Two neuroanatomical signatures in schizophrenia: Expression strengths over the first 2 years of treatment and their relationships to neurodevelopmental compromise and antipsychotic treatment

BACKGROUND AND HYPOTHESIS: Two machine learning derived neuroanatomical signatures were recently described. Signature 1 is associated with widespread grey matter volume reductions and signature 2 with larger basal ganglia and internal capsule volumes. We hypothesized that they represent the neurodevelopmental and treatment-responsive components of schizophrenia respectively. STUDY DESIGN: We assessed the expression strength trajectories of these signatures and evaluated their relationships with indicators of neurodevelopmental compromise and with antipsychotic treatment effects in 83 previously minimally treated individuals with a first episode of a schizophrenia spectrum disorder who received standardized treatment and underwent comprehensive clinical, cognitive and neuroimaging assessments over 24 months. Ninety-six matched healthy case-controls were included. STUDY RESULTS: Linear mixed effect repeated measures models indicated that the patients had stronger expression of signature 1 than controls that remained stable over time and was not related to treatment. Stronger signature 1 expression showed trend associations with lower educational attainment, poorer sensory integration, and worse cognitive performance for working memory, verbal learning and reasoning and problem solving. The most striking finding was that signature 2 expression was similar for patients and controls at baseline but increased significantly with treatment in the patients. Greater increase in signature 2 expression was associated with larger reductions in PANSS total score and increases in BMI and not associated with neurodevelopmental indices. CONCLUSIONS: These findings provide supporting evidence for two distinct neuroanatomical signatures representing the neurodevelopmental and treatment-responsive components of schizophrenia

Associations of premorbid adjustment with type and timing of childhood trauma in first-episode schizophrenia spectrum disorders

CITATION: Smit, A. M. et al. 2021. Associations of premorbid adjustment with type and timing of childhood trauma in first-episode schizophrenia spectrum disorders. South African Journal of Psychiatry, 27:a1639, doi:10.4102/sajpsychiatry.v27i0.1639.The original publication is available at https://sajp.org.zaBackground: Childhood trauma may contribute to poorer premorbid social and academic adjustment which may be a risk factor for schizophrenia. Aim: We explored the relationship between premorbid adjustment and childhood trauma, timing of childhood trauma’s moderating role as well as the association of clinical and treatment-related confounders with premorbid adjustment. Setting: We conducted a secondary analysis in 111 patients with first-episode schizophrenia (FES) disorders that formed part of two parent studies, EONKCS study (n =73) and the Shared Roots study (n =38). Methods: Type of childhood trauma was assessed with the Childhood Trauma Questionnaire, short-form and premorbid adjustment using the Premorbid Adjustment Scale. Timing of childhood trauma was assessed using the Life Events Checklist and life events timeline. Linear regression analyses were used to assess the moderating effect of timing of childhood trauma. Clinical and treatment-related confounders were entered into sequential hierarchical regression models to identify independent predictors of premorbid adjustment across key life stages. Results: Childhood physical neglect was associated with poorer premorbid academic functioning during childhood and early adolescence, and poorer premorbid social functioning during early and late adolescence. By hierarchical regression modelling (r2 = 0.13), higher physical neglect subscale scores (p = 0.011) independently predicted poorer premorbid social adjustment during early adolescence. Timing of childhood trauma did not moderate the relationship between childhood trauma and premorbid functioning. Conclusion: In patients with FES, childhood physical neglect may contribute to poorer premorbid social functioning during early adolescence. This may provide us with an opportunity to identify and treat at-risk individuals earlier.https://sajp.org.za/index.php/sajp/article/view/1639Publisher's versio

Country-level gender inequality is associated with structural differences in the brains of women and men

男女間の不平等と脳の性差 --男女間の不平等は脳構造の性差と関連する--. 京都大学プレスリリース. 2023-05-10.Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women’s worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7, 876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women’s brains and provide initial evidence for neuroscience-informed policies for gender equality

Country-level gender inequality is associated with structural differences in the brains of women and men

Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women's worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women's brains and provide initial evidence for neuroscience-informed policies for gender equality

