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 ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 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 co-localized 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 co-localization 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 antihyperlipidaemic 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 antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.

Understanding e-Cigarette Addictiveness: Triangulation of Focus Group and Netnographic Data.

BACKGROUND: Numerous studies have shown that e-cigarettes are addictive. For example, we previously showed that users of e-cigarette online forums discuss experiences of addiction in a netnographic analysis. However, it is unclear what makes e-cigarettes addictive apart from nicotine. In a focus group analysis, we recently identified 3 unique features of e-cigarettes that users linked to experiences of addiction: the pleasant taste, unobtrusiveness, and unlimited usability of e-cigarettes. OBJECTIVE: This study aimed to validate the previously identified features of e-cigarette addictive potential by triangulating data from the netnographic analysis and focus group discussions. METHODS: Drawing on a netnographic analysis of 3 popular, German-language e-cigarette forums, we studied whether experiences of addiction were linked to specific e-cigarette features. We included 451 threads in the analysis that had been coded for addictive experiences in a previous study by our team. First, we conducted a deductive analysis with preregistered codes to determine whether the features of pleasant taste, unobtrusiveness, and unlimited usability were mentioned in relation to the addictive potential of e-cigarettes in the online forums. Second, an inductive approach was chosen to identify further possible addictive features of e-cigarettes. RESULTS: Our deductive analysis confirmed that the features highlighted in our previous focus group study (pleasant taste, unobtrusiveness, and unlimited usability) were also frequently discussed in online forums in connection to addictive symptoms. In addition, our inductive analysis identified nicotine dosage as a significant feature linked to addiction. Users reported varying their nicotine doses for different reasons, leading to the identification of four distinct user types based on dosing patterns: (1) high doses for intermittent, (2) high doses for constant use, (3) low doses for constant use, and (4) switching between high and low doses depending on the situation. CONCLUSIONS: Our comprehensive analysis of online forum threads revealed that users' experiences of addiction are linked to 4 specific features unique to e-cigarettes: pleasant taste, unobtrusiveness, unlimited usability, and nicotine dosage. Recognizing these addictive features of e-cigarettes is crucial for designing cessation programs and informing public health policies to reduce the addictiveness of e-cigarettes.

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: The aim of our study was to investigate whether and how e-cigarette users report signs of addiction. METHODS: 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. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s40359-021-00682-8.

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 mm3 isotropic resolution). Two trained raters independently assessed all scans for abnormalities, with confirmation and adjudication where needed by neuroradiologists. Participants were referred for diagnostic work-up depending on the potential benefit. 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.

Using DTI to assess white matter microstructure in cerebral small vessel disease (SVD) in multicentre studies.

Diffusion tensor imaging (DTI) metrics such as fractional anisotropy (FA) and mean diffusivity (MD) have been proposed as clinical trial markers of cerebral small vessel disease (SVD) due to their associations with outcomes such as cognition. However, studies investigating this have been predominantly single-centre. As clinical trials are likely to be multisite, further studies are required to determine whether associations with cognition of similar strengths can be detected in a multicentre setting. One hundred and nine patients (mean age =68 years) with symptomatic lacunar infarction and confluent white matter hyperintensities (WMH) on MRI was recruited across six sites as part of the PRESERVE DTI substudy. After handling missing data, 3T-MRI scanning was available from five sites on five scanner models (Siemens and Philips), alongside neuropsychological and quality of life (QoL) assessments. FA median and MD peak height were extracted from DTI histogram analysis. Multiple linear regressions were performed, including normalized brain volume, WMH lesion load, and n° lacunes as covariates, to investigate the association of FA and MD with cognition and QoL. DTI metrics from all white matter were significantly associated with global cognition (standardized ß =0.268), mental flexibility (ß =0.306), verbal fluency (ß =0.376), and Montreal Cognitive Assessment (MoCA) (ß =0.273). The magnitudes of these associations were comparable with those previously reported from single-centre studies found in a systematic literature review. In this multicentre study, we confirmed associations between DTI parameters and cognition, which were similar in strength to those found in previous single-centre studies. The present study supports the use of DTI metrics as biomarkers of disease progression in multicentre studies.

Does perceived vaping addiction predict subsequent vaping cessation behaviour among adults who use nicotine vaping products regularly?

BACKGROUND: This study aimed to investigate whether perceived vaping addiction is a predictor of quitting nicotine vaping product (NVP) use among adults who have ever smoked and currently vape exclusively or predominantly in four countries: Australia, Canada, the US, and England. METHOD: Data analysed (n = 574) came from participants (aged 18 + ) who completed the International Tobacco Control (ITC) Four Country Smoking and Vaping survey in 2018 and again in 2020. Baseline inclusion criteria were: (1) currently not smoking or non-daily smoking; and (2) using NVPs daily/weekly for a period of at least 4 months. Association of self-reported baseline levels of perceived vaping addiction with making any attempts to quit vaping and successful attempts reported at follow-up were examined using logistic regression models, controlling for potential sociodemographic and smoking/vaping-related confounders. RESULTS: Participants who perceived themselves as being addicted to vaping were less likely to attempt to quit vaping than those who perceived themselves as not addicted. Among those who tried, those who perceived themselves being addicted were also less likely to succeed than those who perceived themselves as not addicted. No significant country differences in associations were observed for both outcomes. CONCLUSIONS: Perceived vaping addiction was shown to have predictive utility for vaping cessation behaviours, possibly acting as an indicator of task difficulty, and thus may serve as a useful screening tool for identifying NVP users who may benefit from tailored cessation support programs if they want to stop using these products.

