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Abstract Background The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) randomized trial ( n = 977;ClinicalTrials.gov:NCT03243422) demonstrated that hearing intervention slowed 3‐year cognitive decline by 48% among a subgroup of participants. To further investigate differences by treatment with respect to cognitive benefit, we tested the hypothesis that hearing intervention is associated with improved neurodegeneration blood biomarkers 3‐years post‐randomization and assessed whether combining biomarkers and cognitive results improved power in the trial design. Method The ACHIEVE study is a multicenter, parallel‐arm, randomized trial (hearing intervention vs health education control) on 3‐year cognitive decline among adults 70–84years with untreated hearing loss and without substantial cognitive impairment. Participants were recruited from two populations: (1) a long‐standing cardiovascular health observational study (Atherosclerosis Risk in Communities [ARIC]), and (2) de novo community volunteers. Plasma was collected in year 3 in a subsample ( n = 540) while ARIC participants ( n = 164) also had baseline plasma. Glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) neurodegenerative biomarkers were derived using the Alamar CNS protein panel. Regression models estimated the association of treatment with 3‐year biomarkers and global cognitive differences in the combined sample and by recruitment source and annualized change from baseline in the ARIC sample. We included a simple composite score of the standardized outcomes (Table 2). Result Among the subsample, baseline characteristics were balanced by treatment. There were no significant differences on 3‐year neurodegeneration biomarker levels by treatment in the combined (Table 1) or de novo groups (Table 2). Among ARIC participants, intervention resulted in lower 3‐year GFAP (mean:‐0.415;95%CI:‐0.712,‐0.118) and NfL (mean:‐0.349;95%CI:‐0.652,‐0.046) (Table 2). Annualized change from baseline analyses among ARIC participants (Table 3) revealed intervention was associated with a slower rate of cognitive decline (difference‐in‐means:0.059;95%CI:0.018,0.100) and a slower rate of increase in GFAP (difference‐in‐means: ‐0.060;95%CI:‐0.112,‐0.009). Differences in estimates suggest combined score, relative to cognition alone, may increase power in clinical trials that show a positive effect (ARIC subgroup: p = 0.02vs. 0.08[Table 2] and p = 0.0009vs.0.048[Table 3]). Conclusion Hearing intervention was associated with positive 3‐year effects on neurodegeneration blood biomarkers in ARIC participants which parallels cognitive decline results. Results provides objective evidence of brain changes following hearing intervention and potential signal of a more powerful combined outcome approach for future brain health clinical trials.

Introduction Despite the identification of multiple susceptibility loci by genome-wide association studies (GWAS), considerable chronic obstructive pulmonary disease (COPD) heritability remains unexplained. Aim To identify interaction networks of airway epithelial cell DNA methylation in COPD and further explore potential correlations with airway bacterial composition, as potentially collective regulators of biological pathways influencing COPD severity. Methods Using DNA isolated from bronchial airway brushings of 67 ever-smokers (>20 pack-years) from the SubPopulations and InteRmediate Outcomes Measures in COPD Study (SPIROMICS), we assessed proportion of DNA methylation (β) by epigenome-wide association study (EWAS) and examined associations of differentially methylated CpG probes (DMPs) with risk for moderate-to-severe COPD (N=34) versus absent or mild COPD (N=33). We tested co-methylation modules generated by Weighted Correlation Network Analyses (WGCNA) for associations with moderate-to-severe COPD and with bacterial genus-level relative abundances (16S rRNA sequencing). Results EWAS-identified nominally significant DMPs enriched for lung function GWAS loci. Eigengenes in six WGCNA modules were associated with moderate-to-severe COPD (false discovery rate <0.05). Four of those modules were enriched for forced expiratory volume in 1 s/forced vital capacity GWAS loci, and five overlapped with DMPs from EWAS. Overlapping CpG loci in three COPD-associated modules were adjacent to mucin genes; one had 10 genes highly ranked by connectivity with MUC5B, including important pathway genes: B3GNT6 , DGKI and ITGA8 . CpGs in an independent COPD-associated module showed the most correlations with Rothia , with directionality suggestive of negative associations with moderate-severe COPD. Conclusions Bronchial epithelial DNA methylation modules enriched for lung function GWAS loci associate with COPD severity in SPIROMICS. Potential module relationships to bronchial bacterial composition require further validation.

