudie med systematisk ansats. Databassökningen utfördes i Cinahl, Pubmed, Scopus, Psycinfo och Psycarticle. Artiklarna kvalitetsgranskades utifrån Linköpings universitets granskningsmallar och kvalitetsbedömdes utifrån författarnas kvalitetskrav. Resultat: Resultatet bildade tre kategorier; Levnadsvanor, Socialt stöd och Prevention, vilka står i beroende till varandra. Patienternas levnadsvanor är det huvudsakliga fyndet för att lindra och förhindra metabolt syndrom, men för att kunna genomföra livsstilsinterventioner hos patienter med psykos behövs socialt stöd och information. Dessa faktorer utgör även grunden för det preventiva arbetet för att förhindra metabolt syndrom innan det utvecklats. Konklusion: Sammanfattningsvis kan sägas att de preventiva och lindrande åtgärderna mot metabolt syndrom för personer som behandlas för psykossjukdom är att stödja och uppmuntra patienten till en hälsosammare livsstil, innefattande ökad fysisk aktivitet och förbättrad kosthållning. Det åligger även sjuksköterskans arbetsuppgift att individanpassa vården och skapa en personcentrerad vård, skräddarsydd för den enskilde patientens förmågor och behov. Nyckelord: Psykossjukdom, Metabolt syndrom, Omvårdnad, Sjuksköterska.
Background: Patient with psychosis often suffer from somatic illness that is expressed as metabolic syndrome. Bad living habits such as bad diet, inactivity, drugs etcetera is factors that contribute to the development of metabolic syndrome. Also, the necessary drug treatment is important for the development of metabolic syndrome. These factors sets the patient group in a risk to die up to 25 years earlier than the average population. Aim: The purpose of the study was to highlight preventive and mitigating nursing interventions against metabolic syndrome in people treated for psychiatric diseases. Method: This study was designed and implemented as a general literature study with a systematic approach. The database research was performed in Cinahl, Pubmed, Scopus, Psycinfo and Psycarticle. The articles was quality-reviewed by Linköpings University’s review-templates and was quality assessed by the authors quality requirement. Result: The result formed three categories; Lifestyles, Social support and Prevention, which depend on each other. Patients' living habits are the main finding for relieving and preventing metabolic syndrome, but in order to be able to implement lifestyle interventions in patients with psychosis, social support and information are needed. These factors also form the basis for preventive work to prevent metabolic syndrome before it develops. Conclusion: In summary, it can be said that the preventative and alleviate measures against metabolic syndrome for people treated for psychiatric disease are to support and encourage the patient to a healthier lifestyle, including increased physical activity and improved diet. It is also the duty of the nurse to personalize care and create a person-centered care tailored to the individual's abilities and needs. Keywords: Psychotic Disease, Metabolic Syndrome, Nursing, Nurse.

Evidence from various sources suggests that schizophrenia may result from altered brain development. The adult olfactory epithelium provides an available 'window' on neuronal development because new neurons are formed there throughout life. This thesis set out to test the neurodevelopmental hypothesis of psychotic disease. Two cell-based models, skin fibroblast and olfactory mucosa culture, were employed to investigate this hypothesis. In order to first demonstrate the utility of olfactory mucosa culture as a model of neurodevelopment, and to allow the candidate to gain proficiency in the culture of this tissue, an investigation of the mitogenic and differentiating properties of insulin-like growth factor-I within this system was undertaken. Insulin-like growth factor-I has multiple effects within the developing nervous system but its role in neurogenesis in the adult nervous system is less clear. The adult olfactory mucosa is a site of continuing neurogenesis that expresses insulin-like growth factor-I, its receptor, and its binding proteins. The action of insulin-like growth factor-I was assayed in several serum-free culture systems combined with bromodeoxyuridine labelling of proliferating cells and immunochemistry for specific cell types. Once proficiency in olfactory mucosa culture was gained, this model was applied to biopsied olfactory mucosa from schizophrenia and bipolar disorder patients in order to test the developmental parameters of adhesion, cell proliferation, and