Publications

2018
Yun JH, Lamb A, Chase R, Singh D, Parker MM, Saferali A, Vestbo J, Tal-Singer R, Castaldi PJ, Silverman EK, et al. Blood eosinophil count thresholds and exacerbations in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2018;141 (6) :2037-2047.e10.Abstract
BACKGROUND: Eosinophilic airway inflammation in patients with chronic obstructive pulmonary disease (COPD) is associated with exacerbations and responsivity to steroids, suggesting potential shared mechanisms with eosinophilic asthma. However, there is no consistent blood eosinophil count that has been used to define the increased exacerbation risk. OBJECTIVE: We sought to investigate blood eosinophil counts associated with exacerbation risk in patients with COPD. METHODS: Blood eosinophil counts and exacerbation risk were analyzed in patients with moderate-to-severe COPD by using 2 independent studies of former and current smokers with longitudinal data. The Genetic Epidemiology of COPD (COPDGene) study was analyzed for discovery (n = 1,553), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study was analyzed for validation (n = 1,895). A subset of the ECLIPSE study subjects were used to assess the stability of blood eosinophil counts over time. RESULTS: COPD exacerbation risk increased with higher eosinophil counts. An eosinophil count threshold of 300 cells/μL or greater showed adjusted incidence rate ratios for exacerbations of 1.32 in the COPDGene study (95% CI, 1.10-1.63). The cutoff of 300 cells/μL or greater was validated for prospective risk of exacerbation in the ECLIPSE study, with adjusted incidence rate ratios of 1.22 (95% CI, 1.06-1.41) using 3-year follow-up data. Stratified analysis confirmed that the increased exacerbation risk associated with an eosinophil count of 300 cells/μL or greater was driven by subjects with a history of frequent exacerbations in both the COPDGene and ECLIPSE studies. CONCLUSIONS: Patients with moderate-to-severe COPD and blood eosinophil counts of 300 cells/μL or greater had an increased risk exacerbations in the COPDGene study, which was prospectively validated in the ECLIPSE study.
Sydnor VJ, Rivas-Grajales AM, Lyall AE, Zhang F, Bouix S, Karmacharya S, Shenton ME, Westin C-F, Makris N, Wassermann D, et al. A comparison of three fiber tract delineation methods and their impact on white matter analysis. Neuroimage. 2018;178 :318-331.Abstract
Diffusion magnetic resonance imaging (dMRI) is an important method for studying white matter connectivity in the brain in vivo in both healthy and clinical populations. Improvements in dMRI tractography algorithms, which reconstruct macroscopic three-dimensional white matter fiber pathways, have allowed for methodological advances in the study of white matter; however, insufficient attention has been paid to comparing post-tractography methods that extract white matter fiber tracts of interest from whole-brain tractography. Here we conduct a comparison of three representative and conceptually distinct approaches to fiber tract delineation: 1) a manual multiple region of interest-based approach, 2) an atlas-based approach, and 3) a groupwise fiber clustering approach, by employing methods that exemplify these approaches to delineate the arcuate fasciculus, the middle longitudinal fasciculus, and the uncinate fasciculus in 10 healthy male subjects. We enable qualitative comparisons across methods, conduct quantitative evaluations of tract volume, tract length, mean fractional anisotropy, and true positive and true negative rates, and report measures of intra-method and inter-method agreement. We discuss methodological similarities and differences between the three approaches and the major advantages and drawbacks of each, and review research and clinical contexts for which each method may be most apposite. Emphasis is given to the means by which different white matter fiber tract delineation approaches may systematically produce variable results, despite utilizing the same input tractography and reliance on similar anatomical knowledge.
