Local Volume Change Research Articles

A theoretical model of inflammation- and mechanotransduction-driven asthmatic airway remodelling

Inflammation, airway hyper-responsiveness and airway remodelling are well-established hallmarks of asthma, but their inter-relationships remain elusive. In order to obtain a better understanding of their inter-dependence, we develop a mechanochemical morphoelastic model of the airway wall accounting for local volume changes in airway smooth muscle (ASM) and extracellular matrix in response to transient inflammatory or contractile agonist challenges. We use constrained mixture theory, together with a multiplicative decomposition of growth from the elastic deformation, to model the airway wall as a nonlinear fibre-reinforced elastic cylinder. Local contractile agonist drives ASM cell contraction, generating mechanical stresses in the tissue that drive further release of mitogenic mediators and contractile agonists via underlying mechanotransductive signalling pathways. Our model predictions are consistent with previously described inflammation-induced remodelling within an axisymmetric airway geometry. Additionally, our simulations reveal novel mechanotransductive feedback by which hyper-responsive airways exhibit increased remodelling, for example, via stress-induced release of pro-mitogenic and pro-contractile cytokines. Simulation results also reveal emergence of a persistent contractile tone observed in asthmatics, via either a pathological mechanotransductive feedback loop, a failure to clear agonists from the tissue, or a combination of both. Furthermore, we identify various parameter combinations that may contribute to the existence of different asthma phenotypes, and we illustrate a combination of factors which may predispose severe asthmatics to fatal bronchospasms.

Quantifying local tumor morphological changes with Jacobian map for prediction of pathologic tumor response to chemo-radiotherapy in locally advanced esophageal cancer

We proposed a framework to detect and quantify local tumor morphological changes due to chemo-radiotherapy (CRT) using a Jacobian map and to extract quantitative radiomic features from the Jacobian map to predict the pathologic tumor response in locally advanced esophageal cancer patients. In 20 patients who underwent CRT, a multi-resolution BSpline deformable registration was performed to register the follow-up (post-CRT) CT to the baseline CT image. The Jacobian map (J) was computed as the determinant of the gradient of the deformation vector field. The Jacobian map measured the ratio of local tumor volume change where J < 1 indicated tumor shrinkage and J > 1 denoted expansion. The tumor was manually delineated and corresponding anatomical landmarks were generated on the baseline and follow-up images. Intensity, texture and geometry features were then extracted from the Jacobian map of the tumor to quantify tumor morphological changes. The importance of each Jacobian feature in predicting pathologic tumor response was evaluated by both univariate and multivariate analysis. We constructed a multivariate prediction model by using a support vector machine (SVM) classifier coupled with a least absolute shrinkage and selection operator (LASSO) for feature selection. The SVM-LASSO model was evaluated using ten-times repeated 10-fold cross-validation (10 × 10-fold CV). After registration, the average target registration error was 4.30 ± 1.09 mm (LR:1.63 mm AP:1.59 mm SI:3.05 mm) indicating registration error was within two voxels and close to 4 mm slice thickness. Visually, the Jacobian map showed smoothly-varying local shrinkage and expansion regions in a tumor. Quantitatively, the average median Jacobian was 0.80 ± 0.10 and 1.05 ± 0.15 for responder and non-responder tumors, respectively. These indicated that on average responder tumors had 20% median volume shrinkage while non-responder tumors had 5% median volume expansion. In univariate analysis, the minimum Jacobian (p = 0.009, AUC = 0.98) and median Jacobian (p = 0.004, AUC = 0.95) were the most significant predictors. The SVM-LASSO model achieved the highest accuracy when these two features were selected (sensitivity = 94.4%, specificity = 91.8%, AUC = 0.94). Novel features extracted from the Jacobian map quantified local tumor morphological changes using only baseline tumor contour without post-treatment tumor segmentation. The SVM-LASSO model using the median Jacobian and minimum Jacobian achieved high accuracy in predicting pathologic tumor response. The Jacobian map showed great potential for longitudinal evaluation of tumor response.

Sleep apnoea in the asymptomatic elderly: a real issue for the brain?

