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Objectives: Brain white matter (WM) microstructural changes evaluated by diffusion MRI are well documented in patients with SLE. Yet, the conventional diffusion tensor imaging technique fails to differentiate WM changes that originate from tissue alterations from those due to increased extracellular free water (FW) related to neuroinflammation, microvascular disruption, atrophy, or other extracellular processes. Here, we sought to delineate changes in WM tissue microstructure and extracellular FW volume and examine their relationships with neurocognitive function in SLE patients., Methods: Twenty SLE patients [16 females, aged 36.0 (10.6)] without clinically overt neuropsychiatric manifestation and 61 healthy controls (HCs) [29 females, aged 29.2 (9.4)] underwent diffusion MRI and computerized neuropsychological assessments cross-sectionally. The FW imaging method was applied to compare microstructural tissue changes and extracellular FW volume of the brain WM between SLE patients and HCs. Association between extracellular FW changes and neurocognitive performance was studied., Results: SLE patients had higher WM extracellular FW compared with HCs (family-wise-error-corrected P < 0.05), while no group difference was found in FW-corrected tissue compartment and structural connectivity metrics. Extracellular FW increases in SLE patients were associated with poorer neurocognitive performance that probed sustained attention (P = 0.022) and higher cumulative glucocorticoid dose (P = 0.0041). Such findings remained robust after controlling for age, gender, intelligence quotient, and total WM volume., Conclusion: The association between WM extracellular FW increases and reduced neurocognitive performance suggest possible microvascular degradation and/or neuroinflammation in SLE patients with clinically inactive disease. The mechanistic impact of cumulative glucocorticoids on WM FW deserves further evaluation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The smooth transportation of substances through the brain extracellular space (ECS) is crucial to maintaining brain function; however, the way this occurs under simulated microgravity remains unclear. In this study, tracer-based magnetic resonance imaging (MRI) and D ECS -mapping techniques were used to image the drainage of brain interstitial fluid (ISF) from the ECS of the hippocampus in a tail-suspended hindlimb-unloading rat model at day 3 (HU-3) and 7 (HU-7). The results indicated that drainage of the ISF was accelerated in the HU-3 group but slowed markedly in the HU-7 group. The tortuosity of the ECS decreased in the HU-3 group but increased in the HU-7 group, while the volume fraction of the ECS increased in both groups. The diffusion rate within the ECS increased in the HU-3 group and decreased in the HU-7 group. The alterations to ISF drainage and diffusion in the ECS were recoverable in the HU-3 group, but neither parameter was restored in the HU-7 group. Our findings suggest that early changes to the hippocampal ECS and ISF drainage under simulated microgravity can be detected by tracer-based MRI, providing a new perspective for studying microgravity-induced nano-scale structure abnormities and developing neuroprotective approaches involving the brain ECS., (© 2021. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Severe aortic stenosis (AS) is often characterized by myocardial interstitial fibrosis. Myocardial interstitial fibrosis, classically measured by magnetic resonance imaging, was also shown to be accurately measured by computed tomography (CT)-derived extracellular volume fraction (ECVF). Serum albumin (SA) level (g/dl) has been shown to correlate with ECVF among patients with heart failure and preserved ejection fraction. Our objective was to evaluate the association between SA and ECVF among patients with severe symptomatic AS. Patients with symptomatic severe AS who were evaluated as candidates for intervention between 2016 and 2018 were enrolled prospectively. All patients underwent precontrast and postcontrast CT for estimating myocardial ECVF. Valid ambulatory SA within 6 weeks of the cardiac CT were obtained and classified as (tertiles) <3.8, 3.8 to 4.19, and ≥4.2 g/dl. Patients with acute systemic illness at the time of the albumin test were excluded. The study included 68 patients, mean age 81 ± 6 years, 53% women. Patients with lower SA were more likely to have chronic renal failure, previous percutaneous coronary interventions, and a reduced functional class. The mean ECVF (%) in the study cohort was 41 ± 12%, significantly higher among the patients in the lower SA level groups (50 ± 12% vs 38 ± 7% vs 33 ± 9% in the <3.8 g/dl, 3.8 to 4.19 g/dl and ≥4.2 g/dl groups respectively, p for trend <0.001). A statistically significant inverse correlation was found between SA levels and ECVF (r -0.7, p <0.001). Multivariable analysis showed significant independent association between low SA and ECVF. In conclusion, the SA level is inversely associated with CT-derived ECVF in patients with severe AS., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Fractional extracellular space has been validated as a marker of hepatic fibrotic in cirrhotic patients at CT-scan as well as on dual-energy CT, which takes advantage from iodine uptake. Since no consensus still exists between equilibrium phases performed at 3 or 10 min, the first aim of this work is to evaluate performances at the two different time points. Moreover, correlation between fractional extracellular space and oesophageal varices, directly related to liver fibrosis, has been assessed., Materials and Methods: Dual-Energy equilibrium phases at 3 and 10 min were performed within a follow-up CT-protocol scan in cirrhotic patients. Oesophageal varices were endoscopically assessed according to their size. At the two different time points, correlation between iodine density of the right and left liver lobes and correlation between the fractional extracellular space values were assessed. Correlation between fractional extracellular space and endoscopic grade of oesophageal varices was calculated., Results: No statistical differences were found between the iodine density values from the two liver lobes at the two time points (p = 0.8 at 3'; p = 0.5 at 10'). No statistical difference about fractional extracellular space estimation was found between the two time points (p = 0.17). Correlation between fractional extracellular space values and oesophageal varices was moderate (ρ = 0.45, IC 0.08-0.71, p < 0.05)., Conclusion: Fractional extracellular space assessed on dual-energy CT at equilibrium phases with different timing was substantially similar. The moderate correlation found between fractional extracellular space and endoscopic grade of oesophageal varices confirms that CT-scan is not currently reliable as endoscopy.

Introduction: T1-based method is considered as the gold standard for extracellular volume fraction (ECV) mapping. This technique requires at least a 10 min delay after injection to acquire the post injection T1 map. Quantitative analysis of Dynamic Contrast Enhancement (DCE) images could lead to an earlier estimation of an ECV like parameter (2 min). The purpose of this study was to design a quantitative pixel-wise DCE analysis workflow to assess the feasibility of an early estimation of ECV., Methods: Fourteen patients with mitral valve prolapse were included in this study. The MR protocol, performed on a 3 T MR scanner, included MOLLI sequences for T1 maps acquisition and a standard SR-turboFlash sequence for dynamic acquisition. DCE data were acquired for at least 120 s. We implemented a full DCE analysis pipeline with a pre-processing step using an innovative motion correction algorithm (RC-REG algorithm) and a post-processing step using the extended Tofts Model (ECV ETM ). Estimated ECV ETM maps were compared to standard T1-based ECV maps (ECV T1 ) with both a Pearson correlation analysis and a group-wise analysis., Results: Image and map quality assessment showed systematic improvements using the proposed workflow. Strong correlation was found between ECV ETM , and ECV T1 values (r-square = 0.87)., Conclusion: A DCE analysis workflow based on RC-REG algorithm and ETM analysis can provide good quality parametric maps. Therefore, it is possible to extract ECV values from a 2 min-long DCE acquisition that are strongly correlated with ECV values from the T1 based method., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: To determine whether quantification of liver extracellular volume fraction (fECV) using dual-energy CT (DECT) allows prediction of liver-related events (LREs) in cirrhotic patients., Methods: This retrospective study included 305 cirrhotic patients who underwent dual-source DECT imaging and had serum markers analyzed within 2 weeks of initial CT imaging. The fECV score was measured using an iodine map of equilibrium-phase images obtained 3 min after contrast injection at 100/140 Sn kVp. The association of the fECV score and serum markers with LREs was investigated. A risk model combining the fECV score (< 27 versus ≥ 27%) and serum albumin level (< 4 versus ≥ 4 g/dL) was constructed for LRE prediction., Results: An increased fECV score (odds ratio, 1.27; 95% confidence interval (CI), 1.15, 1.40) was independently associated with decompensated cirrhosis at baseline (n = 85) along with the Model for End-Stage Liver Disease score (odds ratio, 1.32; 95% CI, 1.07, 1.63). Among patients with compensated cirrhosis, 10.5% (23 of 220) experienced LREs during the median follow-up period of 2.0 years (decompensation, n = 14; hepatocellular carcinoma, n = 9). The fECV score (hazard ratio, 1.40; 95% CI, 1.22, 1.62) and serum albumin level (hazard ratio, 0.26; 95% CI, 0.09, 0.73) were independent predictors of LRE. The mean times to LRE among the high (16.5 months, n = 18)-, intermediate (25.6 months, n = 44)-, and low (30.5 months, n = 158)-risk groups were significantly different (p < 0.001)., Conclusions: The fECV score derived from DECT allows prediction of LREs in cirrhotic patients., Key Points: • The extracellular volume fraction (fECV) score derived from the iodine map of dual-energy CT (DECT) was independently associated with the presence of hepatic decompensation. • The fECV score derived from the iodine map of DECT can predict liver-related events (LREs) in patients with cirrhosis. • Equilibrium-phase scanning in dual-energy mode is recommended as part of liver CT in cirrhotic patients because it can provide a prognostic indicator for LRE development.

