Alison Dorothy Murray

BACKGROUND: Brain perivascular spaces (PVS) are emerging magnetic resonance imaging markers of microvascular function and waste metabolite clearance. Although PVS enlargement has been linked to aging and vascular risk, it remains unclear whether PVS morphometry reflects shared familial microvascular characteristics and how these are shaped by individual vascular, physiological, and neuropsychiatric factors. We investigated whether PVS morphometry captures these familial characteristics in addition to individual determinants. METHODS: We analyzed 1183 participants from the Stratifying Depression and Resilience Longitudinally family-based cohort, including 324 individuals with first-degree relatives. Automated magnetic resonance imaging segmentation quantified PVS volume, count, density, and median length in the centrum semiovale and basal ganglia. Linear mixed-effects models assessed associations with age, hypertension, hair cortisol, depressive symptom scores, and hand grip strength while accounting for familial clustering. RESULTS: In 1050 individuals (59.5% female; mean age, 59.3±10.1 years), PVS burden increased with age (PVSvolume%ROI, β=0.18 [95% CI, 0.11–0.26]; P P =0.009; BG, β=0.11 [0.043–0.18]; P =0.002; largely robust to false discovery rate correction), and with higher hair cortisol (PVS count β=0.08 [0.003–0.15]; P =0.041; borderline after false discovery rate correction) and weaker grip strength (PVSvolume%ROI β=−0.09 [−0.16 to −0.02]; P =0.013), in the centrum semiovale. Familial clustering was significant for PVS volume (β=0.22 [0.096–0.52]; P =0.013) and median length (β=0.28 [0.16−0.49]; P =0.0003), independent of other factors. CONCLUSIONS: PVS morphometry reflects shared familial microvascular phenotypes and neuropsychiatric influences beyond hypertension, highlighting both familial and individual determinants of PVS burden and morphology. These findings support PVS morphometry as a neuroimaging marker of cerebral microvascular health.

Background: Rheumatoid arthritis (RA) patients frequently report fatigue, which notably diminishes their quality of life. Emerging research points to a correlation between inflammation-induced fatigue and brain structural alterations. Objectives: This study evaluates the variance in myelin integrity among patients with RA-related fatigue, investigating the potential of magnetization transfer ratio (MTR) as a biomarker, in comparison with healthy controls. Methods: A prospective cohort analysis was conducted comprised 60 RA patients with fatigue, categorized into active (n = 30) and non-active (n = 30) disease states, alongside 20 healthy controls (HC). A 3 Tesla MRI system was utilized to perform diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) sequences. MTR maps were generated using in-house MATLAB code and co-registered with DTI data using SPM8. These were then analyzed through tract-based spatial statistics (TBSS) with threshold-free cluster enhancement (TFCE) and corrected for multiple comparisons. MTR values were assessed using Randomize from the FSL toolkit, applying a general linear model (GLM) for voxel-wise analysis and TFCE for p-value generation, with family-wise error (FWE) control (P < .05) for multiple comparisons. Results: The RF group exhibited significantly lower myelin integrity (TFCE, P < .05) compared to HCs, particularly in the middle cerebellar peduncle and splenium of the corpus callosum, with no marked difference between active and non-active RA disease statuses. There is a discernible disparity in myelin integrity between RA patients with fatigue and healthy individuals, suggesting microstructural white matter alterations that are congruent with DTI findings. Conclusion: This study reveals that rheumatoid arthritis (RA) patients with fatigue exhibit significantly lower myelin integrity, particularly in the middle cerebellar peduncle and splenium of the corpus callosum, compared to healthy controls. Notably, this finding was consistent regardless of the active or non-active status of the RA disease, highlighting persistent white matter alterations in this patents cohort. Advances in knowledge: The research demonstrates that magnetization transfer ratio (MTR) imaging can effectively map microstructural changes in RA patients with fatigue, suggesting its potential as a biomarker for assessing white matter integrity in this condition. While it does not establish a direct causal relationship, it provides valuable insights into the role of MTR mapping in understanding brain alterations in patients with fatigue-related RA.