Development of a novel pre-screen algorithm for cardio-metabolic risk management using a genomics database resource

Thesis (MSc)--Stellenbosch University, 2016.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.AFRIKAANSE OPSOMMING: Die tydige opsporing en behandeling van dislipidemie is 'n belangrike komponent van kardiovaskulêre risikobepaling en intervensie. Die apolipoproteïn E (APOE) ε-2/ε-3/ε-4 polimorfisme wat geassosieer is met abnormale lipied metabolisme toon ‘n genetiese verband tussen kardiovaskulêre siekte (KVS) en laat- aanvang Alzheimer se siekte (AD). Die bevinding dat die fenotipiese uitdrukking van die risiko geassosieerde APOE ε-2 en ε-4 allele afhanklik mag wees van nie-genetiese faktore ondersteun die insluiting van APOE genotipering in kroniese siekte siftingsprogramme. Die gebrek aan goed-gedefinieerde seleksie kriteria vir APOE genotipering beperk egter die gebruik van hierdie biomerker in kliniese praktyk. Die doel van hierdie studie was om 'n pre-toets algoritme te ontwikkel vir identifikasie van ‘n teiken populasie waar APOE genotipering waarde kan byvoeg, tesame met die evaluering van kliniese en leefstyl risikofaktore. Om hierdie doel te bereik is pasiëntdata geanaliseer van ‘n totaal van 580 nie-verwante Koukasiërs wat deelneem aan ‘n kroniese siekte siftingsprogram oor ‘n vyf-jaar periode (2010-2015), met gebruik van ‘n eties goedgekeurde studievraelys. Biochemiese toetse wat uitgevoer is volgens standaard laboratorium protokolle is geëekstraheer uit die navorsingsdatabasis. Genotipering van alle studiedeelnemers is uitgevoer vir die APOE ε-2/ε-3/ε-4 polimorfisme. APOE genotipe verspreiding het betekenisvol verskil (p<0.05) tussen studiedeelnemers met en sonder ‘n familiegeskiedenis van AS. ‘n Positiewe assosiasie is waargeneem tussen vetinname in die dieet en lae-digtheid lipoproteïen (LDL) cholesterol (p=0.001), terwyl ‘n omgekeerde assosiasie met hoë-digtheid lipoproteïen (HDL) cholesterol (p=0.002) waargeneem is in deelnemers met ‘n familiegeskiedenis van AS. Liggaamsmassa-indeks (BMI) was positief geassosieer met LDL cholesterol en omgekeerd geassosieer met HDL cholesterolvlakke (p<0.001), ongeag van AS familiegeskiedenis. Rook was geassosieer met verhoogde trigliserides (p<0.001) and laer HDL cholesterolvlakke (p=0.004) in die totale studiegroep. Alkohol inname was positief geassosieer met BMI (p=0.008) asook trigliseriedvlakke (p=0.021) in deelnemers met ‘n positiewe familiegeskiedenis van AS. Die kliniese uitdrukking van ‘n hipercholesterolemiese fenotipe in APOE ε-4 alleel draers, asook die verlaagde cholesterolvlakke met gereëlde fisiese aktiwiteit, was afhankik van die interaksie tussen AS familiegeskiedenis en APOE genotipe (p<0.001). APOE ε-2 draers sonder ‘n AS familiegeskiedenis het ‘n betekenisvolle verhoging in trigliseriedvlakke getoon (p=0.014). Die modulerende invloed van APOE ε-4 op die verhouding tussen alkohol inname en BMI asook totale cholesterolvlakke is ook bepaal deur die teenwoordigheid al dan nie van ‘n AS familiegeskiedenis (p<0.05). Hierdie studie het gelei tot die byvoeging van ‘n familiegeskiedenis van AS as ‘n nuwe komponent tot die pre-toets algoritme wat ontwikkel is om hoë-risiko individue te selekteer voor APOE genotipering as deel van n kroniese risiko bestuur program. Die leefstyl vraelys wat gebruik is vergemaklik die interpretasie van die kliniese relevansie van die genotipe resultate. Dit is belangrik sodat die noodsaaklikheid van lipied-verlagende farmakoterapie geprioritiseer kan word in deelnemers met erge subtipes van dislipidemie soos familiële hipercholesterolaemie (FH), wat meestal ongediagnoseer en onder-behandel bly in die hoërisiko Suid-Afrikaanse populasie. Inkorporering van die navorsingsresultate in kliniese praktyk behels die aanbeveling van fisiese aktiwiteit as die mees effektiewe risikoverlagende strategie in draers van die APOE ε-4 alleel, soos ook ondersteun word deur intenasionale studies