OBJECTIVE. The purpose of this study was to investigate the association between primary pancreatic ductal adenocarcinoma fractional extracellular space (fECS) estimated from pretreatment CT and tumor response to chemotherapy and patient outcome. MATERIALS AND METHODS. A database search identified the records of patients with locally advanced or metastatic pancreatic ductal adenocarcinoma treated with systemic therapies who had undergone pretreatment CT that included both unenhanced and equilibrium phase images. An ROI was placed on the primary tumor and aorta, and the tumor fECS was calculated as follows: (tumor attenuation in the equilibrium phase - tumor attenuation in the unenhanced phase) / (aortic attenuation in the equilibrium phase - aortic attenuation in the unenhanced phase) × (1 - hematocrit). Response to therapy was assessed in subsequent CT examinations according to the Response Evaluation Criteria in Solid Tumors version 1.1. Relevant clinical variables, including carbohydrate antigen 19-9 level, chemotherapy regimen, and survival were recorded. Multivariate analyses were performed to determine the predictors of treatment response and patient survival. RESULTS. The median primary tumor fECS was 0.41 (range, 0.02-0.69). When dichotomized to high (> 0.41) versus low fECS (≤ 0.41) values, a larger proportion of patients with high tumor fECS values achieved disease control after chemotherapy than did those with low tumor fECS values: full cohort, 27 of 30 versus 19 of 30 ( p = 0.030); cohort with locally advanced disease, 23 of 24 versus 10 of 15 ( p = 0.024). The mean progression-free survival among patients with high primary tumor fECS values was significantly longer than that among those with low fECS values (191 versus 115 days, p = < 0.0001). Primary tumor fECS was an independent predictor of progression-free survival ( p = 0.003) in multivariate analysis. CONCLUSION. High primary tumor fECS value estimated from staging CT was associated with chemotherapy response and progression-free survival of patients with advanced pancreatic ductal adenocarcinoma.

Magnetic resonance electrical properties tomography (MREPT) uses the B1 mapping technique to provide the high-frequency conductivity distribution at Larmor frequency that simultaneously reflects the intracellular and extracellular effects. In biological tissues, the electrical conductivity can be described as the concentration and mobility of charge carriers. For the water molecule diffusivity, diffusion weighted imaging (DWI) measures the random Brownian motion of water molecules within biological tissues. The DWI data can quantitatively access the mobility of microscopic water molecules within biological tissues. By measuring multi-b-value DWI data and the recovered high-frequency conductivity at Larmor frequency, we propose a new method to decompose the conductivity into the total ion concentration and mobility in the extracellular space (ECS) within a routinely applicable MR scan time. Using the measured multi-b-value DWI data, a constrained compartment model is designed to estimate the extracellular volume fraction and extracellular mean diffusivity. With the extracted extracellular volume fraction and water molecule diffusivity, we directly reconstruct the low-frequency electrical properties including the extracellular mean conductivity and extracellular conductivity tensor. To demonstrate the proposed method by comparing the ion concentration and the ion mobility, we conducted human experiments for the proposed low-frequency conductivity imaging. Human experiments verify that the proposed method can recover the low-frequency electrical properties using a conventional MRI scanner., Competing Interests: The authors have declared that no competing interests exist.

Objective: Focal cortical dysplasia (FCD) lesion detection and subtyping remain challenging on conventional MRI. New diffusion models such as the spherical mean technique (SMT) and neurite orientation dispersion and density imaging (NODDI) provide measurements that potentially produce more specific maps of abnormal tissue microstructure. This study aims to assess the SMT and NODDI maps for computational and radiological lesion characterization compared to standard fractional anisotropy (FA) and mean diffusivity (MD)., Methods: SMT, NODDI, FA, and MD maps were calculated for 33 pediatric patients with suspected FCD (18 histologically confirmed). Two neuroradiologists scored lesion visibility on clinical images and diffusion maps. Signal profile changes within lesions and homologous regions were quantified using a surface-based approach. Diffusion parameter changes at multiple cortical depths were statistically compared between FCD type IIa and type IIb., Results: Compared to fluid-attenuated inversion recovery (FLAIR) or T1-weighted imaging, lesions conspicuity on NODDI intracellular volume fraction (ICVF) maps was better/equal/worse in 5/14/14 patients, respectively, while on SMT intra-neurite volume fraction (INVF) in 3/3/27. Compared to FA or MD, lesion conspicuity on the ICVF was better/equal/worse in 27/4/2, while on the INVF in 20/7/6. Quantitative signal profiling demonstrated significant ICVF and INVF reductions in the lesions, whereas SMT microscopic mean, radial, and axial diffusivities were significantly increased. FCD type IIb exhibited greater changes than FCD type IIa. No changes were detected on FA or MD profiles., Significance: FCD lesion-specific signal changes were found in ICVF and INVF but not in FA and MD maps. ICVF and INVF showed greater contrast than FLAIR in some cases and had consistent signal changes specific to FCD, suggesting that they could improve current presurgical pediatric epilepsy imaging protocols and can provide features useful for automated lesion detection., (© 2020 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

The brain extracellular space (ECS) is a system of narrow compartments whose intricate nanometric structure has remained elusive until very recently. Understanding such a complex organisation represents a technological challenge that requires a technique able to resolve these nanoscopic spaces and simultaneously characterize their rheological properties. We recently used single-walled carbon nanotubes (SWCNTs) as near-infrared fluorescent probes to map with nanoscale precision the local organization and rheology of the ECS. Here we expand our method by tracking single nanotubes through super-resolution imaging in rat organotypic hippocampal slices and acute brain slices from adult mice, pioneering the exploration of the adult brain ECS at the nanoscale. We found a highly heterogeneous ECS, where local rheological properties can change drastically within few nanometres. Our results suggest differences in local ECS diffusion environments in organotypic slices when compared to adult mouse slices. Data obtained from super-resolved maps of the SWCNT trajectories indicate that ECS widths may vary between brain tissue models, with a looser, less crowded nano-environment in organotypic cultured slices., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: One of the main features of liver fibrosis is the expansion of the interstitial space. All water-soluble CT contrast agents remain confined in the vascular and interstitial space constituting the fractional extracellular space (fECS). Indirect measure of its expansion can be quantified during equilibrium phase with CT. The goal of this prospective study was to assess the feasibility of dual-energy CT (DECT) with iodine quantification at equilibrium phase in the evaluation of significant fibrosis or cirrhosis., Methods: Thirty-eight cirrhotic patients (according to Child-Pugh and MELD scores), scheduled for liver CT, were enrolled in the study group. Twenty-four patients undergoing CT urography with a 10-min excretory phase were included in the control group. fECS was calculated as the ratio of the iodine concentration of liver parenchyma to that of the aorta, multiplied by 1 minus hematocrit., Results: Final study and control group were, respectively, composed of 22 and 20 patients. Mean hepatic fECS value was statistically greater in study group (P < 0.05). Positive correlation was observed between hepatic fECS value and MELD score (r = 0.64, P < 0.05). Analysis of variance showed statistical differences between control group and the Child-Pugh grades and between Child-Pugh A and B patients and Child-Pugh C patients (P < 0.05). ROC curves analysis yielded an optimum fECS cutoff value of 26.3% for differentiation of control group and cirrhotic patients (AUC 0.88; 86% sensitivity, 85% specificity)., Conclusions: Dual-source DECT is a feasible, noninvasive method for the assessment of significant liver fibrosis or cirrhosis.