Hong Y, O'Donnell LJ, Savadjiev P, Zhang F, Wassermann D, Pasternak O, Johnson H, Paulsen J, Vonsattel J-P, Makris N, et al. Genetic Load Determines Atrophy in Hand Cortico-striatal Pathways in Presymptomatic Huntington's Disease. Hum Brain Mapp. 2018.Abstract
Huntington's disease (HD) is an inherited neurodegenerative disorder that causes progressive breakdown of striatal neurons. Standard white matter integrity measures like fractional anisotropy and mean diffusivity derived from diffusion tensor imaging were analyzed in prodromal-HD subjects; however, they studied either a whole brain or specific subcortical white matter structures with connections to cortical motor areas. In this work, we propose a novel analysis of a longitudinal cohort of 243 prodromal-HD individuals and 88 healthy controls who underwent two or more diffusion MRI scans as part of the PREDICT-HD study. We separately trace specific white matter fiber tracts connecting the striatum (caudate and putamen) with four cortical regions corresponding to the hand, face, trunk, and leg motor areas. A multi-tensor tractography algorithm with an isotropic volume fraction compartment allows estimating diffusion of fast-moving extra-cellular water in regions containing crossing fibers and provides quantification of a microstructural property related to tissue atrophy. The tissue atrophy rate is separately analyzed in eight cortico-striatal pathways as a function of CAG-repeats (genetic load) by statistically regressing out age effect from our cohort. The results demonstrate a statistically significant increase in isotropic volume fraction (atrophy) bilaterally in hand fiber connections to the putamen with increasing CAG-repeats, which connects the genetic abnormality (CAG-repeats) to an imaging-based microstructural marker of tissue integrity in specific white matter pathways in HD. Isotropic volume fraction measures in eight cortico-striatal pathways are also correlated significantly with total motor scores and diagnostic confidence levels, providing evidence of their relevance to HD clinical presentation.
Kinney GL, Santorico SA, Young KA, Cho MH, Castaldi PJ, San José Estépar R, Ross JC, Dy JG, Make BJ, Regan EA, et al. Identification of Chronic Obstructive Pulmonary Disease Axes That Predict All-Cause Mortality: The COPDGene Study. Am J Epidemiol. 2018.Abstract
Chronic Obstructive Pulmonary Disease (COPD) is a syndrome caused by damage to the lungs resulting in decreased pulmonary function and reduced structural integrity. Pulmonary function testing (PFT) is currently used to diagnose and stratify COPD into severity groups and chest computed tomography (CT) imaging is often used to assess structural changes in the lungs. We hypothesized that the combination of PFT and CT phenotypes would provide a more powerful tool for assessing underlying morphologic differences associated with pulmonary function in COPD than PFT alone. We used factor analysis of 26 variables to classify 8,157 participants recruited into the COPDGene cohort between January 2008 and June 2011 from 21 Clinical Centers across the United States. These factors were then used as predictors of all-cause mortality using Cox Proportional Hazards modeling. Five factors explained 80% of the covariance and represented domains for increased emphysema and decreased pulmonary function (Factor 1); airway disease and decreased pulmonary function (Factor 2); gas trapping (Factor 3); CT variability (Factor 4); and hyperinflation (Factor 5). Over 46,079 person-years of follow-up, Factors 1 through 4 were associated with mortality and there was a significant synergistic interaction between Factor 1 and Factor 2 on mortality. Considering CT measures along with PFT in the assessment of COPD can identify patients at particularly high risk for mortality.
de la Hoz RE, Liu X, Doucette JT, Reeves AP, Bienenfeld LA, Wisnivesky JP, Celedón JC, Lynch DA, San José Estépar R. Increased Airway Wall Thickness is Associated with Adverse Longitudinal First-Second Forced Expiratory Volume Trajectories of Former World Trade Center workers. Lung. 2018.Abstract
RATIONALE: Occupational exposures at the WTC site after September 11, 2001 have been associated with several presumably inflammatory lower airway diseases. In this study, we describe the trajectories of expiratory air flow decline, identify subgroups with adverse progression, and investigate the association of a quantitative computed tomography (QCT) imaging measurement of airway wall thickness, and other risk factors for adverse progression. METHODS: We examined the trajectories of expiratory air flow decline in a group of 799 former WTC workers and volunteers with QCT-measured (with two independent systems) wall area percent (WAP) and at least 3 periodic spirometries. We calculated individual regression lines for first-second forced expiratory volume (FEV), identified subjects with rapidly declining and increasing ("gainers"), and compared them to subjects with normal and "stable" FEV decline. We used multivariate logistic regression to model decliner vs. stable trajectories. RESULTS: The mean longitudinal FEVslopes for the entire study population, and its stable, decliner, and gainer subgroups were, respectively, - 35.8, - 8, - 157.6, and + 173.62 ml/year. WAP was associated with "decliner" status (OR 1.08, 95% CI 1.02, 1.14, per 5% increment) compared to stable. Age, weight gain, baseline FEV percent predicted, bronchodilator response, and pre-WTC occupational exposures were also significantly associated with accelerated FEV decline. Analyses of gainers vs. stable subgroup showed WAP as a significant predictor in unadjusted but not consistently in adjusted analyses. CONCLUSIONS: The apparent normal age-related rate of FEV decline results from averaging widely divergent trajectories. WAP is significantly associated with accelerated air flow decline in WTC workers.