Metabolic syndrome risk factor associations with clinical, functional and cognitive outcomes during the first year of treatment in schizophrenia spectrum disorders

Thesis (PhD)--Stellenbosch University, 2021.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.AFRIKAANSE OPSOMMING : Metaboliese sindroom sekondêr to behandeling is ’n belangrike risikofaktor vir kardiovaskulêre siekte wat verbind word met kognitiewe aantasting, swak funksionering en ’n afname in lewensgehalte by skisofrenie spektrum steurings. ’n Toename in gewig en lipiede is egter ook al verbind met kliniese verbetering in pasiënte met chroniese skisofrenie. Terwyl meeste studies wat die verhouding tussen liggaamsmassa en uitkoms ondersoek gedoen is met pasiënte wat met klosapien en olansapien behandel is, is dit onduidelik tot watter mate die rol van gewigstoename as ’n voorspeller van gunstige kliniese uitkomste verder strek om siekte-spesifieke simptoomdomeine in te sluit in eerste-episode pasiënte wat met ander antipsigotiese middels met ’n laer obesogeniese potensiaal behandel word. Die uitwerking van ander kliniese (bv. geslag, middelgebruik, basislyn liggaamsmassa) en behandelings-verwante (bv. die dosis van antipsigotiese middels, hoe getrou medikasie gebruik word) faktore op bogenoemde verband is ook onduidelik. In reaksie op hierdie leemtes in kennis was die oorkoepelende doel van die doktorale studie om die temporele ontwikkeling van risikofaktore vir metaboliese sindroom te ondersoek asook die uitwerking daarvan op kliniese uitkoms oor 12 maande van behandeling in pasiënte met ’n eersteepisode van skisofrenie spektrum steurnisse. Ons het gevind dat ’n toename in liggaamsmassa verband hou met algemene psigopatologiese verbetering sowel as die gedisorganiseerde simptoomdomein van skisofrenie in eerste-episode pasiënte (n=106) oor 12 maande van behandeling, onafhanklik van die graad van antipsigotiese blootstelling (substudie I). Die verband tussen gewigstoename en kliniese verbetering het ook beter algemene eindpunt kognisie na 12 maande van behandeling in ons groep eerste-episode pasiënte ingesluit (n=72) (substudie II). Daar was ook ‘n differensiële effek vir laer basislyn liggaamsmassaindeks as ’n voorspeller van eindpunt-werkgeheue prestasie in middelgebruikers (ongunstig) in vergelyking met nie-gebruikers (gunstig). Die nadelige rol van lae liggaamsmassaindeks as ’n ongunstige prognostiese merker was ook gestaaf deur die verbintenis daarvan met ’n vroeër ouderdom waarop psigose begin het en ernstiger negatiewe simptome in eerste-episode pasiënte (n=69) (substudie III). Die insluiting van ’n diffusie tensor beelding komponent by ons navorsing het ook ’n soortgelyke onderskeidende verbintenis onthul tussen liggaamsmassaindeks en fraksionele anisotropie (FA) van frontaal-limbiese witstof in eerste-episode pasiënte (lae liggaamsmassaindeks, lae FA) teenoor gesonde kontroles (hoë liggaamsmassaindeks, lae FA) met aanpassings vir ouderdom en geslag (substudie III). ’n Uitbreiding van ons navorsing oor strukturele neurobeelding om breinstrukture in te sluit wat betrokke is by fisiologiese, hedoniese en kognitiewe beheer as deel van ’n “kern-eetnetwerk” het kleiner volumes van die anterior hippokampus verder geïndentifiseer as ’n geslag-spesifieke voorspeller van gewigs toename in eerste-episode pasiënte (n=90) (substudie IV). Ons navorsing ondersteun die rol van gewigstoename as ’n voorspeller van gunstige kliniese uitkomstes in pasiënte met ’n eerste episode van skisofrenie wie se getroue volging van behandeling verseker word. In teenstelling hiermee kan ’n laer liggaamsmassa en by uitbreiding die versuim om gewig aan te sit ’n ongunstige prognose merker wees in eersteepisode pasiënte, veral in die wat middels gebruik. Dit sal goed wees as toekomstige studies kliniese, biologiese en neurobeeldings data kan kombineer met die oogmerk om intrinsieke metaboliese profiele te identifiseer met betrekking tot langtermyn uitkoms in eerste-episode skisofrenie.Doctora

