Associations of negative affective biases and depressive symptoms in a community-based sample.

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.

Investigation of the Inter- and Intrascanner Reproducibility and Repeatability of Radiomics Features in T1-Weighted Brain MRI.

BACKGROUND: Radiomics is the high throughput analysis of medical images using computer algorithms, which specifically assess textural features. It has increasingly been proposed as a tool for the development of imaging biomarkers. However, an important acknowledged limitation of radiomics is the lack of reproducibility of features produced. PURPOSE: To assess reproducibility and repeatability of radiomics variables in brain MRI through a multivisit, multicenter study. STUDY TYPE: Retrospective. POPULATION: Fourteen individuals visiting three institutions twice, 10 males with the mean age of 36.3 years and age range 25-51. FIELD STRENGTH: 3D T1W inversion recovery on three 1.5-T General Electric scanners. ASSESSMENT: Radiomics analysis by a consultant radiologist performed on the T1W images of the whole brain on all visits. All possible radiomics features were generated. STATISTICAL TEST: Concordance correlation coefficient (CCC) and dynamic range (DR) for all variables were calculated to assess the test-retest repeatability. Intraclass correlation coefficients (ICCs) were calculated to investigate the reproducibility of features across centers. RESULTS: Of 1596 features generated, 57 from center 1, 15 from center 2, and 22 from center 3 had a CCC > 0.9 and DR > 0.9. Eight variables had CCC > 0.9 and DR > 0.9 in all centers. Forty-one variables had an ICC of >0.9. No variables had CCC > 0.9, DR > 0.9, and ICC > 0.9. DATA CONCLUSION: Repeatability and reproducibility of variables is a significant limitation of radiomics analysis in 3DT1W brain MRI. Careful selection of radiomic features is required. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

Early life predictors of late life cerebral small vessel disease in four prospective cohort studies.

Development of cerebral small vessel disease, a major cause of stroke and dementia, may be influenced by early life factors. It is unclear whether these relationships are independent of each other, of adult socio-economic status or of vascular risk factor exposures. We examined associations between factors from birth (ponderal index, birth weight), childhood (IQ, education, socio-economic status), adult small vessel disease, and brain volumes, using data from four prospective cohort studies: STratifying Resilience And Depression Longitudinally (STRADL) (n = 1080; mean age = 59 years); the Dutch Famine Birth Cohort (n = 118; mean age = 68 years); the Lothian Birth Cohort 1936 (LBC1936; n = 617; mean age = 73 years), and the Simpson's cohort (n = 110; mean age = 78 years). We analysed each small vessel disease feature individually and summed to give a total small vessel disease score (range 1-4) in each cohort separately, then in meta-analysis, adjusted for vascular risk factors and adult socio-economic status. Higher birth weight was associated with fewer lacunes [odds ratio (OR) per 100 g = 0.93, 95% confidence interval (CI) = 0.88 to 0.99], fewer infarcts (OR = 0.94, 95% CI = 0.89 to 0.99), and fewer perivascular spaces (OR = 0.95, 95% CI = 0.91 to 0.99). Higher childhood IQ was associated with lower white matter hyperintensity burden (OR per IQ point = 0.99, 95% CI 0.98 to 0.998), fewer infarcts (OR = 0.98, 95% CI = 0.97 to 0.998), fewer lacunes (OR = 0.98, 95% CI = 0.97 to 0.999), and lower total small vessel disease burden (OR = 0.98, 95% CI = 0.96 to 0.999). Low education was associated with more microbleeds (OR = 1.90, 95% CI = 1.33 to 2.72) and lower total brain volume (mean difference = -178.86 cm3, 95% CI = -325.07 to -32.66). Low childhood socio-economic status was associated with fewer lacunes (OR = 0.62, 95% CI = 0.40 to 0.95). Early life factors are associated with worse small vessel disease in later life, independent of each other, vascular risk factors and adult socio-economic status. Risk for small vessel disease may originate in early life and provide a mechanistic link between early life factors and risk of stroke and dementia. Policies investing in early child development may improve lifelong brain health and contribute to the prevention of dementia and stroke in older age.

A meta-analysis of genome-wide association studies of epigenetic age acceleration.