Ash SY, Harmouche R, Ross JC, Diaz AA, Rahaghi FN, Vegas Sanchez-Ferrero G, Putman RK, Hunninghake GM, Onieva Onieva J, Martinez FJ, et al. Interstitial Features at Chest CT Enhance the Deleterious Effects of Emphysema in the COPDGene Cohort. Radiology. 2018 :172688.Abstract
Purpose To determine if interstitial features at chest CT enhance the effect of emphysema on clinical disease severity in smokers without clinical pulmonary fibrosis. Materials and Methods In this retrospective cohort study, an objective CT analysis tool was used to measure interstitial features (reticular changes, honeycombing, centrilobular nodules, linear scar, nodular changes, subpleural lines, and ground-glass opacities) and emphysema in 8266 participants in a study of chronic obstructive pulmonary disease (COPD) called COPDGene (recruited between October 2006 and January 2011). Additive differences in patients with emphysema with interstitial features and in those without interstitial features were analyzed by using t tests, multivariable linear regression, and Kaplan-Meier analysis. Multivariable linear and Cox regression were used to determine if interstitial features modified the effect of continuously measured emphysema on clinical measures of disease severity and mortality. Results Compared with individuals with emphysema alone, those with emphysema and interstitial features had a higher percentage predicted forced expiratory volume in 1 second (absolute difference, 6.4%; P < .001), a lower percentage predicted diffusing capacity of lung for carbon monoxide (DLCO) (absolute difference, 7.4%; P = .034), a 0.019 higher right ventricular-to-left ventricular (RVLV) volume ratio (P = .029), a 43.2-m shorter 6-minute walk distance (6MWD) (P < .001), a 5.9-point higher St George's Respiratory Questionnaire (SGRQ) score (P < .001), and 82% higher mortality (P < .001). In addition, interstitial features modified the effect of emphysema on percentage predicted DLCO, RVLV volume ratio, 6WMD, SGRQ score, and mortality (P for interaction < .05 for all). Conclusion In smokers, the combined presence of interstitial features and emphysema was associated with worse clinical disease severity and higher mortality than was emphysema alone. In addition, interstitial features enhanced the deleterious effects of emphysema on clinical disease severity and mortality.
Wu Y, Zhang F, Makris N, Ning Y, Norton I, She S, Peng H, Rathi Y, Feng Y, Wu H, et al. Investigation into local white matter abnormality in emotional processing and sensorimotor areas using an automatically annotated fiber clustering in major depressive disorder. Neuroimage. 2018.Abstract
This work presents an automatically annotated fiber cluster (AAFC) method to enable identification of anatomically meaningful white matter structures from the whole brain tractography. The proposed method consists of 1) a study-specific whole brain white matter parcellation using a well-established data-driven groupwise fiber clustering pipeline to segment tractography into multiple fiber clusters, and 2) a novel cluster annotation method to automatically assign an anatomical tract annotation to each fiber cluster by employing cortical parcellation information across multiple subjects. The novelty of the AAFC method is that it leverages group-wise information about the fiber clusters, including their fiber geometry and cortical terminations, to compute a tract anatomical label for each cluster in an automated fashion. We demonstrate the proposed AAFC method in an application of investigating white matter abnormality in emotional processing and sensorimotor areas in major depressive disorder (MDD). Seven tracts of interest related to emotional processing and sensorimotor functions are automatically identified using the proposed AAFC method as well as a comparable method that uses a cortical parcellation alone. Experimental results indicate that our proposed method is more consistent in identifying the tracts across subjects and across hemispheres in terms of the number of fibers. In addition, we perform a between-group statistical analysis in 31 MDD patients and 62 healthy subjects on the identified tracts using our AAFC method. We find statistical differences in diffusion measures in local regions within a fiber tract (e.g. 4 fiber clusters within the identified left hemisphere cingulum bundle (consisting of 14 clusters) are significantly different between the two groups), suggesting the ability of our method in identifying potential abnormality specific to subdivisions of a white matter structure.
