Brain white matter extracellular free-water increases are related to reduced neurocognitive function in systemic lupus erythematosus.

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.

Compartmental diffusion and microstructural properties of human brain gray and white matter studied with double diffusion encoding magnetic resonance spectroscopy of metabolites and water.

Double diffusion encoding (DDE) of the water signal offers a unique ability to separate the effect of microscopic anisotropic diffusion in structural units of tissue from the overall macroscopic orientational distribution of cells. However, the specificity in detected microscopic anisotropy is limited as the signal is averaged over different cell types and across tissue compartments. Performing side-by-side water and metabolite DDE spectroscopic (DDES) experiments provides complementary measures from which intracellular and extracellular microscopic fractional anisotropies (µFA) and diffusivities can be estimated. Metabolites are largely confined to the intracellular space and therefore provide a benchmark for intracellular µFA and diffusivities of specific cell types. By contrast, water DDES measurements allow examination of the separate contributions to water µFA and diffusivity from the intra- and extracellular spaces, by using a wide range of b values to gradually eliminate the extracellular contribution. Here, we aimed to estimate tissue and compartment specific human brain microstructure by combining water and metabolites DDES experiments. We performed our DDES measurements in two brain regions that contain widely different amounts of white matter (WM) and gray matter (GM): parietal white matter (PWM) and occipital gray matter (OGM) in a total of 20 healthy volunteers at 7 Tesla. Metabolite DDES measurements were performed at b = 7199 s/mm2, while water DDES measurements were performed with a range of b values from 918 to 7199 s/mm2. The experimental framework we employed here resulted in a set of insights pertaining to the morphology of the intracellular and extracellular spaces in both gray and white matter. Results of the metabolite DDES experiments in both PWM and OGM suggest a highly anisotropic intracellular space within neurons and glia, with the possible exception of gray matter glia. The water µFA obtained from the DDES results at high b values in both regions converged with that of the metabolite DDES, suggesting that the signal from the extracellular space is indeed effectively suppressed at the highest b value. The µFA measured in the OGM significantly decreased at lower b values, suggesting a considerably lower anisotropy of the extracellular space in GM compared to WM. In PWM, the water µFA remained high even at the lowest b value, indicating a high degree of organization in the interstitial space in WM. Tortuosity values in the cytoplasm for water and tNAA, obtained with correlation analysis of microscopic parallel diffusivity with respect to GM/WM tissue fraction in the volume of interest, are remarkably similar for both molecules, while exhibiting a clear difference between gray and white matter, suggesting a more crowded cytoplasm and more complex cytomorphology of neuronal cell bodies and dendrites in GM than those found in long-range axons in WM.

Recent advances in fluorescent probes for extracellular pH detection and imaging.

Extracellular pH plays vital roles in physiological and pathological processes including tumor metastasis and chemotherapy resistance. Abnormal extracellular pH is known to be associated with various pathological states, such as those in tumors, ischemic stroke, infection, and inflammation. Specifically, dysregulated pH is regarded as a hallmark of cancer because enhanced glycolysis and poor perfusion in most solid malignant tumors create an acidic extracellular environment, which enhances tumor growth, invasion, and metastasis. Close connection between the cell functions with extracellular pH means that precise and real-time measurement of the dynamic change of extracellular pH can provide critical information for not only studying physiological and pathological processes but also diagnosis of cancer and other diseases. This review highlights the recent development of based fluorescent probes for extracellular pH measurement, including design strategies, reaction mechanism and applications for the detection and imaging of extracellular pH.

Nanoscale exploration of the extracellular space in the live brain by combining single carbon nanotube tracking and super-resolution imaging analysis.

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.

Dual-energy CT quantification of fractional extracellular space in cirrhotic patients: comparison between early and delayed equilibrium phases and correlation with oesophageal varices.

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.

Increased extracellular free-water in adult male rats following in utero exposure to maternal immune activation.

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 (FAT), 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 FAT 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.

MRI profiling of focal cortical dysplasia using multi-compartment diffusion models.

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.

Extracellular volume fraction determined by equilibrium contrast-enhanced dual-energy CT as a prognostic factor in patients with stage IV pancreatic ductal adenocarcinoma.

