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Thesis (PhD (Psychiatry))-- Stellenbosch University, 2006. / ENGLISH ABSTRACT: Obsessive-compulsive disorder (OCD), a debilitating psychiatric disorder, affects 2-3% of the general population, and represents a global health problem. Evidence from family studies suggests that genetic factors play a role in mediating disease development. However, the pattern of inheritance is not consistent with monogenic disorders, but is “genetically complex”. Case-control association analysis, which facilitates dissection of the genetic aetiology of complex disorders, has yielded many inconsistent results in OCD studies, making identification of predisposing alleles difficult. These discrepant findings can largely be attributed to inappropriate statistical methodology and the lack of OCD phenotypic resolution. Although classified as a single clinical entity according to structured algorithms, OCD probably represents a final common outcome of multiple underlying aetiologies. Thus, numerous clinical subtypes of the disorder have been proposed; these “intermediate” phenotypes may be more closely related to a particular genetic substrate than the higher order construct of OCD. Furthermore, although genes encoding serotonergic (5-HT) and dopaminergic components are most commonly investigated, it is likely that the behavioural manifestations of OCD are mediated by a broader network of interconnected neurotransmitter and signalling pathways. Consequently, the aim of the present study was two-fold: to address the factors that may have confounded previous genetic case-control association studies and to investigate the genetic aetiology of OCD phenotypes while accounting for these factors. Case and control individuals were drawn from the reportedly genetically homogeneous Afrikaner population. However, as no empirical evidence existed to support the absence of genetic substructure, which would confound genetic association studies, a Bayesian modelbased clustering algorithm (Structure), that groups individuals on the basis of observed genotype data, was employed to assess population stratification in both case and control Afrikaner subjects. OCD patients were clinically stratified by gender, symptom severity, age at onset, the presence of selected co-morbid disorders and the presence of selected symptom dimensions, to facilitate the identification of susceptibility genes more closely related with these subtypes. Candidate genes included those coding for components of the 5-HT (5-HT receptors 1Dβ, 2A, 2C and 6), dopaminergic (dopamine receptors 1, 2, 3 and 4, dopamine transporter and catechol-O-methyltransferase [COMT]), glutamatergic (glutamate receptor subunit 2B [GRIN2B]) and neurodevelopmental pathways (brain-derived neurotrophic factor [BDNF] and homeobox 8 [HoxB8]), as well as previously uninvestigated genes (angiotensinconverting enzyme I, inositol-trisphosphate, phospholipase-C-gamma 1 and estrogen receptor alpha). The relationship between variants in these genes and OCD (or OCD subtypes) was investigated in a single locus and a haplotype context, while meta-analyses using published population-based case-control association data were also conducted. Significant associations noted between distinct COMT variants and OCD implicated COMT in the development of a genetically discrete, gender-dependant, early-onset, tic-related phenotype in males. Furthermore, investigations of variations in BDNF and GRIN2B point towards a genetically distinct, neurodevelopmental subtype of the disorder, mediated, in males at least, primarily by dysfunctions in BDNF. The striking gender dimorphism noted in these associations indicates the possibility of an epigenetic hormonal influence. Moreover, the significant association of polymorphisms within GRIN2B, in both a single locus and haplotype context, suggests the involvement of this gene in mediating a phenotypic subtype characterised by an early-onset, more severe form of the disorder. The present investigation forms part of ongoing research to elucidate genetic components involved in the aetiopathology of OCD and OCD-related subtypes. Such studies may pave the way towards more efficacious pharmacotherapeutic strategies, which will ease the suffering of individuals who are afflicted with this incapacitating condition. / AFRIKAANSE OPSOMMING: Obsessiewe-kompulsiewe steuring (OKS) is 'n aftakelende