The Laboratory of Mathematics in Imaging (LMI) is focused on the application of mathematical theory, analysis, modeling, and signal processing to medical imaging. Research projects within the group cover both novel theoretical contributions and translational clinical efforts. The research team combine strengths in computer science and mathematics with radiology, neuroscience, and novel MRI sequence developmentLearn more

Recent Publications

The Structure of Lung-mimetic Multilamellar Bodies with Lipid Compositions Relevant in Pneumonia

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.
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Genetic load determines atrophy in hand cortico-striatal pathways in presymptomatic Huntington's disease

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.
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Increased Airway Wall Thickness is Associated with Adverse Longitudinal First-Second Forced Expiratory Volume Trajectories of Former World Trade Center workers

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.
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Limbic system structure volumes and associated neurocognitive functioning in former NFL players

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.
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A comparison of three fiber tract delineation methods and their impact on white matter analysis

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.
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Identification of Chronic Obstructive Pulmonary Disease Axes That Predict All-Cause Mortality: The COPDGene Study

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.
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