Distress and neuroticism as mediators of the effect of childhood and adulthood adversity on cognitive performance in the UK Biobank study.

Childhood adversity and adulthood adversity affect cognition later in life. However, the mechanism through which adversity exerts these effects on cognition remains under-researched. We aimed to investigate if the effect of adversity on cognition was mediated by distress or neuroticism. The UK Biobank is a large, population-based, cohort study designed to investigate risk factors of cognitive health. Here, data were analysed using a cross-sectional design. Structural equation models were fitted to the data with childhood adversity or adulthood adversity as independent variables, distress and neuroticism as mediators and executive function and processing speed as latent dependent variables that were derived from the cognitive scores in the UK Biobank. Complete data were available for 64,051 participants in the childhood adversity model and 63,360 participants in the adulthood adversity model. Childhood adversity did not show a direct effect on processing speed. The effect of childhood adversity on executive function was partially mediated by distress and neuroticism. The effects of adulthood adversity on executive function and processing speed were both partially mediated by distress and neuroticism. In conclusion, distress and neuroticism mediated the deleterious effect of childhood and adulthood adversity on cognition and may provide a mechanism underlying the deleterious consequences of adversity.

A psychometric evaluation of the 16-item PHQ-ADS concomitant anxiety and depression scale in the UK biobank using item response theory.

BACKGROUND: The Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS) provides a reliable and valid measure of concomitant depression and anxiety. However, research on its psychometric efficiency and optimal scale length using item-response theory (IRT) has not been reported. This study aimed to optimize the length of the PHQ-ADS scale without losing information by discarding items that were a poor fit to the IRT model. METHODS: The UK Biobank is a large cohort study designed to investigate risk factors for a broad range of disease. PHQ-ADS data were available from n = 152,826 participants (age = 55.87 years; SD = 7.73; 56.4 % female), 30.4 % of the entire UK Biobank sample. Psychometric properties of the PHQ-ADS were investigated using a 2-parameter IRT and Mokken analysis. Item statistics included discrimination, difficulty and Loevinger H coefficients of monotonicity. RESULTS: In the entire 16-item scale, item discrimination ranged from 1.40 to 4.22, with the item 'worrying' showing the highest level of discrimination and the item 'sleep disturbance' showing the lowest. Mokken analysis showed that the 16-item PHQ-ADS scale could be reduced to a 7-item scale without loss of test information. The reduced scale comprised mainly items measuring cognitive-affective symptoms of anxiety/depression, whereas items measuring somatic symptoms were discarded. The revised scale showed high discrimination and scalability. LIMITATIONS: Findings are limited by the use of cross-sectional data that only included the baseline online questionnaire, but not other waves. CONCLUSIONS: IRT is a useful technique for scale reductions which serve the clinical and epidemiological need to optimize screening questionnaires to reduce redundancy and maximize information. A reduced-item 7-item PHQ-ADS scale reduces the response burden on participants in epidemiological research settings, without loss of information.

Subthalamic nucleus shows opposite functional connectivity pattern in Huntington's and Parkinson's disease.

Huntington's and Parkinson's disease are two movement disorders representing mainly opposite states of the basal ganglia inhibitory function. Despite being an integral part of the cortico-subcortico-cortical circuitry, the subthalamic nucleus function has been studied at the level of detail required to isolate its signal only through invasive studies in Huntington's and Parkinson's disease. Here, we tested whether the subthalamic nucleus exhibited opposite functional signatures in early Huntington's and Parkinson's disease. We included both movement disorders in the same whole-brain imaging study, and leveraged ultra-high-field 7T MRI to achieve the very fine resolution needed to investigate the smallest of the basal ganglia nuclei. Eleven of the 12 Huntington's disease carriers were recruited at a premanifest stage, while 16 of the 18 Parkinson's disease patients only exhibited unilateral motor symptoms (15 were at Stage I of Hoehn and Yahr off medication). Our group comparison interaction analyses, including 24 healthy controls, revealed a differential effect of Huntington's and Parkinson's disease on the functional connectivity at rest of the subthalamic nucleus within the sensorimotor network, i.e. an opposite effect compared with their respective age-matched healthy control groups. This differential impact in the subthalamic nucleus included an area precisely corresponding to the deep brain stimulation 'sweet spot'-the area with maximum overall efficacy-in Parkinson's disease. Importantly, the severity of deviation away from controls' resting-state values in the subthalamic nucleus was associated with the severity of motor and cognitive symptoms in both diseases, despite functional connectivity going in opposite directions in each disorder. We also observed an altered, opposite impact of Huntington's and Parkinson's disease on functional connectivity within the sensorimotor cortex, once again with relevant associations with clinical symptoms. The high resolution offered by the 7T scanner has thus made it possible to explore the complex interplay between the disease effects and their contribution on the subthalamic nucleus, and sensorimotor cortex. Taken altogether, these findings reveal for the first time non-invasively in humans a differential, clinically meaningful impact of the pathophysiological process of these two movement disorders on the overall sensorimotor functional connection of the subthalamic nucleus and sensorimotor cortex.

Association of Blood Pressure Lowering Intensity With White Matter Network Integrity in Patients With Cerebral Small Vessel Disease.