Spatial patterns of white matter hyperintensities: a systematic review.

Background: White 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/methods: We 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. Results: A 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. Conclusion: The 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.

Understanding perceived addiction to and addictiveness of electronic cigarettes among electronic cigarette users: a cross-sectional analysis of the International Tobacco Control Smoking and Vaping (ITC 4CV) England Survey.

BACKGROUND AND AIMS: The addictive potential of electronic cigarettes (e-cigarettes) remains to be fully understood. We identified patterns and correlates of perceived addiction to e-cigarettes and perceived addictiveness of e-cigarettes relative to tobacco cigarettes (relative addictiveness) in dual users as well as exclusive e-cigarette users. DESIGN, SETTING AND PARTICIPANTS: Observational study using cross-sectional survey data from England (2016) from the International Tobacco Control Project (ITC) Four Country Smoking and Vaping (4CV) survey. The study comprised 832 current e-cigarette users who had been vaping for at least 4 months. MEASUREMENTS: Perceived addiction to e-cigarettes and relative addictiveness of e-cigarettes were examined. Socio-demographic factors were age, gender and education; markers of addiction included urge to vape, time to first vape after waking and nicotine strength used; vaping and smoking characteristics included frequency and duration of e-cigarette use, intention to quit, adjustable power or temperature, enjoyment, satisfaction relative to tobacco cigarettes and tobacco cigarette smoking status. FINDINGS: A total of 17% of participants reported feeling very addicted to e-cigarettes, while 40% considered e-cigarettes equally/more addictive than tobacco cigarettes. Those who felt very addicted had higher odds of regarding e-cigarettes as more addictive than tobacco cigarettes (odds ratio 3.4, 95% confidence interval 2.3-5.1). All markers of addiction, daily use and enjoyment were associated with higher perceived addiction, whereas time to first vape after waking, daily vaping and perceiving vaping as less satisfying than smoking were associated with relative addictiveness. CONCLUSIONS: Markers of addiction to e-cigarettes appear to correspond with perceived addiction to e-cigarettes, suggesting that self-reported perceived addiction might serve as an indicator of addiction. Prevalence both of markers of addiction and perceived addiction were comparatively low overall, suggesting a limited but relevant addictive potential of e-cigarettes. Additionally, positive and negative reinforcement, reflected here by enjoyment and relative satisfaction, might play a role in e-cigarette addiction.

Safety of Tattoos, Permanent Make-Up, and Medical Implants in Population-Based 3T Magnetic Resonance Brain Imaging: The Rhineland Study.

Excluding persons from magnetic resonance imaging (MRI) research studies based on their medical history or because they have tattoos, can create bias and compromise the validity and generalizability of study results. In the population-based Rhineland Study, we limited exclusion criteria for MRI and allowed participants with passive medical implants, tattoos or permanent make-up to undergo MRI. Thereby, we could include 16.6% more people than would have been possible based on common recommendations. We observed no adverse events or artifacts. This supports that most passive medical implants, tattoos and permanent make-up are MRI suitable and can be scanned in research settings.

Relation Between Sex, Menopause, and White Matter Hyperintensities: The Rhineland Study.

BACKGROUND AND OBJECTIVES: Mounting evidence implies that there are sex differences in white matter hyperintensity (WMH) burden in older people. Questions remain regarding possible differences in WMH burden between men and women of younger age, sex-specific age trajectories and effects of (un)controlled hypertension, and the effect of menopause on WMH. Therefore, our aim was to investigate these sex differences and age dependencies in WMH load across the adult life span and to examine the effect of menopause. METHODS: This cross-sectional analysis was based on participants of the population-based Rhineland Study (30-95 years) who underwent brain MRI. We automatically quantified WMH using T1-weighted, T2-weighted, and fluid-attenuated inversion recovery images. Menopausal status was self-reported. We examined associations of sex and menopause with WMH load (logit-transformed and z-standardized) using linear regression models while adjusting for age, age-squared, and vascular risk factors. We checked for an age × sex and (un)controlled hypertension × sex interaction and stratified for menopausal status comparing men with premenopausal women (persons aged 59 years or younger), men with postmenopausal women (persons aged 45 years or older), and premenopausal with postmenopausal women (age range 45-59 years). RESULTS: Of 3,410 participants with a mean age of 54.3 years (SD = 13.7), 1,973 (57.9%) were women, of which 1,167 (59.1%) were postmenopausal. We found that the increase in WMH load accelerates with age and in a sex-dependent way. Premenopausal women and men of similar age did not differ in WMH burden. WMH burden was higher and accelerated faster in postmenopausal women compared with men of similar age. In addition, we observed changes related to menopause, in that postmenopausal women had more WMH than premenopausal women of similar age. Women with uncontrolled hypertension had a higher WMH burden compared with men, which was unrelated to menopausal status. DISCUSSION: After menopause, women displayed a higher burden of WMH than contemporary premenopausal women and men and an accelerated increase in WMH. Sex-specific effects of uncontrolled hypertension on WMH were not related to menopause. Further studies are warranted to investigate menopause-related physiologic changes that may inform on causal mechanisms involved in cerebral small vessel disease progression.