Lepage C, Muehlmann M, Tripodis Y, Hufschmidt J, Stamm J, Green K, Wrobel P, Schultz V, Weir I, Alosco ML, et al. Limbic system structure volumes and associated neurocognitive functioning in former NFL players. Brain Imaging Behav. 2018.Abstract
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts. CTE has been linked to disruptions in cognition, mood, and behavior. Unfortunately, the diagnosis of CTE can only be made post-mortem. Neuropathological evidence suggests limbic structures may provide an opportunity to characterize CTE in the living. Using 3 T magnetic resonance imaging, we compared select limbic brain regional volumes - the amygdala, hippocampus, and cingulate gyrus - between symptomatic former National Football League (NFL) players (n = 86) and controls (n = 22). Moreover, within the group of former NFL players, we examined the relationship between those limbic structures and neurobehavioral functioning (n = 75). The former NFL group comprised eighty-six men (mean age = 55.2 ± 8.0 years) with at least 12 years of organized football experience, at least 2 years of active participation in the NFL, and self-reported declines in cognition, mood, and behavior within the last 6 months. The control group consisted of men (mean age = 57.0 ± 6.6 years) with no history of contact-sport involvement or traumatic brain injury. All control participants provided neurobehavioral data. Compared to controls, former NFL players exhibited reduced volumes of the amygdala, hippocampus, and cingulate gyrus. Within the NFL group, reduced bilateral cingulate gyrus volume was associated with worse attention and psychomotor speed (r = 0.4 (right), r = 0.42 (left); both p < 0.001), while decreased right hippocampal volume was associated with worse visual memory (r = 0.25, p = 0.027). Reduced volumes of limbic system structures in former NFL players are associated with neurocognitive features of CTE. Volume reductions in the amygdala, hippocampus, and cingulate gyrus may be potential biomarkers of neurodegeneration in those at risk for CTE.
Steer D, Leung S, Meiselman H, Topgaard D, Leal C. The Structure of Lung-mimetic Multilamellar Bodies with Lipid Compositions Relevant in Pneumonia. Langmuir. 2018.Abstract
The hierarchical assembly of lipids, as modulated by composition and environment, plays a significant role in the function of biological membranes and a myriad of diseases. Elevated concentrations of calcium ions and cardiolipin, an anionic tetra-alkyl lipid found in mitochondria and some bacterial cell membranes, have been implicated in pneumonia recently. However, their impact on the physicochemical properties of lipid assemblies in lungs and how it impairs alveoli function is still unknown. We use Small- and Wide- Angle X-ray Scattering (S/WAXS) and Solid-State Nuclear Magnetic Resonance (ssNMR) to probe the structure and dynamics of lung-mimetic multilamellar bodies (MLBs) in the presence of Ca and cardiolipin. We conjecture that cardiolipin overexpressed in the hypophase of alveoli strongly affects the structure of lung-lipid bilayers and their stacking in the MLBs. Specifically, S/WAXS data revealed that cardiolipin induces significant shrinkage of the water-layer separating the concentric bilayers in multilamellar aggregates. ssNMR measurements indicate that this inter-bilayer tightening is due to undulation repulsion damping as cardiolipin renders the glycerol backbone of the membranes significantly more static. In addition to MLB dehydration, cardiolipin promotes intra-bilayer phase separation into saturated-rich and unsaturated-rich lipid domains that couple across multiple layers. Expectedly, addition of Ca screens the electrostatic repulsion between negatively charged lung membranes. However, when cardiolipin is present, addition of Ca results in an apparent inter-bilayer expansion likely due to local structural defects. Combining S/WAXS and ssNMR on systems with compositions pertinent to healthy and unhealthy lung membranes, we propose how alteration of the physiochemical properties of multilamellar bodies can critically impact the breathing cycle.
Valera E, Cao A, Pasternak O, Shenton ME, Kubicki M, Makris N, Adra N. White Matter Correlates of Mild Traumatic Brain Injuries in Women Subjected to Intimate-Partner Violence: A Preliminary Study. J Neurotrauma. 2018.Abstract
A large proportion (range of 44-75%) of women who experience intimate-partner violence (IPV) have been shown to sustain repetitive mild traumatic brain injuries (mTBIs) from their abusers. Further, despite requests for research on TBI-related health outcomes, there are currently only a handful of studies addressing this issue, and only one prior imaging study that has investigated the neural correlates of IPV-related TBIs. In response, we examined specific regions of white matter microstructure in 20 women with histories of IPV. Subjects were imaged on a 3-Tesla Siemens Magnetom TrioTim scanner using diffusion magnetic resonance imaging (MRI). We investigated the association between a score reflecting number and recency of IPV-related mTBIs and fractional anisotropy (FA) in the posterior and superior corona radiata as well as the posterior thalamic radiation, brain regions shown previously to be involved in mTBI. We also investigated the association between several cognitive measures, namely learning, memory, and cognitive flexibility, and FA in the white matter regions of interest (ROIs). We report a negative correlation between the brain injury score and FA in regions of the posterior and superior corona radiata. We failed to find an association between our cognitive measures and FA in these regions, but the interpretation of these results remains inconclusive due to possible power issues. Overall, these data build upon the very small but growing literature demonstrating potential consequences of mTBIs for women experiencing IPV, and further underscore the urgent need for larger and more comprehensive studies in this area.