The link between sleep apnoea and brain structure is unclear; although dysfunction of the hippocampus, middle temporal gyrus and brainstem/cerebellum have been observed previously. However, this link has been little explored in elderly subjects. The aim of this study was to explore the link between sleep apnoea and the brain in an elderly population.226 asymptomatic elderly subjects (age mean±sd 75.3±0.9 years, range 72.3-77.8 years) from the PROOF (Evaluation of Ageing, Autonomic Nervous System Activity and Cardiovascular Events) cohort study were explored using linear voxel-based or cortical thickness with apnoea/hypopnoea index (AHI; mean±sd 15.9±11.5 events·h-1, range 6-63.6 events·h-1) as a covariate of main interest. The brain volumes of 20 control subjects, 18 apnoeic (AHI >29 events·h-1) treated patients and 20 apnoeic untreated patients from this population were compared using voxel-based morphometry, cortical thickness or surface-based analyses.AHI was not associated with any change in local brain volume, cortical thickness or cortex surface. Control subjects, apnoeic treated and untreated patients were not different in terms of local brain volume, cortical thickness or surface.In a specific population of asymptomatic elderly healthy subjects, sleep apnoea does not seem to be associated with a change in local brain volume or in cortical thickness.

Accelerated executive functions decline and gray matter structural changes in middle‐aged type 1 diabetes mellitus patients with proliferative retinopathy

The aim of the present study was to determine trajectories of cognitive and cortical changes over time in middle-aged patients with type 1 diabetes mellitus (T1DM) and proliferative retinopathy. Twenty-five patients and 25 controls underwent neuropsychological assessment and neuroimaging twice in a mean (±SD) of 3.56 ± 0.65 and 3.94 ± 0.91 years, respectively (P = 0.098). Cognitive assessment included the domains of general cognitive ability, memory, information processing speed, executive functions, attention, and motor and psychomotor speed. Symmetrized percentage change in local cortical thickness, surface area, and volume was determined using the FreeSurfer 6 vertex-wise general linear model method. Analyses were performed uncorrected and corrected for baseline systolic blood pressure and depressive symptoms. In patients versus controls, accelerated executive function decline was accompanied by, but not related to, lower left frontal and temporal surface area, left parietal and right frontal thickness, and bilateral frontal and right posterior cingulate volume (family-wise error [FWE]-corrected P < 0.05 for all). In patients, lower executive performance was related to loss of right precuneus surface area (PFWE = 0.005). Higher HbA1c during follow-up was related to executive function decline (r = -0.509, P = 0.016) and loss of left hemisphere surface area (rcorrected analysis = -0.555, P = 0.007). After 3.5 years of follow-up, middle-aged T1DM patients with proliferative retinopathy, mild focal changes in executive functions, and cortical structure were found, which may indicate accelerated aging.

Hyperelastic models for the swelling of soft material plugs in confined spaces

By incorporating local volume change as a parametric constraint into the conventional theory of hyperelasticity it is possible to model a variety of swelling affects. Here we examine the finite strain swelling of a soft solid plug within a rigid tube of circular cross section. The eventual channel wall contact as the swelling proceeds generates a confinement pressure that increases as the plug expands. The contact problem for a solid cylinder plug is one of homogeneous deformation, allowing the pressure-swelling response of classical hyperelastic models to be contrasted with hyperelastic models that display limited chain extensibility. We then examine a cylindrical plug that itself contains an internal channel. Wall contact now gives a deformation in which swelling combines axial lengthening with internal channel narrowing. Of particular interest is the closing behavior as the swelling proceeds. Treating the associated boundary value problem provides asymptotic expressions for the channel radius closing and the contact pressure in the large swelling regime.

Modeling of Mixing Behavior in a Combined Blowing Steelmaking Converter with a Filter-Based Euler–Lagrange Model

A filter-based Euler–Lagrange multiphase flow model is used to study the mixing behavior in a combined blowing steelmaking converter. The Euler-based volume of fluid approach is employed to simulate the top blowing, while the Lagrange-based discrete phase model that embeds the local volume change of rising bubbles for the bottom blowing. A filter-based turbulence method based on the local meshing resolution is proposed aiming to improve the modeling of turbulent eddy viscosities. The model validity is verified through comparison with physical experiments in terms of mixing curves and mixing times. The effects of the bottom gas flow rate on bath flow and mixing behavior are investigated and the inherent reasons for the mixing result are clarified in terms of the characteristics of bottom-blowing plumes, the interaction between plumes and top-blowing jets, and the change of bath flow structure.

