Correspondence between development of cytotoxic edema and cerebrospinal fluid volume and flow in the third ventricle after ischemic stroke.

OBJECTIVES: The importance of monitoring cerebrospinal fluid for the development of edema in ischemic stroke has been emphasized; however, studies on the relationship between intraventricular cerebrospinal fluid behavior and edema through longitudinal observations and analysis are rare. This study aimed to investigate the correlation between the development of cytotoxic edema and cerebrospinal fluid volume and flow in the third ventricle after ischemic stroke. MATERIALS AND METHODS: The ventricle and edema regions were obtained using apparent diffusion coefficients and T2 and subdivided into lateral/ventral 3rd ventricles and cytotoxic/vasogenic (or cyst) edema, respectively. In rat models of ischemic stroke, the volume and flow (via the pseudo-diffusion coefficient [D*]) of the ventricles and edema volumes were longitudinally monitored for up to 45 days after surgery. RESULTS: The volume of cytotoxic edema increased in the hyperacute and acute phases, whereas the volume (r = -0.49) and median D* values (r = -0.48 in the anterior-posterior direction) of the ventral 3rd ventricle both decreased, showing negative correlations with the volume of cytotoxic edema. In contrast, the volume of vasogenic edema/cyst was positively correlated with the volume (r = 0.73) and median D* values (r = 0.78 in the anterior-posterior direction) of the lateral ventricle in the subacute and chronic phases. CONCLUSIONS: This study showed that the evolution of cerebrospinal fluid volume and flow in the ventricles was associated with edema progression at different time points in the ischemic stroke brain. This provides an efficient framework for monitoring and quantifying the interplay between cerebrospinal fluid and edema.

Improved laminar specificity and sensitivity by combining SE and GE BOLD signals.

The most widely used gradient-echo (GE) blood oxygenation level-dependent (BOLD) contrast has high sensitivity, but low specificity due to draining vein contributions, while spin-echo (SE) BOLD approach at ultra-high magnetic fields is highly specific to neural active sites but has lower sensitivity. To obtain high specificity and sensitivity, we propose to utilize a vessel-size-sensitive filter to the GE-BOLD signal, which suppresses macrovascular contributions and to combine selectively retained microvascular GE-BOLD signals with the SE-BOLD signals. To investigate our proposed idea, fMRI with 0.8 mm isotropic resolution was performed on the primary motor and sensory cortices in humans at 7 T by implementing spin- and gradient-echo (SAGE) echo planar imaging (EPI) acquisition. Microvascular-passed sigmoidal filters were designed based upon the vessel-size-sensitive ΔR2*/ΔR2 value for retaining GE-BOLD signals originating from venous vessels with ≤ 45 µm and ≤ 65 µm diameter. Unlike GE-BOLD fMRI, the laminar profile of SAGE-BOLD fMRI with the vessel-size-sensitive filter peaked at ∼ 1.0 mm from the surface of the primary motor and sensory cortices, demonstrating an improvement of laminar specificity over GE-BOLD fMRI. Also, the functional sensitivity of SAGE BOLD at middle layers (0.75-1.5 mm) was improved by ∼ 80% to ∼100% when compared with SE BOLD. In summary, we showed that combined GE- and SE-BOLD fMRI with the vessel-size-sensitive filter indeed yielded improved laminar specificity and sensitivity and is therefore an excellent tool for high spatial resolution ultra-high filed (UHF)-fMRI studies for resolving mesoscopic functional units.

Automated volumetric determination of high R2 * regions in substantia nigra: A feasibility study of quantifying substantia nigra atrophy in progressive supranuclear palsy.

The establishment of an unbiased protocol for the automated volumetric measurement of iron-rich regions in the substantia nigra (SN) is clinically important for diagnosing neurodegenerative diseases exhibiting midbrain atrophy, such as progressive supranuclear palsy (PSP). This study aimed to automatically quantify the volume and surface properties of the iron-rich 3D regions in the SN using the quantitative MRI-R2 * map. Three hundred and sixty-seven slices of R2 * map and susceptibility-weighted imaging (SWI) at 3-T MRI from healthy control (HC) individuals and Parkinson's disease (PD) patients were used to train customized U-net++ convolutional neural network based on expert-segmented masks. Age- and sex-matched participants were selected from HC, PD, and PSP groups to automate the volumetric determination of iron-rich areas in the SN. Dice similarity coefficient values between expert-segmented and detected masks from the proposed network were 0.91 ± 0.07 for R2 * maps and 0.89 ± 0.08 for SWI. Reductions in iron-rich SN volume from the R2 * map (SWI) were observed in PSP with area under the receiver operating characteristic curve values of 0.96 (0.89) and 0.98 (0.92) compared with HC and PD, respectively. The mean curvature of the PSP showed SN deformation along the side closer to the red nucleus. We demonstrated the automated volumetric measurement of iron-rich regions in the SN using deep learning can quantify the SN atrophy in PSP compared with PD and HC.

Efficient Segmentation for Left Atrium With Convolution Neural Network Based on Active Learning in Late Gadolinium Enhancement Magnetic Resonance Imaging.