Background: In previous work, we applied novel in vivo imaging methods to reveal that white matter pathology in patients with first-episode psychosis (FEP) is mainly characterized by excessive extracellular free-water, and to a lesser extent by cellular processes, such as demyelination. Here, we apply a back-translational approach to evaluate whether or not a rodent model of maternal immune activation (MIA) induces patterns of white matter pathology that we observed in patients with FEP. To this end, we examined free-water and tissue-specific white matter alterations in rats born to mothers exposed to the viral mimic polyriboinosinic-polyribocytidylic acid (Poly-I:C) in pregnancy, which is widely used to produce alterations relevant to schizophrenia and is characterized by a robust neuroinflammatory response., Method: Pregnant dams were injected on gestational day 15 with the viral mimic Poly-I:C (4 mg/kg) or saline. Diffusion-weighted magnetic resonance images were acquired from 17 male offspring (9 Poly-I:C and 8 saline) on postnatal day 90, after the emergence of brain structural and behavioral abnormalities. The free-water fraction (FW) and tissue-specific fractional anisotropy (FA T ), as well as conventional fractional anisotropy (FA) were computed across voxels traversing a white matter skeleton. Voxel-wise and whole-brain averaged white matter were tested for significant microstructural alterations in immune-challenged, relative to saline-exposed offspring., Results: Compared to saline-exposed offspring, those exposed to maternal Poly-I:C displayed increased extracellular FW averaged across voxels comprising a white matter skeleton (t(15) = 2.74; p = 0.01). Voxel-wise analysis ascribed these changes to white matter within the corpus callosum, external capsule and the striatum. In contrast, no significant between-group differences emerged for FA T or for conventional FA, measured across average and voxel-wise white matter., Conclusion: We identified excess FW across frontal white matter fibers of rats exposed to prenatal immune activation, analogous to our "bedside" observation in FEP patients. Findings from this initial experiment promote use of the MIA model to examine pathological pathways underlying FW alterations observed in patients with schizophrenia. Establishing these mechanisms has important implications for clinical studies, as free-water imaging reflects a feasible biomarker that has so far yielded consistent findings in the early stages of schizophrenia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To estimate the MRI-derived myocardial extracellular volume (ECV) in healthy subjects together with reference normality interval., Methods: The study was registered on PROSPERO and reported according to PRISMA. In October 2017, a systematic search (MEDLINE/EMBASE) was performed for articles reporting MRI-derived ECV in healthy subjects. The pooled ECV (pECV) with 95% confidence interval (CI) was calculated using the random-effect model; the normality interval was calculated as pECV ± 2 root mean square of all study standard deviations. The Newcastle-Ottawa scale was used for assessing study quality, subgroup/meta-regression analyses for technical/biological covariates, and Egger test for publication bias risk., Results: Of 282 articles, 56 were analyzed totaling 1851 subjects with age 16-68 years, body mass index 23-28 kg/m 2 , and left ventricular ejection fraction 58-74%. Contrast dose varied from 0.075 to 0.200 mmol/kg. Heterogeneity was high (I 2  = 92%). The pECV was 25.6% (95% CI 25.2-26.0%) with a normality interval of 19.6-31.6%. pECV was slightly increasing with age (β = 0.03%, p = 0.038) and slightly decreasing with the percentage of males (β = - 0.02%, p = 0.053). Sequence type significantly (p = 0.003) impacted on pECV: the normal interval was 19.9-31.9% for MOLLI and 20.3-33.5% for ShMOLLI. Contrast type/dose, time of acquisition, and magnetic field strength did not significantly impact pECV (p > 0.093). Quality was moderate or high in 48/56 studies (86%). No risk of publication bias (p = 0.728)., Conclusions: Myocardial pECV in healthy subjects was 25.6%, increasing by 0.03% for each year of age. The ECV normality interval was 19.9-31.9% for MOLLI and 20.3-33.5% for ShMOLLI., Key Points: • The pooled estimate of normal MRI-derived ECV based on 1851 subjects was 25.6%, slightly increasing with age and slightly decreasing with the percentage of males. • MRI-derived ECV was independent of contrast type/dose and field strength but dependent on the imaging sequence. • The modeled normality reference interval of MRI-derived ECV was 19.9-31.9% for the MOLLI sequence and 20.3-33.5% for the ShMOLLI sequence.

Objectives: To assess whether extracellular volume (ECV) fraction with equilibrium contrast-enhanced multidetector computed tomography (MDCT) predicts outcomes for unresectable pancreatic adenocarcinoma patients treated with chemotherapy METHODS: Sixty-seven patients (42 men, 25 women; mean age, 67.5 years; range, 45-83 years) with histologically confirmed surgically unresectable pancreatic adenocarcinoma underwent contrast-enhanced MDCT before systemic chemotherapy. Tumour contrast enhancement (CE) and ECV fraction were calculated using region-of-interest measurement within the pancreatic adenocarcinoma and aorta on unenhanced and equilibrium phase-enhanced CT. The effect on survival variables including age, sex, tumour location, tumour size, TNM stage, carbohydrate antigen (CA) 19-9, carcinoembryonic antigen (CEA), tumour CE and tumour ECV fraction was determined on univariate and multivariate analyses using Cox proportional hazards regression model., Results: Median overall survival was 10.5 months. On univariate analysis, elevated serum CA19-9 (hazard ratio (HR), 1.00; p = 0.006) and CEA (HR, 1.02; p = 0.011) levels were found to be associated with a negative effect on overall survival. Increasing tumour CE (HR, 0.98; p < 0.001) and ECV fraction (HR, 0.97; p = 0.001) were associated with a positive effect. Multivariate analysis revealed that only tumour ECV fraction was an independent predictor of overall survival (HR, 0.97; p = 0.012)., Conclusions: ECV fraction with equilibrium contrast-enhanced MDCT could be a useful imaging biomarker for predicting patient survival after chemotherapy for unresectable pancreatic adenocarcinoma., Key Points: • Tumour aggressiveness and response to therapy are influenced by the extravascular extracellular space. • Extracellular volume (ECV) fraction can be quantified with equilibrium contrast-enhanced CT. • Patients with higher tumour ECV fraction had better prognosis after chemotherapy.

T1 mapping using cardiac magnetic resonance (CMR) is useful for myocardial assessment. However, its prognostic value is not well defined. The aim of this study was to determine whether T1 mapping with CMR can predict reverse cardiac remodeling in patients with non-ischemic dilated cardiomyopathy (NIDCM). We also investigated the predictive prognostic value of T1 mapping with CMR in these patients. We included 33 patients with NIDCM admitted to Nippon Medical School Hospital between February 2012 and October 2015. All patients underwent CMR and echocardiography for clinical assessment within 1 month of admission (13 ± 16 days). Follow-up echocardiography was performed no sooner than 6 months after the initial echocardiogram (536 ± 304 days). We evaluated the correlations between native and post-contrast T1 values/extracellular volume fraction (ECV) and the difference in left ventricular ejection fraction (ΔLVEF) determined at baseline and follow-up echocardiography. No correlation was noted between ΔLVEF and native (p = 0.150, r = - 0.256) or post-contrast T1 values (p = 0.956, r = - 0.010). However, a significant and substantial correlation was found between ΔLVEF and ECV (p = 0.043, r = - 0.355). Four patients were hospitalized for heart failure (HF), but no cardiovascular-related deaths occurred over a median follow-up period of 34 months (interquartile range 25-49 months). Kaplan-Meier curves stratified by the median value of ECV were created. The higher ECV groups experienced a significantly higher incidence of HF-related hospitalization (p = 0.0159). ECV measured by CMR can predict improvements in LVEF in patients with NIDCM. In addition, ECV may be a predictive factor for HF-related hospitalization.