Mechanical Basis of Nafion’s High-Frequency Inductive Impedance

Recent literature has highlighted how the coupling of electrochemical and mechanical phenomena can affect the way batteries and fuel cells perform [1, 2]. Local volume changes and stresses due to water transport play critical roles in the operation of polymer exchange membranes. A non-isobaric version of Newman’s concentrated-solution theory [3] was applied to study hydrated ionomers, in which mechanical effects intricately entangle the transport of material, momentum, and energy. Electrochemical impedance spectroscopy (EIS) provides a useful tool to study the most pronounced effects arising from this electrochemical/mechanical coupling in Nafion. Nafion is relatively compressible, so changes in pressure affect the concentration of sulfonic acid; thus pressure gradients affect the voltage drop. Also, pressure diffusion can drive proton flux, directly coupling current with mechanical state. When AC signals are driven at low frequencies, these piezoelectric effects are minimal and the Warburg signature of water diffusion dominates the impedance. At higher frequencies, however, current oscillates too fast for the water concentration to respond. Pressure effects dominate the impedance. Strikingly, in this high-frequency regime the membrane can resonate, leading to divergent pressure impedances at a fundamental frequency and its harmonics. This resonance can be related to the speed of sound in the membrane. Above this speed, which is much higher than the characteristic diffusion speed, the signal is carried across the ionomer by elastic (mechanical) waves. Inductive loops on the Nyquist plot, and corresponding peaks in the Bode plots, occur as a consequence of this electrochemical-mechanical coupling above the critical resonant frequency. Various mechanical characteristics can be associated with resistance (viscosity), capacitance (elastic modulus), and inductance (mass). A parametric study reveals how transport and mechanical properties affect the magnitudes and shapes of these impedance signatures. The model rationalizes the inductive responses seen experimentally in several recent high-quality Nyquist plots [4]. [1] A. Kusoglu and A.Z. Weber, Electrochemical/Mechanical Coupling in Ion-Conducting Soft Matter, J. Phys. Chem. Lett., 2015, 6(22), pp 4547-4552 [2] G. Bucci, Formulation of the Coupled Electrochemical-Mechanical Boundary-Value Problem, with Applications to Transport of Multiple Charged Species, Acta Mater., 2016, 104, pp 33-51 [3] P. Goyal and C.W. Monroe, New Foundations of Newman’s Theory for Solid Electrolytes: Thermodynamics and Transient Balances, J. Electrochem. Soc., 2017, 164(11), pp E3647-E3660 [4] B.P. Setzler and T.F. Fuller, A Physics-Based Impedance Model of Proton Exchange Membrane Fuel Cells Exhibiting Low-Frequency Inductive Loops, J. Electrochem. Soc., 2015, 162(6), pp F519-F530

On the mechanism of ion-induced bending of nanostructures

This contribution concentrates on ion-induced bending phenomena which may serve as a versatile tool to manufacture nanostructured devices. In particular bending was studied in free standing Au cantilevers. The preparation and irradiation of the cantilevers were performed using a TESCAN LYRA dual beam system. Cantilevers with thicknesses ranging between 90 and 200 nm were irradiated with 30 keV Ga ions normal to the sample surface up to a maximum fluence of ∼3 × 1020 Ga/m2. The bending of the cantilevers towards the incident beam is discussed in terms of local volume change due to accumulation of radiation-induced vacancies and substitutional Ga atoms in the Ga implantation layer, as well as due to accumulation of interstitial type clusters in the region beyond the Ga penetration range. A model is proposed to explain the observations, based on a set of rate equations for concentrations of point defects, i.e. vacancies, self-interstitials and implanted Ga atoms. The influence of preexisting defects is also discussed. The work shows that an in-depth understanding the ion-beam bending can play a predictive role in a quantitative control in for the micro- and nanofabrication of small-sized products.

