Browsing by Author "Luckhoff, Hilmar Klaus"
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- ItemDevelopment of a novel pre-screen algorithm for cardio-metabolic risk management using a genomics database resource(Stellenbosch : Stellenbosch University, 2016-03) Luckhoff, Hilmar Klaus; Kotze, Maritha J.; Janse van Rensburg, Susan; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology. Anatomical Pathology.ENGLISH ABSTRACT: The timely assessment and treatment of dyslipidaemia is an important component of cardiovascular risk screening and intervention. The apolipoprotein E (APOE) ε-2/ε-3/ε-4 polymorphism associated with impaired lipid homeostasis provides a genetic link between cardiovascular disease (CVD) and late-onset Alzheimer’s disease (AD). Realization that the phenotypic expression of the risk associated APOEε-2 and ε-4 alleles may be dependent on non-genetic factors supports the inclusion of APOE genotyping in chronic disease screening programs. The lack of well-defined selection criteria for APOE genotyping, however, limits the use of this biomarker in clinical practice. The aim of the present study was to develop a pre-screen algorithm for identification of a target population most likely to benefit from APOE genotyping, performed in conjunction with a clinical and lifestyle assessment. Towards this goal, comprehensive patient data were evaluated from a total of 580 unrelated Caucasians enrolled in a chronic disease screening program over a five-year period (2010-2015), using an ethically approved study questionnaire. Biochemical tests performed according to standard laboratory protocols were extracted from the research database. All study participants were genotyped for the APOE ε- 2/ε-3/ε-4 polymorphism. APOE genotype distribution differed significantly (p<0.05) between study participants with and without a family history of AD. A positive association between dietary fat intake and lowdensity lipoprotein (LDL) cholesterol (p=0.001), as well as an inverse association with highdensity lipoprotein (HDL) cholesterol (p=0.002), were observed in patients with a family history of AD. Body mass index (BMI) was positively associated with LDL cholesterol and inversely associated with HDL cholesterol levels (p<0.001), irrespectively of an AD family history. Smoking was associated with higher triglycerides (p<0.001) and lower HDL cholesterol levels (p=0.004) in the total study group. Alcohol intake was positively associated with BMI (p=0.008) as well as triglyceride levels (p=0.021) in patients with a positive family history of AD. The clinical expression of a hypercholesterolaemic phenotype in APOE ε-4 allele carriers, as well as apparent mitigation by regular physical activity, were dependent on the interaction between a family history of AD and APOE genotype (p<0.001). APOE ε-2 carriers without an AD family history showed a significant increase in triglyceride levels (p=0.014). The modulating influence of APOE ε-4 on the relationship between alcohol intake and BMI as well as total cholesterol levels was also dependent on the presence or absence of AD family history (p<0.05). This study resulted in the addition of a family history of AD as a novel component to the prescreen algorithm developed for selection of at-risk individuals prior to APOE genotyping performed as part of a chronic disease screening program. The lifestyle questionnaire used in this study furthermore facilitated interpretation of the clinical relevance of variation detected in the APOE gene. This is important to prioritize the use of lipid-lowering medication towards patients with severe subtypes of dyslipidaemia such as familial hypercholesterolaemia (FH), which remains largely undiagnosed and untreated in the highrisk South African population. Incorporating the research findings into clinical practice would suggest that physical activity may be the most effective risk reduction strategy in carriers of the APOEε-4 allele, as supported by international studies.
- ItemMetabolic syndrome risk factor associations with clinical, functional and cognitive outcomes during the first year of treatment in schizophrenia spectrum disorders(Stellenbosch : Stellenbosch University, 2021-03) Luckhoff, Hilmar Klaus; Emsley, Robin; Du Plessis, Stefan S.; Kilian, Sanja; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Psychiatry.ENGLISH SUMMARY : Treatment-emergent metabolic syndrome is an established risk factor for cardiovascular disease known to be associated with cognitive impairment, poor functioning and decreased quality of life in schizophrenia spectrum disorders. However, weight gain and increased lipids have also been correlated with clinical improvement in chronic schizophrenia patients. While most studies investigating the relationships between body mass and treatment outcome were conducted in patients treated with clozapine and olanzapine, it remains unclear to what extent the role of weight gain as a predictor of favourable clinical outcomes extends to include illness-specific symptom domains in first-episode patients treated with other antipsychotics with a lower obesogenic potential. The effects of other clinical (e.g. sex, substance use, baseline body mass) and treatment-related (e.g. antipsychotic dose, medication adherence) confounders on the above relationships is also unclear. In response to these knowledge gaps, the overarching aim of our doctoral studies was to explore the temporal evolution of metabolic syndrome risk factors and their effects on clinical outcome over 12 months of treatment in first-episode schizophrenia spectrum disorder patients. We found that an increase in body mass correlates with global psychopathology improvement as well as the disorganized symptoms domain of schizophrenia in first-episode patients (n=106) over 12 months of treatment, independent of the degree of antipsychotic exposure (sub-study I). The association between weight gain and clinical improvement extended to include better overall end-point cognition after 12 months of treatment in our first-episode patient cohort (n=72) (sub-study II). A differential effect for lower baseline body mass index as a predictor of end-point working memory performance was evident in substance users (unfavourable) compared to their non-using counterparts (favourable). The adverse role of low body mass index as an unfavourable prognostic marker was further substantiated by its associations with an earlier age of psychosis onset and more severe negative symptoms in first-episode patients (n=69) (sub-study III). The inclusion of a diffusion tensor imaging component to our research also revealed a similar differential association of body mass index with fronto-limbic white matter fractional anisotropy (FA) in first-episode patients (low body mass index, low FA) versus healthy controls (high body mass index, low FA) adjusting for age and sex (sub-study III). Extension of our structural neuroimaging research to include brain structures involved in the physiological, hedonic and cognitive control as part of a “core eating network” further identified smaller anterior hippocampal volumes as a sex-specific predictor of weight gain in first-episode patients (n=90) (sub-study IV). Our research supports the role of weight gain as a predictor of favourable clinical outcomes in first-episode schizophrenia patients for whom treatment adherence is assured. In contrast, low body mass and by extension failure to gain weight could represent an unfavourable prognostic marker in first-episode patients, particularly those who use substance users. Future studies would do well to combine clinical, biological and neuroimaging data in order to characterize intrinsic metabolic profiles in relation to long-term treatment outcomes in firstepisode schizophrenia.