Publications

RATIONALE: There is increasing evidence that aberrant processes occurring in the airways may precede the development of idiopathic pulmonary fibrosis (IPF); however, there has been no prior confirmatory data derived from imaging studies. OBJECTIVES: To assess quantitative measures of airway wall thickness (AWT) in populations characterized for interstitial lung abnormalities (ILA) and for IPF. METHODS: Computed tomographic imaging of the chest and measures of AWT were available for 6,073, 615, 1,167, and 38 participants from COPDGene (Genetic Epidemiology of COPD study), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study), and the Framingham Heart Study (FHS) and in patients with IPF from the Brigham and Women’s Hospital Herlihy Registry, respectively. To evaluate these associations, we used multivariable linear regression to compare a standardized measure of AWT (the square root of AWT for airways with an internal perimeter of 10 mm [Pi10]) and characterizations of ILA and IPF by computed tomographic imaging of the chest. RESULTS: In COPDGene, ECLIPSE, and FHS, research participants with ILA had increased measures of Pi10 compared with those without ILA. Patients with IPF had mean measures of Pi10 that were even greater than those noted in research participants with ILA. After adjustment for important covariates (e.g., age, sex, race, body mass index, smoking behavior, and chronic obstructive pulmonary disease severity when appropriate), research participants with ILA had increased measures of Pi10 compared with those without ILA (0.03 mm in COPDGene, 95% confidence interval [CI], 0.02-0.03; P

Genome-wide association studies (GWAS) have identified multiple associations with emphysema apicobasal distribution (EABD), but the biological functions of these variants are unknown. To characterize the functions of EABD-associated variants, we integrated GWAS results with 1) expression quantitative trait loci (eQTL) from the Genotype Tissue Expression (GTEx) project and subjects in the COPDGene (Genetic Epidemiology of COPD) study and 2) cell type epigenomic marks from the Roadmap Epigenomics project. On the basis of these analyses, we selected a variant near ACVR1B (activin A receptor type 1B) for functional validation. SNPs from 168 loci with P values less than 5 × 10 in the largest GWAS meta-analysis of EABD were analyzed. Eighty-four loci overlapped eQTL, with 12 of these loci showing greater than 80% likelihood of harboring a single, shared GWAS and eQTL causal variant. Seventeen cell types were enriched for overlap between EABD loci and Roadmap Epigenomics marks (permutation P

Radiographic abnormalities of the pulmonary vessels, such as vascular pruning, are common in advanced airways disease, but it is unknown if pulmonary vascular volumes are related to measures of lung health and airways disease in healthier populations.In 2,388 participants of the Framingham Heart Study CT sub-study, we calculated total vessel volumes and the small vessel fraction using automated CT image analysis and evaluated associations with measures of lung function, airflow obstruction on spirometry, and emphysema on CT. We further tested if associations of vascular volumes with lung function were present among those with normal FEV and FVC.In fully adjusted linear and logistic models, we found that lower total and small vessel volumes were consistently associated with worse measures of lung health, including lower spirometric volumes, lower diffusing capacity, and/or higher odds of airflow obstruction. For example, each standard deviation lower small vessel fraction (indicating more severe pruning) was associated with a 37% greater odds of obstruction (OR 1.37, 95% CI: 1.11-1.71, p=0.004). A similar pattern was observed in the subset of participants with normal spirometry.Lower total and small vessel pulmonary vascular volumes were associated with poorer measures of lung health and/or greater odds of airflow obstruction in this cohort of generally healthy adults without high burdens of smoking or airways disease. Our findings suggest that quantitative CT assessment may detect subtle pulmonary vasculopathy that occurs in the setting of subclinical and early pulmonary and airways pathology.

PURPOSE: Diffusion encoding with asymmetric gradient waveforms is appealing because the asymmetry provides superior efficiency. However, concomitant gradients may cause a residual gradient moment at the end of the waveform, which can cause significant signal error and image artifacts. The purpose of this study was to develop an asymmetric waveform designs for tensor-valued diffusion encoding that is not sensitive to concomitant gradients. METHODS: The "Maxwell index" was proposed as a scalar invariant to capture the effect of concomitant gradients. Optimization of "Maxwell-compensated" waveforms was performed in which this index was constrained. Resulting waveforms were compared to waveforms from literature, in terms of the measured and predicted impact of concomitant gradients, by numerical analysis as well as experiments in a phantom and in a healthy human brain. RESULTS: Maxwell-compensated waveforms with Maxwell indices below 100 (mT/m) ms showed negligible signal bias in both numerical analysis and experiments. By contrast, several waveforms from literature showed gross signal bias under the same conditions, leading to a signal bias that was large enough to markedly affect parameter maps. Experimental results were accurately predicted by theory. CONCLUSION: Constraining the Maxwell index in the optimization of asymmetric gradient waveforms yields efficient diffusion encoding that negates the effects of concomitant fields while enabling arbitrary shapes of the b-tensor. This waveform design is especially useful in combination with strong gradients, long encoding times, thick slices, simultaneous multi-slice acquisition, and large FOVs.

Murine studies have linked TGF-b signaling to emphysema, and human genome-wide association studies (GWAS) studies of lung function and COPD have identified associated regions near genes in the TGF-b superfamily. However, the functional regulatory mechanisms at these loci have not been identified. We performed the largest GWAS of emphysema patterns to date, identifying ten GWAS loci including an association peak spanning a 200kb region downstream from . Integrative analysis of publicly available eQTL, DNaseI, and chromatin conformation data identified a putative functional variant, rs1690789, that may regulate expression in human fibroblasts. Using chromatin conformation capture, we confirmed that the region containing rs1690789 contacts the promoter in fibroblasts, and CRISPR/Cas-9 targeted deletion of a  100bp region containing rs1690789 resulted in decreased expression in primary human lung fibroblasts. These data provide novel mechanistic evidence linking genetic variation affecting the TGF-b pathway to emphysema in humans.

