Impact of asthma on the brain: evidence from diffusion MRI, CSF biomarkers and cognitive decline

Chronic systemic inflammation increases the risk of neurodegeneration, but the mechanisms remain unclear. Part of the challenge in reaching a nuanced understanding is the presence of multiple risk factors that interact to potentiate adverse consequences. To address modifiable risk factors and mitigate downstream effects, it is necessary, although difficult, to tease apart the contribution of an individual risk factor by accounting for concurrent factors such as advanced age, cardiovascular risk, and genetic predisposition. Using a case-control design, we investigated the influence of asthma, a highly prevalent chronic inflammatory disease of the airways, on brain health in participants recruited to the Wisconsin Alzheimer's Disease Research Center (31 asthma patients, 186 non-asthma controls, aged 45-90 years, 62.2% female, 92.2% cognitively unimpaired), a sample enriched for parental history of Alzheimer's disease. Asthma status was determined using detailed prescription information. We employed multi-shell diffusion weighted imaging scans and the three-compartment neurite orientation dispersion and density imaging model to assess white and gray matter microstructure. We used cerebrospinal fluid biomarkers to examine evidence of Alzheimer's disease pathology, glial activation, neuroinflammation and neurodegeneration. We evaluated cognitive changes over time using a preclinical Alzheimer cognitive composite. Using permutation analysis of linear models, we examined the moderating influence of asthma on relationships between diffusion imaging metrics, CSF biomarkers, and cognitive decline, controlling for age, sex, and cognitive status. We ran additional models controlling for cardiovascular risk and genetic risk of Alzheimer's disease, defined as a carrier of at least one apolipoprotein E (APOE) ε4 allele. Relative to controls, greater Alzheimer's disease pathology (lower amyloid-β42/amyloid-β40, higher phosphorylated-tau-181) and synaptic degeneration (neurogranin) biomarker concentrations were associated with more adverse white matter metrics (e.g. lower neurite density, higher mean diffusivity) in patients with asthma. Higher concentrations of the pleiotropic cytokine IL-6 and the glial marker S100B were associated with more salubrious white matter metrics in asthma, but not in controls. The adverse effects of age on white matter integrity were accelerated in asthma. Finally, we found evidence that in asthma, relative to controls, deterioration in white and gray matter microstructure was associated with accelerated cognitive decline. Taken together, our findings suggest that asthma accelerates white and gray matter microstructural changes associated with aging and increasing neuropathology, that in turn, are associated with more rapid cognitive decline. Effective asthma control, on the other hand, may be protective and slow progression of cognitive symptoms

Temporal dynamics of emotional responding: amygdala recovery predicts emotional traits

An individual’s affective style is influenced by many things, including the manner in which an individual responds to an emotional challenge. Emotional response is composed of a number of factors, two of which are the initial reactivity to an emotional stimulus and the subsequent recovery once the stimulus terminates or ceases to be relevant. However, most neuroimaging studies examining emotional processing in humans focus on the magnitude of initial reactivity to a stimulus rather than the prolonged response. In this study, we use functional magnetic resonance imaging to study the time course of amygdala activity in healthy adults in response to presentation of negative images. We split the amygdala time course into an initial reactivity period and a recovery period beginning after the offset of the stimulus. We find that initial reactivity in the amygdala does not predict trait measures of affective style. Conversely, amygdala recovery shows predictive power such that slower amygdala recovery from negative images predicts greater trait neuroticism, in addition to lower levels of likability of a set of social stimuli (neutral faces). These data underscore the importance of taking into account temporal dynamics when studying affective processing using neuroimaging

ER Stress-Induced Aggresome Trafficking of HtrA1 Protects Against 1! Proteotoxicity