psigiatriese siektetoestand wat 2- 3% van die algemene bevolking affekteer en 'n globale gesondheidsprobleem verteenwoordig. Familiestudies dui daarop dat genetiese faktore 'n rol in die ontwikkeling van hierdie siekte speel. Die patroon van oorerwing is egter nie verenigbaar met dié van monogeniese siektes nie, maar is geneties "kompleks". Geval-kontrole assosiasie-ontleding, wat die disseksie van die genetiese etiologie van komplekse siektes fasiliteer, het teenstrydige resultate in OKS gelewer en dit bemoeilik die identifikasie van predisponerende allele. Die teenstrydige bevindings kan grootliks aan ontoepaslike statistiese metodiek en die gebrek aan fenotipiese differensiasie in OKS toegeskryf word. Alhoewel dit volgens gestruktureer algoritmes as 'n enkele kliniese entiteit geklassifiseer word, verteenwoordig OKS waarskynlik die eindresultaat van veelvoudige onderliggende oorsake. Baie kliniese subtipes van die toestand is al voorgestel en dié "intermediêre' fenotipes mag nader verwant aan 'n spesifieke genetiese substraat as die hoër orde konsep van OKS wees. Verder, alhoewel die gene wat die serotonergiese (5-HT) en dopaminergiese komponente kodeer meestalondersoek word, is dit waarskynlik dat die gedragsmanifestasies van OKS deur 'n breër netwerk van intergekonnekteerde neuro-oordragstof- en seinoordragpaaie meegebring word Gevolglik was die doel van die huidige studie tweevoudig: om faktore wat vorige genetiese geval-kontrole assossiasie-studies verwar het aan te spreek en om die genetiese etiologie van OKS-fenotipes te ondersoek met in ag neming van hierdie faktore. Geval- en kontrole-individue is gekies uit die Afrikaner-bevolking wat as geneties homogeen beskryf kan word. Daar was geen empiriese bewyse vir die afwesigheid van 'n genetiese substruktuur (wat genetiese assossiasie-studies sou verwar),nie. Daarom is 'n Bayesiese model-gebaseerde groeperings-algoritme (Structure), wat individue op grond van waargenome genotipiese data groepeer, gebruik om die populasie-stratifikasie is beide gevalen kontrole- Afrikaner-individue te bepaal. OKS-pasiënte is klinies gestratifiseer volgens geslag, ernstigheid van simptome, ouderdom by aanvang van simptome, die teenwoordigheid van geselekteerde komorbiede siektetoestande en die teenwoordigheid van geselekteerde simptoomdimensies of -groepe, om die identifikasie van moontlike vatbaarheidsgene wat nader verwant is aan die verskillende subtipes te fasiliteer/vergemaklik. Kandidaatgene het ingesluit: dié wat kodeer vir komponente van die 5-HT-(5-HT reseptore IDB, 2A, 2C and 6), dopaminergiese (dopamienreseptore 1, 2, 3 and 4, dopamien-transporter and katesjol-O-metieltransferase [COMTJ), glutamatergiese (glutamaat-reseptor subeenheid 2B [GRIN2B]) and neuro-ontwikkelingspaaie (brein-gederiveerde neurotrofiese faktor [BDNF] en homeobox 8 [HoxB8]), sowel as die gene wat nie voorheen ondersoek is nie (angiotensien-omsettingsensiem I, inositol-trisfosfaat, fosfolipase-C-gamma 1 en estrogeen-reseptor alpha). Die verhouding tussen variante in hierdie gene en OKS (of OKS-subtipes) is ondersoek in 'n enkel-lokus en haplotipe konteks, en meta-analises, wat gepubliseerde bevolkings-gebaseerde geval-kontrole ontledingsdata gebruik het, is ook gedoen. Beduidende assosiasies gevind tussen spesifieke COMT-variante en OKS in mans, het daarop gedui dat COMT in die ontwikkeling van geneties-diskrete, vroeë-aanvang, senutrekking ("tics") -verwante fenotipe in mans betrokke is. Verder het ondersoeke van variasies in BDNF en GRIN2B daarop gedui dat 'n geneties-afsonderlike, neuro-ontwikkelings-subtipe van.OKS wat, ten minste in mans, primêr deur wanfunksie van BDNF meegebring word. Die opvallende geslags verskil wat in hierdie assosiasies gesien word, dui op die moontlikheid van 'n epigenetiese hormonale invloed. Bowendien, die beduidende assosiasie van polimorfismes in GRIN2B in beide die enkel-lokus en haplotipe konteks, dui op die betrokkenheid van hierdie geen in die meebring van 'n fenotipiese subtipe wat deur 'n vroeë aanvang, en meer ernstige vorm van die siekte gekenmerk word. Die huidige ondersoek vorm deel van voortgesette navorsmg om die genetiese komponente wat betrokke is by die etiopatologie van OKS en OKS-subtipes, bloot te lê. Sodanige studies kan die weg baan na meer doeltreffende farmakoterapeutiese strategieë wat die lyding van indi vidue wat deur hierdie aftakelende toestand geraak word, kan verlig.