RATIONALE: Occupational exposures at the WTC site after September 11, 2001 have been associated with several presumably inflammatory lower airway diseases. Pulmonary arterial enlargement, as suggested by an increased ratio of the diameter of the pulmonary artery to the diameter of the aorta (PAAr) has been reported as a computed tomographic (CT) scan marker of adverse respiratory health outcomes, including WTC-related disease. In this study, we sought to utilize a novel quantitative CT (QCT) measurement of PAAr to test the hypothesis that an increased ratio is associated with FEV below each subject’s statistically determined lower limit of normal (FEV

Recently, several biophysical models and signal representations have been proposed for microstructure imaging based on tensor-valued, or multidimensional, diffusion MRI. The acquisition of the necessary data requires non-conventional pulse sequences, and data is therefore not available to the wider diffusion MRI community. To facilitate exploration and development of analysis techniques based on tensor-valued diffusion encoding, we share a comprehensive data set acquired in a healthy human brain. The data encompasses diffusion weighted images using linear, planar and spherical diffusion tensor encoding at multiple b-values and diffusion encoding directions. We also supply data acquired in several phantoms that may support validation. The data is hosted by GitHub: https://github.com/filip-szczepankiewicz/Szczepankiewicz_DIB_2019.

Age- and sex-related alterations in gene transcription have been demonstrated, however the underlying mechanisms are unresolved. Neuroepigenetic pathways regulate gene transcription in the brain. Here, we measure in vivo expression of the epigenetic enzymes, histone deacetylases (HDACs), across healthy human aging and between sexes using [C]Martinostat positron emission tomography (PET) neuroimaging (n = 41). Relative HDAC expression increases with age in cerebral white matter, and correlates with age-associated disruptions in white matter microstructure. A post mortem study confirmed that HDAC1 and HDAC2 paralogs are elevated in white matter tissue from elderly donors. There are also sex-specific in vivo HDAC expression differences in brain regions associated with emotion and memory, including the amygdala and hippocampus. Hippocampus and white matter HDAC expression negatively correlates with emotion regulation skills (n = 23). Age and sex are associated with HDAC expression in vivo, which could drive age- and sex-related transcriptional changes and impact human behavior.

OBJECTIVE: The choroid plexus is an important physiological barrier and produces CSF and neurotrophic, angiogenic, and inflammatory factors involved in brain development. Choroid plexus abnormalities have been implicated in both schizophrenia and bipolar disorder. A previous choroid plexus transcriptomic analysis of schizophrenia identified an upregulation of immune and inflammatory genes that correlated with peripheral inflammatory markers. The purpose of this study was to examine choroid plexus volume in probands across the psychosis spectrum and in their first-degree and axis II cluster A relatives, as well as choroid plexus familiality and choroid plexus covariance with clinical, cognitive, brain, and peripheral marker measures. METHODS: Choroid plexus volume was quantified (using FreeSurfer) in psychosis probands, their first-degree and axis II cluster A relatives, and healthy control subjects, organized by DSM-IV-TR diagnosis. Analyte, structural connectivity, and genotype data were collected from a subset of study subjects. RESULTS: Choroid plexus volume was significantly larger in probands compared with first-degree relatives or healthy control subjects; first-degree relatives had intermediate enlargement compared with healthy control subjects; and total choroid plexus volume was significantly heritable. Larger volume was associated with worse cognition, smaller total gray matter and amygdala volume, larger lateral ventricle volume, and lower structural connectivity in probands. Associations between larger volume and higher levels of interleukin 6 in probands was also observed. CONCLUSIONS: These findings suggest the involvement of the choroid plexus across the psychosis spectrum with a potential pathophysiological mechanism involving the neuroimmune axis, which functions in maintaining brain homeostasis and interacting with the peripheral immune and inflammatory system. The choroid plexus may be an important target in future research.

BACKGROUND: We previously reported that wall area percent (WAP), a quantitative CT (QCT) indicator of airway wall thickness and, presumably, inflammation, is associated with adverse longitudinal expiratory flow trajectories in WTC workers, but that obesity and weight gain also seemed to be independently predictive of the latter. Previous studies have reported no association between WAP and obesity, so we investigated that association in nonsmoking WTC-exposed individuals and healthy unexposed controls. METHODS: We assessed WAP using the Chest Imaging Platform QCT system in a segmental bronchus in 118 former WTC workers, and 89 COPDGene® WTC-unexposed and asymptomatic subjects. We used multiple regression to model WAP vs. body mass index (BMI) in the two groups, adjusting for important subject and CT image characteristics. RESULTS: Unadjusted analyses revealed significant differences between the two groups with regards to WAP, age, gender, scan pixel spacing and slice interval, but not BMI or total lung capacity. In adjusted analysis, there was a significant interaction between BMI and WTC exposure on WAP. BMI was significantly and positively associated with WAP in the WTC group, but not in the COPDGene® group, but stratified analyses revealed that the effect was significant in WTC subjects with clinical evidence of lower airway disease (LAD). DISCUSSION: Unlike non-diseased subjects, BMI was significantly associated with WAP in WTC workers and, in stratified analyses, the association was significant only among those with LAD. Our findings suggest that this adverse effect of obesity on airway structure and inflammation may be confined to already diseased individuals.