A comparison of functional and tractography based networks in cerebral small vessel disease.

OBJECTIVE: MRI measures of network integrity may be useful disease markers in cerebral small vessel disease (SVD). We compared the sensitivity and reproducibility of MRI derived structural and functional network measures in healthy controls and SVD subjects. METHODS: Diffusion tractography and resting state fMRI were used to create connectivity matrices from 26 subjects with symptomatic MRI confirmed lacunar stroke and 19 controls. Matrices were constructed at multiple scales based on a multi-resolution cortical atlas and at multiple thresholds for the matrix density. Network parameters were calculated over the multiple resolutions and thresholds. In addition the reproducibility of structural and functional network parameters was determined in a subset of the subjects (15 SVD, 10 controls) who were scanned twice. RESULTS: Structural networks showed a highly significant loss of network integrity in SVD cases compared to controls, for all network measures. In contrast functional networks showed no difference between SVD and controls. Structural network measures were highly reproducible in both cases and controls, with ICC values consistently over 0.8. In contrast functional network measures showed much poorer reproducibility with ICC values in the range 0.4-0.6 overall, and even lower in SVD cases. CONCLUSIONS: Structural networks identify impaired network integrity, and are highly reproducible, in SVD, supporting their use as markers of SVD disease severity. In contrast, functional networks showed low reproducibility, particularly in SVD cases, and were unable to detect differences between SVD cases and controls with this sample size

Genetic Study of White Matter Integrity in UK Biobank (N=8448) and the Overlap With Stroke, Depression, and Dementia.

BACKGROUND AND PURPOSE: Structural integrity of the white matter is a marker of cerebral small vessel disease, which is the major cause of vascular dementia and a quarter of all strokes. Genetic studies provide a way to obtain novel insights in the disease mechanism underlying cerebral small vessel disease. The aim was to identify common variants associated with microstructural integrity of the white matter and to elucidate the relationships of white matter structural integrity with stroke, major depressive disorder, and Alzheimer disease. METHODS: This genome-wide association analysis included 8448 individuals from UK Biobank-a population-based cohort study that recruited individuals from across the United Kingdom between 2006 and 2010, aged 40 to 69 years. Microstructural integrity was measured as fractional anisotropy- (FA) and mean diffusivity (MD)-derived parameters on diffusion tensor images. White matter hyperintensity volumes (WMHV) were assessed on T2-weighted fluid-attenuated inversion recovery images. RESULTS: We identified 1 novel locus at genome-wide significance (VCAN [versican]: rs13164785; P=3.7×10-18 for MD and rs67827860; P=1.3×10-14 for FA). LD score regression showed a significant genome-wide correlation between FA, MD, and WMHV (FA-WMHV rG 0.39 [SE, 0.15]; MD-WMHV rG 0.56 [SE, 0.19]). In polygenic risk score analysis, FA, MD, and WMHV were significantly associated with lacunar stroke, MD with major depressive disorder, and WMHV with Alzheimer disease. CONCLUSIONS: Genetic variants within the VCAN gene may play a role in the mechanisms underlying microstructural integrity of the white matter in the brain measured as FA and MD. Mechanisms underlying white matter alterations are shared with cerebrovascular disease, and inherited differences in white matter microstructure impact on Alzheimer disease and major depressive disorder

ADvanced IMage Algebra (ADIMA): a novel method for depicting multiple sclerosis lesion heterogeneity, as demonstrated by quantitative MRI.