Background: Alzheimer’s Disease (AD) frequently coexist with cerebrovascular disease (CVD) and makes it difficult for researchers to delineate the two pathologies with available diagnostic criteria. Neuroimaging techniques, especially FDG‐PET can help differentiate the two pathologies based on the characteristic temporo‐parietal metabolic deficitsin AD and regional patchy deficits in CVD. Co‐occurrence of the both patterns can be seen in mixed cases.Existing literature supports a possible role for cardiovascular risk factors in AD pathogenesis. This study aims to determine whether cardiovascular risk factors have a causative association with typical AD pathogenesis or it has an association with mixed AD.Method: Baseline brain FDG‐PET images of participants with a diagnosis of AD from two large clinical trials of hydromethylthionine were classified into “typical AD” and “mixed” patterns through visual analysis. Causal association of independent variable age and dependent variables cardiovascular risk factors, White matter hyperintensities (WMH), AD subtypes and severity of cognitive impairment depicted with ADAS Cog scores were analysed using Structural equation modelling (SEM).Result: Out of a total 794 participants, 533 (67.1%) were classified as typical AD and 261 (32.8%) were classified as mixed. Overall, the people with a mixed pattern were significantly younger than the people with a typical AD pattern. Age significantly influenced cardiovascular risk factors, WMH and typical AD subtype. The severity of cognitive impairment was significantly influenced by cardiovascular risk factors, WMH and typical AD subtype. Interestingly, cardiovascular risk factors had a statistically significant positive influence on typical AD subtype in comparison to mixed.Conclusion: It is well known fact that the cardiovascular risk factors are commonly associated with cerebrovascular disease but contrary to our expectations cardiovascular risk factors have a causal association with typical AD.

Background Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

Background: Major depressive disorder (MDD) was previously associated with negative affective biases. Evidence from larger population-based studies, however, is lacking, including whether biases normalise with remission. We investigated associations between affective bias measures and depressive symptom severity across a large community-based sample, followed by examining differences between remitted individuals and controls.Methods: Participants from Generation Scotland (N = 1109) completed the: (i) Bristol Emotion Recognition Task (BERT), (ii) Face Affective Go/No-go (FAGN), and (iii) Cambridge Gambling Task (CGT). Individuals were classified as MDD-current (n = 43), MDD-remitted (n = 282), or controls (n = 784). Analyses included using affective bias summary measures (primary analyses), followed by detailed emotion/condition analyses of BERT and FAGN (secondary analyses).Results: For summary measures, the only significant finding was an association between greater symptoms and lower risk adjustment for CGT across the sample (individuals with greater symptoms were less likely to bet more, despite increasingly favourable conditions). This was no longer significant when controlling for non-affective cognition. No differences were found for remitted-MDD v. controls. Detailed analysis of BERT and FAGN indicated subtle negative biases across multiple measures of affective cognition with increasing symptom severity, that were independent of non-effective cognition [e.g. greater tendency to rate faces as angry (BERT), and lower accuracy for happy/neutral conditions (FAGN)]. Results for remitted-MDD were inconsistent.Conclusions: This suggests the presence of subtle negative affective biases at the level of emotion/condition in association with depressive symptoms across the sample, over and above those accounted for by non-affective cognition, with no evidence for affective biases in remitted individuals.

Introduction: Childhood trauma and adversity are common across societies and have strong associations with physical and psychiatric morbidity throughout the life-course. One mechanism through which childhood trauma may predispose individuals to poor psychiatric outcomes, such as raised risk of lifetime depression, could be via associations with brain structure. This study aimed to elucidate the associations between childhood trauma scores and brain structure across two large, independent community cohorts. Methods: The two samples comprised (i) a subsample of individuals from Generation Scotland with imaging and in-depth phenotyping, including the CTQ-28 (n=1,024); and (ii) individuals from UK Biobank with imaging and a modified summary CTQ measure (n=27,202). This comprised n=28,226 for mega-analysis. Scans were processed using FreeSurfer image processing software, providing cortical and subcortical as well as global brain metrics. Regression models were used to determine associations between these metrics and childhood trauma measures. Associations between childhood trauma measures and psychiatric phenotypes were also explored. Results: Childhood trauma measures associated with lifetime risk of depression diagnosis with similar ORs across cohorts (OR 1.06, 1.23 GS and UKB respectively), which also related to earlier onset and more recurrent course within both samples. There was also evidence for associations between childhood trauma measures and a range of brain structures. Replicated findings included reduced global brain volumes, reduced cortical surface area but not thickness, with highest effects at mega-analysis seen in the frontal (β=-0.0385, SE=0.0048, p _(FDR) =5.43×10 ⁻¹⁵ ) and parietal lobes (β=-0.0387, SE=0.005, p _(FDR) =1.56×10 ⁻¹⁴ ). At a regional level, one subcortical regional volume in particular – the ventral diencephalon (VDc) – displayed significant associations with childhood trauma measures across the two cohorts and at mega-analysis (β=-0.0232, SE=0.0039, p _(FDR) =2.91×10 ⁻⁸ ). There was also evidence for associations with reduced hippocampus, thalamus, and nucleus accumbens volumes, however these were not as consistent across cohorts. Discussion: There was strong evidence for associations between childhood trauma and reduced global and regional brain volumes across cohorts. In particular, the presence of an association between childhood trauma and the volume of the VDc (which includes the hypothalamic area), with replication, provides further evidence of the importance of neuroendocrine stress response pathways in links between early life stress and clinical outcomes.