Apathy, but not depression, is associated with executive dysfunction in cerebral small vessel disease.

OBJECTIVE: To determine the prevalence of apathy and depression in cerebral small vessel disease (SVD), and the relationships between both apathy and depression with cognition. To examine whether apathy is specifically related to impairment in executive functioning and processing speed. METHODS: 196 patients with a clinical lacunar stroke and an anatomically corresponding lacunar infarct on MRI were compared to 300 stroke-free controls. Apathy and depression were measured using the Geriatric Depression Scale, and cognitive functioning was assessed using an SVD cognitive screening tool, the Brief Memory and Executive Test, which measures executive functioning/processing speed and memory/orientation. Path analysis and binary logistic regression were used to assess the relation between apathy, depression and cognitive impairment. RESULTS: 31 participants with SVD (15.8%) met criteria for apathy only, 23 (11.8%) for both apathy and depression, and 2 (1.0%) for depression only. In the SVD group the presence of apathy was related to global cognition, and specifically to impaired executive functioning/processing speed, but not memory/orientation. The presence of depression was not related to global cognition, impaired executive functioning/processing speed or memory/orientation. CONCLUSIONS: Apathy is a common feature of SVD and is associated with impaired executive functioning/processing speed suggesting the two may share biological mechanisms. Screening for apathy should be considered in SVD, and further work is required to develop and evaluate effective apathy treatment or management in SVD.This work was supported by a Priority Program Grant from the Stroke Association (TSA PPA 2015-02; www.stroke.org.uk). The BMET Study was supported by a grant from the Stroke Association (TSA2008/10). Valerie Lohner is supported by a Stroke Association/British Heart Foundation Program Grant (TSA BHF 2010/01; www.bhf.org.uk). Rebecca Brookes is supported by a BHF Project Grant (PG/13/30/30005). Recruitment to the BMET Study was supported by the English National Institute of Health Research (NIHR) Clinical Stroke Research Network (www.crn.nihr.ac.uk/stroke). Hugh Markus is supported by an NIHR Senior Investigator award (www.nihr.ac.uk) and his work is supported by the Cambridge University Hospital Comprehensive NIHR Biomedical Research Unit (www.cambridge-brc.org.uk)

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Spatial patterns of white matter hyperintensities: a systematic review

BackgroundWhite matter hyperintensities are an important marker of cerebral small vessel disease. This disease burden is commonly described as hyperintense areas in the cerebral white matter, as seen on T2-weighted fluid attenuated inversion recovery magnetic resonance imaging data. Studies have demonstrated associations with various cognitive impairments, neurological diseases, and neuropathologies, as well as clinical and risk factors, such as age, sex, and hypertension. Due to their heterogeneous appearance in location and size, studies have started to investigate spatial distributions and patterns, beyond summarizing this cerebrovascular disease burden in a single metric–its volume. Here, we review the evidence of association of white matter hyperintensity spatial patterns with its risk factors and clinical diagnoses.Design/methodsWe performed a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement. We used the standards for reporting vascular changes on neuroimaging criteria to construct a search string for literature search on PubMed. Studies written in English from the earliest records available until January 31st, 2023, were eligible for inclusion if they reported on spatial patterns of white matter hyperintensities of presumed vascular origin.ResultsA total of 380 studies were identified by the initial literature search, of which 41 studies satisfied the inclusion criteria. These studies included cohorts based on mild cognitive impairment (15/41), Alzheimer’s disease (14/41), Dementia (5/41), Parkinson’s disease (3/41), and subjective cognitive decline (2/41). Additionally, 6 of 41 studies investigated cognitively normal, older cohorts, two of which were population-based, or other clinical findings such as acute ischemic stroke or reduced cardiac output. Cohorts ranged from 32 to 882 patients/participants [median cohort size 191.5 and 51.6% female (range: 17.9–81.3%)]. The studies included in this review have identified spatial heterogeneity of WMHs with various impairments, diseases, and pathologies as well as with sex and (cerebro)vascular risk factors.ConclusionThe results show that studying white matter hyperintensities on a more granular level might give a deeper understanding of the underlying neuropathology and their effects. This motivates further studies examining the spatial patterns of white matter hyperintensities