cell death in a neural tissue. It was previously shown that olfactory cultures from individuals with schizophrenia had increased cell proliferation and attached less frequently than cultures from healthy controls suggesting disrupted neurogenesis. An aim of this study was to replicate those observations in individuals with schizophrenia and and extend them to individuals with bipolar disorder. After completion of the cell and tissue culture assays, microarray analysis of these cell-based models was used to reveal gene expression differences present between patients and healthy controls. Microarray analysis is a complicated technique and the limited amounts of RNA that can be extracted from a single nasal biopsy further compounds this issue. In order to obtain enough material for microarray hybridization RNA samples underwent antisense amplification. Therefore, with the aim of allowing the candidate to gain proficiency in both these techniques prior to microarray analysis of olfactory biopsies from patients with schizophrenia and bipolar disorder, a pilot microarray study of cultured skin fibroblasts from schizophrenia patients and healthy controls was performed. The present findings show that insulin-like growth factor-I and its receptor were expressed by globose basal cells (the neuronal precursor), by neurons and by olfactory ensheathing cells, the special glia of the olfactory nerve. Insulin-like growth factor-I reduced the numbers of proliferating neuronal precursors, induced their differentiation into neurons, and promoted morphological differentiation of neurons. In contrast, this growth factor was mitogenic for olfactory ensheathing cells. The evidence suggests that insulin-like growth factor-I is an autocrine/paracrine signal that induces neuronal precursors to differentiate into olfactory sensory neurons and induces olfactory ensheathing cells to proliferate and that olfactory mucosa culture is valuable in modelling neurodevelopmental processes. When the olfactory musoca culture model was applied to patients with psychosis, a two-fold increase in proliferation of neural cells was found in schizophrenia compared to controls and bipolars. In bipolar cultures there was a 3-fold increase in cell death compared to controls and schizophrenia. Microarray analysis of cultured skin fibroblasts revealed differential expression of over 1000 genes between patients and controls. Inspection of the significant data showed alterations to gene expression between groups in the cell cycle, oxidative phosphorylation, TCA cycle and oxidative stress pathways. Gene expression in each of these pathways was predominately decreased in schizophrenia. Quantitative PCR analysis of selected differentially expressed genes involved with cell cycle regulation validated the increased expression of vitamin D receptor, and decreased expression of proliferating cell nuclear antigen and DEAD (Asp-GIu-Ala-Asp) box polypeptide 5 in skin fibroblasts from patients with schizophrenia. Microarray analysis of biopsied olfactory mucosa showed 146 and 139 differentially expressed genes in schizophrenia and bipolar disorder respectively, compared to controls. Consistent with increased mitosis in schizophrenia biopsy cultures three genes that function to positively influence cell cycle had increased expression. In the bipolar disorder group a dysregulation of the phosphatidylinositolsignalling pathway was seen; five genes that either directly function within or interact with this pathway had decreased expression. There is speculation that the therapeutic effect of psychotropic drugs acting upon this pathway in bipolar disorder involves reduction of neuronal cell death. Increased mitosis of neural cells has now been observed in two separate groups of schizophrenic patients indicating a robust finding. The use of fibroblast and olfactory mucosal tissue can be used to study biological and genetic aspects of neurodevelopment in living humans both with and without psychotic disease. Biopsied olfactory mucosa provides benefits over the use of autopsied material for study of psychotic disease because post-mortem duration and agonal factors that lead to tissue, protein and nucleic acid degradation are not an issue. This study provides evidence for a neurodevelopmental aetiology of schizophrenia and bipolar disorder acting at the level of cell cycle control. Subtle changes in the timing of cell cycle regulation could account for the brain pathologies observed in these diseases. Olfactory mucosa culture is a valuable model of neurodevelopmental processes.