BACKGROUND AND OBJECTIVES: Diffusion tensor imaging (DTI) networks integrate damage from a variety of pathologic processes in cerebral small vessel disease (SVD) and may be a sensitive marker to detect treatment effects. We determined whether brain network analysis could detect treatment effects in the PRESERVE trial data set, in which intensive vs standard blood pressure (BP) lowering was compared. The primary end point of DTI had not shown treatment differences. METHODS: Participants with lacunar stroke were randomized to standard (systolic 130-140 mm Hg) or intensive (systolic ≤ 125 mm Hg) BP lowering and followed for 2 years with MRI at baseline and at 2 years. Graph theory-based metrics were derived from DTI data to produce a measure of network integrity weighted global efficiency and compared with individual MRI markers of DTI, brain volume, and white matter hyperintensities. RESULTS: Data were available in 82 subjects: standard n = 40 (mean age 66.3 ± 1.5 years) and intensive n = 42 (mean age 69.6 ± 1.0 years). The mean (SD) systolic BP was reduced by 13(14) and 23(23) mm Hg in the standard and intensive groups, respectively (p < 0.001 between groups). Significant differences in diffusion network metrics were found, with improved network integrity (weighted global efficiency, p = 0.002) seen with intensive BP lowering. In contrast, there were no significant differences in individual MRI markers including DTI histogram metrics, brain volume, or white matter hyperintensities. DISCUSSION: Brain network analysis may be a sensitive surrogate marker in trials in SVD. This work suggests that measures of brain network efficiency may be more sensitive to the effects of BP control treatment than conventional DTI metrics. TRIAL REGISTRATION INFORMATION: The trial is registered with the ISRCTN Registry (ISRCTN37694103; doi.org/10.1186/ISRCTN37694103) and the NIHR Clinical Research Network (CRN 10962; public-odp.nihr.ac.uk/QvAJAXZfc/opendoc.htm?document=crncc_users%5Cfind%20a%20clinical%20research%20study.qvw&lang=en-US&host=QVS%40crn-prod-odp-pu&anonymous=true). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that intensive BP lowering in patients with SVD results in improved brain network function when assessed by DTI-based brain network metrics.

Central obesity is selectively associated with cerebral gray matter atrophy in 15,634 subjects in the UK Biobank.

BACKGROUND: Obesity is a risk factor for both cardiovascular disease and dementia, but the mechanisms underlying this association are not fully understood. We examined associations between obesity, including estimates of central obesity using different modalities, with brain gray matter (GM) volume in the UK Biobank, a large population-based cohort study. METHODS: To determine relationships between obesity and the brain we used brain MRI, abdominal MRI, dual-energy X-ray absorptiometry (DXA), and bioelectric whole-body impedance. We determined whether obesity was associated with any change in brain gray matter (GM) and white matter (WM) volumes, and brain network efficiency derived from the structural connectome (wiring of the brain) as determined from diffusion-tensor MRI tractography. Using Waist-Hip Ratio (WHR), abdominal MRI and DXA we determined whether any associations were primarily with central rather than peripheral obesity, and whether associations were mediated by known cardiovascular risk factors. We analyzed brain MRI data from 15,634. RESULTS: We found that central obesity, was associated with decreased GM volume (anthropometric data: p = 6.7 × 10-16, DXA: p = 8.3 × 10-81, abdominal MRI: p = 0.0006). Regional associations were found between central obesity and with specific GM subcortical nuclei (thalamus, caudate, pallidum, nucleus accumbens). In contrast, no associations were found with WM volume or structure, or brain network efficiency. The effects of central obesity on GM volume were not mediated by C-reactive protein or blood pressure, glucose, lipids. CONCLUSIONS: Central body-fat distribution rather than the overall body-fat percentage is associated with gray matter changes in people with obesity. Further work is required to identify the factors that mediate the association between central obesity and GM atrophy.

One-year changes in brain microstructure differentiate preclinical Huntington's disease stages.

OBJECTIVE: To determine whether brain imaging markers of tissue microstructure can detect the effect of disease progression across the preclinical stages of Huntington's disease. METHODS: Longitudinal microstructural changes in diffusion imaging metrics (mean diffusivity and fractional anisotropy) were investigated in participants with presymptomatic Huntington's disease (N = 35) stratified into three preclinical subgroups according to their estimated time until onset of symptoms, compared with age- and gender-matched healthy controls (N = 19) over a 1y period. RESULTS: Significant differences were found over the four groups in change of mean diffusivity in the posterior basal ganglia and the splenium of the corpus callosum. This overall effect was driven by significant differences between the group far-from-onset (FAR) of symptoms and the groups midway- (MID) and near-the-onset (NEAR) of symptoms. In particular, an initial decrease of mean diffusivity in the FAR group was followed by a subsequent increase in groups closer to onset of symptoms. The seemingly counter-intuitive decrease of mean diffusivity in the group furthest from onset of symptoms might be an early indicator of neuroinflammatory process preceding the neurodegenerative phase. In contrast, the only clinical measure that was able to capture a difference in 1y changes between the preclinical stages was the UHDRS confidence in motor score. CONCLUSIONS: With sensitivity to longitudinal changes in brain microstructure within and between preclinical stages, and potential differential response to distinct pathophysiological mechanisms, diffusion imaging is a promising state marker for monitoring treatment response and identifying the optimal therapeutic window of opportunity in preclinical Huntington's disease.