'Epigenetic age acceleration' is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. Two commonly used measures, derived from DNA methylation, are Horvath-based (Horvath-EAA) and Hannum-based (Hannum-EAA) epigenetic age acceleration. We conducted genome-wide association studies of Horvath-EAA and Hannum-EAA in 13,493 unrelated individuals of European ancestry, to elucidate genetic determinants of differential epigenetic ageing. We identified ten independent SNPs associated with Horvath-EAA, five of which are novel. We also report 21 Horvath-EAA-associated genes including several involved in metabolism (NHLRC, TPMT) and immune system pathways (TRIM59, EDARADD). GWAS of Hannum-EAA identified one associated variant (rs1005277), and implicated 12 genes including several involved in innate immune system pathways (UBE2D3, MANBA, TRIM46), with metabolic functions (UBE2D3, MANBA), or linked to lifespan regulation (CISD2). Both measures had nominal inverse genetic correlations with father's age at death, a rough proxy for lifespan. Nominally significant genetic correlations between Hannum-EAA and lifestyle factors including smoking behaviours and education support the hypothesis that Hannum-based epigenetic ageing is sensitive to variations in environment, whereas Horvath-EAA is a more stable cellular ageing process. We identified novel SNPs and genes associated with epigenetic age acceleration, and highlighted differences in the genetic architecture of Horvath-based and Hannum-based epigenetic ageing measures. Understanding the biological mechanisms underlying individual differences in the rate of epigenetic ageing could help explain different trajectories of age-related decline.

Blunted medial prefrontal cortico-limbic reward-related effective connectivity and depression.

Major depressive disorder is a leading cause of disability and significant mortality, yet mechanistic understanding remains limited. Over the past decade evidence has accumulated from case-control studies that depressive illness is associated with blunted reward activation in the basal ganglia and other regions such as the medial prefrontal cortex. However it is unclear whether this finding can be replicated in a large number of subjects. The functional anatomy of the medial prefrontal cortex and basal ganglia has been extensively studied and the former has excitatory glutamatergic projections to the latter. Reduced effect of glutamatergic projections from the prefrontal cortex to the nucleus accumbens has been argued to underlie motivational disorders such as depression, and many prominent theories of major depressive disorder propose a role for abnormal cortico-limbic connectivity. However, it is unclear whether there is abnormal reward-linked effective connectivity between the medial prefrontal cortex and basal ganglia related to depression. While resting state connectivity abnormalities have been frequently reported in depression, it has not been possible to directly link these findings to reward-learning studies. Here, we tested two main hypotheses. First, mood symptoms are associated with blunted striatal reward prediction error signals in a large community-based sample of recovered and currently ill patients, similar to reports from a number of studies. Second, event-related directed medial prefrontal cortex to basal ganglia effective connectivity is abnormally increased or decreased related to the severity of mood symptoms. Using a Research Domain Criteria approach, data were acquired from a large community-based sample of subjects who participated in a probabilistic reward learning task during event-related functional MRI. Computational modelling of behaviour, model-free and model-based functional MRI, and effective connectivity dynamic causal modelling analyses were used to test hypotheses. Increased depressive symptom severity was related to decreased reward signals in areas which included the nucleus accumbens in 475 participants. Decreased reward-related effective connectivity from the medial prefrontal cortex to striatum was associated with increased depressive symptom severity in 165 participants. Decreased striatal activity may have been due to decreased cortical to striatal connectivity consistent with glutamatergic and cortical-limbic related theories of depression and resulted in reduced direct pathway basal ganglia output. Further study of basal ganglia pathophysiology is required to better understand these abnormalities in patients with depressive symptoms and syndromes.

The use of positron emission tomography/magnetic resonance imaging in dementia: A literature review.

OBJECTIVES: Positron emission tomography-magnetic resonance imaging (PET/MRI) is an emerging hybrid imaging system in clinical nuclear medicine. Research demonstrates a comparative utility to current unimodal and hybrid methods, including PET-computed tomography (PET/CT), in several medical subspecialities such as neuroimaging. The aim of this review is to critically evaluate the literature from 2016 to 2021 using PET/MRI for the investigation of patients with mild cognitive impairment or dementia, and discuss the evidence base for widening its application into clinical practice. METHODS: A comprehensive literature search using the PubMed database was conducted to retrieve studies using PET/MRI in relation to the topics of mild cognitive impairment, dementia, or Alzheimer's disease between January 2016 and January 2021. This search strategy enabled studies on all dementia types to be included in the analysis. Studies were required to have a minimum of 10 human subjects and incorporate simultaneous PET/MRI. RESULTS: A total of 116 papers were retrieved, with 39 papers included in the final selection. These were broadly categorised into reviews (12), technical/methodological papers (11) and new data studies (16). For the current review, discussion focused on findings from the new data studies. CONCLUSIONS: PET/MRI offers additional insight into the underlying anatomical, metabolic and functional changes associated with dementia when compared with unimodal methods and PET/CT, particularly relating to brain regions including the hippocampus and default mode network. Furthermore, the improved diagnostic utility of PET/MRI, as reported by radiologists, offers improved classification of dementia patients, with important implications for clinical management.