Hamoda HM, Makhlouf AT, Fitzsimmons J, Rathi Y, Makris N, Mesholam-Gately RI, Wojcik JD, Goldstein J, McCarley RW, Seidman LJ, et al. Abnormalities in thalamo-cortical connections in patients with first-episode schizophrenia: a two-tensor tractography study. Brain Imaging Behav. 2018.Abstract
The "cognitive dysmetria" hypothesis suggests that impairments in cognition and behavior in patients with schizophrenia can be explained by disruptions in the cortico-cerebellar-thalamic-cortical circuit. In this study we examine thalamo-cortical connections in patients with first-episode schizophrenia (FESZ). White matter pathways are investigated that connect the thalamus with three frontal cortex regions including the anterior cingulate cortex (ACC), ventrolateral prefrontal cortex (VLPFC), and lateral oribitofrontal cortex (LOFC). We use a novel method of two-tensor tractography in 26 patients with FESZ compared to 31 healthy controls (HC), who did not differ on age, sex, or education. Dependent measures were fractional anisotropy (FA), Axial Diffusivity (AD), and Radial Diffusivity (RD). Subjects were also assessed using clinical functioning measures including the Global Assessment of Functioning (GAF) Scale, the Global Social Functioning Scale (GF: Social), and the Global Role Functioning Scale (GF: Role). FESZ patients showed decreased FA in the right thalamus-right ACC and right-thalamus-right LOFC pathways compared to healthy controls (HCs). In the right thalamus-right VLPFC tract, we found decreased FA and increased RD in the FESZ group compared to HCs. After correcting for multiple comparisons, reductions in FA in the right thalamus- right ACC and the right thalamus- right VLPC tracts remained significant. Moreover, reductions in FA were significantly associated with lower global functioning scores as well as lower social and role functioning scores. We report the first diffusion tensor imaging study of white matter pathways connecting the thalamus to three frontal regions. Findings of white matter alterations and clinical associations in the thalamic-cortical component of the cortico-cerebellar-thalamic-cortical circuit in patients with FESZ support the cognitive dysmetria hypothesis and further suggest the possible involvement of myelin sheath pathology and axonal membrane disruption in the pathogenesis of the disorder.
Durmo F, Lätt J, Rydelius A, Engelholm S, Kinhult S, Askaner K, Englund E, Bengzon J, Nilsson M, Björkman-Burtscher IM, et al. Brain Tumor Characterization Using Multibiometric Evaluation of MRI. Tomography. 2018;4 (1) :14-25.Abstract
The aim was to evaluate volume, diffusion, and perfusion metrics for better presurgical differentiation between high-grade gliomas (HGG), low-grade gliomas (LGG), and metastases (MET). For this retrospective study, 43 patients with histologically verified intracranial HGG (n = 18), LGG (n = 10), and MET (n = 15) were chosen. Preoperative magnetic resonance data included pre- and post-gadolinium contrast-enhanced T1-weighted fluid-attenuated inversion recover, cerebral blood flow (CBF), cerebral blood volume (CBV), fractional anisotropy, and apparent diffusion coefficient maps used for quantification of magnetic resonance biometrics by manual delineation of regions of interest. A binary logistic regression model was applied for multiparametric analysis and receiver operating characteristic (ROC) analysis. Statistically significant differences were found for normalized-ADC-tumor (nADC-T), normalized-CBF-tumor (nCBF-T), normalized-CBV-tumor (nCBV-T), and normalized-CBF-edema (nCBF-E) between LGG and HGG, and when these metrics were combined, HGG could be distinguished from LGG with a sensitivity and specificity of 100%. The only metric to distinguish HGG from MET was the normalized-ADC-E with a sensitivity of 68.8% and a specificity of 80%. LGG can be distinguished from MET by combining edema volume (Vol-E), Vol-E/tumor volume (Vol-T), nADC-T, nCBF-T, nCBV-T, and nADC-E with a sensitivity of 93.3% and a specificity of 100%. The present study confirms the usability of a multibiometric approach including volume, perfusion, and diffusion metrics in differentially diagnosing brain tumors in preoperative patients and adds to the growing body of evidence in the clinical field in need of validation and standardization.