Sexual dysfunction in first-episode schizophrenia spectrum disorders

Sexual dysfunction (SD) is common in patients with schizophrenia. In this study, we examined the prevalence and correlates of SD in a sample of patients with first-episode schizophrenia spectrum disorders (FES) (n ​= ​77). Sexual functioning was examined using the Arizona Sexual Experiences Scale. Clinical measures of interest included the duration of untreated psychosis, psychopathology, depressive symptoms, functionality, and quality of life. Biochemical testing was also performed to measure prolactin, lipid profiles, and fasting glucose levels. In total, 27 (35%) patients met the criteria for SD, which was significantly more prevalent in females than in males (p ​= ​0.027). Higher depression scores, poorer social and occupational functioning, and lower high-density lipoprotein cholesterol levels predicted overall SD. Female sex, more pronounced global psychopathology, and poorer quality of life were also predictors of domain-specific SD, adjusting for the extent of antipsychotic exposure. In conclusion, SD has a high prevalence in patients with FES, particularly females. There is a need for a more nuanced understanding of SD in recent-onset schizophrenia, and to establish its relevance in terms of comorbid depressive symptoms and poor quality of life. SD may require specific attention and tailored treatment in females with FES

Genomic medicine and risk prediction across the disease spectrum

Genomic medicine is based on the knowledge that virtually every medical condition, disease susceptibility or response to treatment is caused, regulated or influenced by genes. Genetic testing may therefore add value across the disease spectrum, ranging from single-gene disorders with a Mendelian inheritance pattern to complex multi-factorial diseases. The critical factors for genomic risk prediction are to determine: (1) where the genomic footprint of a particular susceptibility or dysfunction resides within this continuum, and (2) to what extent the genetic determinants are modified by environmental exposures. Regarding the small subset of highly penetrant monogenic disorders, a positive family history and early disease onset are mostly sufficient to determine the appropriateness of genetic testing in the index case and to inform pre-symptomatic diagnosis in at-risk family members. In more prevalent polygenic noncommunicable diseases (NCDs), the use of appropriate eligibility criteria is required to ensure a balance between benefit and risk. An additional screening step may therefore be necessary to identify individuals most likely to benefit from genetic testing. This need provided the stimulus for the development of a pathology-supported genetic testing (PSGT) service as a new model for the translational implementation of genomic medicine in clinical practice. PSGT is linked to the establishment of a research database proven to be an invaluable resource for the validation of novel and previously described gene-disease associations replicated in the South African population for a broad range of NCDs associated with increased cardio-metabolic risk. The clinical importance of inquiry concerning family history in determining eligibility for personalized genotyping was supported beyond its current limited role in diagnosing or screening for monogenic subtypes of NCDs. With the recent introduction of advanced microarray-based breast cancer subtyping, genetic testing has extended beyond the genome of the host to also include tumor gene expression profiling for chemotherapy selection. The decreasing cost of next generation sequencing over recent years, together with improvement of both laboratory and computational protocols, enables the mapping of rare genetic disorders and discovery of shared genetic risk factors as novel therapeutic targets across diagnostic boundaries. This article reviews the challenges, successes, increasing inter-disciplinary integration and evolving strategies for extending PSGT towards exome and whole genome sequencing (WGS) within a dynamic framework. Specific points of overlap are highlighte