Automated classification of depression from structural brain measures across two independent community-based cohorts.

Major depressive disorder (MDD) has been the subject of many neuroimaging case-control classification studies. Although some studies report accuracies ≥80%, most have investigated relatively small samples of clinically-ascertained, currently symptomatic cases, and did not attempt replication in larger samples. We here first aimed to replicate previously reported classification accuracies in a small, well-phenotyped community-based group of current MDD cases with clinical interview-based diagnoses (from STratifying Resilience and Depression Longitudinally cohort, 'STRADL'). We performed a set of exploratory predictive classification analyses with measures related to brain morphometry and white matter integrity. We applied three classifier types-SVM, penalised logistic regression or decision tree-either with or without optimisation, and with or without feature selection. We then determined whether similar accuracies could be replicated in a larger independent population-based sample with self-reported current depression (UK Biobank cohort). Additional analyses extended to lifetime MDD diagnoses-remitted MDD in STRADL, and lifetime-experienced MDD in UK Biobank. The highest cross-validation accuracy (75%) was achieved in the initial current MDD sample with a decision tree classifier and cortical surface area features. The most frequently selected decision tree split variables included surface areas of bilateral caudal anterior cingulate, left lingual gyrus, left superior frontal, right precentral and paracentral regions. High accuracy was not achieved in the larger samples with self-reported current depression (53.73%), with remitted MDD (57.48%), or with lifetime-experienced MDD (52.68-60.29%). Our results indicate that high predictive classification accuracies may not immediately translate to larger samples with broader criteria for depression, and may not be robust across different classification approaches.

Circulating asymmetric dimethylarginine and cognitive decline: A 4-year follow-up study of the 1936 Aberdeen Birth Cohort.

BACKGROUND: The underlying mechanisms leading to dementia and Alzheimer's disease (AD) are unclear. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, may be associated with cognitive decline, but population-based evidence is lacking. METHODS: Change in cognitive performance was assessed in participants of the Aberdeen Birth Cohort of 1936 using longitudinal Raven's progressive matrices (RPM) between 2000 and 2004. Multiple linear regression was used to estimate the association between ADMA concentrations in 2000 and change in cognitive performance after adjustment for potential confounders. RESULTS: A total of 93 participants had complete information on cognitive performance between 2000 and 2004. Mean plasma ADMA concentrations were approximately 0.4 µmol/L lower in those participants with stable or improved RPM scores over follow-up compared with participants whose cognitive performance worsened. In confounder-adjusted analysis, one SD (0.06 µmol/L) increase in ADMA at 63 years of age was associated with an average reduction in RPM of 1.26 points (95% CI 0.14-2.26) after 4 years. CONCLUSION: Raised plasma ADMA concentrations predicted worsening cognitive performance after approximately 4 years in this cohort of adults in late-middle age. These findings have implications for future research, including presymptomatic diagnosis or novel therapeutic targets for dementia and AD.

Brain hyperintensities in magnetic resonance imaging of patients with mild acute focal neurology.

PURPOSE: Hyperintensities are common in neuroimaging scans of patients with mild acute focal neurology. However, their pathogenic role and clinical significance is not well understood. We assessed whether there was an association between hyperintensity score with diagnostic category and clinical assessments/measures. METHODS: One hundred patients (51 ± 12 years; 45:55 women:men), with symptomatology suggestive of short duration ischemia referred for magnetic resonance imaging, were prospectively recruited in NHS Grampian between 2012 and 2014. Hyperintensities were quantified, on T2 and FLAIR, using the Scheltens score. RESULTS: The most frequent diagnosis was minor stroke (33%), migraine (25%) and transient ischemic attack (17%). The mean total Scheltens score was 28.49 ± 11.93 with all participants having various loads of hyperintensities. Statistically significant correlations between hyperintensity scores and clinical assessments/measures (age, systolic blood pressure, pulse pressure, MoCA) at the global level were also reflected regionally. These provide further supporting data in terms of the robustness of the Scheltens scale. CONCLUSION: Hyperintensities could serve as a diagnostic and prognostic imaging biomarker for patients, presenting with mild acute focal neurology, warranting application of automated quantification methods. However, larger cohorts are required to provide a definitive answer especially as this is a heterogenous group of patients.

