Publications

2019
Lizano P, Lutz O, Ling G, Lee AM, Eum S, Bishop JR, Kelly S, Pasternak O, Clementz B, Pearlson G, et al. Association of Choroid Plexus Enlargement With Cognitive, Inflammatory, and Structural Phenotypes Across the Psychosis Spectrum. Am J Psychiatry. 2019;176 (7) :564-572.Abstract
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.
de la Hoz RE, Liu X, Celedón JC, Doucette JT, Jeon Y, Reeves AP, San José Estépar R. Association of Obesity with Quantitative Chest CT Measured Airway Wall Thickness in WTC Workers with Lower Airway Disease. Lung. 2019;197 (4) :517-522.Abstract
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.
Sullivan J-L, Bagevalu B, Glass C, Sholl L, Kraft M, Martinez FD, Bastarrika G, de-Torres JP, San José Estépar R, Guerra S, et al. B Cell Adaptive Immune Profile in Emphysema-Predominant COPD. Am J Respir Crit Care Med. 2019.
Parker MM, Hao Y, Guo F, Pham B, Chase R, Platig J, Cho MH, Hersh CP, Thannickal VJ, Crapo J, et al. Identification of an emphysema-associated genetic variant near with regulatory effects in lung fibroblasts. Elife. 2019;8.Abstract
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.
de la Hoz RE, Jeon Y, Reeves AP, San José Estépar R, Liu X, Doucette JT, Celedón JC, Nolan A. Increased pulmonary artery diameter is associated with reduced FEV in former World Trade Center workers. Clin Respir J. 2019.Abstract
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
Szczepankiewicz F, Hoge S, Westin C-F. Linear, planar and spherical tensor-valued diffusion MRI data by free waveform encoding in healthy brain, water, oil and liquid crystals. Data Brief. 2019;25 :104208.Abstract
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.
Eisenberg HM, Shenton ME, Pasternak O, Simard MJ, Okonkwo DO, Aldrich C, He F, Jain S, Hayman E. An MRI Pilot Study of Intravenous Glyburide in Traumatic Brain Injury. J Neurotrauma. 2019.Abstract
Preclinical studies of traumatic brain injury (TBI) show that Glyburide reduces edema and hemorrhagic progression of contusions. We conducted a small Phase 2, three-institution, randomized placebo-controlled trial of subjects with TBI, to assess the safety and efficacy of intravenous (IV) Glyburide. Twenty-eight subjects were randomized and underwent a 72-hour infusion of IV Glyburide or placebo, beginning within 10 hours of trauma. Of the 28 subjects, 25 had Glasgow Coma Scale scores of 6-10, and 14 had contusions. There were no differences in adverse or severe adverse events between groups. The MRI percent change at 72-168 hours from screening/baseline was compared between the Glyburide and Placebo groups. Analysis of contusions (7 per group) showed that lesion volumes (hemorrhage plus edema) increased 1036% with placebo vs. 136% with Glyburide (P=0.15), and that hemorrhage volumes increased 11.6% with placebo but decreased 29.6% with Glyburide (P=0.62). Three diffusion MRI measures of edema were quantified: mean diffusivity (MD), free water (FW), and tissue MD (MDt), corresponding to overall, extracellular and intracellular water, respectively. The percent change with time for each measure was compared in lesions (n=14) vs. uninjured white matter (n=24) in subjects receiving placebo (n=20) or Glyburide (n=18). For placebo, the percent change in lesions for all 3 measures was significantly different compared to uninjured white matter (ANOVA, P<0.02), consistent with worsening of edema in untreated contusions. In contrast, for Glyburide, the percent change in lesions for all 3 measures was not significantly different compared to uninjured white matter. Further study of IV Glyburide in contusion-TBI is warranted.
Topgaard D. Multiple dimensions for random walks. J Magn Reson. 2019.Abstract
Current trends in diffusion NMR and MRI methods development are reviewed. While great efforts are still directed towards further improving the spectral, spatial, and relaxation rate resolution of basic diffusion measurements, recent improvements in magnetic field gradient technology on whole-body scanners have enabled an exciting line of research involving MRI implementations of advanced diffusion NMR methods with motion-encoding gradient waveforms designed for multidimensional separation and correlation of properties like short-time diffusivity, restriction, anisotropy, flow, and exchange, thereby opening up for highly specific characterization of microstructure and heterogeneity in healthy and diseased tissues in a clinical setting.