OBJECTIVES: To evaluate the feasibility of equilibrium contrast-enhanced dual-energy CT (DECT), as compared with single-energy CT (SECT) and to calculate extracellular volume (ECV) fraction to predict the survival outcomes of pancreatic ductal adenocarcinoma (PDAC) patients with distant metastases (stage IV) treated with chemotherapy. METHODS: The study cohort included a total of 66 patients with stage IV PDAC who underwent DECT before systemic chemotherapy between July 2014 and March 2017. Unenhanced and 120-kVp equivalent images during the equilibrium phase were used to calculate tumor SECT-derived ECV fractions, and iodine density images were obtained from equilibrium-phase DECT for DECT-derived ECV fractions. Correlations between SECT- and DECT-derived ECV fractions were identified using the Pearson correlation coefficient and Bland-Altman analysis. The effects of clinical prognostic factors and tumor SECT- and DECT-derived ECV fractions on progression-free survival (PFS) and overall survival (OS) were assessed by univariate and multivariate analyses using Cox proportional hazards models. RESULTS: The correlation between SECT- and DECT-derived ECV fractions was strong (r = 0.965; p < 0.001). The Bland-Altman plot between SECT- and DECT-derived ECV fractions showed a small bias (- 3.4%). Increasing tumor SECT- and DECT-derived ECV fractions were associated with a positive effect on PFS (SECT, p = 0.002; DECT, p = 0.007) and OS (DECT, p = 0.014; DECT, p = 0.015). Only tumor DECT-derived ECV fraction was an independent predictor of PFS (p = 0.018) and OS (p = 0.022) in patients with stage IV PDAC treated with chemotherapy on multivariate analysis. CONCLUSIONS: The ECV fraction determined by equilibrium contrast-enhanced DECT can potentially predict the survival of patients with stage IV PDAC treated with chemotherapy. KEY POINTS: • Extracellular volume fraction of stage IV pancreatic ductal adenocarcinoma determined by dual-energy CT was strongly correlated to that with single-energy CT (r = 0.965, p < 0.001). • Tumor extracellular volume fraction was an independent predictor of progression-free survival (p = 0.018) and overall survival (p = 0.022). • Extracellular volume fraction determined by dual-energy CT could be a useful imaging biomarker to predict the survival of patients with stage IV pancreatic ductal adenocarcinoma treated with chemotherapy.

Quantification of liver extracellular volume using dual-energy CT: utility for prediction of liver-related events in cirrhosis.

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.

Estimation of Fractional Extracellular Space at CT for Predicting Chemotherapy Response and Survival in Pancreatic Ductal Adenocarcinoma.

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.

The Effect of Thymoquinone on the Characteristics of the Brain Extracellular Space in Transient Middle Cerebral Artery Occlusion Rats.

The extracellular space (ECS) is the space between the neurons and the capillaries in the brain. The volume fraction (α) and the tortuosity (λ) are the main parameters used to describe its characteristics. Thymoquinone has been proved to possess anti-oxidant and anti-inflammatory activity. In this study, we used a gadolinium-diethylenetriaminepentacetate (Gd-DTPA)-enhanced magnetic resonance imaging (MRI) system to determine the effects of thymoquinone on ECS parameters in transient middle cerebral artery occlusion rats (tMCAO) to prove the neuroprotective effect of thymoquinone on brain tissue damage caused by ischemic stroke. Neurological examinations, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (H&E) staining and assaying of ECS parameters using MRI were performed 24 h after surgery. We found that thymoquinone could improve the behavioural performance by neurological examinations. TTC staining indicated that thymoquinone significantly decreased the percentage of hemi-cerebral infarction. Also, H&E staining showed that thymoquinone could inhibit the neuron necrosis in the hippocampal CA1 region. We found that thymoquinone treatment could inhibit the changes in ECS diffusion parameters, which might prove that thymoquinone might protect brain tissue damage caused by ischemic stroke. Thymoquinone can protect the brain against cerebral ischemia-reperfusion injury, effectively ameliorate abnormalities in characteristics of ECS and decrease cerebral infarction in tMCAO rats.

Dual-source dual-energy CT in the evaluation of hepatic fractional extracellular space in cirrhosis.

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.

Dynamic contrast-enhanced MRI in oncology: how we do it.

Magnetic resonance imaging (MRI) is particularly attractive for clinical application in perfusion imaging thanks to the absence of ionizing radiation and limited volumes of contrast agent (CA) necessary. Dynamic contrast-enhanced MRI (DCE-MRI) involves sequentially acquiring T1-weighted images through an organ of interest during the passage of a bolus administration of CA. It is a particularly flexible approach to perfusion imaging as the signal intensity time course allows not only rapid qualitative assessment, but also quantitative measures of intrinsic perfusion and permeability parameters. We examine aspects of the T1-weighted image series acquisition, CA administration, post-processing that constitute a DCE-MRI study in clinical practice, before considering some heuristics that may aid in interpreting the resulting contrast enhancement time series. While qualitative DCE-MRI has a well-established role in the diagnostic assessment of a range of tumours, and a central role in MR mammography, clinical use of quantitative DCE-MRI remains limited outside of clinical trials. The recent publication of proposals for standardized acquisition and analysis protocols for DCE-MRI by the Quantitative Imaging Biomarker Alliance may be an opportunity to consolidate and advance clinical practice.