Evidence from various sources suggests that schizophrenia may result from altered brain development. The adult olfactory epithelium provides an available 'window' on neuronal development because new neurons are formed there throughout life. This thesis set out to test the neurodevelopmental hypothesis of psychotic disease. Two cell-based models, skin fibroblast and olfactory mucosa culture, were employed to investigate this hypothesis. In order to first demonstrate the utility of olfactory mucosa culture as a model of neurodevelopment, and to allow the candidate to gain proficiency in the culture of this tissue, an investigation of the mitogenic and differentiating properties of insulin-like growth factor-I within this system was undertaken. Insulin-like growth factor-I has multiple effects within the developing nervous system but its role in neurogenesis in the adult nervous system is less clear. The adult olfactory mucosa is a site of continuing neurogenesis that expresses insulin-like growth factor-I, its receptor, and its binding proteins. The action of insulin-like growth factor-I was assayed in several serum-free culture systems combined with bromodeoxyuridine labelling of proliferating cells and immunochemistry for specific cell types. Once proficiency in olfactory mucosa culture was gained, this model was applied to biopsied olfactory mucosa from schizophrenia and bipolar disorder patients in order to test the developmental parameters of adhesion, cell proliferation, and cell death in a neural tissue. It was previously shown that olfactory cultures from individuals with schizophrenia had increased cell proliferation and attached less frequently than cultures from healthy controls suggesting disrupted neurogenesis. An aim of this study was to replicate those observations in individuals with schizophrenia and and extend them to individuals with bipolar disorder. After completion of the cell and tissue culture assays, microarray analysis of these cell-based models was used to reveal gene expression differences present between patients and healthy controls. Microarray analysis is a complicated technique and the limited amounts of RNA that can be extracted from a single nasal biopsy further compounds this issue. In order to obtain enough material for microarray hybridization RNA samples underwent antisense amplification. Therefore, with the aim of allowing the candidate to gain proficiency in both these techniques prior to microarray analysis of olfactory biopsies from patients with schizophrenia and bipolar disorder, a pilot microarray study of cultured skin fibroblasts from schizophrenia patients and healthy controls was performed. The present findings show that insulin-like growth factor-I and its receptor were expressed by globose basal cells (the neuronal precursor), by neurons and by olfactory ensheathing cells, the special glia of the olfactory nerve. Insulin-like growth factor-I reduced the numbers of proliferating neuronal precursors, induced their differentiation into neurons, and promoted morphological differentiation of neurons. In contrast, this growth factor was mitogenic for olfactory ensheathing cells. The evidence suggests that insulin-like growth factor-I is an autocrine/paracrine signal that induces neuronal precursors to differentiate into olfactory sensory neurons and induces olfactory ensheathing cells to proliferate and that olfactory mucosa culture is valuable in modelling neurodevelopmental processes. When the olfactory musoca culture model was applied to patients with psychosis, a two-fold increase in proliferation of neural cells was found in schizophrenia compared to controls and bipolars. In bipolar cultures there was a 3-fold increase in cell death compared to controls and schizophrenia. Microarray analysis of cultured skin fibroblasts revealed differential expression of over 1000 genes between patients and controls. Inspection of the significant data showed alterations to gene expression between groups in the cell cycle, oxidative phosphorylation, TCA cycle and oxidative stress pathways. Gene expression in each of these pathways was predominately decreased in schizophrenia. Quantitative PCR analysis of selected differentially expressed genes involved with cell cycle regulation validated the increased expression of vitamin D receptor, and decreased expression of proliferating cell nuclear antigen and DEAD (Asp-GIu-Ala-Asp) box polypeptide 5 in skin fibroblasts from patients with schizophrenia. Microarray analysis of biopsied olfactory mucosa showed 146 and 139 differentially expressed genes in schizophrenia and bipolar disorder respectively, compared to controls. Consistent with increased mitosis in schizophrenia biopsy cultures three genes that function to positively influence cell cycle had increased expression. In the bipolar disorder group a dysregulation of the phosphatidylinositolsignalling pathway was seen; five genes that either directly function within or interact with this pathway had decreased expression. There is speculation that the therapeutic effect of psychotropic drugs acting upon this pathway in bipolar disorder involves reduction of neuronal cell death. Increased mitosis of neural cells has now been observed in two separate groups of schizophrenic patients indicating a robust finding. The use of fibroblast and olfactory mucosal tissue can be used to study biological and genetic aspects of neurodevelopment in living humans both with and without psychotic disease. Biopsied olfactory mucosa provides benefits over the use of autopsied material for study of psychotic disease because post-mortem duration and agonal factors that lead to tissue, protein and nucleic acid degradation are not an issue. This study provides evidence for a neurodevelopmental aetiology of schizophrenia and bipolar disorder acting at the level of cell cycle control. Subtle changes in the timing of cell cycle regulation could account for the brain pathologies observed in these diseases. Olfactory mucosa culture is a valuable model of neurodevelopmental processes.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Biomedical Sciences
Full Text

Background: There is earlier research in the field of recovery and from a patient perspective. However, it is relatively unexplored if you look within the specific group of patients who suffers from a psychotic disease, and in a context of what support the patient desire from the nurse in the open psychiatric care unit. Aim: To describe what type of support patient with psychotic disease would like from the nurse, in the open psychiatric care unit. Method: The study´s methodology is qualitative and inductive. The study is built on five interviews from patients in a psychiatric open care unit who suffers from psychotic diseases. The interviews have been analysed based on qualitative content analysis. Result: The result indicates that the patients express a desire that the nurse supports them in four areas to focus on health, to get support with its problems, to be able to tell and someone listens and through time given, be able to get to know the nurse, which is the foundation of comfort and stability. Conclusion: The result responds to the purpose of the study, and the result also reveals that it's a difference in what support´s requested between de two groups of patients, one with the severe mental illness and the other who´s studied -patients who suffers from psychotic disease. The conclusion is made by compare the earlier research with the result from this study.