Issues in quantification of registered respiratory gated PET/CT in the lung

PET/CT quantification of lung tissue is limited by several difficulties: the lung density and local volume changes during respiration, the anatomical mismatch between PET and CT and the relative contributions of tissue, air and blood to the PET signal (the tissue fraction effect). Air fraction correction (AFC) has been shown to improve PET image quantification in the lungs. Methods to correct for the movement and anatomical mismatch involve respiratory gating and image registration techniques. While conventional registration methods only account for spatial mismatch, the Jacobian determinant of the deformable registration transformation field can be used to estimate local volume changes and could therefore potentially be used to correct (i.e. Jacobian Correction, JC) the PET signal for changes in concentration due to local volume changes. This work aims to investigate the relationship between variations in the lung due to respiration, specifically density, tracer concentration and local volume changes. In particular, we study the effect of AFC and JC on PET quantitation after registration of respiratory gated PET/CT patient data. Six patients suffering from lung cancer with solitary pulmonary nodules underwent F-FDG PET/cine-CT. The PET data were gated into six respiratory gates using displacement gating based on a real-time position management (RPM) signal and reconstructed with matched gated CT. The PET tracer concentration and tissue density were extracted from registered gated PET and CT images before and after corrections (AFC or JC) and compared to the values from the reference images. Before correction, we observed a linear correlation between the PET tracer concentration values and density. Across all gates and patients, the maximum relative change in PET tracer concentration before (after) AFC was found to be 16.2% (4.1%) and the maximum relative change in tissue density and PET tracer concentration before (after) JC was found to be 17.1% (5.5%) and 16.2% (6.8%) respectively. Overall our results show that both AFC or JC largely explain the observed changes in PET tracer activity over the respiratory cycle. We also speculate that a second order effect is related to change in fluid content but this needs further investigation. Consequently, either AFC or JC is recommended when combining lung PET images from different gates to reduce noise.

Penultimate deglacial warming across the Mediterranean Sea revealed by clumped isotopes in foraminifera

The variability of seawater temperature through time is a critical measure of climate change, yet its reconstruction remains problematic in many regions. Mg/Ca and oxygen isotope (δ18OC) measurements in foraminiferal carbonate shells can be combined to reconstruct seawater temperature and δ18O (δ18OSW). The latter is a measure of changes in local hydrology (e.g., precipitation/evaporation, freshwater inputs) and global ice volume. But diagenetic processes may affect foraminiferal Mg/Ca. This restricts its potential in many places, including the Mediterranean Sea, a strategic region for deciphering global climate and sea-level changes. High alkalinity/salinity conditions especially bias Mg/Ca temperatures in the eastern Mediterranean (eMed). Here we advance the understanding of both western Mediterranean (wMed) and eMed hydrographic variability through the penultimate glacial termination (TII) and last interglacial, by applying the clumped isotope (Δ47) paleothermometer to planktic foraminifera with a novel data-processing approach. Results suggest that North Atlantic cooling during Heinrich stadial 11 (HS11) affected surface-water temperatures much more in the wMed (during winter/spring) than in the eMed (during summer). The method’s paired Δ47 and δ18OC data also portray δ18OSW. These records reveal a clear HS11 freshwater signal, which attenuated toward the eMed, and also that last interglacial surface warming in the eMed was strongly amplified by water-column stratification during the deposition of the organic-rich (sapropel) interval known as S5.

Textural and chemical evolution of pyroxene during hydration and deformation: A consequence of retrograde metamorphism