Retinal layer assessments as potential biomarkers for brain atrophy in the Rhineland Study.

Retinal assessments have been discussed as biomarkers for brain atrophy. However, available studies did not investigate all retinal layers due to older technology, reported inconsistent results, or were based on small sample sizes. We included 2872 eligible participants of the Rhineland Study with data on spectral domain-optical coherence tomography (SD-OCT) and brain magnetic resonance imaging (MRI). We used multiple linear regression to examine relationships between retinal measurements and volumetric brain measures as well as fractional anisotropy (FA) as measure of microstructural integrity of white matter (WM) for different brain regions. Mean (SD) age was 53.8 ± 13.2 years (range 30-94) and 57% were women. Volumes of the inner retina were associated with total brain and grey matter (GM) volume, and even stronger with WM volume and FA. In contrast, the outer retina was mainly associated with GM volume, while both, inner and outer retina, were associated with hippocampus volume. While we extend previously reported associations between the inner retina and brain measures, we found additional associations of the outer retina with parts of the brain. This indicates that easily accessible retinal SD-OCT assessments may serve as biomarkers for clinical monitoring of neurodegenerative diseases and merit further research.

Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities.

Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-ß, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.

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.

Nonlinear temporal dynamics of cerebral small vessel disease: The RUN DMC study.

OBJECTIVE: To investigate the temporal dynamics of cerebral small vessel disease (SVD) by 3 consecutive assessments over a period of 9 years, distinguishing progression from regression. METHODS: Changes in SVD markers of 276 participants of the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC) cohort were assessed at 3 time points over 9 years. We assessed white matter hyperintensities (WMH) volume by semiautomatic segmentation and rated lacunes and microbleeds manually. We categorized baseline WMH severity as mild, moderate, or severe according to the modified Fazekas scale. We performed mixed-effects regression analysis including a quadratic term for increasing age. RESULTS: Mean WMH progression over 9 years was 4.7 mL (0.54 mL/y; interquartile range 0.95-5.5 mL), 20.3% of patients had incident lacunes (2.3%/y), and 18.9% had incident microbleeds (2.2%/y). WMH volume declined in 9.4% of the participants during the first follow-up interval, but only for 1 participant (0.4%) throughout the whole follow-up. Lacunes disappeared in 3.6% and microbleeds in 5.7% of the participants. WMH progression accelerated over time: including a quadratic term for increasing age during follow-up significantly improved the model (p < 0.001). SVD progression was predominantly seen in participants with moderate to severe WMH at baseline compared to those with mild WMH (odds ratio [OR] 35.5, 95% confidence interval [CI] 15.8-80.0, p < 0.001 for WMH progression; OR 5.7, 95% CI 2.8-11.2, p < 0.001 for incident lacunes; and OR 2.9, 95% CI 1.4-5.9, p = 0.003 for incident microbleeds). CONCLUSIONS: SVD progression is nonlinear, accelerating over time, and a highly dynamic process, with progression interrupted by reduction in some, in a population that on average shows progression.

Refilling the half-empty glass--Investigating the potential role of the Interpretation Modification Paradigm for Depression (IMP-D).

BACKGROUND AND OBJECTIVES: Cognitive biases are known to cause and maintain depression. However, little research has been done on techniques targeting interpretation tendencies found in depression, despite the promising findings of anxiety studies. This paper presents two experiments, investigating the suitability of an Interpretation Modification Paradigm for Depression (IMP-D) in healthy individuals, which has already proven its effectiveness in anxiety (Beard & Amir, 2008). Different from other paradigms, the IMP-D aims at modifying an interpretation bias on response- and on a more implicit reaction time-level, making this task less susceptible to demand effects. METHODS: The Word-Sentence Association Paradigm for Depression (Hindash & Amir, 2011) was modified and administered in healthy volunteers (experiment I: N = 81; experiment II: N = 105). To enhance a positive interpretation bias, endorsing benign and rejecting negative interpretations of ambiguous scenarios was reinforced through feedback. This intervention was compared to the opposite training (both experiments) and a control training (experiment II only). RESULTS: Both experiments revealed a significant increase in bias towards benign interpretations on the level of overt decisions, while only in the first experiment a change was found on a reaction time level. These modifications are not reflected in group-differences in emotional vulnerability. LIMITATIONS: Possible limitations regarding the reliability of inter-dependent response and reaction time measures are discussed. CONCLUSIONS: The IMP-D is able to modify interpretation biases, but adaptations are required to maximize its beneficial effects.