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.

Early changes to the extracellular space in the hippocampus under simulated microgravity conditions.

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 DECS-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.

Relation of Serum Albumin Levels to Myocardial Extracellular Volume in Patients With Severe Aortic Stenosis.

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.

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.

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.

The Spatial Distribution of Water Components with Similar T2 May Provide Insight into Pathways for Large Molecule Transportation in the Brain.

PURPOSE: Although there is no lymphatic system in the central nervous system (CNS), there seems to be a mechanism to remove macro molecules from the brain. Cerebrospinal fluid (CSF) and interstitial fluid (ISF) are thought to be parts of this pathway, but the details are not known. In this study, MR signal of the extracellular water was decomposed into components with distinct T2's, to obtain some information about distribution of waste material in the brain. METHODS: Images were acquired using a Curr, Purcell, Meiboom, Gill (CPMG) imaging sequence. In order to reduce T1 contamination and the signal oscillation, hard pulses were used as refocusing pulses. The signal was then decomposed into many T2 components using non-negative least squares (NNLS) in pixel-by-pixel basis. Finally, a color map was generated by assigning different color for each T2 component, then adding them together. RESULTS: From the multi-echo images, it was possible to decompose the decaying signal into separate T2 components. By adjusting the color table to create the color map, it is possible to visualize the extracellular water distribution, as well as their T2 values. Several observation points include: (1) CSF inside ventricles has very long T2 (~2 s), and seems to be relatively homogeneous, (2) subarachnoid CSF also have long T2, but there are short T2 component at the brain surface, at the surface of dura, at the blood vessels in the subarachnoid space, etc., (3) in the brain parenchyma, short T2 components (longer than intracellular component but shorter than CSF) exists along the white matter, in the choroid plexus, etc. These can be considered as distribution of macromolecules (waste materials) in the brain. CONCLUSION: From T2 component analysis it is possible to obtain some insight into pathways for the transport of large molecules in the CNS, where no lymphatic system is present.

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.

Myocardial Tissue Reverse Remodeling After Guideline-Directed Medical Therapy in Idiopathic Dilated Cardiomyopathy.

BACKGROUND: The prognosis of patients with idiopathic dilated cardiomyopathy (DCM) has improved remarkably in recent decades with guideline-directed medical therapy. Left ventricular (LV) reverse remodeling (LVRR) is one of the major therapeutic goals. Whether myocardial fibrosis or inflammation would reverse associated with LVRR remains unknown. METHODS: A total of 157 prospectively enrolled patients with DCM underwent baseline and follow-up cardiovascular magnetic resonance examinations with a median interval of 13.7 months (interquartile range, 12.2-18.5 months). LVRR was defined as an absolute increase in LV ejection fraction of >10% to the final value of ≥35% and a relative decrease in LV end-diastolic volume of >10%. Statistical analyses were performed using paired t test and student t test, logistic regression analysis, and linear regression analysis. RESULTS: Forty-eight (31%) patients reached LVRR. At baseline, younger age, worse New York Heart Association class, new-onset heart failure, lower LV ejection fraction, absence of late gadolinium enhancement, lower myocardial T2, and extracellular volume were significant predictors of LVRR. During the follow-up, patients with and without LVRR both showed a significant decrease of myocardial native T1 (LVRR: [baseline] 1303.0±43.6 ms; [follow-up] 1244.7±51.8 ms; without LVRR: [baseline] 1308.5±80.5 ms; [follow-up] 1287.6±74.9 ms, both P<0.001), matrix and cellular volumes while no significant difference was observed in T2 or extracellular volume values after treatment. CONCLUSIONS: In patients with idiopathic DCM, the absence of late gadolinium enhancement, lower T2, and extracellular volume values at baseline are significant predictors of LVRR. The myocardial T1, matrix, and cell volume decrease significantly in patients with LVRR after guideline-directed medical therapy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: ChiCTR1800017058.

Design and evaluation of an abbreviated pixelwise dynamic contrast enhancement analysis protocol for early extracellular volume fraction estimation.

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 (ECVETM). Estimated ECVETM maps were compared to standard T1-based ECV maps (ECVT1) 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 ECVETM, and ECVT1 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.

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.

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.

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.

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.

Extracellular electrical conductivity property imaging by decomposition of high-frequency conductivity at Larmor-frequency using multi-b-value diffusion-weighted imaging.

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.

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.

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.

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.

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.

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.