Centimetre-sized grains of Al-rich clinopyroxene within the granulitic anorthosites of the Bergen Arcs, W-Norway undergo deformation by faults and micro-shear zones (kinks) along which fluid has been introduced. The clinopyroxene (11wt% Al2O3) reacts to the deformation and hydration in two different ways: reaction to garnet (Alm41Prp32Grs21) plus a less aluminous pyroxene (3wt% Al2O3) along kinks and the replacement of the Al-rich clinopyroxene by chlorite along cleavage planes. These reactions only take place in the hydrated part of a hand specimen that is separated from dry, unreacted granulite by a sharp interface that defines the limit of hydration. We use electron probe microanalysis (EPMA) and X-Ray mapping together with electron backscatter diffraction (EBSD) mapping to investigate the spatial and possible temporal relationships between these two parageneses. Gresens' analysis (Gresens, 1967) has been used to determine the mass balance and the local volume changes associated with the two reactions. The reaction to garnet+low-Al clinopyroxene induces a loss in volume of the solid phases whereas the chlorite formation gains volume. Strain variations result in local variation in undulose extinction in the parent clinopyroxene. EBSD results suggest that the density-increasing reaction to garnet+low-Al clinopyroxene takes place where the strain is highest whereas the density-decreasing reaction to chlorite forms away from shear zones where EBSD shows no significant strain. Modelling of phase equilibria suggest that the thermodynamic pressure of the assemblage within the shear zones is >6kbar higher than the pressure conditions for the whole rock for the same range of temperature (~650°C). This result suggests that the stress redistribution within a rock may play a role in determining the reactions that take place during retrograde metamorphism.

Patterns of progressive atrophy vary with age in Alzheimer's disease patients

Age is not only the greatest risk factor for Alzheimer's disease (AD) but also a key modifier of disease presentation and progression. Here, we investigate how longitudinal atrophy patterns vary with age in mild cognitive impairment (MCI) and AD. Data comprised serial longitudinal 1.5-T magnetic resonance imaging scans from 153 AD, 339 MCI, and 191 control subjects. Voxel-wise maps of longitudinal volume change were obtained and aligned across subjects. Local volume change was then modeled in terms of diagnostic group and an interaction between group and age, adjusted for total intracranial volume, white-matter hyperintensity volume, and apolipoprotein E genotype. Results were significant at p < 0.05 with family-wise error correction for multiple comparisons. An age-by-group interaction revealed that younger AD patients had significantly faster atrophy rates in the bilateral precuneus, parietal, and superior temporal lobes. These results suggest younger AD patients have predominantly posterior progressive atrophy, unexplained by white-matter hyperintensity, apolipoprotein E, or total intracranial volume. Clinical trials may benefit from adapting outcome measures for patient groups with lower average ages, to capture progressive atrophy in posterior cortices.

In Situ Neutron Diffraction Studies of the Ion Exchange Synthesis Mechanism of Li2Mg2P3O9N: Evidence for a Hidden Phase Transition.

Motivated by predictions made using a bond valence sum difference map (BVS-DM) analysis, the novel Li-ion conductor Li2Mg2P3O9N was synthesized by ion exchange from a Na2Mg2P3O9N precursor. Impedance spectroscopy measurements indicate that Li2Mg2P3O9N has a room temperature Li-ion conductivity of about 10-6 S/cm (comparable to LiPON), which is 6 orders of magnitude higher than the extrapolated Na-ion conductivity of Na2Mg2P3O9N at this temperature. The structure of Li2Mg2P3O9N was determined from ex situ synchrotron and time-of-flight neutron diffraction data to retain the P213 space group, though with a cubic lattice parameter of a = 9.11176(8) Å that is significantly smaller than the a = 9.2439(1) Å of Na2Mg2P3O9N. The two Li-ion sites are found to be very substantially displaced (∼0.5 Å) relative to the analogous Na sites in the precursor phase. The non-molten salt ion exchange method used to prepare Li2Mg2P3O9N produces a minimal background in powder diffraction experiments, and was therefore exploited for the first time to follow a Li+/Na+ ion exchange reaction using in situ powder neutron diffraction. Lattice parameter changes during ion exchange suggest that the reaction proceeds through a Na2-xLixMg2P3O9N solid solution (stage 1) followed by a two-phase reaction (stage 2) to form Li2Mg2P3O9N. However, full Rietveld refinements of the in situ neutron diffraction data indicate that the actual transformation mechanism is more complex and instead involves two thermodynamically distinct solid solutions in which the Li exclusively occupies the Li1 site at low Li contents (stage 1a) and then migrates to the Li3 site at higher Li contents (stage 1b), a crossover driven by the different signs of the local volume change at these sites. In addition to highlighting the importance of obtaining full structural data in situ throughout the ion exchange process, these results provide insights into the general question of what constitutes a thermodynamic phase.