BACKGROUND: Although chronic obstructive pulmonary disease (COPD) and heart failure with preserved ejection fraction often coexist with overlapping clinical features, they are usually studied separately. The SPIROMICS HF (Subpopulations and Intermediate Outcome Measures in COPD and Heart Failure Study) is testing hypotheses that new computed tomography emphysema subtypes are associated with specific cardiovascular phenotypes (eg, cor pulmonale , cor pulmonale parvus ), common airway branch variants are associated with right heart dysfunction, and symptomatic tobacco-exposed persons with preserved spirometry have signs of increased left ventricular afterload. METHODS: SPIROMICS is a multicenter observational study of COPD with extensive pulmonary phenotyping of participants with ≥20 pack-years smoking and nonsmoking controls. COPD and COPD severity were defined by standard spirometric criteria and symptomatic tobacco-exposed persons with preserved spirometry by ≥20 pack-years, normal spirometry, and COPD Assessment Test score >10. SPIROMICS HF selected all participants in SPIROMICS visit 5 at major sites. Its comprehensive speckle-tracking echocardiography, which included physiological perturbations of leg raise and low-intensity exercise, was harmonized prospectively with the Multi-Ethnic Study of Atherosclerosis Early Heart Failure and HeartSHARE (Combining Omics, Deep Phenotyping, and Electronic Health Records for Heart Failure Subtypes and Treatment Targets) studies. The cardiopulmonary magnetic resonance imaging protocol with gadolinium administration included myocardial fibrosis sequences, pulmonary angiography, time-resolved 3-dimensional cine magnetic resonance imaging (4-dimensional flow) of venous return, and metronome-paced tachypnea to induce dynamic hyperinflation. Coronary artery calcium was assessed on computed tomography scans. The Kansas City Cardiomyopathy Questionnaire was administered. RESULTS: Of the final sample of 753 participants, 57% had COPD (15% mild, 27% moderate, and 15% severe), 18% had symptomatic tobacco-exposed persons with preserved spirometry, 16% were smoking controls, and 8% were nonsmoking controls. Reproducibility of the main measures from speckle-tracking echocardiography (intraclass correlation coefficient, 0.83–0.99), exercise echocardiography (intraclass correlation coefficient, 0.71–0.99) and magnetic resonance imaging (intraclass correlation coefficient, 0.57–0.99) were good-to-excellent, including in severe COPD. CONCLUSIONS: SPIROMICS HF aims to characterize and understand cardiopulmonary interactions in COPD and COPD-related phenotypes to inform targeted treatments for combined cardiopulmonary failure.

Abstract Rationale Inflammation is central to chronic obstructive pulmonary disease (COPD) pathogenesis but incompletely represented in COPD prognostic models. The neutrophil-to-lymphocyte ratio (NLR) is a readily available inflammatory biomarker. Objectives To explore the associations of NLR with smoking status, clinical features of COPD, and future adverse outcomes. Methods We analyzed NLR calculated from the complete blood count of participants who currently or formerly smoked (n = 2,624) and tobacco-naive control subjects (n = 187) in the SPIROMICS multicenter observational cohort study. We assessed the stability of NLR at 6 weeks and 1 year, the association with select blood biomarkers, and the impact of smoking on NLR and cell counts. We stratified participants by NLR quartiles to compare cross-sectional clinical features at enrollment, prospectively observed exacerbations at 1 year, and mortality during longitudinal follow up. Results Higher NLR quartiles were broadly associated with more severe clinical features of COPD. NLR values were repeatable at 6 weeks (intraclass correlation coefficient, 0.74) and 1 year (intraclass correlation coefficient, 0.62). The impact of smoking on NLR varied with the severity of airflow limitation, mediated by an interaction between smoking, forced expiratory volume in 1 second percent predicted, and neutrophil counts but not lymphocyte counts. The highest NLR quartile (&gt;3.11) was associated with an increased risk of exacerbation over 1 year (adjusted odds ratio, 1.51; 95% confidence interval, 1.18, 1.92) and increased risk of mortality (adjusted hazard ratio, 1.41; 95% confidence interval, 1.20, 1.66) compared with quartiles 1–3. Conclusions Elevated NLR in stable COPD is a widely available biomarker associated with increased risk for exacerbation and death. The impact of cigarette smoking on NLR varies with disease severity.

