A Comparison of Accelerated and Non-accelerated MRI Scans for Brain Volume and Boundary Shift Integral Measures of Volume Change: Evidence from the ADNI Dataset

The aim of this study was to assess whether the use of accelerated MRI scans in place of non-accelerated scans influenced brain volume and atrophy rate measures in controls and subjects with mild cognitive impairment and Alzheimer’s disease. We used data from 861 subjects at baseline, 573 subjects at 6 months and 384 subjects at 12 months from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We calculated whole-brain, ventricular and hippocampal atrophy rates using the k-means boundary shift integral (BSI). Scan quality was visually assessed and the proportion of good quality accelerated and non-accelerated scans compared. We also compared MMSE scores, vascular burden and age between subjects with poor quality scans with those with good quality scans. Finally, we estimated sample size requirements for a hypothetical clinical trial when using atrophy rates from accelerated scans and non-accelerated scans. No significant differences in whole-brain, ventricular and hippocampal volumes and atrophy rates were found between accelerated and non-accelerated scans. Twice as many non-accelerated scan pairs suffered from at least some motion artefacts compared with accelerated scan pairs (p ≤ 0.001), which may influence the BSI. Subjects whose accelerated scans had significant motion had a higher mean vascular burden and age (p ≤ 0.05) whilst subjects whose non-accelerated scans had significant motion had poorer MMSE scores (p ≤ 0.05). No difference in estimated sample size requirements was found when using accelerated vs. non-accelerated scans. Accelerated scans reduce scan time and are better tolerated. Therefore it may be advantageous to use accelerated over non-accelerated scans in clinical trials that use ADNI-type protocols, especially in more cognitively impaired subjects

Visualizing and exploring patterns of large mutational events with SigProfilerMatrixGenerator

BACKGROUND: All cancers harbor somatic mutations in their genomes. In principle, mutations affecting between one and fifty base pairs are generally classified as small mutational events. Conversely, large mutational events affect more than fifty base pairs, and, in most cases, they encompass copy-number and structural variants affecting many thousands of base pairs. Prior studies have demonstrated that examining patterns of somatic mutations can be leveraged to provide both biological and clinical insights, thus, resulting in an extensive repertoire of tools for evaluating small mutational events. Recently, classification schemas for examining large-scale mutational events have emerged and shown their utility across the spectrum of human cancers. However, there has been no computationally efficient bioinformatics tool that allows visualizing and exploring these large-scale mutational events. RESULTS: Here, we present a new version of SigProfilerMatrixGenerator that now delivers integrated capabilities for examining large mutational events. The tool provides support for examining copy-number variants and structural variants under two previously developed classification schemas and it supports data from numerous algorithms and data modalities. SigProfilerMatrixGenerator is written in Python with an R wrapper package provided for users that prefer working in an R environment. CONCLUSIONS: The new version of SigProfilerMatrixGenerator provides the first standardized bioinformatics tool for optimized exploration and visualization of two previously developed classification schemas for copy number and structural variants. The tool is freely available at https://github.com/AlexandrovLab/SigProfilerMatrixGenerator with an extensive documentation at https://osf.io/s93d5/wiki/home/

Differential hippocampal shapes in posterior cortical atrophy patients: A comparison with control and typical AD subjects.

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by predominant visual deficits and parieto-occipital atrophy, and is typically associated with Alzheimer's disease (AD) pathology. In AD, assessment of hippocampal atrophy is widely used in diagnosis, research, and clinical trials; its utility in PCA remains unclear. Given the posterior emphasis of PCA, we hypothesized that hippocampal shape measures may give additional group differentiation information compared with whole-hippocampal volume assessments. We investigated hippocampal volume and shape in subjects with PCA (n = 47), typical AD (n = 29), and controls (n = 48). Hippocampi were outlined on MRI scans and their 3D meshes were generated. We compared hippocampal volume and shape between disease groups. Mean adjusted hippocampal volumes were ∼8% smaller in PCA subjects (P < 0.001) and ∼22% smaller in tAD subject (P < 0.001) compared with controls. Significant inward deformations in the superior hippocampal tail were observed in PCA compared with controls even after adjustment for hippocampal volume. Inward deformations in large areas of the hippocampus were seen in tAD subjects compared with controls and PCA subjects, but only localized shape differences remained after adjusting for hippocampal volume. The shape differences observed, even allowing for volume differences, suggest that PCA and tAD are each associated with different patterns of hippocampal tissue loss that may contribute to the differential range and extent of episodic memory dysfunction in the two groups. Hum Brain Mapp, 2015. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc

Patterns of progressive atrophy vary with age in Alzheimer's disease patients

Age is not only the greatest risk factor for Alzheimer's disease (AD) but also a key modifier of disease presentation and progression. Here, we investigate how longitudinal atrophy patterns vary with age in mild cognitive impairment (MCI) and AD. Data comprised serial longitudinal 1.5-T magnetic resonance imaging scans from 153 AD, 339 MCI, and 191 control subjects. Voxel-wise maps of longitudinal volume change were obtained and aligned across subjects. Local volume change was then modeled in terms of diagnostic group and an interaction between group and age, adjusted for total intracranial volume, white-matter hyperintensity volume, and apolipoprotein E genotype. Results were significant at p < 0.05 with family-wise error correction for multiple comparisons. An age-by-group interaction revealed that younger AD patients had significantly faster atrophy rates in the bilateral precuneus, parietal, and superior temporal lobes. These results suggest younger AD patients have predominantly posterior progressive atrophy, unexplained by white-matter hyperintensity, apolipoprotein E, or total intracranial volume. Clinical trials may benefit from adapting outcome measures for patient groups with lower average ages, to capture progressive atrophy in posterior cortices

Presumed small vessel disease, imaging and cognition markers in the Alzheimer's Disease Neuroimaging Initiative

MRI-derived features of presumed cerebral small vessel disease are frequently found in Alzheimer’s disease. Influences of such markers on disease-progression measures are poorly understood. We measured markers of presumed small vessel disease (white matter hyperintensity volumes; cerebral microbleeds) on baseline images of newly enrolled individuals in the Alzheimer’s Disease Neuroimaging Initiative cohort (GO and 2) and used linear mixed models to relate these to subsequent atrophy and neuropsychological score change. We also assessed heterogeneity in white matter hyperintensity positioning within biomarker abnormality sequences, driven by the data, using the Subtype and Stage Inference algorithm. This study recruited both sexes and included: controls: [n = 159, mean(SD) age = 74(6) years]; early and late mild cognitive impairment [ns = 265 and 139, respectively, mean(SD) ages =71(7) and 72(8) years, respectively]; Alzheimer’s disease [n = 103, mean(SD) age = 75(8)] and significant memory concern [n = 72, mean(SD) age = 72(6) years]. Baseline demographic and vascular risk-factor data, and longitudinal cognitive scores (Mini-Mental State Examination; logical memory; and Trails A and B) were collected. Whole-brain and hippocampal volume change metrics were calculated. White matter hyperintensity volumes were associated with greater whole-brain and hippocampal volume changes independently of cerebral microbleeds (a doubling of baseline white matter hyperintensity was associated with an increase in atrophy rate of 0.3 ml/year for brain and 0.013 ml/year for hippocampus). Cerebral microbleeds were found in 15% of individuals and the presence of a microbleed, as opposed to none, was associated with increases in atrophy rate of 1.4 ml/year for whole brain and 0.021 ml/year for hippocampus. White matter hyperintensities were predictive of greater decline in all neuropsychological scores, while cerebral microbleeds were predictive of decline in logical memory (immediate recall) and Mini-Mental State Examination scores. We identified distinct groups with specific sequences of biomarker abnormality using continuous baseline measures and brain volume change. Four clusters were found; Group 1 showed early Alzheimer’s pathology; Group 2 showed early neurodegeneration; Group 3 had early mixed Alzheimer’s and cerebrovascular pathology; Group 4 had early neuropsychological score abnormalities. White matter hyperintensity volumes becoming abnormal was a late event for Groups 1 and 4 and an early event for 2 and 3. In summary, white matter hyperintensities and microbleeds were independently associated with progressive neurodegeneration (brain atrophy rates) and cognitive decline (change in neuropsychological scores). Mechanisms involving white matter hyperintensities and progression and microbleeds and progression may be partially separate. Distinct sequences of biomarker progression were found. White matter hyperintensity development was an early event in two sequences

Morphology and microstructure of chromite crystals in chromitites from the Merensky Reef (Bushveld Complex, South Africa)