BACKGROUND: There are modest correlations between multiple sclerosis (MS) disability and white matter lesion (WML) volumes, as measured by T2-weighted (T2w) magnetic resonance imaging (MRI) scans (T2-WML). This may partly reflect pathological heterogeneity in WMLs, which is not apparent on T2w scans. OBJECTIVE: To determine if ADvanced IMage Algebra (ADIMA), a novel MRI post-processing method, can reveal WML heterogeneity from proton-density weighted (PDw) and T2w images. METHODS: We obtained conventional PDw and T2w images from 10 patients with relapsing-remitting MS (RRMS) and ADIMA images were calculated from these. We classified all WML into bright (ADIMA-b) and dark (ADIMA-d) sub-regions, which were segmented. We obtained conventional T2-WML and T1-WML volumes for comparison, as well as the following quantitative magnetic resonance parameters: magnetisation transfer ratio (MTR), T1 and T2. Also, we assessed the reproducibility of the segmentation for ADIMA-b, ADIMA-d and T2-WML. RESULTS: Our study's ADIMA-derived volumes correlated with conventional lesion volumes (p < 0.05). ADIMA-b exhibited higher T1 and T2, and lower MTR than the T2-WML (p < 0.001). Despite the similarity in T1 values between ADIMA-b and T1-WML, these regions were only partly overlapping with each other. ADIMA-d exhibited quantitative characteristics similar to T2-WML; however, they were only partly overlapping. Mean intra- and inter-observer coefficients of variation for ADIMA-b, ADIMA-d and T2-WML volumes were all < 6 % and < 10 %, respectively. CONCLUSION: ADIMA enabled the simple classification of WML into two groups having different quantitative magnetic resonance properties, which can be reproducibly distinguished

Physical signatures of discontinuities of the time-dependent exchange-correlation potential

The exact exchange-correlation (XC) potential in time-dependent density-functional theory (TDDFT) is known to develop steps and discontinuities upon change of the particle number in spatially confined regions or isolated subsystems. We demonstrate that the self-interaction corrected adiabatic local-density approximation for the XC potential has this property, using the example of electron loss of a model quantum well system. We then study the influence of the XC potential discontinuity in a real-time simulation of a dissociation process of an asymmetric double quantum well system, and show that it dramatically affects the population of the resulting isolated single quantum wells. This indicates the importance of a proper account of the discontinuities in TDDFT descriptions of ionization, dissociation or charge transfer processes.Comment: 17 pages, 6 figure

NOTCH3 variants are more common than expected in the general population and associated with stroke and vascular dementia: an analysis of 200 000 participants

Background: Cysteine-altering NOTCH3 variants identical to those causing the rare monogenic form of stroke, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), have been reported more common than expected in the general population, but their clinical significance and contribution to stroke and dementia risk in the community remain unclear. Methods: Cysteine-altering NOTCH3 variants were identified in UK Biobank whole-exome sequencing data (N=200 632). Frequency of stroke, vascular dementia and other clinical features of CADASIL, and MRI white matter hyperintensity volume were compared between variant carriers and non-carriers. MRIs from those with variants were visually rated, each matched with three controls. Results: Of 200 632 participants with exome sequencing data available, 443 (~1 in 450) carried 67 different cysteine-altering NOTCH3 variants. After adjustment for various covariates, NOTCH3 variant carriers had increased risk of stroke (OR: 2.33, p=0.0004) and vascular dementia (OR: 5.00, p=0.007), and increased white matter hyperintensity volume (standardised difference: 0.52, p<0.001) and white matter ultrastructural damage on diffusion MRI (standardised difference: 0.72, p<0.001). On visual analysis of MRIs from 47 carriers and 148 matched controls, variants were associated with presence of lacunes (OR: 5.97, p<0.001) and cerebral microbleeds (OR: 4.38, p<0.001). White matter hyperintensity prevalence was most increased in the anterior temporal lobes (OR: 7.65, p<0.001) and external capsule (OR: 13.32, p<0.001). Conclusions: Cysteine-changing NOTCH3 variants are more common in the general population than expected from CADASIL prevalence and are risk factors for apparently ‘sporadic’ stroke and vascular dementia. They are associated with MRI changes of small vessel disease, in a distribution similar to that seen in CADASIL

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments.

BACKGROUND: No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes--the "sentinel lesion approach". METHODS/DESIGN: MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. RESULTS: Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. CONCLUSIONS: In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS--the sentinel lesion approach--serving as proof of principle for its future wider applicability. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00395200).RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Involvement of the reward network is associated with apathy in cerebral small vessel disease.