Objectives: Bipolar disorder (BP) is a debilitating psychiatric disease that is not well understood. Previous diffusion magnetic resonance imaging (dMRI) studies of BP patients found prominent microstructural white matter (WM) abnormalities of reduced fractional anisotropy (FA). Because FA is a nonspecific measure, relating these abnormalities to a specific pathology is difficult. Here, dMRI specificity was increased by free water (FW) imaging, which allows identification of changes in extracellular space (FW) from neuronal tissue (fractional anisotropy of tissue [FA-t]). Previous studies identified increased FW in early schizophrenia (SZ) stages which was replaced by widespread decreased FA-t in chronic stages. This is the first analysis utilizing this method to compare BP patients and controls., Methods: 3 Tesla diffusion weighted imaging (3T DWI) data were acquired for 17 chronic BP and 28 healthy control (HC) participants at Oxford University. Tract-based spatial statistics was utilized to generate a WM skeleton. FW imaging deconstructed the diffusion signal into extracellular FW and tissue FA-t maps. These maps were projected onto the skeleton and FA, FA-t, and FW were compared between groups., Results: We found significantly lower FA in BP patients when compared to HC in areas that overlapped with extensive FW increases. There were no FA-t differences., Conclusions: Our study suggests that chronic BP shows similar WM changes to early SZ, suggesting that extracellular FW increases could be a transient indication of recent psychotic episodes. Since FW increase in SZ has been suggested to be related to neuroinflammation, we theorize that neuroinflammation might be a shared pathology between chronic BP and early SZ., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Coronary artery disease (CAD) remains the major cause of cardiac morbidity and mortality worldwide, despite the advances in treatment with coronary revascularization and modern antiremodeling therapy. Risk stratification in CAD patients is primarily based on left ventricular volumes, ejection fraction (LVEF), risk scores, and the presence and extent of late gadolinium enhancement (LGE). The prognostic role of T1 mapping in noninfarcted myocardium in CAD patients has not yet been determined., Objectives: This study sought to examine prognostic significance of native T1 mapping of noninfarcted myocardium in patients with CAD., Methods: A prospective, observational, multicenter longitudinal study of consecutive patients undergoing routine cardiac magnetic resonance imaging with T1 mapping and LGE. The primary endpoint was all-cause mortality. Major adverse cardiocerebrovascular events (MACCE) (cardiac mortality, nonfatal acute coronary syndrome, stroke, and appropriate device discharge) are also reported., Results: A total of 34 deaths and 71 MACCE (n = 665, males n = 424, median age [interquartile range] 57 [22] years; 64%; median follow-up period of 17 [11] months) were observed. Native T1 and extracellular volume were univariate predictors of outcome. Native T1 and LGE were stronger predictors of survival and MACCE compared with extracellular volume, LVEF, cardiac volumes, and clinical scores (p < 0.001). Native T1 of noninfarcted myocardium was the sole independent predictor of all-cause mortality (chi-square = 21.7; p < 0.001), which was accentuated in the absence of LGE or LVEF ≤35%. For MACCE, native T1 and LGE extent were joint independent predictors (chi-square = 25.6; p < 0.001)., Conclusions: Characterization of noninfarcted myocardium by native T1 is an important predictor of outcome in CAD patients, over and above the traditional risk stratifiers. The current study's results provide a basis for a novel risk stratification model in CAD based on a complementary assessment of noninfarcted myocardium and post-infarction scar, by native T1 mapping and LGE, respectively., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Bral2 is a link protein stabilizing the binding between lecticans and hyaluronan in perineuronal nets and axonal coats (ACs) in specific brain regions. Using the real-time iontophoretic method and diffusion-weighted magnetic resonance, we determined the extracellular space (ECS) volume fraction (α), tortuosity (λ), and apparent diffusion coefficient of water (ADC W ) in the thalamic ventral posteromedial nucleus (VPM) and sensorimotor cortex of young adult (3-6 months) and aged (14-20 months) Bral2-deficient (Bral2 -/- ) mice and age-matched wild-type (wt) controls. The results were correlated with an analysis of extracellular matrix composition. In the cortex, no changes between wt and Bral2 -/- were detected, either in the young or aged mice. In the VPM of aged but not in young Bral2 -/- mice, we observed a significant decrease in α and ADC W in comparison with age-matched controls. Bral2 deficiency led to a reduction of both aggrecan- and brevican-associated perineuronal nets and a complete disruption of brevican-based ACs in young as well as aged VPM. Our data suggest that aging is a critical point that reveals the effect of Bral2 deficiency on VPM diffusion. This effect is probably mediated through the enhanced age-related damage of neurons lacking protective ACs, or the exhausting of compensatory mechanisms maintaining unchanged diffusion parameters in young Bral2 -/- animals. A decreased ECS volume in aged Bral2 -/- mice may influence the diffusion of neuroactive substances, and thus extrasynaptic and also indirectly synaptic transmission in this important nucleus of the somatosensory pathway., (© 2017 Wiley Periodicals, Inc.)

Background Previous studies suggested that enlarged perivascular spaces are neuroimaging markers of cerebral small vessel disease. However, it is not clear whether enlarged perivascular spaces are associated with cognitive impairment. We aimed to determine the cross-sectional relationship between enlarged perivascular spaces and small vessel disease, and to investigate the relationship between enlarged perivascular spaces and subsequent cognitive impairment in patients with recent cerebral ischemic event. Methods Anonymized data were accessed from the virtual international stroke trial archive. We rated number of lacunes, white matter hyperintensities, brain atrophy, and enlarged perivascular spaces with validated scales on magnetic resonance brain images after the index stroke. We defined cognitive impairment as a mini mental state examination score of ≤26, recorded at one year post stroke. We examined the associations between enlarged perivascular spaces and clinical and imaging markers of small vessel disease at presentation and clinical evidence of cognitive impairment at one year using linear and logistic regression models. Results We analyzed data on 430 patients with mean (±SD) age 64.7 (±12.7) years, 276 (64%) males. In linear regression analysis, age (β = 0.24; p < 0.001), hypertension (β = 0.09; p = 0.025), and deep white matter hyperintensities (β = 0.31; p < 0.001) were associated with enlarged perivascular spaces. In logistic regression analysis, basal ganglia enlarged perivascular spaces were independently associated with cognitive impairment at one year after adjusting for clinical confounders (OR = 1.72, 95% CI = 1.22-2.42) and for clinical and imaging confounders (OR = 1.54; 95% CI = 1.03-2.31). Conclusions Our data show that in patients with ischemic cerebral events, enlarged perivascular spaces are cross-sectionally associated with age, hypertension, and white matter hyperintensities and suggest that enlarged perivascular spaces in the basal ganglia are associated with cognitive impairment after one year.

Purpose: The changes in muscle composition and its heterogeneity during aging are associated with muscle weakness in elderly persons independent of decreases in muscle mass or muscle thickness (MT). Both the assessment of echo intensity (EI) with ultrasound imaging and the evaluation of the extracellular water/intracellular water (ECW/ICW) ratio with segmental bioelectrical impedance spectroscopy (BIS) are non-invasive and convenient methods and seem valuable for muscle quality determination. However, no previous study has evaluated both EI and the ECW/ICW ratio simultaneously to investigate their relationship to muscle strength. The purpose of the present study was to investigate whether both EI and the ECW/ICW ratio are independently associated with muscle strength in elderly women., Methods: A total of 179 elderly women with a mean age of 74.1 ± 4.9 years, living independently in the community, were enrolled. The MT and EI of the quadriceps femoris were measured using transverse ultrasound imaging. The ECW/ICW ratio in the upper thigh was calculated from segmental BIS. The maximum knee extensor strength and the presence of knee pain were also assessed., Results: Knee extensor strength showed a significant positive correlation with MT, and significant negative correlations with EI, the ECW/ICW ratio, and age. Stepwise regression analysis revealed that knee extensor strength in elderly women was predicted by MT, EI, and the ECW/ICW ratio., Conclusions: This study suggests that the simultaneous application of EI and the ECW/ICW ratio is useful in assessing muscle strength, and accurately estimates the changes in muscle quality related to muscle weakness.

Heart failure with preserved ejection fraction (HFpEF) presents a major challenge in modern cardiology. Although this syndrome is of increasing prevalence and is associated with unfavorable outcomes, treatment trials have failed to establish effective therapies. Currently, solutions to this dilemma are being investigated, including categorizing and characterizing patients more diversely to individualize treatment. In this regard, new imaging techniques might provide important information. Diastolic dysfunction is a diagnostic and pathophysiological cornerstone in HFpEF and is believed to be caused by systemic inflammation with the development of interstitial myocardial fibrosis and myocardial stiffening. Cardiac magnetic resonance (CMR) T 1 -mapping is a novel tool, which allows noninvasive quantification of the extracellular space and diffuse myocardial fibrosis. This review provides an overview of the potential of myocardial tissue characterization with CMR T 1 mapping in HFpEF patients, outlining its diagnostic and prognostic implications and discussing future directions. We conclude that CMR T 1 mapping is potentially an effective tool for patient characterization in large-scale epidemiological, diagnostic, and therapeutic HFpEF trials beyond traditional imaging parameters., (Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Duchenne muscular dystrophy (DMD) is a genetic, X-linked recessive disease with an associated cardiomyopathy characterized by myocardial fibrosis leading to heart failure, arrhythmias, and death. Earlier detection and treatment of cardiac involvement in DMD hold potential to improve outcomes. Cardiovascular magnetic resonance (CMR) extracellular volume (ECV) quantification using T1 mapping is a histologically validated, non-invasive marker of diffuse fibrosis. This study aims to determine the ECV in a pediatric DMD population, and correlate it with metrics of left ventricular function. A retrospective review of pediatric DMD subjects who underwent CMR at a single institution. A total of 47 DMD patients (mean age 14 ± 2 years) were included for analysis. Global myocardial ECV was significantly higher in the DMD group (29 ± 6%) compared with published normal values (24 ± 2%, p = 0.0001). Higher ECV values correlate with indices of left ventricular function, including decreased left ventricular ejection fraction (r = -0.46, p = 0.001) and indexed left ventricular end diastolic volume (r = 0.41, p = 0.004). ECV was not significantly higher in DMD patients with late gadolinium enhancement (LGE) (30 ± 7%) compared to DMD patients without LGE (27 ± 5%, p = 0.0717). CMR T1 mapping is a feasible method for quantification of ECV in patients with DMD. Global myocardial ECV is significantly higher in the DMD population compared to healthy controls and correlates with other metrics of myocardial function. Global myocardial ECV may serve as an important tool to determine cardiac involvement in DMD population and help guide medical management.