Abstract Introduction Resilient smokers, who maintain respiratory health despite smoking, remain poorly characterized. Airway epithelial cell gene expression in resilient smokers can provide insight into mechanisms and pathways that may protect smokers from developing smoking-related lung disease. The objective of this study is to identify genes and potential pathways associated with lung-related resilience. Methods Resilient smokers were defined based on a previously published multi-dimensional definition which includes the absence of: 1) spirometric airflow limitation, 2) symptoms (cough/sputum, dyspnea), 3) radiographic (HRCT) abnormalities, 4) exacerbations, and 5) an accelerated FEV1 decline. “Non-resilient” smokers had preserved spirometry but showed abnormalities in at least one domain of resilience. We analyzed airway epithelial brush samples from 21 resilient and 34 non-resilient smokers from SPIROMICS. Differential gene expression was performed using DESeq2 package in R, which estimates differential expression using generalized linear models. We adjusted for sequencing batch, age (continuous), race, gender, and current smoking status. While controlling for these covariates we evaluated differential gene expression between resilient and non-resilient smokers, the interaction between resilience and smoking status, and in each sub-category of resilient (absence of symptoms, radiographic abnormalities, exacerbations, and accelerated decline in FEV1). Results We identified 98 genes that were differentially expressed (FDR ≤0.1) when comparing resilient to non-resilient smokers, 20 of those genes were up regulated in resilient smokers (Figure 1). Notable genes included cadherin-12 (CDH12), aspartate beta-hydroxylase (ASPH), and protein kinase AMP-activated alpha 2 (PRKAA2). CDH12 is involved in cell adhesion and epithelial integrity. ASPH influences cell adhesion and signaling. PRKAA2 plays role in cellular homeostasis and stress response, which may be altered in non-resilient smokers, affecting cellular metabolism and inflammation. BPI folding containing family A member (BPIFA1) was significantly associated with smoking status in the interaction analysis, suggesting its role in modulating the impact of smoking on resilience. BPIFA1 has anti-microbial properties, regulates immune responses, and contributes mucosal surface protection. Sub-category analysis identified 17 genes associated with resilience to symptoms and 2 genes related to physiologic resilience (FEV1 decline), though no significant genes were associated with radiographic or exacerbation resilience. Conclusion Differential gene expression of airway epithelial cells identified distinct expression patterns between resilient and non-resilient smokers. Specifically, genes associated with epithelial cell adhesion, signaling, and cellular homeostasis were up regulated in resilient smokers. These findings suggest that resilient smokers may have transcriptomic profiles and potential mechanisms that mitigate the effects of cigarette smoke.