The Merensky Reef of the Bushveld Complex consists of two chromitite layers separated by coarse-grained melanorite. Microstructural analysis of the chromitite layers using electron backscatter diffraction analysis (EBSD), high-resolution X-ray microtomography and crystal size distribution analyses distinguished two populations of chromite crystals: fine-grained idiomorphic and large silicate inclusion-bearing crystals. The lower chromitite layer contains both populations, whereas the upper contains only fine idiomorphic grains. Most of the inclusion-bearing chromites have characteristic amoeboidal shapes that have been previously explained as products of sintering of pre-existing smaller idiomorphic crystals. Two possible mechanisms have been proposed for sintering of chromite crystals: (1) amalgamation of a cluster of grains with the same original crystallographic orientation; and (2) sintering of randomly orientated crystals followed by annealing into a single grain. The EBSD data show no evidence for clusters of similarly oriented grains among the idiomorphic population, nor for earlier presence of idiomorphic subgrains spatially related to inclusions, and therefore are evidence against both of the proposed sintering mechanisms. Electron backscatter diffraction analysis maps show deformation-related misorientations and curved subgrain boundaries within the large, amoeboidal crystals, and absence of such features in the fine-grained population. Microstructures observed in the lower chromitite layer are interpreted as the result of deformation during compaction of the orthocumulate layers, and constitute evidence for the formation of the amoeboid morphologies at an early stage of consolidation.An alternative model is proposed whereby silicate inclusions are incorporated during maturation and recrystallisation of initially dendritic chromite crystals, formed as a result of supercooling during emplacement of the lower chromite layer against cooler anorthosite during the magma influx that formed the Merensky Reef. The upper chromite layer formed from a subsequent magma influx, and hence lacked a mechanism to form dendritic chromite. This accounts for the difference between the two layers

APOE ε4 Is Associated with Disproportionate Progressive Hippocampal Atrophy in AD.

To investigate whether APOE ε4 carriers have higher hippocampal atrophy rates than non-carriers in Alzheimer's disease (AD), mild cognitive impairment (MCI) and controls, and if so, whether higher hippocampal atrophy rates are still observed after adjusting for concurrent whole-brain atrophy rates

Population Pharmacokinetics of Telapristone (CDB-4124) and its Active Monodemethylated Metabolite CDB-4453, with a Mixture Model for Total Clearance

Telapristone is a selective progesterone antagonist that is being developed for the long-term treatment of symptoms associated with endometriosis and uterine fibroids. The population pharmacokinetics of telapristone (CDB-4124) and CDB-4453 was investigated using nonlinear mixed-effects modeling. Data from two clinical studies (n = 32) were included in the analysis. A two-compartment (parent) one compartment (metabolite) mixture model (with two populations for apparent clearance) with first-order absorption and elimination adequately described the pharmacokinetics of telapristone and CDB-4453. Telapristone was rapidly absorbed with an absorption rate constant (Ka) of 1.26 h−1. Moderate renal impairment resulted in a 74% decrease in Ka. The population estimates for oral clearance (CL/F) for the two populations were 11.6 and 3.34 L/h, respectively, with 25% of the subjects being allocated to the high-clearance group. Apparent volume of distribution for the central compartment (V2/F) was 37.4 L, apparent inter-compartmental clearance (Q/F) was 21.9 L/h, and apparent peripheral volume of distribution for the parent (V4/F) was 120 L. The ratio of the fraction of telapristone converted to CDB-4453 to the distribution volume of CDB-4453 (Fmetest) was 0.20/L. Apparent volume of distribution of the metabolite compartment (V3/F) was fixed to 1 L and apparent clearance of the metabolite (CLM/F) was 2.43 L/h. A two-compartment parent-metabolite model adequately described the pharmacokinetics of telapristone and CDB-4453. The clearance of telapristone was separated into two populations and could be the result of metabolism via polymorphic CYP3A5

Trust in the public sector: Is there any evidence for a long-term decline?

Concerns with declining public trust in government have become a permanent element of the contemporary political discourse. This concern also extends to levels of citizens’ trust in the public administration and public services. Trust is said to be declining, and this decline is generally seen as detrimental to public service delivery. In this article, we examine the main elements in this discussion, review the existing international survey data and summarise the main findings for OECD countries. Citizens’ trust in the public sector is found to fluctuate, and the data generally do not show consistently declining levels of trust. Furthermore, in some countries there simply is insufficient data to come to any conclusions at all about time trends in citizen trust in the public sector. Points for practitioners This article summarises some of the survey material on citizens’ trust in the public administration. It allows practitioners to compare trends in public trust in their country across time and space. The findings lead us to reject the hypothesis of a universal decline of trust in the public sector. The article warns against using opinion poll results without considering context. The long-term and comparative perspective on citizens’ trust in the public sector is all too often absent from the policy discourse that is frequently based on assumptions and ad-hoc approaches