Abnormal Gray Matter Shape, Thickness, and Volume in the Motor Cortico-Subcortical Loop in Idiopathic Rapid Eye Movement Sleep Behavior Disorder: Association with Clinical and Motor Features.

Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a major risk factor for Parkinson's disease and dementia with Lewy bodies. Anatomical gray matter abnormalities in the motor cortico-subcortical loop areas remain under studied in iRBD patients. We acquired T1-weighted images and administrated quantitative motor tasks in 41 patients with polysomnography-confirmed iRBD and 41 healthy subjects. Cortical thickness and voxel-based morphometry (VBM) analyses were performed to investigate local cortical thickness and gray matter volume changes, vertex-based shape analysis to investigate shape of subcortical structures, and structure-based volumetric analyses to investigate volumes of subcortical and brainstem structures. Cortical thickness analysis revealed thinning in iRBD patients in bilateral medial superior frontal, orbitofrontal, anterior cingulate cortices, and the right dorsolateral primary motor cortex. VBM results showed lower gray matter volume in iRBD patients in the frontal lobes, anterior cingulate gyri, and caudate nucleus. Shape analysis revealed extensive surface contraction in the external and internal segments of the left pallidum. Clinical and motor impaired features in iRBD were associated with anomalies of the motor cortico-subcortical loop. In summary, iRBD patients showed numerous gray matter structural abnormalities in the motor cortico-subcortical loop, which are associated with lower motor performance and clinical manifestations of iRBD.

Reversible and Irreversible Electric Field Induced Morphological and Interfacial Transformations of Hybrid Lead Iodide Perovskites.

We report reversible and irreversible strain effects and interfacial atomic mixing in MAPbI3/ITO under influence of external electric bias and photoillumination. Using conductive-probe atomic force microscopy, we locally applied a bias voltage between the MAPbI3/ITO and the conductive tip and observed local dynamic strain effects and current under conditions of forward bias. We found that the reversible part of the strain is associated with a current spike at the current onset stage and can therefore be related to an electrochemical process accompanied by local molar volume change. Similar partly reversible surface deformation was observed when the tip-sample contact was illuminated by light. Time-of-flight secondary ion mass spectrometry of electrically biased regions revealed massive atomic mixing at the buried MAPbI3/ITO interface, while the top MAPbI3 surface, subjected to strong morphological damage at the tip-surface contact, revealed less significant chemical decomposition.

A Set-Based Mixed Effect Model for Gene-Environment Interaction and Its Application to Neuroimaging Phenotypes.

Imaging genetics is an emerging field for the investigation of neuro-mechanisms linked to genetic variation. Although imaging genetics has recently shown great promise in understanding biological mechanisms for brain development and psychiatric disorders, studying the link between genetic variants and neuroimaging phenotypes remains statistically challenging due to the high-dimensionality of both genetic and neuroimaging data. This becomes even more challenging when studying gene-environment interaction (G×E) on neuroimaging phenotypes. In this study, we proposed a set-based mixed effect model for gene-environment interaction (MixGE) on neuroimaging phenotypes, such as structural volumes and tensor-based morphometry (TBM). MixGE incorporates both fixed and random effects of G×E to investigate homogeneous and heterogeneous contributions of multiple genetic variants and their interaction with environmental risks to phenotypes. We discuss the construction of score statistics for the terms associated with fixed and random effects of G×E to avoid direct parameter estimation in the MixGE model, which would greatly increase computational cost. We also describe how the score statistics can be combined into a single significance value to increase statistical power. We evaluated MixGE using simulated and real Alzheimer's Disease Neuroimaging Initiative (ADNI) data, and showed statistical power superior to other burden and variance component methods. We then demonstrated the use of MixGE for exploring the voxelwise effect of G×E on TBM, made feasible by the computational efficiency of MixGE. Through this, we discovered a potential interaction effect of gene ABCA7 and cardiovascular risk on local volume change of the right superior parietal cortex, which warrants further investigation.

Detection of smoothly distributed spatial outliers, with applications to identifying the distribution of parenchymal hyperinflation following an airway challenge in asthmatics.