Abstract Rationale: MUC5B and MUC5AC are neighboring genes on chromosome 11p15 that encode the two predominant mucins secreted in the respiratory airways. Increased airway mucin concentrations and an imbalance between these two mucins drive COPD symptoms and the development of airflow obstruction or COPD, but the epigenomic regulation of this loci has not been characterized in the airways. Methods: We isolated DNA from bronchial airway brushings of 72 participants with &gt;20 pack-years smoking history from the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS). 36 participants had GOLD-based moderate-to-severe COPD (FEV1/FVC&lt;0.70, FEV1&lt;80%) and 36 were without or with mild COPD. We used the Illumina Infinium Methylation EPIC BeadChip Array to assess proportion of DNA methylation (β) spanning 689,937 CpG sites. We evaluated proportional DNA methylation (β) at 96 CpG loci within a 103kB region using matrixQTL for cis-expression quantitative trait methylation (eQTM: 10kB flanks relative to MUC5AC/MUC5B) integrating bulk RNA-seq data and mQTL models integrating gene sequencing data to identify DNA variation associated with proportion eQTM methylation. Models included age, sex, BMI, clinical site, current smoking vs past smoking, total pack-years, three ancestral components of ancestry, chipset, and position. Results: We identified a top eQTM, cg00524486, marginally associated with MUC5B expression (coefficient estimate=8.75, punadjusted=0.0014, pFDR=0.065, Figure 1B). This eQTM was associated with CT scan parametric response mapping-based functional small airways disease (PRM-fSAD, beta coefficient[β]=3.64, p=0.011). We tested for DNA variation associated with methylation of this top eQTM which identified two methylation quantitative trait loci (mQTL: rs885454 [β=0.044, minor allele frequency[MAF]=0.09, pFDR=0.01], rs868902 [β=0.020, MAF=0.43, pFDR=0.08, Figure 1A) associated with cg00524486 methylation, of which the more frequent mQTL, rs868902, was marginally associated with PRM-fSAD (p=0.07) in the larger SPIROMICS cohort with MUC5B DNA sequencing data. Conclusions: This preliminary multi-omic study of the lower airway epithelium demonstrates that the expression of MUC5B is epigenetically regulated by neighboring CpG probe methylation (eQTM) represented by DNA variation (mQTL). These studies require further confirmation in a larger dataset of airway samples and support a role for epigenetic variation as a biologic contributor and biomarker of early COPD pathogenesis.

Abstract Rationale Chronic obstructive pulmonary disease (COPD) manifests later in life and is a leading cause of death worldwide. While smoking-related lung pathology is a long-recognized COPD etiotype, emerging evidence suggests that early-life growth conditions also play an important role. A recently-developed index of early-life growth conditions – the difference between attained height and genotype-predicted height (height-GaP) – has been validated against prospectevely ascertained adverse early-life growth conditions. This study used height-GaP to evaluate the association of early-life growth conditions with COPD phenotype and prognosis later in life. Methods Among current and former smokers with spirometry-defined COPD in the SubPopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS), we computed height-GaP as the difference between attained height and genotype-predicted height. Regression models were fit for respiratory mortality (defined by primary diagnostic code), dyspnea prevalence (Medical Research Council dyspnea rating &gt;1), chronic bronchitis prevalence, airflow obstruction severity as quantified by FEV1Q, and functional capacity (six-minute walk distance), adjusting for age, age2, sex, race-ethnicity, genotype-predicted height, cigarette smoking status and pack-years. Sensitivity analyses accounted for competing risks of death (Fine-Gray subdistribution hazard model) and accounted for later-life height loss (restricting sample to participants under 50 years). Results Among 1,258 participants with COPD (mean±SD age: 65.4±8.0 years, 42.4% female, mean±SD pack-years: 53.6±28.2, mean±SD FEV1%: 63.3±23.9%), there were 202 respiratory deaths over a median 7.5 years of follow-up (Figure). Larger height-GaP deficit was associated with higher respiratory mortality (adjusted hazard ratio [aHR]: 1.30 [95%CI: 1.12 to 1.50] per 1-SD increment in height-GaP deficit). This association remained significant after accounting for competing events (p=0.001) and when restricted to participants under 50 years (p=0.032). Larger height-GaP deficit was associated with higher dyspnea prevalence (adjusted prevalence ratio: 1.13 [95%CI: 1.02 to 1.25] per 1-SD increment in height-GaP deficit), lower FEV1Q (adjusted mean difference: -0.37 [95%CI: -0.45 to -0.29] per 1-SD height-GaP deficit), and shorter 6-minute walk (adjusted mean difference: -16.6 m [95%CI: -23.1 m to -10.0 m] per 1-SD increment in height-GaP deficit), but not chronic bronchitis or CAT score ≥10 (p&gt;0.05 for each). Conclusions Among current and former smokers with COPD, a quantitative index of early-life conditions was associated with higher respiratory mortality, in addition to dyspnea, airflow obstruction severity and reduced functional capacity. These results suggest that early-life growth conditions may influence COPD phenotype and prognosis later in life.