Bakgrund: Det finns tidigare forskning inom området återhämtning och ur ett patientperspektiv. Det är däremot relativt outforskat om fokus riktas mot gruppen psykossjuka och i en kontext av vad de önskar för stöd av just sjuksköterskan inom ramen för den öppna psykiatrin. Syfte: Att beskriva vad patienter med psykossjukdom i den psykiatriska öppenvården önskar för stöd av sjuksköterskan i sin återhämtning. Metod: Studie bygger på fem intervjuade patienter som har kontakt med ett psykiatriskt öppenvårdsteam specialiserat på psykossjukdomar. Studien genomfördes med en induktiv ansats. Insamlade data analyserades utifrån kvalitativ innehållsanalys. Resultat: Det framkommer att patienterna uttrycker en önskan om att sjuksköterskan ger stöd inom fyra huvudområden; att ha fokus på det friska, att få stöd med sina problem, att få berätta för någon som vill lyssna och att få tid att lära känna sjuksköterskan är grunden till en trygg och god relation. Slutsatser: Resultatet svarar på studiens syfte, utifrån resultatet i förhållande till tidigare forskning kan också slutsatsen dras att det är skillnad i vilket stöd som efterfrågas mellan gruppen ”svårt psykiskt sjuka”, som bakgrunden i huvudsak utgörs av, mot gruppen av psykossjuka personer.

The metabolic syndrome is a constellation of vascular risk factors including abdominal obesity, hypertension, diabetes, hypertriglyceridaemia and low high density lipoprotein cholesterol. The aim of the study was to explore the link between the metabolic syndrome and its components, and psychosis in Alzheimer’s disease. The participants were selected from the Human Serum Metabolome Project. 246 participants with Alzheimer’s disease were assessed at baseline and 151 were followed up a year later. The neuropsychiatric inventory was used to capture information about psychiatric symptoms including delusions and hallucinations. The vascular risk factors were determined from the history from the participant and carer; abdominal obesity however was measured during the study. Hypertriglyceridaemia and high density lipoprotein cholesterol data were unavailable and so the study focuses on the link between the metabolic syndrome components of obesity, hypertension and diabetes, and psychosis in Alzheimer’s disease. Although not part of the metabolic syndrome criteria, a history of hypercholesterolaemia was used in conjunction with the available metabolic syndrome components and the link between the resulting vascular syndrome and psychosis in Alzheimer’s disease was studied. Two measure of psychosis were used for the research. First of all, a factor representing psychosis was derived by factor analysis of the neuropsychiatric inventory data. Secondly, a direct measure of psychosis using the delusions and hallucinations items from the neuropsychiatric inventory was used. Cross-sectional and longitudinal analyses were conducted. The majority of the analyses conducted failed to find a significant link between the measures. Male sex, a lower Mini Mental State Examination score as well as the use of antipsychotics and memantine were found to be significantly associated with psychosis at baseline. Overall this study does not support the link between the metabolic syndrome or its components and psychosis in Alzheimer’s disease. Future research looking at subsets of Alzheimer’s patients with more clearly defined lipid triglyceride and high density lipoprotein cholesterol data will be useful.