Valenciano M, Kissling E, Larrauri A, Nunes B, Pitigoi D, O Donnell J, Reuss A, Horváth JK, Paradowska-Stankiewicz I, Rizzo C, et al. Exploring the effect of previous inactivated influenza vaccination on seasonal influenza vaccine effectiveness against medically-attended influenza: results of the European I-MOVE multicentre test-negative case-control study, 2011/12-2016/17. Influenza Other Respir Viruses. 2018.Abstract
BACKGROUND: Results of previous influenza vaccination effects on current season influenza vaccine effectiveness (VE) are inconsistent. OBJECTIVES: To explore previous influenza vaccination effects on current season VE among population targeted for vaccination. METHODS: We used 2011/12 to 2016/17 I-MOVE primary care multicentre test-negative data. For each season we compared current season adjusted VE (aVE) between individuals vaccinated and unvaccinated in previous season. Using unvaccinated in both seasons as a reference, we then compared aVE between vaccinated in: both seasons, current only, and previous only. RESULTS: We included 941, 2645 and 959 influenza like illness patients positive for influenza A(H1N1)pdm09, A(H3N2), and B, respectively and 5532 controls. In 2011/12, 2014/15, 2016/17 A(H3N2) aVE point estimates among those vaccinated in previous season, were -68%, - 21% and -19% respectively; among unvaccinated in previous season 33%, 48%, 46% respectively (aVE not computable for influenza A(H1N1)pdm09 and B). Compared to current season vaccination only, VE for both seasons vaccination was a) similar in two of four seasons for A(H3N2) (absolute difference (ad) 6%, 8%); b) lower in three of four seasons for influenza A(H1N1)pdm09 (ad 18%, 26%, 29%), in two seasons for influenza A(H3N2) (ad 27%, 39%), in two of three seasons for influenza B (ad 26% and 37%); c) higher in one season for influenza A(H1N1)pdm09 (ad 20%), and influenza B (ad 24%). CONCLUSIONS: We did not identify any pattern of previous influenza vaccination effect. Prospective cohort studies documenting influenza infections, vaccinations, vaccine types, are needed to understand previous influenza vaccinations' effects. This article is protected by copyright. All rights reserved.
Ross JC, Castaldi PJ, Cho MH, Hersh CP, Rahaghi FN, Sánchez-Ferrero GV, Parker MM, Litonjua AA, Sparrow D, Dy JG, et al. Longitudinal Modeling of Lung Function Trajectories in Smokers with and without COPD. Am J Respir Crit Care Med. 2018.Abstract
RATIONALE: The relationship between longitudinal lung function trajectories, chest computed tomography (CT) imaging, and genetic predisposition to COPD has not been explored. OBJECTIVES: 1) To model trajectories using a data-driven approach applied to longitudinal data spanning adulthood in the Normative Aging Study (NAS), and 2) to apply these models to demographically similar subjects in the COPDGene Study with detailed phenotypic characterization including chest CT. METHODS: We modeled lung function trajectories in 1,060 subjects in NAS with a median follow-up time of 29 years. We assigned 3,546 non-Hispanic white males in COPDGene to these trajectories for further analysis. We assessed phenotypic and genetic differences between trajectories and across age strata. MEASUREMENTS AND MAIN RESULTS: We identified four trajectories in NAS with differing levels of maximum lung function and rate of decline. In COPDGene, 617 (17%) subjects were assigned to the lowest trajectory and had the greatest radiologic burden of disease (P<0.01); 1,283 (36%) subjects were assigned to a low trajectory with evidence of airways disease preceding emphysema on CT; 1,411 (40%) and 237 (7%) subjects were assigned to the remaining two trajectories and tended to have preserved lung function and negligible emphysema. The genetic contribution to these trajectories was as high as 83% (p=0.02), and membership in lower lung function trajectories was associated with greater parental histories of COPD, decreased exercise capacity, greater dyspnea, and more frequent COPD exacerbations. CONCLUSIONS: Data-driven analysis identifies four lung function trajectories. Trajectory membership has a genetic basis and is associated with distinct lung structural abnormalities.