BACKGROUND This study assessed an innovative tracer-based magnetic resonance imaging (MRI) system to visualize the dynamic transportation of tracers in regions of deep brain extracellular space (ECS) and to measure transportation ability and ECS structure. MATERIAL AND METHODS Gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) was the chosen tracer and was injected into the caudate nucleus and thalamus. Real-time dynamic transportation of Gd-DTPA in ECS was observed and the results were verified by laser scanning confocal microscopy. Using Transwell assay across the blood-brain barrier, a modified diffusion equation was further simplified. Effective diffusion coefficient D* and tortuosity λ were calculated. Immunohistochemical staining and Western blot analysis were used to investigate the extracellular matrix contributing to ECS structure. RESULTS Tracers injected into the caudate nucleus were transported to the ipsilateral frontal and temporal cortices away from the injection points, while both of them injected into the thalamus were only distributed on site. Although the caudate nucleus was closely adjacent to the thalamus, tracer transportation between partitions was not observed. In addition, D* and the λ showed statistically significant differences between partitions. ECS was shown to be a physiologically partitioned system, and its division is characterized by the unique distribution territory and transportation ability of substances located in it. Versican and Tenascin R are possible contributors to the tortuosity of ECS. CONCLUSIONS Tracer-based MRI will improve our understanding of the brain microenvironment, improve the techniques for local delivery of drugs, and highlight brain tissue engineering fields in the future.

Importance: Among myriad changes occurring during the evolution of heart failure with preserved ejection fraction (HFpEF), cardiomyocyte-extracellular matrix interactions from excess collagen may affect microvascular, mechanical, and electrical function., Objective: To investigate whether myocardial fibrosis (MF) is similarly prevalent both in those with HFpEF and those at risk for HFpEF, similarly associating with disease severity and outcomes., Design, Setting, and Participants: Observational cohort study from June 1, 2010, to September 17, 2015, with follow-up until December 14, 2015, at a cardiovascular magnetic resonance (CMR) center serving an integrated health system. Consecutive patients with preserved systolic function referred for CMR were eligible. Cardiovascular magnetic resonance was used to exclude patients with cardiac amyloidosis (n = 19)., Exposures: Myocardial fibrosis quantified by extracellular volume (ECV) CMR measures., Main Outcome and Measures: Baseline BNP; subsequent hospitalization for heart failure or death., Results: Of 1174 patients identified (537 [46%] female; median [interquartile range {IQR}] age, 56 [44-66] years), 250 were "at risk" for HFpEF given elevated brain-type natriuretic peptide (BNP) level; 160 had HFpEF by documented clinical diagnosis, and 745 did not have HFpEF. Patients either at risk for HFpEF or with HFpEF demonstrated similarly higher prevalence/extent of MF and worse prognosis compared with patients with no HFpEF. Among those at risk for HFpEF or with HFpEF, the actual diagnosis of HFpEF was not associated with significant differences in MF (median ECV, 28.2%; IQR, 26.2%-30.7% vs 28.3%; IQR, 25.5%-31.4%; P = .60) or prognosis (log-rank 0.8; P = .38). Over a median of 1.9 years, 61 patients at risk for HFpEF or with HFpEF experienced adverse events (19 hospitalization for heart failure, 48 deaths, 6 with both). In those with HFpEF, ECV was associated with baseline log BNP (disease severity surrogate) in multivariable linear regression models, and was associated with outcomes in multivariable Cox regression models (eg, hazard ratio 1.75 per 5% increase in ECV, 95% CI, 1.25-2.45; P = .001 in stepwise model) whether grouped with patients at risk for HFpEF or not., Conclusions and Relevance: Among myriad changes occurring during the apparent evolution of HFpEF where elevated BNP is prevalent, MF was similarly prevalent in those with or at risk for HFpEF. Conceivably, MF might precede clinical HFpEF diagnosis. Regardless, MF was associated with disease severity (ie, BNP) and outcomes. Whether cells and secretomes mediating MF represent therapeutic targets in HFpEF warrants further evaluation.

Background: Mixed vascular and neurodegenerative dementia, such as Alzheimer's disease (AD) with concomitant cerebrovascular disease, has emerged as the leading cause of age-related cognitive impairment. The brain white matter (WM) microstructural changes in neurodegeneration well-documented by diffusion tensor imaging (DTI) can originate from brain tissue or extracellular free water changes. The differential microstructural and free water changes in AD with and without cerebrovascular disease, especially in normal-appearing WM, remain largely unknown. To cover these gaps, we aimed to characterize the WM free water and tissue microstructural changes in AD and mixed dementia as well as their associations with cognition using a novel free water imaging method., Methods: We compared WM free water and free water-corrected DTI measures as well as white matter hyperintensity (WMH) in patients with AD with and without cerebrovascular disease, patients with vascular dementia, and age-matched healthy control subjects., Results: The cerebrovascular disease groups had higher free water than the non-cerebrovascular disease groups. Importantly, besides the cerebrovascular disease groups, patients with AD without cerebrovascular disease also had increased free water in normal-appearing WM compared with healthy control subjects, reflecting mild vascular damage. Such free water increases in WM or normal-appearing WM (but not WMH) contributed to dementia severity. Whole-brain voxel-wise analysis revealed a close association between widespread free water increases and poorer attention, executive functioning, visual construction, and motor performance, whereas only left hemispheric free water increases were related to language deficits. Moreover, compared with the original DTI metrics, the free water-corrected DTI metric revealed tissue damage-specific (frontal and occipital) microstructural differences between the cerebrovascular disease and non-cerebrovascular disease groups. In contrast to both lobar and subcortical/brainstem free water increases, only focal lobar microstructural damage was associated with poorer cognitive performance., Conclusions: Our findings suggest that free water analysis isolates probable mild vascular damage from WM microstructural alterations and underscore the importance of normal-appearing WM changes underlying cognitive and functional impairment in AD with and without cerebrovascular disease. Further developed, the combined free water and tissue neuroimaging assays could help in differential diagnosis, treatment planning, and disease monitoring of patients with mixed dementia.

Solution reflux and edema hamper the convection-enhanced delivery of the standard treatment for glioma. Therefore, a real-time magnetic resonance imaging (MRI) method was developed to monitor the dosing process, but a quantitative analysis of local diffusion and clearance parameters has not been assessed. The objective of this study was to compare diffusion into the extracellular space (ECS) at different stages of rat C6 gliomas, and analyze the effects of the extracellular matrix (ECM) on the diffusion process. At 10 and 20 days, after successful glioma modeling, gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) was introduced into the ECS of rat C6 gliomas. Diffusion parameters and half-life of the reagent were then detected using MRI, and quantified according to the mathematical model of diffusion. The main ECM components [chondroitin sulfate proteoglycans (CSPGs), collagen IV, and tenascin C] were detected by immunohistochemical and immunoblot analyses. In 20-day gliomas, Gd-DTPA diffused more slowly and derived higher tortuosity, with lower clearance rate and longer half-life compared to 10-day gliomas. The increased glioma ECM was associated with different diffusion and clearance parameters in 20-day rat gliomas compared to 10-day gliomas. ECS parameters were altered with C6 glioma progression from increased ECM content. Our study might help better understand the glioma microenvironment and provide benefits for interstitial drug delivery to treat brain gliomas.

Background Diffuse myocardial fibrosis can be quantified by calculating extra-cellular volume (ECV) from native and post-contrast T1 values using dedicated single bolus contrast medium injection protocols. Purpose To evaluate differences in T1 maps and myocardial ECV measurements in routine stress/rest perfusion cardiovascular magnetic resonance (CMR) examinations after injection of single and double dose of contrast medium. Material and Methods Thirty-seven consecutive patients (30 men; mean age, 62 ± 13 years) underwent clinically indicated adenosine stress/rest perfusion CMR examination to rule out myocardial ischemia following a conventional split-dose contrast medium injection strategy. Native and post-contrast T1 mapping was performed 15 min after the first (0.1 mmol/kg) and second (0.1 mmol/kg) dose of contrast medium using a breath-held Modified Look-Locker Inversion recovery (MOLLI) sequence. Student's t-test for paired samples, Bland-Altman plots, and concordance-correlation coefficients (CCC) for agreement between T1 and ECV calculations after single and double dose of contrast medium were calculated. Intra- and inter-observer agreement for measurements was also analyzed. Results Myocardial T1 values after single and double dose of contrast medium significantly differed (mean difference of 114.1 ± 19.9 ms, P < 0.01). A single dose of contrast agent provided slightly higher ECV values (mean difference of 2.3 ± 1.1%). CCC for ECV calculations was 0.66. Intra- and inter-observer agreement for all measurements was excellent (CCC ≥ 0.83). Conclusion Quantification of myocardial ECV on conventional stress/rest perfusion CMR examination is feasible. T1 maps obtained 15 min after 0.1 mmol/kg of contrast medium provide slightly higher myocardial T1 measurements and ECV values compared with T1 maps obtained after a total dose of 0.2 mmol/kg.