Gilbert TM, Zürcher NR, Catanese MC, Tseng C-EJ, Di Biase MA, Lyall AE, Hightower BG, Parmar AJ, Bhanot A, Wu CJ, et al. Neuroepigenetic signatures of age and sex in the living human brain. Nat Commun. 2019;10 (1) :2945.Abstract
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.
Synn AJ, Li W, San José Estépar R, Zhang C, Washko GR, O'Connor GT, Araki T, Hatabu H, Bankier AA, Mittleman MA, et al. Radiographic Pulmonary Vessel Volume, Lung Function, and Airways Disease in the Framingham Heart Study. Eur Respir J. 2019.Abstract
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.
Duering M, Adam R, Wollenweber FA, Bayer-Karpinska A, Baykara E, Cubillos-Pinilla LY, Gesierich B, Araque Caballero MÁ, Stoecklein S, Ewers M, et al. Within-lesion heterogeneity of subcortical DWI lesion evolution, and stroke outcome: A voxel-based analysis. J Cereb Blood Flow Metab. 2019 :271678X19865916.Abstract
The fate of subcortical diffusion-weighted imaging (DWI) lesions in stroke patients is highly variable, ranging from complete tissue loss to no visible lesion on follow-up. Little is known about within-lesion heterogeneity and its relevance for stroke outcome. Patients with subcortical stroke and recruited through the prospective DEDEMAS study (NCT01334749) were examined at baseline ( = 45), six months ( = 45), and three years ( = 28) post-stroke. We performed high-resolution structural MRI including DWI. Tissue fate was determined voxel-wise using fully automated tissue segmentation. Within-lesion heterogeneity at baseline was assessed by free water diffusion imaging measures. The majority of DWI lesions (66%) showed cavitation on six months follow-up but the proportion of tissue turning into a cavity was small (9 ± 13.5% of the DWI lesion). On average, 69 ± 25% of the initial lesion resolved without any visually apparent signal abnormality. The extent of cavitation at six months post-stroke was independently associated with clinical outcome, i.e. modified Rankin scale score at six months (OR = 4.71,  = 0.005). DWI lesion size and the free water-corrected tissue mean diffusivity at baseline independently predicted cavitation. In conclusion, the proportion of cavitating tissue is typically small, but relevant for clinical outcome. Within-lesion heterogeneity at baseline on advanced diffusion imaging is predictive of tissue fate.
Szczepankiewicz F, Westin C-F, Nilsson M. Maxwell-compensated design of asymmetric gradient waveforms for tensor-valued diffusion encoding. Magn Reson Med. 2019;82 (4) :1424-1437.Abstract
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.
Wu W, McAnulty G, Hamoda HM, Sarill K, Karmacharya S, Gagoski B, Ning L, Grant EP, Shenton ME, Waber DP, et al. Detecting microstructural white matter abnormalities of frontal pathways in children with ADHD using advanced diffusion models. Brain Imaging Behav. 2019.Abstract
Studies using diffusion tensor imaging (DTI) have documented alterations in the attention and executive system in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). While abnormalities in the frontal lobe have also been reported, the associated white matter fiber bundles have not been investigated comprehensively due to the complexity in tracing them through fiber crossings. Furthermore, most studies have used a non-specific DTI model to understand white matter abnormalities. We present results from a first study that uses a multi-shell diffusion MRI (dMRI) data set coupled with an advanced multi-fiber tractography algorithm to probe microstructural measures related to axonal/cellular density and volume of fronto-striato-thalamic pathways in children with ADHD (N = 30) and healthy controls (N = 28). Head motion was firstly examined as a priority in order to assure that no group difference existed. We investigated 45 different white matter fiber bundles in the brain. After correcting for multiple comparisons, we found lower axonal/cellular packing density and volume in ADHD children in 8 of the 45 fiber bundles, primarily in the right hemisphere as follows: 1) Superior longitudinal fasciculus-II (SLF-II) (right), 2) Thalamus to precentral gyrus (right), 3) Thalamus to superior-frontal gyrus (right), 4) Caudate to medial orbitofrontal gyrus (right), 5) Caudate to precentral gyrus (right), 6) Thalamus to paracentral gyrus (left), 7) Caudate to caudal middlefrontal gyrus (left), and 8) Cingulum (bilateral). Our results demonstrate reduced axonal/cellular density and volume in certain frontal lobe white matter fiber tracts, which sub-serve the attention function and executive control systems. Further, our work shows specific microstructural abnormalities in the striato-thalamo-cortical connections, which have not been previously reported in children with ADHD.