Abstract Rationale Increased risk of coronavirus disease (COVID-19) hospitalization and death has been reported among patients with clinical lung disease. Objectives To test the association of objective measures of prepandemic lung function and structure with COVID-19 outcomes in U.S. adults. Methods Prepandemic obstruction (FEV1/FVC &lt; 0.70) and restriction (FEV1/FVC ⩾ 0.7, FVC &lt; 80%) were defined based on the most recent spirometry exam conducted in 11 prospective U.S. general population–based cohorts. Severe obstruction was classified by FEV1 &lt; 50%. Percentage emphysema, percentage high-attenuation areas, and interstitial lung abnormalities were defined on computed tomography in a subset. Incident COVID-19 was ascertained via questionnaires, serosurvey, and medical records from 2020 to 2023 and classified as severe (hospitalized or fatal) or nonsevere. Cause-specific hazard models were adjusted for sociodemographics, anthropometry, smoking, comorbidities, and COVID-19 vaccination status. Measurements and Main Results Among 29,323 participants (mean age, 67 yr), there were 748 severe incident COVID-19 cases over median follow-up of 17.3 months from March 1, 2020. Greater hazards of severe COVID-19 were associated with severe obstruction (vs. normal; adjusted hazard ratio [aHR], 2.11; 95% confidence interval [CI], 1.02–1.27), restriction (vs. normal; aHR, 1.40; 95% CI, 1.12–1.76), and percentage emphysema (highest vs. lowest quartile; aHR, 1.64; 95% CI, 1.03–2.61), but not greater high-attenuation areas or interstitial lung abnormalities. COVID-19 vaccination provided greater absolute risk reduction in these groups. Results were similar in participants without smoking, obesity, or clinical cardiopulmonary disease. Conclusions Prepandemic severe spirometric obstruction, spirometric restriction, and greater percentage emphysema lung on computed tomography were associated with risk of severe COVID-19. These findings support enhanced COVID-19 risk mitigation for individuals with impaired lung health and warrant further mechanistic studies on interactions of lung function, structure, and vulnerability to acute respiratory illnesses.

AbstractBackgroundPrior longitudinal studies among older adults have documented associations between hearing loss and changes in brain morphology. Whether interventions involving hearing aids can reduce age‐related atrophy is unknown. A substudy within the Aging and Cognitive Health Evaluation in Elders (ACHIEVE, Clinicaltrials.gov Identifier: NCT03243422) randomized controlled trial tested the effect of a best‐practices hearing intervention versus health education control on three‐year change in cortical thickness among older adults with hearing loss.MethodThe ACHIEVE study enrolled 977 community‐dwelling adults aged 70‐84 years at baseline (2018‐2019) with untreated hearing loss (better ear pure tone average [0.5‐4 kHz] ≥30 and <70 dB HL) and without substantial cognitive impairment from four sites across the U.S. (Jackson, MS, Forsyth County, NC, Minneapolis, MN, Washington County, MD). Participants were randomized to a hearing intervention (provision of hearing aids and related technologies, counseling, and education) or a health education control (individual sessions with a health educator covering topics relevant to chronic disease and disability prevention). Three‐dimensional magnetic resonance imaging was performed on 3 Tesla Siemens scanners in a subsample of 445 participants at the ACHIEVE baseline and three‐year follow‐up. Linear mixed effects models were used in intention‐to‐treat analyses to estimate three‐year change in cortical thickness. All models adjusted for baseline measures of hearing loss, recruitment source, site, age, sex, and education. Missing outcome and covariate data was imputed to mitigate bias caused by informative attrition.ResultAt baseline, 224 participants were women (50.3%), 52 participants were Black (11.7%), and the mean (SD) age was 76.4 (4.0) years old (Table 1). Compared to the health education control, the hearing intervention exhibited a nominally protective effect on three‐year change in average cortical thickness (Figure 1). The greatest effect size for cortical thickness was observed in the occipital lobe, while the smallest effect size was detected in the temporal lobe. Statistically significant effects were detected in the pars orbitalis, rostral anterior cingulate, posterior cingulate, and isthmus cingulate (Figure 2).ConclusionHearing aid use may reduce decline in cortical thickness among older adults. The effects of hearing aids may be greatest in regions other than those associated with the auditory cortex.