Purpose: To compare MR hepatic fractional extracellular space (fECS) to liver stiffness (LS) with magnetic resonance elastography (MRE) for evaluation of liver fibrosis., Methods and Materials: 71 consecutive patients with suspected chronic liver disease underwent standard liver MRI with MR elastography and additional delayed Gd-DTPA-enhanced sequences at 5 and 10 min in order to calculate hepatic fECS (%) and LS (kilopascals, kPa). Two radiologists blinded to clinical history examined MR images and calculated fECS and LS in identical locations for every patient. Interobserver agreement was calculated using the intraclass correlation coefficient. Pearson's correlation was calculated for LS and fECS measures, as was the area under the receiver operatic curve (AUROC), sensitivity and specificity of fECS to predict liver stiffness ≥2.93 and ≥5 kPa. The sensitivity of fECS for detecting fibrosis was separately analyzed in the subgroup of patients without anatomic findings of cirrhosis., Results: Substantial to excellent interobserver agreement for both LS and fECS measurements was seen with intraclass correlation of 0.88 (95% CI 0.81-0.92) for LS, 0.77 (95% CI 0.66-0.85) for fECS 5 and 0.76 (95% CI 0.64-0.84) for fECS 10 . A significant correlation was found between MRE and fECS 5 (r = 0.47, p < 0.0001) and fECS 10 (r = 0.44, p < 0.0001). The performance of fECS improved for detection of advanced fibrosis (≥5 kPa) with AUROC, sensitivity and specificity of 0.72, 38%, and 94% for fECS 5 and 0.72, 67%, and 66% for fECS 10 ., Conclusion: fECS correlates modestly with MRE-determined LS. fECS at MRI is a simple calculation to perform and may represent a practical way to suggest the presence of fibrosis during routine liver evaluation., Competing Interests: There is no conflict of interest.

The extracellular space (ECS) in the brain provides an extrasynaptic transfer channel among neurons, axons and glial cells. It is particularly important in the early stage after birth, when angiogenesis is not yet complete and the ECS may provide the main pathway for metabolite transport. However, the characteristics of extracellular transport remain unclear. In this study, a novel magnetic resonance imaging (MRI) method was used to perform real-time visualization and quantification of diffusion in the brain ECS of infant (postnatal day 10 (P10)) and adult rats. Using a modified diffusion equation and the linear relationship between the signal intensity and the gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) concentration, diffusion parameters were obtained; these parameters include the effective diffusion coefficient (D*), clearance rate (k'), tortuosity (λ) and the volume fraction of distribution (Vd%). There were significant differences in the diffusion parameters between P10 and adult rats. This finding provides a reference for future treatment of brain diseases using drugs administered via interstitial pathways., (Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.)

Objectives: To quantify the barrier sterols and image the lipid structures in the matrix of acquired cholesteatoma and compare the distribution with that found in stratum corneum from normal skin, with the goal to resolve their potential influence on cholesteatoma growth., Methods: High-performance thin-layer chromatography (HPTLC) was used to achieve a quantitative biochemical determination of the sterols. The intercellular lipids were visualized by Coherent Anti-Stokes Raman scattering (CARS) microscopy, which enables label-free imaging of the lipids in intact tissue samples., Results: The results show that the total lipid content of the cholesteatoma matrix is similar to that of stratum corneum from skin and that the cholesteatoma matrix unquestionably contains cholesterol. The cholesterol content in the cholesteatoma matrix is increased by over 30% (w/w dry weight) compared to the control. The cholesterol sulfate content is below 1% of the total lipids in both the cholesteatoma and the control. Cholesterol ester was reduced by over 30% when compared to the control., Conclusions: The content of cholesterol in the cholesteatoma matrix is significantly different from that in stratum corneum from skin, and we confirm that the main structure of the cholesteatoma resembles very thick stratum corneum., (© The Author(s) 2016.)

Unlabelled: The natural history and pathophysiological significance of tissue remodeling in the myocardial remote zone after acute ST-elevation myocardial infarction (STEMI) is incompletely understood. Extracellular volume (ECV) in myocardial regions of interest can now be measured with cardiac magnetic resonance imaging. Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI [British Heart Foundation Magnetic Resonance Imaging in Acute ST-Segment Elevation Myocardial Infarction study]). Cardiac magnetic resonance was performed at 1.5 Tesla at 2 days and 6 months post STEMI. T1 modified Look-Locker inversion recovery mapping was performed before and 15 minutes after contrast (0.15 mmol/kg gadoterate meglumine) in 140 patients at 2 days post STEMI (mean age: 59 years, 76% male) and in 131 patients at 6 months post STEMI. Remote zone ECV was lower than infarct zone ECV (25.6±2.8% versus 51.4±8.9%; P<0.001). In multivariable regression, left ventricular ejection fraction was inversely associated with remote zone ECV (P<0.001), and diabetes mellitus was positively associated with remote zone ECV (P=0.010). No ST-segment resolution (P=0.034) and extent of ischemic area at risk (P<0.001) were multivariable associates of the change in remote zone ECV at 6 months (ΔECV). ΔECV was a multivariable associate of the change in left ventricular end-diastolic volume at 6 months (regression coefficient [95% confidence interval]: 1.43 (0.10-2.76); P=0.036). ΔECV is implicated in the pathophysiology of left ventricular remodeling post STEMI, but because the effect size is small, ΔECV has limited use as a clinical biomarker of remodeling., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02072850., (© 2016 The Authors.)

Background: Cardiac involvement determines outcome in patients with systemic amyloidosis. There is major unmet need for quantification of cardiac amyloid burden, which is currently only met in part through semi-quantitative bone scintigraphy or Cardiovascular Magnetic Resonance (CMR), which measures ECVCMR. Other accessible tests are needed., Objectives: To develop cardiac computed tomography to diagnose and quantify cardiac amyloidosis by measuring the myocardial Extracellular Volume, ECVCT., Methods: Twenty-six patients (21 male, 64 ± 14 years) with a biopsy-proven systemic amyloidosis (ATTR n = 18; AL n = 8) were compared with twenty-seven patients (19 male, 68 ± 8 years) with severe aortic stenosis (AS). All patients had undergone echocardiography, bone scintigraphy, NT-pro-BNP measurement and EQ-CMR. Dynamic Equilibrium CT (DynEQ-CT) was performed using a prospectively gated cardiac scan prior to and after (5 and 15 minutes) a standard Iodixanol (1 ml/kg) bolus to measure ECVCT. ECVCT was compared to the reference ECVCMR and conventional amyloid measures: bone scintigraphy and clinical markers of cardiac amyloid severity (NT-pro-BNP, Troponin, LVEF, LV mass, LA and RA area)., Results: ECVCT and ECVCMR results were well correlated (r(2) = 0.85 vs r(2) = 0.74 for 5 and 15 minutes post bolus respectively). ECVCT was higher in amyloidosis than AS (0.54 ± 0.11 vs 0.28 ± 0.04, p<0.001) with no overlap. ECVCT tracked clinical markers of cardiac amyloid severity (NT-pro-BNP, Troponin, LVEF, LV mass, LA and RA area), and bone scintigraphy amyloid burden (p<0.001)., Conclusion: Dynamic Equilibrium CT, a 5 minute contrast-enhanced gated cardiac CT, has potential for non-invasive diagnosis and quantification of cardiac amyloidosis., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Post-contrast T1 values are closely related to the degree of myocardial extracellular space expansion. We determined the relationship between post-contrast T1 values and left ventricular (LV) diastolic function, LV remodeling, and neurohormonal activation in patients with dilated cardiomyopathy (DCM)., Materials and Methods: Fifty-nine patients with DCM (mean age, 55 ± 15 years; 41 males and 18 females) who underwent both 1.5T magnetic resonance imaging and echocardiography were enrolled. The post-contrast 10-minute T1 value was generated from inversion time scout images obtained using the Look-Locker inversion recovery sequence and a curve-fitting algorithm. The T1 sample volume was obtained from three interventricular septal points, and the mean T1 value was used for analysis. The N-Terminal pro-B-type natriuretic peptide (NT-proBNP) level was measured in 40 patients., Results: The mean LV ejection fraction was 24 ± 9% and the post-T1 value was 254.5 ± 46.4 ms. The post-contrast T1 value was significantly correlated with systolic longitudinal septal velocity (s'), peak late diastolic velocity of the mitral annulus (a'), the diastolic elastance index (Ed, [E/e']/stroke volume), LV mass/volume ratio, LV end-diastolic wall stress, and LV end-systolic wall stress. In a multivariate analysis without NT-proBNP, T1 values were independently correlated with Ed (β = -0.351, p = 0.016) and the LV mass/volume ratio (β = 0.495, p = 0.001). When NT-proBNP was used in the analysis, NT-proBNP was independently correlated with the T1 values (β = -0.339, p = 0.017)., Conclusion: Post-contrast T1 is closely related to LV remodeling, diastolic function, and neurohormonal activation in patients with DCM.

