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 association between chronotype and nonrestorative sleep

Nonrestorative sleep (NRS), characterized by a lack of refreshment upon awakening, has received little attention in the sleep literature even though it can occur and cause impairment apart from other sleep difficulties associated with insomnia. The Restorative Sleep Questionnaire (RSQ; Drake et al., 2014) is one of the first validated self-report instruments for investigating NRS severity, presenting new opportunities to explore what factors predict and perhaps contribute to unrefreshing sleep. The present study sought to determine whether inherent circadian preference for morning or evening activity, known as chronotype, predicted restorative sleep in 164 college undergraduates who completed daily RSQs over two weeks. Participants who endorsed greater orientation to evening activity on the morningness-eveningness questionnaire (Terman, Rifkin, Jacobs, & White, 2001) reported significantly less average restorative sleep across their full sampling period, and this association was maintained after accounting for demographic factors, number of sleep-relevant psychiatric and medical diagnoses, sleep diary parameters, self-reported status as an insomniac, and ratings of sleep quality. Furthermore, when analyses were conducted separately for weekday and weekend RSQ scores, eveningness significantly predicted NRS above extraneous variables only during the workweek, not during Saturday and Sunday. These findings have implications for the developing conceptualization of NRS, and continue the work of elucidating the interconnections between common sleep disturbances and the circadian system. (Published By University of Alabama Libraries

An idiosyncratic zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver

Abstract A perimetastatic capsule is a strong positive prognostic factor in liver metastases, but its origin remains unclear. Here, we systematically quantify the capsule’s extent and cellular composition in 263 patients with colorectal cancer liver metastases to investigate its clinical significance and origin. We show that survival improves proportionally with increasing encapsulation and decreasing tumor-hepatocyte contact. Immunostaining reveals the gradual zonation of the capsule, transitioning from benign-like NGFRhigh stroma at the liver edge to FAPhigh stroma towards the tumor. Encapsulation correlates with decreased tumor viability and preoperative chemotherapy. In mice, chemotherapy and tumor cell ablation induce capsule formation. Our results suggest that encapsulation develops where tumor invasion into the liver plates stalls, representing a reparative process rather than tumor-induced desmoplasia. We propose a model of metastases growth, where the efficient tumor colonization of the liver parenchyma and a reparative liver injury reaction are opposing determinants of metastasis aggressiveness

Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms

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