The development of predictive biomarkers in neuroscience is increasingly enabling bioprediction of adverse behavioural events, from psychosis to impulsive violent reaction. Because many brain-based disorders can be thought of as end-states of a long development, bioprediction carries immense therapeutic potential. In this thesis, I analyse issues raised by the development of bioprediction of brain-based disorder. I argue that ethical analysis of probabilities and risk information bioprediction provides is confounded by philosophical and social structures that have, until recently, functioned nominally well by assuming categorical (binary) concepts of disorder, especially regarding brain-disorder. Through an analysis of the philosophical concept of disorder, I argue that we can and ought to reorient disorder around probability of future harm and stratify disorder based on the magnitude of risk. Rejection of binary concepts in favour of this non-binary (probability-based) one enables synergy with bioprediction and circumnavigation of ethical concerns raised about proposed disorders of risk in psychiatry and neurology; I specifically consider psychosis and dementia risk. I then show how probabilistic thinking enables consideration of the implications of bioprediction for two areas salient in mental health: moral responsibility and justice. Using the example of epilepsy and driving as a model of obligations to protect others against risk of harm, I discuss how the development of bioprediction is poised to enhance moral responsibility. I then engage with legal cases and science surrounding a predictive biomarker of impulsive violent reaction to propose that bioprediction can sometimes rightly diminish responsibility. Finally, I show the relevance of bioprediction to theories of distributive justice that assign priority to the worse off. Because bioprediction enables the identification of those who are worse off in a way of which we have previously been ignorant, a commitment to assign priority to the worse off requires development of and equal access to biopredictive technologies.

A number of behavioural symptoms are commonly displayed by Alzheimer's disease (AD) sufferers. Behavioural disturbances in AD can include affective symptoms, agitation, aggression and psychosis (Burns et al. 1990a Burns et al. 1990b Burns et al. 1990c). Alois Alzheimer was the first to document psychosis in the disease bearing his name, during his description of the clinical presentation of a patient upon admission to the Frankfurt asylum in 1906 (Alzheimer 1995 Schneider and Dagerman 2004).

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that results in severe cognitive impairment and eventually is fatal. In addition to memory loss, AD patients also present with psychosis and emotional psychological symptoms. Neuropathologically, the disease is characterized by aggregation of amyloid-beta protein that accumulates into plaques and hyperphosporylation of tau protein which results in neurofibrillary tangles. Further, neuropathology in AD results in broad neuroinflammation. In recent years, there has been a research focus on novel treatments for AD because current medications have not been particularly effective and have significant side effects. In the current study, we analyzed whether PD340, a novel anti-inflammatory which inhibits the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) would be effective to alleviate behavioral impairments in the 3xTg mouse model of AD. The 3xTg model is unique in comparison to previous rodent models of AD because it express three dementia-related transgenes and demonstrates a clear age-dependent onset of AD pathology. Mice were bred in our animal colony. Beginning at four months of age, a specialized diet was presented to the animals that contained 0, 3, 10, or 25 mg/kg of PD340. At approximately 6 months of age, which is before any neuropathology presents in this model, animals were behaviorally tested on three different tasks: The Barnes maze, which is a test of spatial memory; Prepulse inhibition (PPI), which is a measure of sensorimotor gating and is related to psychosis and cognition; and the elevated T-maze, which is a test of anxiety. Both males and females were tested. Results from Barnes maze testing revealed that females, but not males, administered 25 mg/kg of PD340 demonstrated a significant improvement in spatial bias towards the goal during acquisition. Regarding PPI, there were no sex differences, but groups receiving the 3 or 25 mg/kg dose of PD340 demonstrated significantly improved performance over animals administered the 0 mg/kg dose of PD340 dependent upon the auditory decibel level of the stimulus presented. On the elevated T-maze, there were no significant group differences, demonstrating anxiety is not present at 6 months of age in this model. Behavioral tests will also be performed at 12 and 15 months of age in these animals. However, at 6 months of age, it appears that PD340 is effective in alleviating behavioral deficits related to cognitive impairment in a mouse model of AD. Future work will analyze neuropathology in the hippocampus and prefrontal cortex, two brain areas that degenerate in AD and are important in cognitive function.