INTRODUCTION: Apathy is a common yet under-recognised feature of cerebral small vessel disease (SVD), but its underlying neurobiological basis is not yet understood. We hypothesized that damage to the reward network is associated with an increase of apathy in patients with SVD. METHODS: In 114 participants with symptomatic SVD, defined as a magnetic resonance imaging confirmed lacunar stroke and confluent white matter hyperintensities, we used diffusion tensor imaging tractography to derive structural brain networks and graph theory to determine network efficiency. We determined which parts of the network correlated with apathy symptoms. We tested whether apathy was selectively associated with involvement of the reward network, compared with two "control networks" (visual and motor). RESULTS: Apathy symptoms negatively correlated with connectivity in network clusters encompassing numerous areas of the brain. Network efficiencies within the reward network correlated negatively with apathy scores; (r = - 0.344, p < 0.001), and remained significantly correlated after co-varying for the two control networks. Of the three networks tested, only variability in the reward network independently explained variance in apathetic symptoms, whereas this was not observed for the motor or visual networks. LIMITATIONS: The analysis refers only to cerebrum and not cerebellum. The apathy measure is derivative of depression measure. DISCUSSION: Our results suggest that reduced neural efficiency, particularly in the reward network, is associated with increased apathy in patients with SVD. Treatments which improve connectivity in this network may improve apathy in SVD, which in turn may improve psychiatric outcome after stroke

Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study.

OBJECTIVE: To evaluate the effects of oral delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on MRI lesion activity and load, atrophy, and magnetization transfer ratio (MTR) measures from the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study. METHODS: CONFIRM was a 2-year, placebo-controlled study of the efficacy and safety of DMF 240 mg twice (BID) or 3 times daily (TID) in 1,417 patients with relapsing-remitting multiple sclerosis (RRMS); subcutaneous glatiramer acetate 20 mg once daily was included as an active reference comparator. The number and volume of T2-hyperintense, T1-hypointense, and gadolinium-enhancing (Gd+) lesions, as well as whole brain volume and MTR, were assessed in 681 patients (MRI cohort). RESULTS: DMF BID and TID produced significant and consistent reductions vs placebo in the number of new or enlarging T2-hyperintense lesions and new nonenhancing T1-hypointense lesions after 1 and 2 years of treatment and in the number of Gd+ lesions at week 24, year 1, and year 2. Lesion volumes were also significantly reduced. Reductions in brain atrophy and MTR changes with DMF relative to placebo did not reach statistical significance. CONCLUSIONS: The robust effects on MRI active lesion counts and total lesion volume in patients with RRMS demonstrate the ability of DMF to exert beneficial effects on inflammatory lesion activity in multiple sclerosis, and support DMF therapy as a valuable new treatment option in RRMS. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence of reduction in brain lesion number and volume, as assessed by MRI, over 2 years of delayed-release DMF treatment

Native vegetation of southeast NSW: a revised classification and map for the coast and eastern tablelands

Native vegetation of the NSW south coast, escarpment and southeast tablelands was classified into 191 floristic assemblages at a level of detail appropriate for the discrimination of Threatened Ecological Communities and other vegetation units referred to in government legislation. Assemblages were derived by a numerical analysis of 10832 field sample quadrats including 8523 compiled from 63 previous vegetation surveys. Past bias in the distribution of field data towards land under public tenure was corrected by extensive surveys carried out on private land. The classification revises and integrates the units described in recent vegetation studies of Eden, Cumberland Plain and Sydney-south coast into a single, consistent classification. Relationships between floristic assemblages and climate, terrain, substrate and vegetation structure were used to map the distribution of communities prior to clearing at 1:100 000 scale. The extent of clearing was mapped using interpretations of remote imagery (1991–2001) from previous work, standardised and merged into a single coverage and supplemented with additional work. Profiles for each assemblage, which we term ‘communities’ or ‘map units’, describe their species composition, vegetation structure, environmental habitat, the extent of clearing and conservation status. Lists of diagnostic species were defined using a statistical fidelity measure and a procedure for using these for community identification is described. Approximately 66% of the study area retains a cover of native vegetation, primarily in areas with low fertility soils and dissected topography. Communities subject to over-clearing (>70%) are concentrated in a few large areas characterised by clay/loam soils and flat to undulating terrain. These include the Sydney metropolis, Wingecarribee Plateau, Illawarra Plain, Shoalhaven floodplain, Araluen Valley and Bega Valley, and various smaller river valleys. Forty-one percent of remaining native vegetation is protected within conservation reserves while 31% occurs on private land, 20% in State Forests and 8% on other Crown lands. Forty-five Threatened Ecological Communities (TECs) were recorded in the study area. The majority of TECs are represented by a single map unit, although in some cases a TEC is included within a broader map unit. Twelve TECs are represented by combinations of two or more map units