Greater extracellular free-water in first-episode psychosis predicts better neurocognitive functioning.

Free Water Imaging is a novel diffusion magnetic resonance (MR) imaging method that is able to separate changes affecting the extracellular space from those that reflect changes in neuronal cells and processes. A previous Free Water Imaging study in schizophrenia identified significantly greater extracellular water volume in the early stages of the disorder; however, its clinical and functional sequelae have not yet been investigated. Here, we applied Free Water Imaging to a larger cohort of 63 first-episode patients with psychosis and 70 healthy matched controls to better understand the functional significance of greater extracellular water. We used diffusion MR imaging data and the Tract-Based Spatial Statistics analytic pipeline to first analyze fractional anisotropy (FA), the most commonly employed metric for assessing white matter. This comparison was then followed by Free Water Imaging analysis, where two parameters, the fractional volume of extracellular free-water (FW) and cellular tissue FA (FA-t), were estimated and compared across the entire white matter skeleton between groups, and correlated with cognitive measures at baseline and following 12 weeks of antipsychotic treatment. Our results indicated lower FA across the whole brain in patients compared with healthy controls that overlap with significant increases in FW, with only limited decreases in FA-t. In addition, higher FW correlated with better neurocognitive functioning following 12 weeks of antipsychotic treatment. We believe this is the first study to suggest that an extracellular water increase during the first-episode of psychosis, which may be indicative of an acute neuroinflammatory process, and/or cerebral edema may predict better functional outcome.

Point estimate and reference normality interval of MRI-derived myocardial extracellular volume in healthy subjects: a systematic review and meta-analysis.

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/m2, and left ventricular ejection fraction 58-74%. Contrast dose varied from 0.075 to 0.200 mmol/kg. Heterogeneity was high (I2 = 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 (ß = 0.03%, p = 0.038) and slightly decreasing with the percentage of males (ß = - 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.

Extracellular volume fraction determined by equilibrium contrast-enhanced multidetector computed tomography as a prognostic factor in unresectable pancreatic adenocarcinoma treated with chemotherapy.

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.

MR extracellular volume mapping and non-contrast T1ρ mapping allow early detection of myocardial fibrosis in diabetic monkeys.

OBJECTIVE: To detect diffuse myocardial fibrosis in different severity levels of left ventricular diastolic dysfunction (DD) in spontaneous type 2 diabetes mellitus (T2DM) rhesus monkeys. METHODS: Eighteen spontaneous T2DM and nine healthy monkeys were studied. Echocardiography was performed for diastolic function classification. Cardiac magnetic resonance (CMR) imaging was performed to obtain extracellular volume fraction (ECV) maps and T1ρ maps at two different spin-locking frequencies. ECV values, T1ρ values, and myocardial fibrosis index (mFI) values which are based on the dispersion of T1ρ, were calculated. Global peak diastolic longitudinal strain rates (GSrL) were also obtained. RESULTS: Echocardiography results showed mild DD in nine T2DM monkeys and moderate DD in the other nine. The global ECV values were significantly different among healthy animals as compared with animals with mild DD or moderate DD, and the ECV values of animals with moderate DD were significantly higher as compared with those of mild DD. The mFI values increased progressively from healthy animals to those with mild DD and then to those with moderate DD. Diastolic function indicators (e.g., early diastolic mitral annulus velocity, GSrL) correlated well with ECV and mFI. CONCLUSIONS: Monkeys with T2DM exhibit increased ECV, T1ρ, and mFI values, which may be indicative of the expansion of extracellular volume and the deposition of excessive collagen. T1ρ mapping may have the potential to be used for diffuse myocardial fibrosis assessment. KEY POINTS: • Monkeys with T2DM exhibit increased ECV, T1ρ, and mFI values, which may be indicative of the expansion of extracellular volume and the deposition of excessive collagen. • The relationship between diastolic dysfunction and diffuse myocardial fibrosis may be demonstrated by imaging markers. • Non-contrast T1ρ mapping may have the potential to be used for diffuse myocardial assessment.

A deficiency of the link protein Bral2 affects the size of the extracellular space in the thalamus of aged mice.

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 (ADCW ) 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 ADCW 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.

Patients with chronic bipolar disorder exhibit widespread increases in extracellular free water.

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.

Extracellular volume fraction assessed using cardiovascular magnetic resonance can predict improvement in left ventricular ejection fraction in patients with dilated cardiomyopathy.

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.