An epigenetic score for BMI based on DNA methylation correlates with poor physical health and major disease in the Lothian Birth Cohort.

BACKGROUND: The relationship between obesity and adverse health is well established, but little is known about the contribution of DNA methylation to obesity-related health outcomes. This study tests associations between an epigenetic score for body mass index (BMI) and health-related, cognitive, psychosocial and lifestyle outcomes in the Lothian Birth Cohort 1936. This study also tests whether these associations are independent of phenotypic BMI. METHOD: Analyses were conducted using data from the Lothian Birth Cohort 1936 (n = 892). Weights for the epigenetic BMI score were derived using penalised regression on methylation data from unrelated Generation Scotland participants (n = 2562). Associations were tested for replication in an independent sample: the Lothian Birth Cohort 1921 (n = 433). RESULTS: A higher epigenetic BMI score was associated with higher BMI (R2 = 0.1), greater body weight (R2 = 0.06), greater time taken to walk 6 m, poorer lung function and poorer general physical health (all R2 = 0.02), greater levels of triglycerides (R2 = 0.09), greater %total HbA1c (R2 = 0.06), lower levels of high-density lipoprotein cholesterol (HDL; R2 = 0.08), higher HDL ratio (HDL/total cholesterol; R2 = 0.03), lower health-related quality of life, physical inactivity, and greater social deprivation (all R2 = 0.02). The epigenetic BMI score (per SD) was also associated with type 2 diabetes (OR 2.17, 95% CI 1.67, 2.84), cardiovascular disease (OR 1.45, 95% CI 1.24, 1.71) and high blood pressure (OR 1.30, 95% CI 1.13, 1.49; all p < 0.00026 after Bonferroni correction). Associations were replicated for BMI (R2 = 0.06), body weight (R2 = 0.04), health-related quality of life (R2 = 0.02), HbA1c (R2 = 0.07) and triglycerides (R2 = 0.07; all p < 0.0045 after Bonferroni correction). CONCLUSIONS: We observed and replicated associations between an epigenetic score for BMI and variables related to poor physical health and metabolic syndrome. Regression models with both epigenetic and phenotypic BMI scores as predictors accounted for a greater proportion of variance in all outcome variables than either predictor alone, demonstrating independent and additive effects of epigenetic and phenotypic BMI scores.

Functional and structural magnetic resonance imaging correlates of fatigue in patients with rheumatoid arthritis.

OBJECTIVES: Fatigue is a major burden among patients with RA, yet is poorly understood. We sought to conduct the first imaging study to investigate the neurobiological correlates of fatigue in RA and to improve upon the methodological limitations of previous neuroimaging studies that have investigated this symptom in other populations. METHODS: Chronically fatigued RA patients were clinically characterized before undertaking a combined functional and structural mode MRI brain scan. The functional sequences were acquired during a fatigue-evoking task, then network-to-whole-brain analyses were undertaken. The structural analyses employed voxel-based morphometry in order to quantify regional grey matter volume. The scan was repeated 6 months later to test reproducibility. RESULTS: Fifty-four participants attended both scans [n = 41 female; baseline mean (s.d.) age 54.94 (11.41) years]. A number of significant functional and structural neural imaging correlates of fatigue were identified. Notably, patients who reported higher levels of fatigue demonstrated higher levels of functional connectivity between the Dorsal Attention Network and medial prefrontal gyri, a finding that was reproduced in the repeat scans. Structurally, greater putamen grey matter volumes significantly correlated with greater levels of fatigue. CONCLUSION: Fatigue in RA is associated with functional and structural MRI changes in the brain. The newly identified and reproduced neural imaging correlates provide a basis for future targeting and stratification of this key patient priority.

Increased diastolic blood pressure is associated with MRI biomarkers of dementia-related brain pathology in normative ageing.