Vegas-Sánchez-Ferrero G, Ledesma-Carbayo MJ, Washko GR, San José Estépar R. Harmonization of chest CT scans for different doses and reconstruction methods. Med Phys. 2019.Abstract
PURPOSE: To develop and validate a CT harmonization technique by combining noise-stabilization and autocalibration methodologies to provide reliable densitometry measurements in heterogeneous acquisition protocols. METHODS: We propose to reduce the effects of spatially-variant noise such as non-uniform patterns of noise and biases. The method combines the statistical characterization of the signal-to-noise relationship in the CT image intensities, which allows us to estimate both the signal and spatially-variant variance of noise, with an autocalibration technique that reduces the non-uniform biases caused by noise and reconstruction techniques. The method is firstly validated with anthropomorphic synthetic images that simulate CT acquisitions with variable scanning parameters: different dosage, non-homogeneous variance of noise, and various reconstruction methods. We finally evaluate these effects and the ability of our method to provide consistent densitometric measurements in a cohort of clinical chest CT scans from two vendors (Siemens, n=54 subjects; and GE, n=50 subjects) acquired with several reconstruction algorithms (filtered back-projection and iterative reconstructions) with high-dose and low-dose protocols. RESULTS: The harmonization reduces the effect of non-homogeneous noise without compromising the resolution of the images (25% RMSE reduction in both clinical datasets). An analysis through hierarchical linear models showed that the average biases induced by differences in dosage and reconstruction methods are also reduced up to 74:20%, enabling comparable results between highdose and low-dose reconstructions. We also assessed the statistical similarity between acquisitions obtaining increases of up to 30 percentage points and showing that the low-dose vs. high-dose comparisons of harmonized data obtain similar and even higher similarity than the observed for high-dose vs. high-dose comparisons of non-harmonized data. CONCLUSION: The proposed harmonization technique allows to compare measures of low-dose with high-dose acquisitions without using a specific reconstruction as a reference. Since the harmonization does not require a precalibration with a phantom, it can be applied to retrospective studies. This approach might be suitable for multicenter trials for which a reference reconstruction is not feasible or hard to define due to differences in vendors, models and reconstruction techniques. This article is protected by copyright. All rights reserved.
Savadjiev P, Chong J, Dohan A, Agnus V, Forghani R, Reinhold C, Gallix B. Image-based biomarkers for solid tumor quantification. Eur Radiol. 2019.Abstract
The last few decades have witnessed tremendous technological developments in image-based biomarkers for tumor quantification and characterization. Initially limited to manual one- and two-dimensional size measurements, image biomarkers have evolved to harness developments not only in image acquisition technology but also in image processing and analysis algorithms. At the same time, clinical validation remains a major challenge for the vast majority of these novel techniques, and there is still a major gap between the latest technological developments and image biomarkers used in everyday clinical practice. Currently, the imaging biomarker field is attracting increasing attention not only because of the tremendous interest in cutting-edge therapeutic developments and personalized medicine but also because of the recent progress in the application of artificial intelligence (AI) algorithms to large-scale datasets. Thus, the goal of the present article is to review the current state of the art for image biomarkers and their use for characterization and predictive quantification of solid tumors. Beginning with an overview of validated imaging biomarkers in current clinical practice, we proceed to a review of AI-based methods for tumor characterization, such as radiomics-based approaches and deep learning.Key Points• Recent years have seen tremendous technological developments in image-based biomarkers for tumor quantification and characterization.• Image-based biomarkers can be used on an ongoing basis, in a non-invasive (or mildly invasive) way, to monitor the development and progression of the disease or its response to therapy.• We review the current state of the art for image biomarkers, as well as the recent developments in artificial intelligence (AI) algorithms for image processing and analysis.