Objective: The purpose of this study was to determine whether contrast-enhanced CT quantification of the hepatic fractional extracellular space (ECS) correlates with the severity of diffuse liver disease., Materials and Methods: The cases of 70 patients without (46 men, 24 women; mean age, 59.1 years) and 36 patients with (23 men, 13 women; mean age, 63.1 years) cirrhosis who had undergone unenhanced and 10-minute delayed phase contrast-enhanced CT were retrospectively identified. By consensus one experienced radiologist and one trainee measured the CT attenuation of the liver and aorta to estimate the fractional ECS, defined as the ratio of the difference between the attenuation of the liver on 10-minute and unenhanced images to the difference between the attenuation of the aorta on 10-minute and unenhanced images multiplied by 1 minus the hematocrit. Findings were correlated with each patient's Model of End-Stage Liver Disease (MELD) score., Results: The mean MELD score was higher in patients with than in those without cirrhosis (14.3 ± 7.3 versus 7.20 ± 2.4, p < 0.0001). The mean fractional ECS was significantly greater in patients with cirrhosis than in those without cirrhosis (41.0% ± 9.0% versus 23.8% ± 6.3%, p < 0.0001). The fractional ECS correlated with the MELD score (r = 0.572, p < 0.0001) and was predictive of cirrhosis with an area under the receiver operating characteristic curve of 0.953 (p < 0.0001). The sensitivity and specificity of an expanded fractional ECS greater than 30% for the prediction of cirrhosis were 92% and 83%. Multivariate linear regression revealed that the fractional ECS is complementary to the MELD score as a predictor of cirrhosis (p < 0.0001)., Conclusion: Noninvasive contrast-enhanced CT quantification of the fractional ECS correlates with the MELD score, an indicator of the severity of liver disease, and merits further study.

Purpose: Myocardial extracellular volume fraction (ECVF) is a surrogate imaging biomarker of diffuse myocardial fibrosis, a hallmark of pathologic ventricular remodeling. Low dose cardiac CT is emerging as a promising modality to detect diffuse interstitial myocardial fibrosis due to its fast acquisition and low radiation; however, the insufficient contrast in the low dose CT images poses great challenge to measure ECVF from the image., Methods: To deal with this difficulty, the authors present a complete ECVF measurement framework including a point-guided myocardial modeling, a deformable model-based myocardium segmentation, nonrigid registration of pre- and post-CT, and ECVF calculation., Results: The proposed method was evaluated on 20 patients by two observers. Compared to the manually delineated reference segmentations, the accuracy of our segmentation in terms of true positive volume fraction (TPVF), false positive volume fraction (FPVF), and average surface distance (ASD), were 92.18% ± 3.52%, 0.31% ± 0.10%, 0.69 ± 0.14 mm, respectively. The interobserver variability measured by concordance correlation coefficient regarding TPVF, FPVF, and ASD were 0.95, 0.90, 0.94, respectively, demonstrating excellent agreement. Bland-Altman method showed 95% limits of agreement between ECVF at CT and ECVF at MR., Conclusions: The proposed framework demonstrates its efficiency, accuracy, and noninvasiveness in ECVF measurement and dramatically advances the ECVF at cardiac CT toward its clinical use.

Purpose: In vitro it has been shown that the functional activity of P-glycoprotein (Pgp), an important drug transporter responsible for multidrug resistance, can be strongly increased by extracellular acidosis. Here mitogen-activated protein kinases (MAPK) (p38, ERK1/2) seem to play an important role for signal transduction. However, it is unclear whether these effects are also relevant in vivo., Methods: With the newly developed PET tracer Schiff base-based (68)Ga-MFL6.MZ the functional Pgp activity was visualized under acidic conditions and during inhibition of MAPKs non-invasively by means of microPET in rat tumours. Tumours were acidified either by inspiratory hypoxia (8% O(2)) or by injection of lactic acid. Inhibitors of the MAPK were injected intratumourally., Results: With increasing tumour volume the tumour pH changed from 7.0 to 6.7 and simultaneously the Pgp activity increased almost linearly. When the tumour was acidified by direct lactic acid injection the PET tracer uptake was reduced by 20% indicating a higher transport rate out of the cells. Changing the inspiratory O(2) fraction to 8% dynamically led to a reduction of extracellular pH and in parallel to a decrease of tracer concentration. While inhibition of the p38 pathway reduced the Pgp transport rate, inhibition of ERK1/2 had practically no impact., Conclusion: An acidic extracellular environment significantly stimulates the Pgp activity. The p38 MAPK pathway plays an important role for Pgp regulation in vivo, whereas ERK1/2 is of minor importance. From these results new strategies for overcoming multidrug resistance (e.g. reducing tumour acidosis, inhibition of p38) may be developed.

Diffusion in the extracellular space (ECS) of the brain is constrained by the volume fraction and the tortuosity and a modified diffusion equation represents the transport behavior of many molecules in the brain. Deviations from the equation reveal loss of molecules across the blood-brain barrier, through cellular uptake, binding, or other mechanisms. Early diffusion measurements used radiolabeled sucrose and other tracers. Presently, the real-time iontophoresis (RTI) method is employed for small ions and the integrative optical imaging (IOI) method for fluorescent macromolecules, including dextrans or proteins. Theoretical models and simulations of the ECS have explored the influence of ECS geometry, effects of dead-space microdomains, extracellular matrix, and interaction of macromolecules with ECS channels. Extensive experimental studies with the RTI method employing the cation tetramethylammonium (TMA) in normal brain tissue show that the volume fraction of the ECS typically is approximately 20% and the tortuosity is approximately 1.6 (i.e., free diffusion coefficient of TMA is reduced by 2.6), although there are regional variations. These parameters change during development and aging. Diffusion properties have been characterized in several interventions, including brain stimulation, osmotic challenge, and knockout of extracellular matrix components. Measurements have also been made during ischemia, in models of Alzheimer's and Parkinson's diseases, and in human gliomas. Overall, these studies improve our conception of ECS structure and the roles of glia and extracellular matrix in modulating the ECS microenvironment. Knowledge of ECS diffusion properties is valuable in contexts ranging from understanding extrasynaptic volume transmission to the development of paradigms for drug delivery to the brain.

FDG-PET is used to measure the metabolic rate of glucose. Transport and phosphorylation determine the amount of hexose analog that is phosphorylated and trapped. Competition occurs for both events, such that extracellular glucose concentration affects the FDG image. This study investigated the effect of glucose concentration on the rate of FDG accumulation in three cell lines. The results show that extracellular glucose concentration has a greater impact on the rate of FDG accumulation than the relative abundance of GLUT transporter subtypes.

Objectives: It has recently been established that patients with nonerosive reflux disease have on biopsy within esophageal epithelium a lesion known as dilated intercellular spaces (DIS)., Methods: To further explore the nature and implications of this lesion, in vitro models of nonerosive acid and acid-pepsin damage were created in Ussing chamber-mounted rabbit esophageal epithelium. Using these models circuit analysis and permeability studies were carried out, the latter using dextran of varying size and human epidermal growth factor (EGF)., Results: Luminal HCl, pH 1.1, or HCl, pH 2.0 + pepsin, 1 mg/ml, for 30 min significantly reduced transepithelial electrical resistance (RT) but produced no gross erosions or histologic evidence of cell necrosis. Transmission electron microscopy, however, documented the presence of DIS. Circuit analysis on healthy esophageal epithelium showed that shunt resistance (RS) was much lower than apical membrane, basolateral membrane and transcellular resistances (Ra, Rb, and Rcell, respectively) and approached that of RT. Further, circuit analysis on acid and acid-pepsin damaged tissues showed that the declines in RT resulted from declines in RS. Moreover, the declines in RT (and so RS) were associated with a linear increase in permeability to 4 kD dextrans as well as an increase in permeability to 6 kD EGF and dextrans as large as 20 kD., Conclusions: In nonerosive acid-damaged esophageal epithelium DIS develop in association with and as a marker of reduced transepithelial resistance and increased shunt permeability. This change in shunt permeability upon acid or acid-pepsin exposure is substantial, permitting dextran molecules as large as 20 kD (33 A) to diffuse across the epithelium. Also, this shunt leak enables luminal EGF at 6 kD to diffuse across the acid-damaged epithelium and by so doing enables it to access its receptors on epithelial basal cells. We hypothesize that the shunt leak of EGF may in part account for the development of a reparative phenomenon on esophageal biopsy in patients with nonerosive reflux disease known as basal cell hyperplasia.