Background: hypertension is a risk for brain ageing, but the mechanisms underlying this effect remain unclear. Magnetic resonance imaging (MRI) detected biomarkers of brain ageing include white matter hyperintensities (WMHs), a marker of cerebrovascular disease, and hippocampal volume, a marker of Alzheimer's disease pathology. Objective: to examine relationships between blood pressure (BP) components and brain pathology in older adults. Subjects: two hundred and twenty-seven members of the Aberdeen 1936 Birth Cohort between ages 64 and 68 years. Methods: BP was assessed biennially between 64 and 68 years and brain MRI performed at 68 years. The risk factors of interest were diastolic and systolic BP and their visit-to-visit variability. Outcomes were WMH abundance and hippocampal volume. Regression models, controlling for confounding factors, examined their relationships. Results: higher diastolic BP predicted increased WMH (ß = 0.13, P = 0.044) and smaller hippocampi (ß = -0.25, P = 0.006). In contrast, increased systolic BP predicted larger hippocampi (ß = 0.22, P = 0.013). Variability of diastolic BP predicted lower hippocampal volume (ß = -0.15, P = 0.033). These relationships were independent of confounding life-course risk factors. Anti-hypertensive medication did not modify these relationships, but was independently associated with increased WMH (ß = 0.17, P = 0.011). Conclusion: increased diastolic BP is associated with biomarkers of both cerebrovascular and Alzheimer's diseases, whereas the role of systolic BP is less clear, with evidence for a protective effect on hippocampal volume. These differing relationships emphasise the importance of considering individual BP components with regard to brain ageing and pathology. Interventions targeting diastolic hypertension and its chronic variability may provide new strategies able to slow the accumulation of these harmful pathologies.

A brain imaging repository of normal structural MRI across the life course: Brain Images of Normal Subjects (BRAINS).

The Brain Images of Normal Subjects (BRAINS) Imagebank (http://www.brainsimagebank.ac.uk) is an integrated repository project hosted by the University of Edinburgh and sponsored by the Scottish Imaging Network: A Platform for Scientific Excellence (SINAPSE) collaborators. BRAINS provide sharing and archiving of detailed normal human brain imaging and relevant phenotypic data already collected in studies of healthy volunteers across the life-course. It particularly focusses on the extremes of age (currently older age, and in future perinatal) where variability is largest, and which are under-represented in existing databanks. BRAINS is a living imagebank where new data will be added when available. Currently BRAINS contains data from 808 healthy volunteers, from 15 to 81years of age, from 7 projects in 3 centres. Additional completed and ongoing studies of normal individuals from 1st to 10th decades are in preparation and will be included as they become available. BRAINS holds several MRI structural sequences, including T1, T2, T2* and fluid attenuated inversion recovery (FLAIR), available in DICOM (http://dicom.nema.org/); in future Diffusion Tensor Imaging (DTI) will be added where available. Images are linked to a wide range of 'textual data', such as age, medical history, physiological measures (e.g. blood pressure), medication use, cognitive ability, and perinatal information for pre/post-natal subjects. The imagebank can be searched to include or exclude ranges of these variables to create better estimates of 'what is normal' at different ages.

Late-life deficits in cognitive, physical and emotional functions, childhood intelligence and occupational profile: a life-course examination of the Aberdeen 1936 Birth Cohort (ABC1936).

OBJECTIVES: the 'triad of impairment' phenomenon describes the co-occurrence of age-related cognitive, emotional and physical functioning deficits. We investigated how occupational profile and childhood intelligence contribute to the triad of impairment in late life. METHODS: we analysed data of a subsample of the Aberdeen Birth Cohort of 1936 (n = 346). Data were collected on participants' childhood intelligence, late-life cognitive ability, physical functioning, depressive symptoms and main lifetime occupation. We summarised the various occupational and impairment measures into two latent variables, 'occupational profile' and the 'triad of impairment'. We used a series of data reduction approaches and structural equation models (SEMs) of increasing complexity to test both the validity of the models and to understand causal relationships between the life-course risks for the triad of impairment. RESULTS: occupational profile had a significant effect on the triad of impairment independent of childhood intelligence. Childhood intelligence was the predominant influence on the triad of impairment and exerted its effect directly and indirectly via its influence on occupation. The direct effect of childhood intelligence exceeded the independent influence of the occupational profile on impairment by a factor of 1.7-1.8 and was greater by a factor of ∼4 from the indirect pathway (via occupation). CONCLUSIONS: childhood intelligence was the predominant influence on the triad of impairment in late life, independently of the occupational profile. Efforts to reduce impairment in older adults should be informed by a life-course approach with special attention to the early-life environment.