Parkinson’s Disease affects 10 million people worldwide, with 40% of patients developing an associated psychosis which has been identified by studies as the number one source of caretaker distress and is related to increased mortality. This is further complicated by the fact that typical antipsychotic drugs worsen many of the motor symptoms implicated in Parkinson’s Disease, with only one commercially available drug able to ameliorate both symptoms. This problem ushers the development of novel drugs to treat these symptoms, as first tested on research animals. Complicating matters, drug effectiveness on the degree of psychosis is hard to obtain in animals without a reliable biomarker. However, a hallmark of psychotic states is thought to be the reduced coordination between brain structures, through neuronal synchronization, as demonstrated by steady-state responses and is suggested to be a potential biomarker of psychosis. By building a MATLAB software we were able to analyze the degree of neural synchronization between structures, during an auditory steady-state response, in rats that had been unilaterally lesioned by the 6-Hydroxydopamine model of Parkinson’s Disease, before and after administration of the psychotomimetic drug MK801. These rats had been chronically implanted with 128-channel multi electrode array, enabling us to measure the strength of coherence between several limbic structures, associated with auditory processing, from the sampled local field potential, identifying the degree of synchronization in the animal brain. As our data demonstrate that coherence levels dropped in the psychotic drug state, for structures in both the healthy and the Parkinsonian hemisphere, we are able to further demonstrate the validity of coherence measures as a biomarker for psychosis. These results demonstrate that our software can be used as a tool to assess the therapeutic response of drugs developed, aimed at treating Parkinson’s associated psychosis.
Parkinsons sjukdom drabbar 10 miljoner världen över, där 40% av patienterna utvecklar en associerad psykos vilket har visats vara en av de största stressfaktorerna för deras vårdgivare och är även förknippat med en högre dödlighetsgrad. Denna situation förvärras av det faktum att de vanliga antipsykotiska drogerna kan förvärra många av de motoriska symptom som utgörs av Parkinsons sjukdom och det finns i dagsläget enbart en enda kommersiell drog som kan dämpa bägge symptom samtidigt. Detta problem frammanar vidare utveckling av nya läkemedel som kan behandla dessa symptom, som innebär att de först måste testas på försöksdjur. En komplikation som uppstår i relation till detta är svårigheten att utvärdera om läkemedel har någon terapeutisk effekt på de psykotiska tillstånden, enbart genom att observera försöksdjurens beteenden, och en pålitlig biomarkör krävs istället. En lösning kan dock finnas i det faktum att psykotiska tillstånd karaktäriseras av en reducerad förmåga för olika hjärnområden att koordinera genom neural synkronisering vilket demonstreras av ‘steady- state’ responser. Detta föreslår att ett mått på graden av koordineringsförmåga kan agera som en möjlig biomarkör för psykotiska tillstånd. Genom att konstruera ett MATLAB-program kunde vi analysera graden av synkronicitet mellan hjärnstrukturer, under den auditiva steady- state responsen i råttor som hade blivit ensidigt lesionerade genom 6-Hydroxiddopamin modellen av Parkinsons sjukdom, före och efter administration av den psykotomimetiska drogen MK801. Dessa råttor hade blivit kroniskt implanterade med 128 elektroder vilket möjliggjorde att vi kunde mäta styrkan i koherens i den lokala fält potentialen mellan limbiska strukturer, som är associerade med auditiv processering, vilket möjliggjorde identifiering av3dessa strukturers synkronicitet. Vår data demonstrerar att koherensen minskade under det psykotiska drogtillståndet för limbiska strukturer både i den intakta och den lesionerade hjärnhalvan. Detta är en vidare demonstration av att koherensnivåer kan agera som en biomarkör för det psykotiska tillståndet, liksom att vår mjukvara kan nyttjas som ett verktyg för att utvärdera nya läkemedels behandlingsförmåga på Parkinsons psykos.

