Quantitative Imaging Metrics for the Assessment of Pulmonary Pathophysiology: An Official American Thoracic Society and Fleischner Society Joint Workshop Report.

Multiple thoracic imaging modalities have been developed to link structure to function in the diagnosis and monitoring of lung disease. Volumetric computed tomography (CT) renders three-dimensional maps of lung structures and may be combined with positron emission tomography (PET) to obtain dynamic physiological data. Magnetic resonance imaging (MRI) using ultrashort-echo time (UTE) sequences has improved signal detection from lung parenchyma; contrast agents are used to deduce airway function, ventilation-perfusion-diffusion, and mechanics. Proton MRI can measure regional ventilation-perfusion ratio. Quantitative imaging (QI)-derived endpoints have been developed to identify structure-function phenotypes, including air-blood-tissue volume partition, bronchovascular remodeling, emphysema, fibrosis, and textural patterns indicating architectural alteration. Coregistered landmarks on paired images obtained at different lung volumes are used to infer airway caliber, air trapping, gas and blood transport, compliance, and deformation. This document summarizes fundamental "good practice" stereological principles in QI study design and analysis; evaluates technical capabilities and limitations of common imaging modalities; and assesses major QI endpoints regarding underlying assumptions and limitations, ability to detect and stratify heterogeneous, overlapping pathophysiology, and monitor disease progression and therapeutic response, correlated with and complementary to, functional indices. The goal is to promote unbiased quantification and interpretation of in vivo imaging data, compare metrics obtained using different QI modalities to ensure accurate and reproducible metric derivation, and avoid misrepresentation of inferred physiological processes. The role of imaging-based computational modeling in advancing these goals is emphasized. Fundamental principles outlined herein are critical for all forms of QI irrespective of acquisition modality or disease entity.

Reduced Cognitive Assessment Scores Among Individuals With Magnetic Resonance Imaging-Detected Vascular Brain Injury.

Background and Purpose- Little is known about the association between covert vascular brain injury and cognitive impairment in middle-aged populations. We investigated if scores on a cognitive screen were lower in individuals with higher cardiovascular risk, and those with covert vascular brain injury. Methods- Seven thousand five hundred forty-seven adults, aged 35 to 69 years, free of cardiovascular disease underwent a cognitive assessment using the Digital Symbol Substitution test and Montreal Cognitive Assessment, and magnetic resonance imaging (MRI) to detect covert vascular brain injury (high white matter hyperintensities, lacunar, and nonlacunar brain infarctions). Cardiovascular risk factors were quantified using the INTERHEART (A Global Study of Risk Factors for Acute Myocardial Infarction) risk score. Multivariable mixed models tested for independent determinants of reduced cognitive scores. The population attributable risk of risk factors and MRI vascular brain injury on low cognitive scores was calculated. Results- The mean age of participants was 58 (SD, 9) years; 55% were women. Montreal Cognitive Assessment and Digital Symbol Substitution test scores decreased significantly with increasing age (P<0.0001), INTERHEART risk score (P<0.0001), and among individuals with high white matter hyperintensities, nonlacunar brain infarction, and individuals with 3+ silent brain infarctions. Adjusted for age, sex, education, ethnicity covariates, Digital Symbol Substitution test was significantly lowered by 1.0 (95% CI, -1.3 to -0.7) point per 5-point cardiovascular risk score increase, 1.9 (95% CI, -3.2 to -0.6) per high white matter hyperintensities, 3.5 (95% CI, -6.4 to -0.7) per nonlacunar stroke, and 6.8 (95% CI, -11.5 to -2.2) when 3+ silent brain infarctions were present. No postsecondary education accounted for 15% (95% CI, 12-17), moderate and high levels of cardiovascular risk factors accounted for 19% (95% CI, 8-30), and MRI vascular brain injury accounted for 10% (95% CI, -3 to 22) of low test scores. Conclusions- Among a middle-aged community-dwelling population, scores on a cognitive screen were lower in individuals with higher cardiovascular risk factors or MRI vascular brain injury. Much of the population attributable risk of low cognitive scores can be attributed to lower educational attainment, higher cardiovascular risk factors, and MRI vascular brain injury.

Rapid single-breath hyperpolarized noble gas MRI-based biomarkers of airspace enlargement.