High temperature requirement A1 (HtrA1) belongs to an ancient protein family that is linked to various human disorders. The precise role of exon 1-encoded N-terminal domains and how these influence the biological functions of human HtrA1 remain elusive. In this study, we traced the evolutionary origins of these N-terminal domains to a single gene fusion event in the most recent common ancestor of vertebrates. We hypothesized that human HtrA1 is implicated in unfolded protein response. In highly secretory cells of the retinal pigmented epithelia, endoplasmic reticulum (ER) stress upregulated HtrA1. HtrA1 co-localized with vimentin intermediate filaments in highly arborized fashion. Upon ER stress, HtrA1 tracked along intermediate filaments, which collapsed and bundled in an aggresome at the microtubule organizing center. Gene silencing of HtrA1 altered the schedule and amplitude of adaptive signaling and concomitantly resulted in apoptosis. Restoration of wild-type HtrA1, but not its protease inactive mutant, was necessary and sufficient to protect from apoptosis. A variant of HtrA1 that harbored exon 1 substitutions displayed reduced efficacy in rescuing cells from proteotoxicity. Our results illuminate the integration of HtrA1 in the toolkit of mammalian cells against protein misfolding and the implications of defects in HtrA1 in proteostasis

How culturally unique are pandemic effects? Evaluating cultural similarities and differences in effects of age, biological sex, and political beliefs on COVID impacts

Despite being bio-epidemiological phenomena, the causes and effects of pandemics are culturally influenced in ways that go beyond national boundaries. However, they are often studied in isolated pockets, and this fact makes it difficult to parse the unique influence of specific cultural psychologies. To help fill in this gap, the present study applies existing cultural theories via linear mixed modeling to test the influence of unique cultural factors in a multi-national sample (that moves beyond Western nations) on the effects of age, biological sex, and political beliefs on pandemic outcomes that include adverse financial impacts, adverse resource impacts, adverse psychological impacts, and the health impacts of COVID. Our study spanned 19 nations (participant N = 14,133) and involved translations into 9 languages. Linear mixed models revealed similarities across cultures, with both young persons and women reporting worse outcomes from COVID across the multi-national sample. However, these effects were generally qualified by culture-specific variance, and overall more evidence emerged for effects unique to each culture than effects similar across cultures. Follow-up analyses suggested this cultural variability was consistent with models of pre-existing inequalities and socioecological stressors exacerbating the effects of the pandemic. Collectively, this evidence highlights the importance of developing culturally flexible models for understanding the cross-cultural nature of pandemic psychology beyond typical WEIRD approaches

Factors Influencing the Implementation of Organized Physical Activity and Fruit and Vegetable Snacks in the HOP\u27N After-School Obesity Prevention Program

Objective: To identify barriers and facilitators for improving the after-school organized physical activity (PA) and snack quality. Methods: After-school staff (Year 1, n = 20; Year 2, n = 17) participated in qualitative, semistructured interviews about the implementation of an after-school obesity prevention intervention. Interviews were recorded, transcribed, coded for common themes, and analyzed using NVivo software. Results: Several factors influencing implementation of PA and fruit and vegetable (FV) consumption were revealed. Facilitators for PA included: staff training, equipment/gym space, and scheduling organized PA. Physical activity barriers included prioritizing PA and lack of school administration support. Fruit and vegetable facilitators included requesting healthier snacks. Fruit and vegetable barriers included cost and low priority of snack. Conclusions and Implications: The success of improving after-school PA and FV snack quality is dependent on many factors, including several organizational system and staff variables. Future research should focus on systemic changes in the after-school environment to increase the priority of daily PA and a healthy snack