Diaz AA, Martinez CH, Harmouche R, Young TP, McDonald M-L, Ross JC, Han ML, Bowler R, Make B, Regan EA, et al. Pectoralis muscle area and mortality in smokers without airflow obstruction. Respir Res. 2018;19 (1) :62.Abstract
BACKGROUND: Low muscle mass is associated with increased mortality in the general population but its prognostic value in at-risk smokers, those without expiratory airflow obstruction, is unknown. We aimed to test the hypothesis that reduced muscle mass is associated with increased mortality in at-risk smokers. METHODS: Measures of both pectoralis and paravertebral erector spinae muscle cross-sectional area (PMA and PVMA, respectively) as well as emphysema on chest computed tomography (CT) scans were performed in 3705 current and former at-risk smokers (≥10 pack-years) aged 45-80 years enrolled into the COPDGene Study between 2008 and 2013. Vital status was ascertained through death certificate. The association between low muscle mass and mortality was assessed using Cox regression analysis. RESULTS: During a median of 6.5 years of follow-up, 212 (5.7%) at-risk smokers died. At-risk smokers in the lowest (vs. highest) sex-specific quartile of PMA but not PVMA had 84% higher risk of death in adjusted models for demographics, smoking, dyspnea, comorbidities, exercise capacity, lung function, emphysema on CT, and coronary artery calcium content (hazard ratio [HR] 1.85 95% Confidence interval [1.14-3.00] P = 0.01). Results were consistent when the PMA index (PMA/height) was used instead of quartiles. The association between PMA and death was modified by smoking status (P = 0.04). Current smokers had a significantly increased risk of death (lowest vs. highest PMA quartile, HR 2.25 [1.25-4.03] P = 0.007) while former smokers did not. CONCLUSIONS: Low muscle mass as measured on chest CT scans is associated with increased mortality in current smokers without airflow obstruction. TRIAL REGISTRATION: NCT00608764.
Ash SY, Rahaghi FN, Come CE, Ross JC, Colon AG, Cardet-Guisasola JC, Dunican EM, Bleecker ER, Castro M, Fahy JV, et al. Pruning of the Pulmonary Vasculature in Asthma: The SARP Cohort. Am J Respir Crit Care Med. 2018.Abstract
RATIONALE: Loss of the peripheral pulmonary vasculature, termed vascular pruning, is associated with disease severity in patients with chronic obstructive pulmonary disease. OBJECTIVES: To determine if pulmonary vascular pruning is associated with asthma severity and exacerbations. METHODS: We measured the total pulmonary blood vessel volume (TBV) and the blood vessel volume of vessels less than 5mm2 in cross sectional area (BV5) and of vessels less than 10mm2 (BV10) in cross sectional area on non-contrast computed tomographic scans of participants from the Severe Asthma Research Program. Lower values of the BV5 to TBV ratio (BV5/TBV) and the BV10 to TBV ratio (BV10/TBV) represented vascular pruning (loss of the peripheral pulmonary vasculature). MEASUREMENTS AND MAIN RESULTS: Compared to healthy controls, severe asthmatics had more pulmonary vascular pruning. Among asthmatics, those with poor asthma control had more pruning than those well-controlled disease. Pruning of the pulmonary vasculature was also associated with lower percent predicted forced expiratory volume in one second and forced vital capacity, greater peripheral and sputum eosinophilia and higher bronchoalveolar lavage SAA/LXA4, but not with low attenuation area or with sputum neutrophilia. Compared with individuals with less pruning, individuals with the most vascular pruning had a 150% greater odds of reporting an asthma exacerbation (OR 2.50; CI: 1.05, 5.98; p=0.039 for BV10/TBV), and reported 45% more asthma exacerbations during follow-up (IRR 1.45; CI: 1.02, 2.06; p=0.036 for BV10/TBV). CONCLUSIONS: Pruning of the peripheral pulmonary vasculature is associated with asthma severity, control and exacerbations, as well as with lung function and eosinophilia.
González G, Ash S, San José Estépar R, Washko GR. Reply to: Over-fitting and Use of Mismatched Cohorts in Deep Learning Models: Preventable Design Limitations. Am J Respir Crit Care Med. 2018.