Structural brain complexity and cognitive decline in late life--a longitudinal study in the Aberdeen 1936 Birth Cohort.

Brain morphology and cognitive ability change with age. Gray and white matter volumes decrease markedly by the 7th decade of life when cognitive decreases first become readily detectable. As a consequence, the shape complexity of the cortical mantle may also change. The purposes of this study are to examine changes over a five year period in brain structural complexity in late life, and to investigate cognitive correlates of any changes. Brain magnetic resonance images at 1.5 Tesla were acquired from the Aberdeen 1936 Birth Cohort at about ages 68 years (243 participants) and 73 years (148 participants returned). Measures of brain complexity were extracted using Fractal Dimension (FD) and calculated using the box-counting method. White matter complexity, brain volumes and cognitive performance were measured at both 68 and 73 years. Childhood ability was measured at age 11 using the Moray House Test. FD and brain volume decrease significantly from age 68 to 73 years. Using a multilevel linear modeling approach, we conclude that individual decreases in late life white matter complexity are not associated with differences in executive function but are linked to information processing speed, auditory-verbal learning, and reasoning in specific models-with adjustment for childhood mental ability. A significant association was found after adjustment for age, brain volume and childhood mental ability. Complexity of white matter is associated with higher fluid cognitive ability and, in a longitudinal study, predicts retention of cognitive ability within late life.

Neural correlates of fatigue in granulomatosis with polyangiitis: a functional magnetic resonance imaging study.

OBJECTIVE: The aim of this study was to investigate the neurophysiological effects of fatigue among patients with granulomatosis with polyangiitis (GPA). METHODS: A case-control functional MRI (fMRI) study was conducted. Stable GPA subjects were recruited according to fatigue status, with those reporting fatigue defined as cases and those not defined as controls. In addition, a control group of general population subjects with idiopathic fatigue were studied. During fMRI, all participants performed a fatigue-inducing cognitive task. Functional data were acquired with a 3 T MRI scanner during periods of task activity and rest. Analyses of the differences in blood oxygen level dependent (BOLD) signal were then performed using SPM8 software and comparisons were made between case and control groups. RESULTS: GPA cases (n = 12) were demographically matched to GPA controls (n = 14) and were clinically similar apart from the higher reporting of fatigue, by design, and depressive symptoms (P = 0.0007). After adjusting for depressive symptoms, comparison of BOLD signals revealed significantly greater activation in the right thalamus, left paracentral lobule, left medial frontal gyrus and right medial globus pallidus among GPA cases. When compared with the similarly fatigued population control group (n = 13), GPA cases shared many overlapping areas of activation. However, in addition, the population control group revealed significantly greater activation elsewhere, principally the left precentral gyrus, right superior frontal gyrus and right cingulate gyrus. CONCLUSION: fMRI has identified specific differences in the neurophysiology of fatigued GPA subjects. Future application of this promising biomarker may inform the precise mechanisms of this clinically important symptom.

Homocysteine, antioxidant micronutrients and late onset dementia.

PURPOSE: To distinguish between contributions to dementia made by homocysteine, folate, B12 and antioxidant micronutrients. METHODS: This is a follow-up study of a sample reported in 2002. Homocysteine was measured at baseline in 201 individuals born in 1921 and without dementia at age 77 years and followed up to age 88 years. Baseline macro- and micronutrient status was estimated from BMI, the MONICA food frequency questionnaire, plasma folate, B12 and, in a subgroup (N = 173), plasma antioxidant micronutrients. Time to dementia onset during follow-up was compared between participants grouped by homocysteine concentration using Cox regression. Model 1 adjusted for age, sex, childhood IQ, education, socioeconomic deprivation, presence of heart disease, hypertension, plasma folate and B12. In model 2 plasma, antioxidants were added to these covariables. RESULTS: During a mean follow-up of about 5 years, there were 39 incident dementia cases among 201 participants. In model 1, being in the highest homocysteine group (>14 µmol/L) was associated with a 234 % increased risk (HR 3.34, 95 % CI 1.16-9.57) of any dementia. After inclusion of plasma antioxidants in model 2, there were 32 incident dementia cases from a subsample (N = 173). Homocysteine >14 µmol was associated with a 272 % increased dementia risk (HR = 3.72, 95 % CI 1.06-13.08). CONCLUSIONS: High homocysteine increases the risk of dementia. The association between tHcy and dementia is independent of plasma folate, B12 and antioxidant micronutrient status.

