Identification and evaluation of biomarkers for Huntington’s disease

Huntington’s disease (HD) is a devastating, incurable inherited neurodegenerative disorder that commonly affects adults in mid-life. Despite encouraging results from in vitro and animal trials, disease-modifying therapeutic trials in HD are limited by a lack of tools to track disease progression. HD is clinically heterogeneous, and current clinical rating scales lack sensitivity and specificity, particularly over relatively short time periods. Improvements in the precision of objective measurement of disease progression in HD could lead to state markers (biomarkers) better able to predict onset, detect progression and measure the effects of therapeutic intervention. Biomarkers capable of detecting disease-related changes in premanifest gene carriers will be essential for clinical trials of treatments to delay onset. Imaging, clinical and cognitive assessment as well as laboratory markers have all been proposed as biomarkers, but few measures have been quantified over short time intervals or shown to be predictive of clinical change over longer periods. A robust panel of biomarkers from a number of modalities will be necessary to progress to interventional clinical trials of disease-modifying therapies in HD, using biomarkers to measure the success or failure of an intervention. Such cross-validation requires simultaneous multimodal biomarker evaluation within a suitable cohort of subjects studied longitudinally. This thesis describes a multi-modal approach to the discovery and evaluation of potential biomarkers for Huntington's disease in a large cohort of human volunteers. After reviewing the relevant features of Huntington's disease and current state of biomarker research in Huntington's disease, several approaches to, and outcomes from, biomarker discovery and evaluation are described, including proteomic profiling, targeted ELISA, multiplex inflammatory profiling and measurement of whole-brain atrophy by longitudinal magnetic resonance imaging. The thesis draws together these different approaches and summarises the contributions to both biomarker research and our understanding of the neurobiology of HD that the work has generated

Sitting Time and Waist Circumference Are Associated With Glycemia in U.K. South Asians: Data from 1,228 adults screened for the PODOSA trial

OBJECTIVE-To investigate the independent contributions of waist circumference, physical activity, and sedentary behavior on glycemia in South Asians living in Scotland. RESEARCH DESIGN AND METHODS-Participants were 1,228 (523 men and 705 women) adults of Indian or Pakistani origin screened for the Prevention of Type 2 Diabetes and Obesity in South Asians (PODOSA) trial. All undertook an oral glucose tolerance test, had physical activity and sitting time assessed by International Physical Activity Questionnaire, and had waist circumference measured. RESULTS-Mean +/- SD age and waist circumference were 49.8 +/- 10.1 years and 99.2 +/- 10.2 cm, respectively. One hundred ninety-one participants had impaired fasting glycemia or impaired glucose tolerance, and 97 had possible type 2 diabetes. In multivariate regression analysis, ay (0.012 mmol.L-1.year [95% CI 0.006-0.017]) and waist circumference (0.018 mmol.L-1.cm(-1) [0.012-0.024]) were significantly independently associated with fasting glucose concentration, and age (0.032 mmol.L-1.year(-1) [0.016-0.049]), waist (0.057 mmolL(-1).cm(-1) [0.040-0.074]), and sitting time (0.097 mmol.L-1.h(-1).day(-1) [0.036-0.158]) were significantly independently associated with 2-h glucose concentration. Vigorous activity time had a borderline significant association with 2-h glucose concentration (-0.819 mmol.L-1.h(-1).day-1 [-1.672 to 0.034]) in the multivariate model. CONCLUSIONS-These data highlight an important relationship between sitting time and 2-h glucose levels in U.K. South Asians, independent of physical activity and waist circumference. Although the data are cross-sectional and thus do not permit firm conclusions about causality to be drawn, the results suggest that further study investigating the effects of sitting time on glycemia and other aspects of metabolic risk in South Asian populations is warrante

Association between SGLT2 inhibitor treatment and diabetic ketoacidosis and mortality in people with type 2 diabetes admitted to hospital with COVID-19

   Objective  To determine the association between prescription of SGLT2 inhibitors and diabetic ketoacidosis (DKA) incidence or mortality in people with type 2 diabetes hospitalized with COVID-19.  Research Design and Methods  This was a retrospective cohort study based on secondary analysis of data from a large nationwide audit from a network of 40 centres in United Kingdom with data collection up to December 2020 that was originally designed to describe risk factors associated with adverse outcomes among people with diabetes who were admitted to hospital with COVID-19.. The primary outcome for this analysis was DKA on or during hospital admission. The secondary outcome was mortality. Crude, age-sex adjusted and multivariable logistic regression models, were used to generate odds ratios and 95% confidence intervals for people prescribed SGLT2 inhibitor compared to those not prescribed SGLT2 inhibitor.   Results  The original national audit included 3067 people with type 2 diabetes who were admitted to hospital with COVID-19, of whom 230 (7.5%) were prescribed SGLT2 inhibitors prior to hospital admission. Mean (SD) age of the overall cohort was 72 years, 62.3% were men and 34.9% were prescribed insulin. Overall, 2.8% of the total population had DKA and 35.6% people died. The adjusted odds of DKA were not significantly different between those prescribed SGLT2 inhibitors and those not (OR 0.56, 0.16-1.97). The adjusted odds of mortality associated with SGLT2 inhibitors were similar in the total study population (OR 1.13, 0.78-1.63 ), in the sub-group prescribed insulin (OR 1.02, 0.59-1.77), and in the sub-group that developed DKA (OR 0.21, 0.01-8.76).  Conclusions We demonstrate a low risk of DKA and high mortality rate in people with type 2 diabetes admitted to hospital with COVID-19 and limited power but no evidence of increased risk of DKA or in-hospital mortality associated with prescription of SGLT2 inhibitors. </p

Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research

Update on the correlation of the highest energy cosmic rays with nearby extragalactic matter

Data collected by the Pierre Auger Observatory through 31 August 2007 showed evidence for anisotropy in the arrival directions of cosmic rays above the Greisen-Zatsepin-Kuz'min energy threshold, \nobreak{$6\times 10^{19}$eV}. The anisotropy was measured by the fraction of arrival directions that are less than $3.1^\circ$ from the position of an active galactic nucleus within 75 Mpc (using the V\'eron-Cetty and V\'eron $12^{\rm th}$ catalog). An updated measurement of this fraction is reported here using the arrival directions of cosmic rays recorded above the same energy threshold through 31 December 2009. The number of arrival directions has increased from 27 to 69, allowing a more precise measurement. The correlating fraction is $(38^{+7}_{-6})$, compared with $21$ expected for isotropic cosmic rays. This is down from the early estimate of $(69^{+11}_{-13})$. The enlarged set of arrival directions is examined also in relation to other populations of nearby extragalactic objects: galaxies in the 2 Microns All Sky Survey and active galactic nuclei detected in hard X-rays by the Swift Burst Alert Telescope. A celestial region around the position of the radiogalaxy Cen A has the largest excess of arrival directions relative to isotropic expectations. The 2-point autocorrelation function is shown for the enlarged set of arrival directions and compared to the isotropic expectation.Comment: Accepted for publication in Astroparticle Physics on 31 August 201

Search for First Harmonic Modulation in the Right Ascension Distribution of Cosmic Rays Detected at the Pierre Auger Observatory

We present the results of searches for dipolar-type anisotropies in different energy ranges above $2.5\times 10^{17}$ eV with the surface detector array of the Pierre Auger Observatory, reporting on both the phase and the amplitude measurements of the first harmonic modulation in the right-ascension distribution. Upper limits on the amplitudes are obtained, which provide the most stringent bounds at present, being below 2% at 99% $C.L.$ for EeV energies. We also compare our results to those of previous experiments as well as with some theoretical expectations.Comment: 28 pages, 11 figure

A proteomics analysis of 5xFAD mouse brain regions reveals the lysosome-associated protein Arl8b as a candidate biomarker for Alzheimer’s disease

BACKGROUND: Alzheimer's disease (AD) is characterized by the intra- and extracellular accumulation of amyloid-ß (Aß) peptides. How Aß aggregates perturb the proteome in brains of patients and AD transgenic mouse models, remains largely unclear. State-of-the-art mass spectrometry (MS) methods can comprehensively detect proteomic alterations, providing relevant insights unobtainable with transcriptomics investigations. Analyses of the relationship between progressive Aß aggregation and protein abundance changes in brains of 5xFAD transgenic mice have not been reported previously. METHODS: We quantified progressive Aß aggregation in hippocampus and cortex of 5xFAD mice and controls with immunohistochemistry and membrane filter assays. Protein changes in different mouse tissues were analyzed by MS-based proteomics using label-free quantification; resulting MS data were processed using an established pipeline. Results were contrasted with existing proteomic data sets from postmortem AD patient brains. Finally, abundance changes in the candidate marker Arl8b were validated in cerebrospinal fluid (CSF) from AD patients and controls using ELISAs. RESULTS: Experiments revealed faster accumulation of Aß42 peptides in hippocampus than in cortex of 5xFAD mice, with more protein abundance changes in hippocampus, indicating that Aß42 aggregate deposition is associated with brain region-specific proteome perturbations. Generating time-resolved data sets, we defined Aß aggregate-correlated and anticorrelated proteome changes, a fraction of which was conserved in postmortem AD patient brain tissue, suggesting that proteome changes in 5xFAD mice mimic disease-relevant changes in human AD. We detected a positive correlation between Aß42 aggregate deposition in the hippocampus of 5xFAD mice and the abundance of the lysosome-associated small GTPase Arl8b, which accumulated together with axonal lysosomal membranes in close proximity of extracellular Aß plaques in 5xFAD brains. Abnormal aggregation of Arl8b was observed in human AD brain tissue. Arl8b protein levels were significantly increased in CSF of AD patients. CONCLUSIONS: We report a comprehensive biochemical and proteomic investigation of hippocampal and cortical brain tissue derived from 5xFAD transgenic mice, providing a valuable resource to the neuroscientific community. We identified Arl8b, with significant abundance changes in 5xFAD and AD patient brains. Arl8b might enable the measurement of progressive lysosome accumulation in AD patients and have clinical utility as a candidate biomarker

EXPRESS: Statement on imaging and pulmonary hypertension from the Pulmonary Vascular Research Institute (PVRI)

Pulmonary hypertension is highly heterogeneous and despite treatment advances it remains a life shortening condition. There have been significant advances in imaging technologies, but despite evidence of their potential clinical utility practice remains variable, dependent in part on imaging availability and expertise. This statement summarises current and emerging imaging modalities and their potential role in the diagnosis and assessment of suspected pulmonary hypertension. It also includes a review of commonly encountered clinical and radiological scenarios, and imaging and modeling-based biomarkers. An expert panel was formed including clinicians, radiologists, imaging scientists and computational modelers. Section editors generated a series of summary statements 1based on a review of the literature and professional experience and following consensus review, a diagnostic algorithm and fifty five statements were agreed. The diagnostic algorithm and summary statements, emphasise the key role and added value of imaging in the diagnosis and assessment of pulmonary hypertension and highlight areas requiring further research