Unlabelled: Brain edema significantly contributes to the clinical course of human brain tumor patients. There is evidence that an enlargement of the extracellular space (ECS) is involved in the development of brain edema. Although T2-weighted magnetic resonance (T2-MR) images represent brain edema by its increased water content, they do not differentiate ECS enlargement from increased intracellular water content., Methods: On the basis of the known distribution of bromide in the ECS, we used (76)Br-bromide and PET to measure the regional ECS in 9 brain tumor patients. Transport rate constants and the distribution volume (DV) of (76)Br-bromide in normal brain and tumor were derived from dynamic PET scans and the measured (76)Br-bromide concentration in arterial plasma. We evaluated different models regarding their reliability in estimating the ECS., Results: Assuming that the DV of (76)Br-bromide represents the ECS, robust estimates were possible for all investigated regions. In normal brain, ECS was within a narrow range-for example, occipital lobe, 19.9% +/- 3.1%-and was lower in 2 dexamethasone-treated patients compared with untreated patients. In 7 of 9 tumors, increased ECS ranged between 43.8% and 61.1%. ECS increases were confined to the tumor mass and did not extend into peritumoral edematous brain. Two patients with large hyperintense lesions according to T2-MR images showed normal ECS values within the lesion., Conclusion: (76)Br-Bromide PET allows a quantitative measurement of the ECS in brain edema and in normal brain. The discrepancies between lesions shown by T2-MRI and regional ECS enlargement as measured with PET challenge the concept of tumor-induced brain edema.

Epidural mass lesions may cause ischemia due to progressive intracranial hypertension. In order to investigate the impact of intracranial pressure on accumulation of neuroactive substances, we gradually raised intracranial pressure in five halothane anesthetized cats by inflation of an epidural balloon. We evaluated in the parietal cortex contralateral to the site of balloon inflation, alterations of extracellular glutamate and purine catabolites and of the lactate/pyruvate ratio in relation to changes of intracranial, cerebral perfusion and mean arterial blood pressure. In a complementary experiment, regional cerebral blood flow was assessed by sequential positron emission tomography. In this simplified mass lesion model, extracellular glutamate increased in all cats at a late, critical stage after tentorial herniation, when intracranial pressure had increased to more than 90 mm Hg, cerebral perfusion pressure had decreased below 40-50 mm Hg. Positron emission tomography assessments revealed that the ischemic threshold for glutamate accumulation was in the range of 15-20 mL/100 g/min. Purine catabolites and the lactate/pyruvate ratio increased somewhat earlier than glutamate, but also after reaching the critical, terminal stage. We conclude that in this model of progressive epidural compression, glutamate-mediated excitotoxic processes at sites remote from the initial focal lesion depend on processes such as delayed ischemia in combination with tentorial herniation and systemic hypotension. These processes seem to be initiated by a decrease of cerebral perfusion pressure below a threshold of 40-50 mm Hg.

Objective: To evaluate interstitial glycerol as a marker of ischaemia by studying the changes in glycerol in direct relation to changes in regional cerebral metabolic rate of oxygen (CMRO(2)), the lactate/pyruvate ratio (LP ratio), and glutamate., Methods: Transorbital 2 hour middle cerebral artery occlusion (MCAO) was performed in eight monkeys, which were studied with continuous microdialysis for 24 hours. Interstitial fluids were collected by microdialysis and analysed for glycerol, lactate, pyruvate, and glutamate with an enzymatic assay and high performance liquid chromatography. Sequential PET studies of cerebral blood flow (CBF), CMRO(2), oxygen extraction ratio (OER), and cerebral blood volume (CBV) were performed. The microdialysis probe regions were classified as severe ischaemia or penumbra, depending on whether the mean CMRO(2) side to side ratio was below or above 60%, respectively., Results: A nine-fold, sustained increase in glycerol was registered after MCAO in severe ischaemia regions. In penumbra regions, the increase in glycerol was five-fold, but the glycerol concentration returned to baseline within 8 hours of clip removal. The difference between severe ischaemia and penumbra glycerol values was statistically significant. As expected from previous studies, the interstitial LP ratio and glutamate increased markedly in severe ischaemia, with a less pronounced change in penumbra regions. There was a time lag between the biochemical changes in severe ischaemia regions, with the LP ratio preceding glutamate, followed by glycerol., Conclusions: A marked, sustained increase in interstitial glycerol is indicative of severe ischaemia in this stroke model. A transient, diminutive increase in interstitial glycerol may reflect a penumbra situation. Interstitial glycerol in combination with other biochemical markers such as the LP ratio and glutamate may be useful for clinical monitoring of the ischaemic brain, reflecting a sequence of secondary pathophysiological events.

The transdermal extraction of interstitial fluid by low-frequency ultrasound offers a potential minimally invasive method of obtaining a fluid sample for at-home blood glucose monitoring. Here we show that the application of low-frequency ultrasound (20 kHz) enhances the transdermal transport of interstitial fluid across hairless rat skin. Using 3H2O as a tracer injected intravenously, a measurable amount of water (>1 microL) was extracted without producing any histologic evidence of injury, even after repeated exposures. Piezoelectric transducers were imbedded in the extraction chamber and used to correlate ultrasound spectral properties to the amount of fluid extracted. Results indicate that the highest amount of water extracted occurs when the acoustic coupling media on the surface of the skin is cavitating, resulting in mild ablation of the stratum corneum and a reduction in its resistance to water mass transfer.

Purpose: Many mammographic and sonographic features of breast abscess overlap with those of carcinoma. We reviewed the usefulness of interstitial fluid and hypoechoic walls in the sonographic diagnosis of breast abscess., Methods: The sonograms and records of 65 patients with breast infection and 60 contemporaneous patients with breast cancer were retrospectively reviewed., Results: Of 49 abscesses identified in patients with breast infection, 14 (29%) had adjacent interstitial fluid that was sonographically visible, and 15 (31%) had a hypoechoic wall. No patients with breast cancer had either sign. The overall sensitivity of the presence of either sign was 55%, and the specificity was 100%., Conclusions: Two sonographic findings, interstitial fluid and a hypoechoic wall, are relatively specific for breast abscess and may aid in the diagnosis of breast disease., (Copyright 2000 John Wiley & Sons, Inc.)

Elastic arteries consist of three primary components: elastin fibers, extracellular collagen matrix and smooth muscle cells. However, the relative contribution of elastin and collagen fibers to overall ultrasonic scattering from an intact arterial wall is poorly understood. To define the principal source of extracellular scattering from the medial layer of elastic arteries, canine ascending aortas (n = 10) were excised, fixed and sectioned for insonification. Subsequently, aortic specimens were restudied after treatment to dissolve all tissue components except extracellular collagen matrix (n = 5) and elastin fibers (n = 5). Histological staining revealed very few elastin fibers and sparse intact collagen in collagen-isolated and elastin-isolated tissues, respectively. Integrated backscatter, attenuation and backscatter coefficients differentiated these two treated tissues. The backscatter coefficient for elastin-isolated tissue demonstrated a fivefold increase over collagen-isolated tissue, suggesting that elastin fibers represent a primary scattering component within elastic arteries, and the collagen fibers may provide a secondary component of scattering.

Objective: To determine the relative distribution of fluid within the extracellular fluid volume (ECFV) after infusing either normal saline or 5% albumin in septic, critically ill patients., Design: Prospective, randomized, unblinded, interventional study., Setting: Intensive care unit in a 450-bed, tertiary care, teaching hospital., Patients: Septic, critically ill patients (n = 18)., Interventions: Infusion of either normal saline or 5% albumin to a hemodynamic end point determined by the patient's clinician., Measurements and Main Results: Plasma volume (PV), ECFV, cardiac index, and arterial oxygen content were measured immediately before (baseline) and after each fluid infusion. PV and ECFV were measured by dilution of 131I-albumin and 35S sodium sulfate, respectively. Interstitial fluid volume (ISFV) was calculated as ECFV - PV. Baseline values for PV, ISFV, ECFV, and oxygen delivery index did not differ between treatment groups. Infusion of normal saline increased the ECFV by approximately the volume infused, and the expansion of the PV to ISFV was in a ratio of 1:3. Infusion of 5% albumin increased the ECFV by double the volume infused, with both the PV and ISFV expanding by approximately equal amounts. Oxygen delivery index did not increase after either infusion due to the effect of hemodilution., Conclusion: Expansion of the ECFV in excess of the volume of 5% albumin infused suggests that fluid may move from the intracellular fluid volume to the ECFV in septic patients who receive this fluid.