Disrupted limbic-prefrontal effective connectivity in response to fearful faces in lifetime depression.

BACKGROUND: Multiple brain imaging studies of negative emotional bias in major depressive disorder (MDD) have used images of fearful facial expressions and focused on the amygdala and the prefrontal cortex. The results have, however, been inconsistent, potentially due to small sample sizes (typically N<50). It remains unclear if any alterations are a characteristic of current depression or of past experience of depression, and whether there are MDD-related changes in effective connectivity between the two brain regions. METHODS: Activations and effective connectivity between the amygdala and dorsolateral prefrontal cortex (DLPFC) in response to fearful face stimuli were studied in a large population-based sample from Generation Scotland. Participants either had no history of MDD (N=664 in activation analyses, N=474 in connectivity analyses) or had a diagnosis of MDD during their lifetime (LMDD, N=290 in activation analyses, N=214 in connectivity analyses). The within-scanner task involved implicit facial emotion processing of neutral and fearful faces. RESULTS: Compared to controls, LMDD was associated with increased activations in left amygdala (PFWE=0.031,kE=4) and left DLPFC (PFWE=0.002,kE=33), increased mean bilateral amygdala activation (ß=0.0715,P=0.0314), and increased inhibition from left amygdala to left DLPFC, all in response to fearful faces contrasted to baseline. Results did not appear to be attributable to depressive illness severity or antidepressant medication status at scan time. LIMITATIONS: Most studied participants had past rather than current depression, average severity of ongoing depression symptoms was low, and a substantial proportion of participants were receiving medication. The study was not longitudinal and the participants were only assessed a single time. CONCLUSIONS: LMDD is associated with hyperactivity of the amygdala and DLPFC, and with stronger amygdala to DLPFC inhibitory connectivity, all in response to fearful faces, unrelated to depression severity at scan time. These results help reduce inconsistency in past literature and suggest disruption of 'bottom-up' limbic-prefrontal effective connectivity in depression.

Fatigue-related brain white matter changes in granulomatosis with polyangiitis.

OBJECTIVE: To determine the association between brain white matter (WM) damage and persistent fatigue among patients with granulomatosis with polyangiitis (GPA). METHODS: A case-control MRI study was conducted. Both cases, defined as GPA patients with chronic fatigue, and controls, defined as GPA patients without fatigue, underwent MRI brain scanning. Standard T1, T2 and FLAIR images were acquired and Scheltens white matter hyperintensity scores (SWMHS) reported in order to quantify macroscopic damage. In addition, diffusion tensor imaging (DTI) data were analysed using track-based spatial statistics to measure structural integrity and thus microscopic damage. RESULTS: No statistically significant differences in macroscopic damage were observed between cases (n = 14) and controls (n = 14) (median SWMHS 6, interquartile range 3-7 vs median SWMHS 3.5, interquartile range 3-8; P = 0.52). Compared with controls, there were no regions of WM where cases recorded reduced structural integrity; however, significantly greater structural integrity was registered in the regions of the fornix and cingulum nerve bundles of cases (P < 0.05, corrected for multiple comparisons). CONCLUSION: This study found no evidence to suggest that GPA-related fatigue is associated with either macroscopic or microscopic damage of the WM. On the contrary, regions of significantly greater structural integrity were observed among fatigued cases, which may reflect sustained activation secondary to chronic fatigue exposure.

Childhood socioeconomic status and adult brain size: childhood socioeconomic status influences adult hippocampal size.

OBJECTIVE: To investigate in older adults without dementia the relationships between socioeconomic status (SES) in childhood and magnetic resonance imaging (MRI)-derived brain volume measures typical of brain aging and Alzheimer's disease (AD). METHODS: Using a cross-sectional and longitudinal observation approach, we invited volunteers without dementia, all born in 1936, and who were participants in the 1947 Scottish Mental Survey, for MR brain imaging; 249 of 320 (77%) agreed. We measured whole brain and hippocampal volumes and recorded childhood SES history, the number of years of education undertaken, and adult SES history. Mental ability at age 11 years was recorded in 1947 and was also available. RESULTS: Analysis shows a significant association between childhood SES and hippocampal volume after adjusting for mental ability at age 11 years, adult SES, gender, and education. INTERPRETATION: A significant association between childhood SES and hippocampal volumes in late life is consistent with the established neurodevelopmental findings that early life conditions have an effect on structural brain development. This remains detectable more than 50 years later.