Miller ER, Putman RK, Diaz AA, Xu H, San José Estépar R, Araki T, Nishino M, Poli de Frías S, Hida T, Ross J, et al. Increased Airway Wall Thickness in Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis. Ann Am Thorac Soc. 2019;16 (4) :447-454.Abstract
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 < 0.001; 0.02 mm in ECLIPSE, 95% CI, 0.005-0.04; P = 0.01; 0.07 mm in FHS, 95% CI, 0.01-0.1; P = 0.01). Compared with COPDGene participants without ILA older than 60 years of age, patients with IPF were also noted to have increased measures of Pi10 (2.0 mm, 95% CI, 2.0-2.1; P < 0.001). Among research participants with ILA, increases in Pi10 were correlated with reductions in lung volumes in some but not all populations. CONCLUSIONS: These results demonstrate that measurable increases in AWT are consistently noted in research participants with ILA and in patients with IPF. These findings suggest that abnormalities of the airways may play a role in, or be correlated with, early pathogenesis of pulmonary fibrosis.
Boueiz A, Pham B, Chase R, Lamb A, Lee S, Naing ZZC, Cho MH, Parker MM, Sakornsakolpat P, Hersh CP, et al. Integrative Genomics Analysis Identifies ACVR1B as a Candidate Causal Gene of Emphysema Distribution. Am J Respir Cell Mol Biol. 2019;60 (4) :388-398.Abstract
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 < 0.05), with the strongest enrichment observed in CD4, CD8, and regulatory T cells. We selected a putative causal variant, rs7962469, associated with ACVR1B expression in lung tissue for additional functional investigation, and reporter assays confirmed allele-specific regulatory activity for this variant in human bronchial epithelial and Jurkat immune cell lines. ACVR1B expression levels exhibit a nominally significant association with emphysema distribution. EABD-associated loci are preferentially enriched in regulatory elements of multiple cell types, most notably T-cell subsets. Multiple EABD loci colocalize to regulatory elements that are active across multiple tissues and cell types, and functional analyses confirm the presence of an EABD-associated functional variant that regulates ACVR1B expression, indicating that transforming growth factor-β signaling plays a role in the EABD phenotype. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).
Sjöström H, Surova Y, Nilsson M, Granberg T, Westman E, van Westen D, Svenningsson P, Hansson O. Mapping of apparent susceptibility yields promising diagnostic separation of progressive supranuclear palsy from other causes of parkinsonism. Sci Rep. 2019;9 (1) :6079.Abstract
There is a need for methods that distinguish Parkinson's disease (PD) from progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), which have similar characteristics in the early stages of the disease. In this prospective study, we evaluate mapping of apparent susceptibility based on susceptibility weighted imaging (SWI) for differential diagnosis. We included 134 patients with PD, 11 with PSP, 10 with MSA and 44 healthy controls. SWI data were processed into maps of apparent susceptibility. In PSP, apparent susceptibility was increased in the red nucleus compared to all other groups, and in globus pallidus, putamen, substantia nigra and the dentate nucleus compared to PD and controls. In MSA, putaminal susceptibility was increased compared to PD and controls. Including all studied regions and using discriminant analysis between PSP and PD, 100% sensitivity and 97% specificity was achieved, and 91% sensitivity and 90% specificity in separating PSP from MSA. Correlations between putaminal susceptibility and disease severity in PD could warrant further research into using susceptibility mapping for monitoring disease progression and in clinical trials. Our study indicates that susceptibility in deep nuclei could play a role in the diagnosis of atypical parkinsonism, especially in PSP.