Abstract Rationale Among tobacco-exposed persons with preserved spirometry (TEPSs), we previously demonstrated that different lung volume indices—specifically, elevated total lung capacity (TLC) versus elevated ratio of functional residual capacity to TLC (FRC/TLC)—identify different lung disease characteristics in the COPDGene cohort. Objective We sought to determine differential disease characteristics and trajectories associated with lung volume indices among TEPSs in the SPIROMICS cohort. Methods We categorized TEPSs (n = 814) by tertiles (low, intermediate, and high) of TLC or residual volume–to-TLC ratio (RV/TLC) derived from baseline computed tomography images and then examined clinical and spirometric disease trajectories in mutually exclusive categories of participants with high TLC without high RV/TLC ([TLC]high) versus high RV/TLC without high TLC ([RV/TLC]high). We examined differences in computed tomography–measured emphysema (Hounsfield units [HU] ⩽−950; parametric response mapping [PRM] of emphysema), air trapping (HU⩽−856; PRM of functional small airway disease; a disease probability measure for non-emphysematous gas trapping), airway geometry (the mean square root of wall area of a hypothetical airway with 10 mm internal perimeter), respiratory symptoms (on the modified Medical Research Council Dyspnea Scale; COPD Assessment Test [CAT]; St. George’s Respiratory Questionnaire [SGRQ]; and Short Form-12 [SF12]), and outcomes (annualized exacerbation rate) between the two categories at baseline and over follow-up time up to 8.5 years, using regression modeling adjusted for age, sex, height, weight, and smoking status (current vs. former smoker) and burden (pack-years). Results In TEPSs, the pattern of spirometric disease progression differed between participants with [TLC]high and those with [RV/TLC]high: There was increased forced vital capacity with stable forced expiratory volume in 1 second in participants with [TLC]high, versus unchanged forced vital capacity but nominally decreased forced expiratory volume in 1 second in those with [RV/TLC]high. Compared with participants with [TLC]high, TEPSs with [RV/TLC]high had less emphysema (by HU ⩽−950) but more airway disease (by HU ⩽−856; PRM of functional small airway disease; disease probability measure for gas trapping, and mean square root of wall area of a hypothetical airway with 10 mm internal perimeter), more respiratory symptoms (on the modified Medical Research Council Dyspnea Scale, CAT, SGRQ, and SF12), and more severe exacerbations at baseline. Over an average follow-up of 4.1 ± 2.4 years (range = 0.5–8.5 yr), TEPSs with [RV/TLC]high also had a higher likelihood of developing more severe spirometric disease (preserved ratio impaired spirometry or Global Initiative for Chronic Obstructive Lung Disease Classification 2) and worsening of their respiratory symptoms (on the CAT and SGRQ). Although the incidence rates of respiratory exacerbations, hospitalizations, and mortality were not significantly different between the two categories over the follow-up period, TEPSs with [RV/TLC]high were more likely to have been prescribed a respiratory inhaler at their last follow-up visit. Conclusions In these TEPSs from the SPIROMICS cohort, lung volume stratification by TLC versus RV/TLC identifies two pre-COPD phenotypes with distinct respiratory symptoms, radiographic features, and clinical trajectories. The characteristics of these pre-COPD phenotypes match those previously described in the COPDGene cohort using TLC versus FRC/TLC stratification.