Cortisol, cognition and the ageing prefrontal cortex

The structural and functional decline of the ageing human brain varies by brain region, cognitive function and individual. The underlying biological mechanisms are poorly understood. One potentially important mechanism is exposure to glucocorticoids (GCs; cortisol in humans); GC production is increasingly varied with age in humans, and chronic exposure to high levels is hypothesised to result in cognitive decline via cerebral remodelling. However, studies of GC exposure in humans are scarce and methodological differences confound cross-study comparison. Furthermore, there has been little focus on the effects of GCs on the frontal lobes and key white matter tracts in the ageing brain. This thesis therefore examines relationships among cortisol levels, structural brain measures and cognitive performance in 90 healthy, elderly community-dwelling males from the Lothian Birth Cohort 1936. Salivary cortisol samples characterised diurnal (morning and evening) and reactive profiles (before and after a cognitive test battery). Structural variables comprised Diffusion Tensor Imaging measures of major brain tracts and a novel manual parcellation method for the frontal lobes. The latter was based on a systematic review of current manual methods in the context of putative function and cytoarchitecture. Manual frontal lobe brain parcellation conferred greater spatial and volumetric accuracy when compared to both single- and multi-atlas parcellation at the lobar level. Cognitive ability was assessed via tests of general cognitive ability, and neuropsychological tests thought to show differential sensitivity to the integrity of frontal lobe sub-regions. The majority of, but not all frontal lobe test scores shared considerable overlap with general cognitive ability, and cognitive scores correlated most consistently with the volumes of the anterior cingulate. This is discussed in light of the diverse connective profile of the cingulate and a need to integrate information over more diffuse cognitive networks according to proposed de-differentiation or compensation in ageing. Individuals with higher morning, evening or pre-test cortisol levels showed consistently negative relationships with specific regional volumes and tract integrity. Participants whose cortisol levels increased between the start and end of cognitive testing showed selectively larger regional volumes and lower tract diffusivity (correlation magnitudes <.44). The significant relationships between cortisol levels and cognition indicated that flatter diurnal slopes or higher pre-test levels related to poorer test performance. In contrast, higher levels in the morning generally correlated with better scores (correlation magnitudes <.25). Interpretation of all findings was moderated by sensitivity to type I error, given the large number of comparisons conducted. Though there were limited candidates for mediation analysis, cortisol-function relationships were partially mediated by tract integrity (but not sub-regional frontal volumes) for memory and post-error slowing. This thesis offers a novel perspective on the complex interplay among glucocorticoids, cognition and the structure of the ageing brain. The findings suggest some role for cortisol exposure in determining age-related decline in complex cognition, mediated via brain structure

The genetic relationship between educational attainment and cognitive performance in major psychiatric disorders

Cognitive deficits are a core feature of psychiatric disorders like schizophrenia and bipolar disorder. Evidence supports a genome-wide polygenic score (GPS) for educational attainment (GPSEDU) can be used to explain variability in cognitive performance. We aimed to identify different cognitive domains associated with GPSEDU in a transdiagnostic clinical cohort of chronic psychiatric patients with known cognitive deficits. Bipolar and schizophrenia patients from the PsyCourse cohort (N = 730; 43% female) were used. Likewise, we tested whether GPSs for schizophrenia (GPSSZ) and bipolar disorder (GPSBD) were associated with cognitive outcomes. GPSEDU explained 1.5% of variance in the backward verbal digit span, 1.9% in the number of correctly recalled words of the Verbal Learning and Memory Test, and 1.1% in crystallized intelligence. These effects were robust to the influences of treatment and diagnosis. No significant associations between GPSSZ or GPSBD with cognitive outcomes were found. Furthermore, these risk scores did not confound the effect of GPSEDU on cognitive outcomes. GPSEDU explains a small fraction of cognitive performance in adults with psychiatric disorders, specifically for domains related to linguistic learning and working memory. Investigating such a proxy-phenotype longitudinally, could give intriguing insight into the disease course, highlighting at what time genes play a more influential role on cognitive performance. Better understanding the origin of these deficits might help identify those patients at risk for lower levels of functioning and poor social outcomes. Polygenic estimates may in the future be part of predictive models for more personalized interventions.peerReviewe

Impact of body mass index on the psychopathological profile of obese women Impacto do índice de massa corporal no perfil psicopatológico de mulheres obesas

OBJECTIVE: Obesity is a complex condition associated with a host of medical disorders. One common assumption is that obesity is also related to psychological and emotional complications. However, some studies have shown that obesity itself does not appear to be systematically associated with psychopathological outcomes.The objective of the present study was to evaluate the impact that the various degrees of obesity have on the psychopathological profile of obese patients. METHOD: The study sample consisted of 217 women classified as obese (body mass index > 30 kg/m²) who sought medical treatment for weight loss and were consecutively invited to participate in the study. Anthropometric data were registered for all participants. Psychiatric evaluations were performed using the Beck Depression Inventory and Symptom Checklist-90. Multiple regression analysis was used in order to determine whether any of the studied variables (age, level of education, Beck Depression Inventory score and body mass index) were independently correlated with the score on the different subscales of the Symptom Checklist-90. RESULTS: Only body mass index was found to correlate significantly with the score on the somatization subscale of the Symptom Checklist-90 (r = 0.148, p = 0.035). This correlation remained significant after multiple regression analysis (p = 0.03). No correlation was found between body mass index and the score on any of the other subscales. CONCLUSION: The degree of obesity did not correlate with any of the psychological profiles commonly described in the medical literature, including depression and anxiety. The correlation between obesity and somatization, although weak, might simply be related to an overlapping of symptoms.<br>OBJETIVO: A obesidade é uma condição complexa associada a uma ampla variedade de desordens médicas, incluindo alguns distúrbios emocionais e psicológicos. Entretanto, alguns estudos têm demonstrado que a obesidade, per se, não parece estar sistematicamente associada a alterações psicopatológicas. O objetivo deste estudo foi avaliar o impacto da severidade da obesidade no perfil psicopatológico de pacientes com obesidade, utilizando o Symptom Checklist-90. MÉTODO: Foram selecionados 217 pacientes do sexo feminino, com obesidade (índice de massa corporal > 30 kg/m²), que procuraram tratamento para perda de peso. Os participantes tiveram seus dados antropométricos registrados. A avaliação psiquiátrica foi realizada utilizando o Inventário de Depressão de Beck e o Symptom Checklist-90. A Regressão Linear Múltipla foi utilizada para avaliar quais variáveis (idade, nível educacional, Inventário de Depressão de Beck e índice de massa corporal) apresentariam uma correlação independente com as subscalas do Symptom Checklist-90. RESULTADOS : Uma correlação significativa foi encontrada apenas entre o índice de massa corporal e o domínio Somatização (r = 0,148, p = 0,035). Esta correlação permaneceu após análise de regressão múltipla (p = 0,03). Nenhuma correlação foi encontrada entre índice de massa corporal e os outros domínios. CONCLUSÃO: A gravidade da obesidade não se correlacionou com diversos dos perfis psicopatológicos comumente encontrados na literatura, como depressão e ansiedade. A correlação entre obesidade e somatização, embora fraca, pode estar relacionada simplesmente a uma sobreposição de sintomas