Zhang F, Ning L, O'Donnell LJ, Pasternak O. MK-curve - Characterizing the relation between mean kurtosis and alterations in the diffusion MRI signal. Neuroimage. 2019;196 :68-80.Abstract
Diffusion kurtosis imaging (DKI) is a diffusion MRI (dMRI) technique to quantify brain microstructural properties. While DKI measures are sensitive to tissue alterations, they are also affected by signal alterations caused by imaging artifacts such as noise, motion and Gibbs ringing. Consequently, DKI often yields output parameter values (e.g. mean kurtosis; MK) that are implausible. These include implausible values that are outside of the range dictated by physics/biology, and visually apparent implausible values that form unexpected discontinuities, being too high or too low comparing with their neighborhood. These implausible values will introduce bias into any following data analyses (e.g. between-population statistical computation). Existing studies have attempted to correct implausible DKI parameter values in multiple ways; however, these approaches are not always effective. In this study, we propose a novel method for detecting and correcting voxels with implausible values to enable improved DKI parameter estimation. In particular, we focus on MK parameter estimation. We first characterize the relation between MK and alterations in the dMRI signal including diffusion weighted images (DWIs) and the baseline (b0) images. This is done by calculating MK for a range of synthetic DWI or b0 for each voxel, and generating curves (MK-curve) representing how alterations to the input dMRI signals affect the resulting output MK. We find that voxels with implausible MK values are more likely caused by artifacts in the b0 images than artifacts in DWIs with higher b-values. Accordingly, two characteristic b0 values, which define a range of synthetic b0 values that generate implausible MK values, are identified on the MK-curve. Based on this characterization, we propose an automatic approach for detection of voxels with implausible MK values by comparing a voxel's original b0 signal to the identified two characteristic b0 values, along with a correction strategy to replace the original b0 in each detected implausible voxel with a synthetic b0 value computed from the MK-curve. We evaluate the method on a DKI phantom dataset and dMRI datasets from the Human Connectome Project (HCP), and we compare the proposed correction method with other previously proposed correction methods. Results show that our proposed method is able to identify and correct most voxels with implausible DKI parameter values as well as voxels with implausible diffusion tensor parameter values.
Kikinis Z, Makris N, Sydnor VJ, Bouix S, Pasternak O, Coman IL, Antshel KM, Fremont W, Kubicki MR, Shenton ME, et al. Abnormalities in gray matter microstructure in young adults with 22q11.2 deletion syndrome. Neuroimage Clin. 2019;21 :101611.Abstract
BACKGROUND: 22q11.2 Deletion Syndrome (22q11DS) is a genetic, neurodevelopmental disorder characterized by a chromosomal deletion and a distinct cognitive profile. Although abnormalities in the macrostructure of the cortex have been identified in individuals with 22q11DS, it is not known if there are additional microstructural changes in gray matter regions in this syndrome, and/or if such microstructural changes are associated with cognitive functioning. METHODS: This study employed a novel diffusion MRI measure, the Heterogeneity of Fractional Anisotropy (HFA), to examine variability in the microstructural organization of the cortex in healthy young adults (N = 30) and those with 22q11DS (N = 56). Diffusion MRI, structural MRI, clinical and cognitive data were acquired. RESULTS: Compared to controls, individuals with 22q11DS evinced increased HFA in cortical association (p = .003, d = 0.86) and paralimbic (p < .0001, d = 1.2) brain areas, whereas no significant differences were found between the two groups in primary cortical brain areas. Additionally, increased HFA of the right paralimbic area was associated with poorer performance on tests of response inhibition, i.e., the Stroop Test (rho = -0.37 p = .005) and the Gordon Diagnostic System Vigilance Commission (rho = -0.41 p = .002) in the 22q11DS group. No significant correlations were found between HFA and cognitive abilities in the healthy control group. CONCLUSIONS: These findings suggest that cortical microstructural disorganization may be a neural correlate of response inhibition in individuals with 22q11DS. Given that the migration pattern of neural crest cells is disrupted at the time of early brain development in 22q11DS, we hypothesize that these neural alterations may be neurodevelopmental in origin, and reflect cortical dysfunction associated with cognitive deficits.

Pages