Methacholine challenge tests are used to measure changes in pulmonary function that indicate symptoms of asthma. In addition to pulmonary function tests, which measure global changes in pulmonary function, computed tomography images taken at full inspiration before and after administration of methacholine provide local air volume changes (hyper-inflation post methacholine) at individual acinar units, indicating local airway hyperresponsiveness. Some of the acini may have extreme air volume changes relative to the global average, indicating hyperresponsiveness, and those extreme values may occur in clusters. We propose a Gaussian mixture model with a spatial smoothness penalty to improve prediction of hyperresponsive locations that occur in spatial clusters. A simulation study provides evidence that the spatial smoothness penalty improves prediction under different data-generating mechanisms. We apply this method to computed tomography data from Seoul National University Hospital on five healthy and ten asthmatic subjects. Copyright © 2017 John Wiley & Sons, Ltd.

Biomechanical CT metrics are associated with patient outcomes in COPD.

Traditional metrics of lung disease such as those derived from spirometry and static single-volume CT images are used to explain respiratory morbidity in patients with COPD, but are insufficient. We hypothesised that the mean Jacobian determinant, a measure of local lung expansion and contraction with respiration, would contribute independently to clinically relevant functional outcomes. We applied image registration techniques to paired inspiratory-expiratory CT scans and derived the Jacobian determinant of the deformation field between the two lung volumes to map local volume change with respiration. We analysed 490 participants with COPD with multivariable regression models to assess strengths of association between traditional CT metrics of disease and the Jacobian determinant with respiratory morbidity including dyspnoea (modified Medical Research Council), St Georges Respiratory Questionnaire (SGRQ) score, 6-min walk distance (6MWD) and the Body Mass Index, Airflow Obstruction, Dyspnoea and Exercise Capacity (BODE) index, as well as all-cause mortality. The Jacobian determinant was significantly associated with SGRQ (adjusted regression coefficient β=-11.75,95% CI -21.6 to -1.7; p=0.020), and with 6MWD (β=321.15, 95% CI 134.1 to 508.1; p<0.001), independent of age, sex, race, body mass index, FEV1, smoking pack-years, CT emphysema, CT gas trapping, airway wall thickness and CT scanner type. The mean Jacobian determinant was also independently associated with the BODE index (β=-0.41, 95% CI -0.80 to -0.02; p=0.039) and mortality on follow-up (adjusted HR=4.26, 95% CI 0.93 to 19.23; p=0.064). Biomechanical metrics representing local lung expansion and contraction improve prediction of respiratory morbidity and mortality and offer additional prognostic information beyond traditional measures of lung function and static single-volume CT metrics. NCT00608764; Post-results.

Entorhinal and transentorhinal atrophy in mild cognitive impairment using longitudinal diffeomorphometry

IntroductionAutopsy findings have shown the entorhinal cortex and transentorhinal cortex are among the earliest sites of accumulation of pathology in patients developing Alzheimer's disease. MethodsHere, we study this region in subjects with mild cognitive impairment (n = 36) and in control subjects (n = 16). The cortical areas are manually segmented, and local volume and shape changes are quantified using diffeomorphometry, including a novel mapping procedure that reduces variability in anatomic definitions over time. ResultsWe find significant thickness and volume changes localized to the transentorhinal cortex through high field strength atlasing. DiscussionThis demonstrates that in vivo neuroimaging biomarkers can detect these early changes among subjects with mild cognitive impairment.

Manifold Learning of COPD.

Analysis of CT scans for studying Chronic Obstructive Pulmonary Disease (COPD) is generally limited to mean scores of disease extent. However, the evolution of local pulmonary damage may vary between patients with discordant effects on lung physiology. This limits the explanatory power of mean values in clinical studies. We present local disease and deformation distributions to address this limitation. The disease distribution aims to quantify two aspects of parenchymal damage: locally diffuse/dense disease and global homogeneity/heterogeneity. The deformation distribution links parenchymal damage to local volume change. These distributions are exploited to quantify inter-patient differences. We used manifold learning to model variations of these distributions in 743 patients from the COPDGene study. We applied manifold fusion to combine distinct aspects of COPD into a single model. We demonstrated the utility of the distributions by comparing associations between learned embeddings and measures of severity. We also illustrated the potential to identify trajectories of disease progression in a manifold space of COPD.