Thesis (PhD (Psychiatry))--University of Stellenbosch, 2006. / Lipoid Proteinosis (LiP) is a rare hereditary disease, which often results in bilateral, symmetrical and circumscribed calcifications in the mesial temporal region (especially the amygdala). While several case studies have been published on individuals with this illness, there have been few systematic investigations of the neuropsychiatry and neuropsychology of a series of patients. Thirty-seven LiP patients were extensively assessed with standardized neuropsychiatric and neuropsychological measures. Of these, 27 patients from the Northern Cape in South Africa were matched (for age, gender, education, language, geographical area) with 53 controls. There was a high incidence of neuropsychiatric disorders in LiP (more than half of the subjects reported a history of depression or anxiety and 12% had a diagnosis of schizophrenia). Despite a wide variance, LiP subjects performed poorly on facial recognition for emotions and on most neuropsychological measures including intelligence, recall and executive functioning. These findings are consistent with involvement of the mesial temporal areas in mood, anxiety, and psychotic symptoms, and in the cognitive-affective processes. Future work aimed at delineating the associations between the clinical and neuropsychological findings reported here, for example, with brain-imaging techniques, is needed.

Thesis(DMed (Psychiatry))-- University of Stellenbosch, 2007. / Alcohol-induced psychotic disorder (also known as alcohol hallucinosis) is a complication of alcohol abuse that requires clinical differentiation from alcohol withdrawal delirium and schizophrenia. Although extensively described, few studies utilized standardized research instruments and brain-imaging has thus far been limited to case reports. The aim of this study was to prospectively compare four population groups (ie. patients with alcohol-induced psychotic disorder, schizophrenia, uncomplicated alcohol dependence and a healthy volunteer group) according to demographic, psychopathological and brainimaging variables utilizing (i) rating scales and (ii) single photon emission computed tomography (SPECT). The third component of the study was designed to investigate the (iii) effect of anti-psychotic treatment on the psychopathology and regional cerebral blood flow (rCBF) before and after six weeks of treatment with haloperidol. Effort was made to ensure exclusion of comorbid medical disorders, including substance abuse. The study provides further supportive evidence that alcohol-induced psychotic disorder can be distinguished from schizophrenia. Statistically significant differences in rCBF were demonstrated between the alcohol-induced psychotic disorder and other groups. Changes in frontal, temporal, parietal, occipital, thalamic and cerebellar rCBF showed statistically significant negative correlations with post-treatment improvement on psychopathological variables and imply dysfunction of these areas in alcohol-induced psychotic disorder. The study was unable to distinguish between pharmacological effects and improvement acccomplished by abstinence from alcohol. / Stellenbosch: Stellenbosch University

Thesis (MMed)--University of Stellenbosch, 2004. / ENGLISH ABSTRACT: Numerous tests exist for the assessment of general cognitive functioning. Most of these tests were developed within the discipline of psychology. Neuropsychological tests are very useful, but have some limitations. Administration of the tests is limited to a psychologist, is very timeconsuming in that it can take 3-8 hours to administer and often need specialized equipment. At the other end of the continuum are very brief screening tests. General practitioners, psychiatrists and occupational therapists, in addition to psychologists, also use these tests. Although useful, the short tests only provide limited information. An intermediate level test streamlining the assessment process between the very short and longer neuropsychological tests is therefore introduced by this study. The Bedside Cognitive Assessment Battery (BCAB) was developed in 1995 and are since used, at Tygerberg Hospital's Memory Clinic, to assess patients and teach students. The test comprehensively assesses the six main classes of cognitive functioning, namely attention and concentration, speech, memory, motor functioning, perceptual functioning and executive functioning. Approximately 35-45 minutes is required for administration and training is needed to administer the BCAB. No specialized equipment is needed for administration. The battery can therefore be used at the bedside, in the office or at old age homes. The aims of this study were to validate the BCAB for use with people aged eighteen years and older, and provide normative values for use in clinical settings. The test was revised in 1997 and 2001, and extensively so in 2002, but was never formally evaluated for validity. Well-known single tests were used to compile the BCAB. Most of these tests have proven validity and reliability, but only for foreign populations. In addition, some items were reformulated and others created by the researchers. The introduction of normative values would also be useful to assist in the delineation of