Özarslan E, Yolcu C, Herberthson M, Knutsson H, Westin C-F. Influence of the Size and Curvedness of Neural Projections on the Orientationally Averaged Diffusion MR Signal. Front Phys. 2018;6.Abstract
Neuronal and glial projections can be envisioned to be tubes of infinitesimal diameter as far as diffusion magnetic resonance (MR) measurements via clinical scanners are concerned. Recent experimental studies indicate that the decay of the orientationally-averaged signal in white-matter may be characterized by the power-law, () ∝ , where is the wavenumber determined by the parameters of the pulsed field gradient measurements. One particular study by McKinnon . [1] reports a distinctively faster decay in gray-matter. Here, we assess the role of the size and curvature of the neurites and glial arborizations in these experimental findings. To this end, we studied the signal decay for diffusion along general curves at all three temporal regimes of the traditional pulsed field gradient measurements. We show that for curvy projections, employment of longer pulse durations leads to a disappearance of the decay, while such decay is robust when narrow gradient pulses are used. Thus, in clinical acquisitions, the lack of such a decay for a fibrous specimen can be seen as indicative of fibers that are curved. We note that the above discussion is valid for an intermediate range of -values as the true asymptotic behavior of the signal decay is () ∝ for narrow pulses (through Debye-Porod law) or steeper for longer pulses. This study is expected to provide insights for interpreting the diffusion-weighted images of the central nervous system and aid in the design of acquisition strategies.
Lyall AE, Savadjiev P, Del Re EC, Seitz J, O'Donnell LJ, Westin C-F, Mesholam-Gately RI, Petryshen T, Wojcik JD, Nestor P, et al. Utilizing Mutual Information Analysis to Explore the Relationship Between Gray and White Matter Structural Pathologies in Schizophrenia. Schizophr Bull. 2018.Abstract
Schizophrenia has been characterized as a neurodevelopmental disorder, with structural brain abnormalities reported at all stages. However, at present, it remains unclear whether gray and white matter abnormalities represent related or independent pathologies in schizophrenia. In this study, we present findings from an integrative analysis exploring the morphological relationship between gray and white matter in 45 schizophrenia participants and 49 healthy controls. We utilized mutual information (MI), a measure of how much information two variables share, to assess the morphological dependence between gray and white matter in three segments of the corpus callsoum, and the gray matter regions these segments connect: (1) the genu and the left and right rostral middle frontal gyrus (rMFG), (2) the isthmus and the left and right superior temporal gyrus (STG), (3) the splenium and the left and right lateral occipital gyrus (LOG). We report significantly reduced MI between white matter tract dispersion of the right hemispheric callosal connections to the STG and both cortical thickness and area in the right STG in schizophrenia patients, despite a lack of group differences in cortical thickness, surface area, or dispersion. We believe that this reduction in morphological dependence between gray and white matter may reflect a possible decoupling of the developmental processes that shape morphological features of white and gray matter early in life. The present study also demonstrates the importance of studying the relationship between gray and white matter measures, as opposed to restricting analyses to gray and white matter measures independently.
Surova Y, Nilsson M, Lampinen B, Lätt J, Hall S, Widner H, van Westen D, Hansson O. Alteration of putaminal fractional anisotropy in Parkinson's disease: a longitudinal diffusion kurtosis imaging study. Neuroradiology. 2018;60 (3) :247-254.Abstract
PURPOSE: In Parkinson's disease (PD), pathological microstructural changes occur that may be detected using diffusion magnetic resonance imaging (dMRI). However, there are few longitudinal studies that explore the effect of disease progression on diffusion indices. METHODS: We prospectively included 76 patients with PD and 38 healthy controls (HC), all of whom underwent diffusion kurtosis imaging (DKI) as part of the prospective Swedish BioFINDER study at baseline and 2 years later. Annualized rates of change in DKI parameters, including fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK), were estimated in the gray matter (GM) by placing regions of interest (ROIs) in the basal ganglia and the thalamus, and in the white matter (WM) by tract-based spatial statistics (TBSS) analysis. RESULTS: When adjusting for potential confounding factors (age, gender, baseline-follow-up interval, and software upgrade of MRI scanner), only a decrease in FA in the putamen of PD patients (β = - 0.248, P < .01) over 2 years was significantly different from the changes observed in HC over the same time period. This 2-year decrease in FA in the putamen in PD correlated with higher L-dopa equivalent dose at baseline (Spearman's rho = .399, P < .0001). CONCLUSION: The study indicates that in PD microstructural changes in the putamen occur selectively over a 2-year period and can be detected with DKI.

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