O estudo dos sintomas neuropsiquiátricos em Doença de Alzheimer (DA) através do agrupamento destes em síndromes tem sido cada vez mais utilizado, uma vez que permitiria detectar diferenças em sua prevalência, em sua evolução, em relação a determinantes psicossociais e a correlatos neurobiológicos. O objetivo deste estudo foi identificar regiões de redução de substância cinzenta em áreas corticais associadas com sintomas e síndromes neuropsiquiátricos específicos, provenientes da Escala Inventário Neuropsiquiátricos (NPI), em pacientes com DA e comprometimento cognitivo sem demência (CIND). O método de morfometria baseada no voxel (VBM) com DARTEL (Diffeomorphic Anatomical Registration Using Exponentiated Lie Algebra) foi utilizado para verificar a correlação entre presença de sintomas e síndromes neuropsiquiátricos específicos e redução regional de volume de substância cinzenta em análise em todo cérebro e em regiões previstas a priori. As síndromes utilizadas foram SN1/Agitação (agitação, alterações de sono e apetite), SN2/Hiperatividade (desinibição, comportamento motor aberrante e irritabilidade), SN3/Afetiva (depressão e apatia) e SN4/Psicose (delírios e alucinações). A presença de delírios foi associada a volume de substância cinzenta reduzido em giro frontal inferior direito (BA45); depressão com xvii redução de substância cinzenta em giro temporal médio e inferior direito (BA 37/22) e giro frontal inferior (BA09-DLPFC) e giro parahipocampal esquerdos; ansiedade com redução em giro frontal médio esquerdo (BA10); e alterações de apetite com redução em córtex anterior cingulado esquerdo (BA32) em pacientes com DA. A presença de SN1/Agitação foi associada a volume de substância cinzenta reduzido em giro frontal médio direito (BA09-DLPFC); SN2/Hiperatividade com redução em giro temporal superior direito (BA22) e frontal inferior bilateral (BA47); e SN4/Psicose com redução em giro pré-central (BA44), temporal superior (BA22) e ínsula direitos em DA. No grupo CIND, somente SN1/Agitação evidenciou associação com redução de substância cinzenta regional. Atrofia de áreas corticais específicas parecem relacionadas aos sintomas e síndromes neuropsiquiátricos em DA. Síndromes neuropsiquiátricas em DA mostraram-se correlacionadas à atrofia de estruturas centrais de alguns circuitos neuronais envolvidos na fisiopatologia de transtornos psiquiátricos
The study of neuropsychiatric symptoms in patients with Alzheimer\'s disease (AD) by grouping these symptoms into syndromes has been increasingly used because it would detect differences in its prevalence and evolution, in relation to psychosocial determinants and neurobiological correlates. The aim of this study was to identify regions of reduced gray matter in cortical areas associated with specific neuropsychiatric symptoms and syndromes from the Neuropsychiatric Inventory (NPI) in patients with AD and cognitive impairment, no dementia (CIND). Voxel-based morphometry (VBM) plus Dartel (Diffeomorphic Anatomical Registration Exponentiated Using Lie Algebra) was used to verify the correlation between the presence of specific neuropsychiatric symptoms and syndromes and regional gray matter volume reduction throughout the brain and in regions predicted a priori. The syndromes were NS1/ Agitation (agitation, sleep and eating disorders), NS2/Hyperactivity (disinhibition, aberrant motor behavior and irritability), NS3/Affective (depression and apathy) and NS4/Psychosis (delusions and hallucinations). The presence of delusions was associated with gray matter volume reduction in right inferior frontal gyrus (BA45), depression with reduced gray matter in right inferior middle temporal gyrus (BA 37/22) and left inferior frontal gyrus (BA09-DLPFC) and left parahippocampal gyrus; anxiety with reduction in left middle frontal gyrus (BA10), and eating disorders with reduction in left anterior cingulate cortex (BA32) in patients with AD. The presence of NS1/Agitation was associated with gray matter volume reduction in the right middle frontal gyrus (BA09-DLPFC); NS2/ Hyperactivity with reduction in right superior temporal gyrus (BA22) and bilateral inferior frontal (BA47) and NS4/Psychosis with a reduction in right precentral gyrus (BA44), right superior temporal (BA22) and in right insula in AD. In the CIND group, only SN1/Agitation showed association with regional gray matter reduction. Atrophies of specific cortical areas were showed to be related to symptoms and neuropsychiatric syndromes in patients with AD