cognitively intact and impaired individuals. This study succeeded in providing a table of normative values. One-hundred-and-sixty Afrikaans and English participants, and fourteen Xhosa participants were assessed in their mother tongue language. This project thus also introduced a Xhosa version of the BCAB. The purpose of the Xhosa version was to address the lack of culturally relevant cognitive assessment instruments. Results were evaluated for the effects of the variables' language, gender, age and education. The effect of language was most noticeable in the Xhosa group. Gender did not affect results as dramatically as age and especially, education. These significant effects on the aforementioned variables have been described in previous reports. The BCAB is thus relevant and useful as a detector of mild to moderate impairment. It can also be used to identify specific impairment. This can narrow down the investigation of psychologists, thus saving time and money. In addition, medical and nonmedical staff can use the BCAB. Some limitations were also identified. The sample used may limit the generalization of results. Some test items also need revision, along with further validation studies. Clinicians are therefore advised to use the BCAB only in addition to complete clinical examinations when making decisions regarding a patient's cognitive status. The BCAB appears to be a valid tool for bedside assessment. However, this study could only set the stage for further research, especially studies concerned with establishing normative values. / AFRIKAANSE OPSOMMING: Verskeie toetse bestaan vir die evaluering van algemene kognitiewe funksionering, waarvan die meeste ontwikkel is binne die sielkunde. Neuro-sielkundige toetse is baie bruikbaar, maar het sekere beperkings. Administrasie van die toetse is beperk tot sielkundiges, maar tydrowend weens 'n tydsduur van drie tot agt uur, en verg dikwels gespesialiseerde toerusting. Aan die ander kant is heelwat kart siftings-toetse beskikbaar. Aigemene praktisyns, sielkundiges en arbeidsterapeute, asook sielkundiges, gebruik dit. Hoewel bruikbaar, bied die kart toetse beperkte inligting. 'n lntermediere vlak toets om die evaluerings-proses tussen kart en langer neuro-sielkundige toetse te integreer word met hierdie studie beoog. Die Bedkant Kognitiewe Evaluasie Battery (BKEB) is in 1995 ontwikkel en gebruik in die Geheue-kliniek van die Tygerberg Hospitaal om pasiente te evalueer en studente op te lei. Die toets is gerig op die omvattende evaluering van die ses hoof-klasse van kognitiewe funksionering. Hierdie klasse omvat aandag en konsentrasie, spraak, geheue, motoriese funksionering, perseptuele funksionering en uitvoerende funksionering. Sowat 35 tot 45 minute word benodig vir administrasie terwyl opleiding vereis word vir die neem van die toets. Geen gespesialiseerde toerusting is nodig nie. Die battery kan dus by die bedkant, in die kantoor of in ouetehuise gebruik word. Die doelwitte van hierdie studie is om die BKEB te evalueer in gebruik by 18-jariges en ouer, en normatiewe waardes te bepaal vir gebruik in kliniese omgewings. Die toets is in 1997 en 2001 hersien. In 2002 is dit uitvoerig hersien, maar nooit ge-evalueer vir geldigheid nie. Bekende enkel-toetse is gebruik am die BKEB saam te stel. Dit is as geldig en betroubaar bewys, hoewel slegs onder buitelandse bevolkingsgroepe. Hierbenewens is sekere items herformuleer en ander bygewerk deur die navorsers. Normatiewe waardes sal oak handig wees in die afbakening van kognitief normaal-funksionerende en kognitief-ingekorte individue. Hierdie studie het daarin geslaag am 'n tabel van normatiewe waardes daar te stel. Een-honderd-en-sestig Afrikaans- en Engels-sprekendes, en 14 Xhosa-sprekendes is tydens hierdie studie in hulle moedertaal ge-evalueer. Hierdie projek het dus oak 'n Xhosaweergawe van die BKEB geskep. Die doel van die Xhosa-weergawe was am die gebrek aan 'n kultureel toepaslike kognitiewe instrument te beklemtoon. Resultate is ge-evalueer gedagtig aan veranderlikes soos taal, geslag, ouderdom en opleidingsvlak. Taal het die grootste invloed gehad op uitslae van Xhosa-deelnemers. Geslag het nie die uitslae so dramaties bernvloed soos ouderdom, en veral opleidingsvlak nie. Literatuur het meestal die groot uitwerking van hierdie veranderlikes bevestig. Die BKEB is dus relevant en handig in die naspeuring van ligte tot matige kognitiewe ingekortheid. Dit kan ook gebruik word om spesifieke kognitiewe ingekortheid te identifiseer. Die kan die omvang van ondersoek deur sielkundiges vernou, wat kan lei tot In groot besparing in tyd en geld. Hierbenewens kan mediese en nie-mediese personeel aangewend word in die gebruik van die BKEB. Sekere tekortkominge is ge·,dentifiseer. Die steekproef mag egter die veralgemening van die uitslae beperk. Sekere toets-items mag ook hersiening vereis, tesame met verdere geldigheid-studies. Kliniese praktisyns word daarom aangeraai om die BKEB slegs in aanvulling tot omvattende kliniese ondersoeke te gebruik vir besluite m.b.t. In pasient se kognitiewe status. Die BKEB kom voor as In geldige instrument vir bedkant evaluering. Hierdie studie kon egter slegs die tafel dek vir verdere ondersoek, veral t.o.v. studies wat poog om normatiewe waardes daar te stel.