Prevalence of harm in Mindfulness-Based Stress Reduction

Background: Mindfulness meditation has become a common method for reducing stress, stress-related psychopathology and some physical symptoms. As mindfulness programs become ubiquitous, concerns have been raised about their unknown potential for harm. We estimate multiple indices of harm following Mindfulness-based Stress Reduction (MBSR) on two primary outcomes: global psychological and physical symptoms. In secondary analyses we estimate multiple indices of harm on anxiety and depressive symptoms, discomfort in interpersonal relations, paranoid ideation and psychoticism. Methods: Intent-to-treat analyses with multiple imputation for missing data were used on pre- and post-test data from a large, observational dataset (n = 2155) of community health clinic MBSR classes and from MBSR (n = 156) and waitlist control (n = 118) participants from three randomized controlled trials conducted contemporaneous to community classes in the same city by the same health clinic MBSR teachers. We estimate change in symptoms, proportion of participants with increased symptoms, proportion of participants reporting greater than a 35% increase in symptoms, and for global psychological symptoms, clinically significant harm. Results: We find no evidence that MBSR leads to higher rates of harm relative to waitlist control on any primary or secondary outcome. On many indices of harm across multiple outcomes, community MBSR was significantly preventative of harm. Conclusions: Engagement in MBSR is not predictive of increased rates of harm relative to no treatment. Rather, MBSR may be protective against multiple indices of harm. Research characterizing the relatively small proportion of MBSR participants that experience harm remains important

Factors influencing the implementation of organized physical activity and fruit and vegetable snacks in the HOP’N After-School Obesity Prevention Program

Objective: To identify barriers and facilitators for improving the after-school organized physical activity (PA) and snack quality. Methods: After-school staff (Year 1, n = 20; Year 2, n = 17) participated in qualitative, semistructured interviews about the implementation of an after-school obesity prevention intervention. Interviews were recorded, transcribed, coded for common themes, and analyzed using NVivo software. Results: Several factors influencing implementation of PA and fruit and vegetable (FV) consumption were revealed. Facilitators for PA included: staff training, equipment/gym space, and scheduling organized PA. Physical activity barriers included prioritizing PA and lack of school administration support. Fruit and vegetable facilitators included requesting healthier snacks. Fruit and vegetable barriers included cost and low priority of snack. Conclusions and Implications: The success of improving after-school PA and FV snack quality is dependent on many factors, including several organizational system and staff variables. Future research should focus on systemic changes in the after-school environment to increase the priority of daily PA and a healthy snack

Rapid changes in histone deacetylases and inflammatory gene expression in expert meditators

Background: A growing body of research shows that mindfulness meditation can alter neural, behavioral and biochemical processes. However, the mechanisms responsible for such clinically relevant effects remain elusive. Methods: Here we explored the impact of a day of intensive practice of mindfulness meditation in experienced subjects (n=19) on the expression of circadian, chromatin modulatory and inflammatory genes in peripheral blood mononuclear cells (PBMC). In parallel, we analyzed a control group of subjects with no meditation experience who engaged in leisure activities in the same environment (n=21). PBMC from all participants were obtained before (t1) and after (t2) the intervention (t2-t1=8h) and gene expression was analyzed using custom pathway focused quantitative-real time PCR assays. Both groups were also presented with the Trier Social Stress Test (TSST). Results: Core clock gene expression at baseline (t1) was similar between groups and their rhythmicity was not influenced in meditators by the intensive day of practice. Similarly, we found that all the epigenetic regulatory enzymes and inflammatory genes analyzed exhibited similar basal expression levels in the two groups. In contrast, after the brief intervention we detected reduced expression of histone deacetylase genes (HDAC 2, 3 and 9), alterations in global modification of histones (H4ac; H3K4me3) and decreased expression of pro-inflammatory genes (RIPK2 and COX2) in meditators compared with controls. We found that the expression of RIPK2 and HDAC2 genes was associated with a faster cortisol recovery to the TSST in both groups. Conclusions: The regulation of HDACs and inflammatory pathways may represent some of the mechanisms underlying the therapeutic potential of mindfulness-based interventions. Our findings set the foundation for future studies to further assess meditation strategies for the treatment of chronic inflammatory conditions. © 2013 Elsevier Ltd.This work was supported by grants from the National Center for Complementary and Alternative Medicine of NIH to RJD and AL (P01-AT004952) and by grants to RJD from the Fetzer Institute, the John Templeton Foundation and an anonymous donorPeer Reviewe