Background Patients infected with the human immunodeficiency virus (HIV), the causative agent of the acquired immunodeficiency syndrome (AIDS), have high rates of psychiatric morbidity. The effects of HIV on the Central Nervous System may lead to psychiatric morbidity even before the appearance of the full-blown AIDS syndrome. Sero-prevalence studies of patients with psychoses have found an estimated 5-20% to be HIV positive. However, sero-prevalence estimates vary from study to study due to the differences in sampling by geographic location, socio-economic class, race and ethnicity, and psychiatric-diagnostic composition. The Republic of South Africa has some of the highest prevalence rates in the world and research in this field is escalating rapidly. However research on HIV in patients with mental illness, particularly psychosis is very sparse. Aim of the study To determine the prevalence of HIV sero-positivity amongst patients admitted to Town Hill hospital presenting with first episode psychosis. Method All patients presenting to Town Hill hospital with first episode of psychotic symptoms were recruited to participate in the study. The treating doctor in collaboration with the multi-disciplinary team made the diagnosis of Psychosis. A total number of 63 patients participated in the study. Results. 23.8% of the patients tested positive for the human immunodeficiency virus. Conclusions. The prevalence of HIV sero-positivity is high amongst patients presenting with first episode psychosis. The HIV epidemic could have an important effect on the aetiology and clinical presentation of psychosis. Recommendations State mental health authorities should pursue the promotion of voluntary HIV testing programs, in patients presenting with first episode psychosis as soon as they are capable of giving informed consent.
Thesis (M.Med.)-University of KwaZulu-Natal, Durban, 2007.

Cardiovascular disease (CVD) is the leading cause of death in people with psychosis. For over a decade, extensive research has shown that people who have a psychotic illness are more likely to live an unhealthy lifestyle and engage in health risk behaviours compared with the general population. The current thesis extends this prior research, using the World Health Organisation (WHO) as a framework to identify risk factors that are responsible for morbidity and mortality among the psychosis population. Out of the eleven health risk factors outlined by WHO, the first three manuscripts focus on two of these risk factors while the remaining manuscripts draw eight risk factors together to provide an overall picture of the health profile in people with psychosis. This research was based on the 2010 Australian national psychosis survey using a large representative sample of adults aged 18-64 years with psychotic disorders (n =1825). The first aim of the thesis was to identify factors associated with individual WHO risk factors in people with psychosis. Paper 1 explored factors associated with dietary inadequacy defined by the consumption of less than four daily servings of fruit and vegetables. Quantitative findings derived from this paper indicated that almost three quarters of participants failed to conform to dietary guidelines, and substance use was the major contributing factor for this dietary non-compliance. Paper 2 extended these findings by providing a comparison of nutrient intake in individuals with psychosis and the general population based on a smaller subset of this population. The former group consumed more fat, vitamins and minerals compared with the normal population. Most people with psychosis did not meet the recommended dietary intake for various nutrients. Paper 3 undertook an investigation into arterial stiffness and peripheral resistance and found that male gender, higher age and a family history of hypertension was positively associated with both of these blood pressure components. In this paper, unmodifiable risk factors were more related with increasing pulse pressure and mean arterial pressure, compared with modifiable risk factors relating to poor health behaviours. The second aim of this thesis was to investigate the absolute number of the WHO-defined risk factors, present in people with psychosis. A risk factor count represents a novel approach to obtaining an overall picture of risks that are associated with disability and death. Paper 4 looked at the total number of these CV risks present in people with psychosis, with a particular focus on young people aged 18-24 years. This paper showed that young men and women had an average of 2-3 risk factors out of 8 WHO-defined risk factors. Paper 5 expanded these findings by examining the total number of CV risks in people with psychosis aged 18-64 years. Relative to the younger participants, older people with psychosis had more risk factors, and risk appeared to increase with increasing age. Taken together, these findings presented within the following chapters, heighten our understanding of the physical health profile and excess mortality in people with psychosis, using risk factors well-validated by the WHO, that make a substantial contribution to morbidity and mortality.
Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, Adelaide Medical School, 2017.