Growing interest in the research community has been shown in clinical neuroscience to assess neurotransmitter profiling both in healthy and diseased subjects. A large body of research in this field focuses on schizophrenia to characterise its glutamatergic level according to the most recent hypothesis of NMDA (N-Methyl-D-aspartic acid) receptors hypofunction. Magnetic Resonance Spectroscopy (MRS) is able to detect some of the most common neurotransmitters but a number of issues, such as low signal to noise ratio (SNR), spectra overlapping and line broadening prevents MRS from being clinically relevant for neuropsychiatry. Four important aims were considered relevant for this work. Firstly, we aimed to compare the reliability of conventional and timing-optimized sequences for the detection and measurement of most of the visible metabolites and, in particular, for glutamate (Glu), glutamine (GIn) and gamma-aminobutyric acid (GABA) to assess the best available sequence for a study in schizophrenia. Secondly, we also intended to investigate whether glutamatergic activity might predict the oscillatory activity and how this link might survive or not in schizophrenia. Thirdly, we wanted to study whether the well known animal model of schizophrenia, the rearing in isolation model, exacerbates the effect of ketamine and determines more profound changes on neurotransmitter profile in rats. Fourthly, a further goal focuses on the improved data acquisition and on the data processing to reliably resolve GABA and to be able to quantify a wider range of metabolites. To address those points five studies were performed. The first work (Chapter 3) describes a study of reproducibility on sequences which have been reported in the literature to be capable to detect Glu and GIn. The study was performed on 14 healthy subjects by scanning them twice and repositioning between the two scans. The absolute percentage difference was then computed to assess the accuracy per sequence and metabolite. A good compromise was found in PRESS sequence (TE=80 ms) which was exploited subsequently for the following study on schizophrenic patients (Chapter 4). Twenty-seven early stage schizophrenic patients and twenty-three aged-matched controls were recruited to undergo a protocol including, in two separate sessions, MRS and electroencephalography (EEG). Anterior Cingulate Cortex Glu was found to predict the induced theta activity in healthy controls but not in patients. Furthermore, the NAA values have also been found to be reduced in schizophrenia and linked to N100, an Event Related Potential (ERP) which is well known to be decreased in schizophrenia. Following on from the findings of the study on the early stage of schizophrenia, further investigations were undertaken to study the psychotic state occurring in the disease via a functional MRS, where 25mg/kg of ketamine (NMDA antagonist) injection was administered to two groups of rats. The two groups were group-housed and reared in isolation. This work was able to show increase of prefrontal GIn levels in both groups but showed a selective GABA decrease only in isolated rats. It would have been very interesting to be able to detect GABA changes in the study at 3T but the used protocol did not allow its accurate quantification. Simulations and reliability tests (Chapter 6)were then utilized to optimize a standard sequence to obtain an accurate and reliable GABA concentration. The optimized sequence reproduces the quantification with 12% of accuracy. The preliminary results of the last study (Chapter 7) give an evidence of the potential of combined use of Monte Carlo, Levenberg-Marquardt and NNLS methods embedded in a novel fitting approach for two-dimensional spectra. The three appendices at the end of this work illustrate the details of some of the algorithms and softwares used throughout the studies.