BACKGROUND: Multi-b diffusion-weighted hyperpolarized-gas MRI measures pulmonary airspace-enlargement using apparent diffusion coefficients (ADCs) and mean-linear-intercepts (Lm ). PURPOSE: To develop single-breath 3D multi-b diffusion-weighted 3 He and 129 Xe MRI using k-space undersampling. Rapid, cost-efficient, single-breath acquisitions may facilitate clinical translation. STUDY TYPE: Prospective. SUBJECTS: We evaluated 12 participants, including nine subjects (mean age = 69 ± 9) who were included in the retrospective experiment and three chronic pulmonary obstruction disease (COPD) patients (mean age = 81 ± 6) who participated in the prospective study. FIELD STRENGTH: A whole-body 3 T 2D/3D fast gradient recall echo (FGRE) sequence. ASSESSMENT: Hyperpolarized 3 He/129 Xe MRI, spirometry, plethysmography computed tomography (CT). We evaluated 129 Xe ADC/morphometry estimates by retrospectively undersampling previously acquired fully sampled multibreath, multi-b diffusion-weighted data. Next, we prospectively evaluated the feasibility of accelerated (AF = 7) 3 He MRI static-ventilation/T2 * (extra short-TE, b = 0 image) and ADC/morphometry (five b-values) maps using a single gas-dose and 16-second breath-hold. To conservatively evaluate cost-improvement, we compared total costs of single vs. multiple 129 Xe doses. STATISTICAL TESTS: Multivariate analysis of variance, independent t-tests and voxel-by-voxel basis difference test. RESULTS: For the retrospectively undersampled 129 Xe data, a nonsignificant mean difference for ADC/Lm of 14%/12%, 12%/8%, and 11%/9% was observed (all, P > 0.4) between the fully sampled and accelerated data for the never-smoker, COPD, and alpha-1 antitrypsin deficiency (AATD) groups, respectively. The control never-smoker group had significantly lower ADC (P < 0.001) and Lm (P < 0.001) than the COPD/AATD group for both fully sampled and accelerated data. For the prospectively acquired 3 He MRI data, static-ventilation, T2 *, ADC, and morphometry maps were acquired using a single 16-second breath-hold scan and single gas dose. Accelerated imaging resulted in cost savings of ~$US 1000/patient, a conservative estimate based on 129 Xe MRI dose savings (single vs. five doses). DATA CONCLUSION: This is a proof-of-concept demonstration of accelerated (7×) morphometry that shows that less cost- and time-efficient multibreath methods that lead to variability and patient fatigue may be avoided in the future. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018.

Sensitive three-dimensional ultrasound assessment of carotid atherosclerosis by weighted average of local vessel wall and plaque thickness change.

PURPOSE: Vitamin B deficiency has been identified as a risk factor for vascular events. However, the reduction of vascular events was not shown in large randomized controlled trials evaluating B-Vitamin therapy. There is an important requirement to develop sensitive biomarkers to be used as efficacy targets for B-Vitamin therapy as well as other dietary treatments and lifestyle regimes that are being developed. Carotid vessel-wall-plus-plaque thickness change (VWT-Change) measured from 3D ultrasound has been shown to be sensitive to atorvastatin therapies in previous studies. However, B-Vitamin treatment is expected to confer a smaller beneficial effect in carotid atherosclerosis than the strong dose of atorvastatin. This paper introduces a sensitive atherosclerosis biomarker based on the weighted mean VWT-Change measurement from 3D ultrasound with a purpose to detect statistically significant effect of B-Vitamin therapy. METHODS: Of the 56 subjects analyzed in this study, 27 were randomized to receive a B-Vitamin tablet daily and 29 received a placebo tablet daily. Participants were scanned at baseline and 1.9 ± 0.8 yr later. The 3D VWT map at each scanning session was computed by matching the outer wall and lumen surfaces on a point-by-point basis. The 3D annual VWT-Change maps were obtained by first registering the 3D VWT maps obtained at the baseline and follow-up scanning sessions, and then taking the point-wise difference in VWT and dividing the result by the years elapsed from the baseline to the follow-up scanning session. The 3D VWT-Change maps constructed for all patients were mapped to a 2D carotid template to adjust for the anatomic variability of the arteries. A weight at each point of the carotid template was assigned based on the degree of correlation between the VWT-Change measurements exhibited at that point and the treatment received (i.e., B-Vitamin or placebo) quantified by mutual information. The weighted mean of VWT-Change for each patient, denoted by ΔVWT¯Weighted, was computed according to this weight. T-tests were performed to compare the sensitivity of ΔVWT¯Weighted with existing biomarkers in detecting treatment effects. These biomarkers included changes in intima-media thickness (IMT), total plaque area (TPA), vessel wall volume (VWV), unweighted average of VWT-Change (ΔVWT¯) and a previously described biomarker, denoted by ΔVWT¯S, that quantifies the mean VWT-Change specific to regions of interest identified by a feature selection algorithm. RESULTS: Among the six biomarkers evaluated, the effect of B Vitamins was detected only by ΔVWT¯Weighted in this cohort (P=4.4×10-3). The sample sizes per treatment group required to detect an effect as large as exhibited in this study were 139, 178, 41 for ΔVWV, ΔVWT¯ and ΔVWT¯Weighted respectively. CONCLUSION: The proposed weighted mean of VWT-Change is more sensitive than existing biomarkers in detecting treatment effects. This measurement tool will allow for many proof-of-principal studies to be performed for various novel treatments before a more costly study involving a larger population is held to validate the results.