Incidental findings on 3 T neuroimaging: cross-sectional observations from the population-based Rhineland Study

Purpose!#!Development of best practices for dealing with incidental findings on neuroimaging requires insight in their frequency and clinical relevance.!##!Methods!#!Here, we delineate prevalence estimates with 95% confidence intervals and clinical management of incidental findings, based on the first 3589 participants of the population-based Rhineland Study (age range 30-95 years) who underwent 3 Tesla structural neuroimaging (3D, 0.8 mm!##!Results!#!Of 3589 participants (mean age 55 ± 14 years, 2072 women), 867 had at least one possible incidental finding (24.2%). Most common were pituitary abnormalities (12.3%), arachnoid cysts (4.1%), developmental venous anomalies (2.5%), non-acute infarcts (1.8%), cavernomas (1.0%), and meningiomas (0.7%). Forty-six participants were informed about their findings, which was hitherto unknown in 40 of them (1.1%). Of these, in 19 participants (48%), a wait-and-see policy was applied and nine (23%) received treatment, while lesions in the remainder were benign, could not be confirmed, or the participant refused to inform us about their clinical diagnosis.!##!Conclusion!#!Nearly one-quarter of participants had an incidental finding, but only 5% of those required referral, that mostly remained without direct clinical consequences

Addictive potential of e-cigarettes as reported in e-cigarette online forums: netnographic analysis of subjective experiences.

BACKGROUND: While e-cigarettes usually contain nicotine, their addictive potential is not yet fully understood. We hypothesized that if e-cigarettes are addictive, users will experience typical symptoms of addiction. OBJECTIVE & METHODS: The aim of our study was to investigate whether and how e-cigarette users report signs of addiction. We identified 3 large German-language e-cigarette online forums via a systematic Google search. Based on a netnographic approach, we used deductive content analysis to investigate relevant posts in these forums. Netnography has the advantage of limiting the social desirability bias that prevails in face-to-face research, such as focus groups. The data were coded according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for tobacco use disorder, adapted for e-cigarettes. The DSM-5 criteria were used to portray a broad spectrum of possible experiences of addiction. RESULTS: Overall, 5337 threads in 3 forums were screened, and 451 threads containing relevant information were included in the analysis. Users reported experiences consistent with the DSM-5 criteria, such as craving e-cigarettes, excessive time spent vaping, and health issues related to e-cigarette use. However, our analysis also showed that users reported the absence of typical tobacco use disorder criteria, such as successful attempts to reduce the nicotine dosage. For most themes, reports of their absence were more frequent than of their presence. The absence of perceived addiction was mostly reported in contrast to prior tobacco smoking. CONCLUSIONS: This is the first study to use a netnographic approach to explore unfiltered self-reports of experiences of e-cigarette addiction by users in online forums. As hypothesized, some but not all users reported subjective experiences that corresponded to the criteria of tobacco use disorder as defined by the DSM-5. Nevertheless, subjective reports also indicated that many e-cigarette users felt in control of their behavior, especially in contrast to their prior use of tobacco cigarettes. The finding that some e-cigarette users subjectively experience addiction highlights the need for effective cessation programs to support users who experience their e-cigarette use as burdensome. This research can guide the refinement of instruments to assess e-cigarette addiction and guide cessation programs

Path analysis model.

<p>Path analysis model showing that the magnitude of apathetic symptoms, but not depressive symptoms, is associated with memory/orientation and executive functioning/ processing speed. Premorbid IQ and age were both regressed into the model (not displayed). There was a strong covariance between age and depressive symptoms (<i>β</i> = -.30, <i>p <</i> .001), and between premorbid IQ and executive function/processing speed (<i>β</i> = .35, <i>p <</i> .001) and memory/orientation (<i>β</i> = .16, <i>p =</i> .019). * p < .05; ** p < .005.</p

Demographic and clinical variables for participants with SVD and controls.

<p>Demographic and clinical variables for participants with SVD and controls.</p