BACKGROUND: To propose fully automatic segmentation of left atrium using active learning with limited dataset in late gadolinium enhancement in cardiac magnetic resonance imaging (LGE-CMRI). METHODS: An active learning framework was developed to segment the left atrium in cardiac LGE-CMRI. Patients (n = 98) with atrial fibrillation from the Korea University Anam Hospital were enrolled. First, 20 cases were delineated for ground truths by two experts and used for training a draft model. Second, the 20 cases from the first step and 50 new cases, corrected in a human-in-the-loop manner after predicting using the draft model, were used to train the next model; all 98 cases (70 cases from the second step and 28 new cases) were trained. An additional 20 LGE-CMRI were evaluated in each step. RESULTS: The Dice coefficients for the three steps were 0.85 ± 0.06, 0.89 ± 0.02, and 0.90 ± 0.02, respectively. The biases (95% confidence interval) in the Bland-Altman plots of each step were 6.36% (-14.90-27.61), 6.21% (-9.62-22.03), and 2.68% (-8.57-13.93). Deep active learning-based annotation times were 218 ± 31 seconds, 36.70 ± 18 seconds, and 36.56 ± 15 seconds, respectively. CONCLUSION: Deep active learning reduced annotation time and enabled efficient training on limited LGE-CMRI.

Improvement of sensitivity and specificity for laminar BOLD fMRI with double spin-echo EPI in humans at 7 T.

Mapping mesoscopic cortical functional units such as columns or laminae is increasingly pursued by ultra-high field (UHF) functional magnetic resonance imaging (fMRI). The most popular approach for high-resolution fMRI is currently gradient-echo (GE) blood oxygenation level-dependent (BOLD) fMRI. However, its spatial accuracy is reduced due to its sensitivity to draining vessels, including pial veins, whereas spin-echo (SE) BOLD signal is expected to have higher spatial accuracy, albeit with lower sensitivity than the GE-BOLD signal. Here, we introduce a new double spin-echo (dSE) echo-planar imaging (EPI) method to improve the sensitivity of SE-BOLD contrast by averaging two spin-echoes using three radiofrequency pulses. Human fMRI experiments were performed with slices perpendicular to the central sulcus between motor and sensory cortices at 7 T during fist-clenching with touching. First, we evaluated the feasibility of single-shot dSE-EPI for BOLD fMRI with 1.5 mm isotropic resolution and found that dSE-BOLD fMRI has higher signal-to-noise ratio (SNR), temporal SNR (tSNR), and higher functional sensitivity than conventional SE-BOLD fMRI. Second, to investigate the laminar specificity of dSE-BOLD fMRI, we implemented a multi-shot approach to achieve 0.8-mm isotropic resolution with sliding-window reconstruction. Unlike GE-BOLD fMRI, the cortical profile of dSE-BOLD fMRI peaked at ~ 1.0 mm from the surface of the primary motor and sensory cortices, demonstrating an improvement of laminar specificity in humans over GE-BOLD fMRI. The proposed multi-shot dSE-EPI method is viable for high spatial resolution UHF-fMRI studies in the pursuit of resolving mesoscopic functional units.

Differential Effect of Iron and Myelin on Susceptibility MRI in the Substantia Nigra.

Background The heterogeneous composition of substantia nigra (SN), including iron, nigrosome-1 substructure, and myelinated white matter, complicates the interpretation of MRI signals. Purpose To investigate R2* and quantitative susceptibility mapping (QSM) in the SN subdivisions of participants with Parkinson disease and healthy control subjects. Materials and Methods In this prospective study conducted from November 2018 to November 2019, participants with Parkinson disease and sex-matched healthy control subjects underwent 3-T MRI. R2* and QSM values were measured and compared in the anterior SN and posterior SN at the rostral (superior) and caudal (inferior) levels. Postmortem MRI and histology correlation of midbrain tissues was evaluated to investigate the effect of myelin and iron in the SN on R2* and QSM values. Results Forty individuals were evaluated: 20 healthy control subjects (mean age, 61 years ± 3 [standard deviation]; 10 men) and 20 participants with Parkinson disease (mean age, 61 years ± 4; 10 men). The R2* values of participants with Parkinson disease were higher in all subdivisions of the SN compared with R2* values in healthy control subjects (all P < .05). For QSM, no evidence of a difference was found in the rostral posterior SN (healthy control subjects, 54.1 ppb ± 21.0; Parkinson disease, 62.2 ppb ± 19.8; P = .49). The combination of rostral R2* and caudal QSM values resulted in an area under the receiver operating characteristic curve of 0.84. R2* values showed higher correlation with QSM values at the caudal level than at the rostral level within each group (all P < .001). Postmortem investigation demonstrated that R2* and QSM values showed weak correlation in the myelin-rich areas (r = 0.22 and r = 0.36, P < .001) and strong correlation in myelin-scanty areas (r ranged from approximately 0.52 to approximately 0.78, P < .001) in the SN. Conclusion Considering the iron and myelin distribution in the substantia nigra subdivisions, the subdivisional analysis of substantia nigra using R2* and quantitative susceptibility mapping might aid in specifically differentiating individuals with Parkinson disease from healthy control subjects. © RSNA, 2021 Online supplemental material is available for this article.

Mapping of microvascular architecture in the brain of an Alzheimer's disease mouse model using MRI.

Increasing evidence suggests that alterations in cerebral microvasculature play a critical role in the pathogenesis of Alzheimer's disease (AD). The objective of this study was to characterize and evaluate the cerebral microvascular architecture of AD transgenic (Tg) mice and compare it with that of non-Tg mice using brain microvascular indices obtained by MRI. Seven non-Tg mice and 10 5xFAD Tg mice were scanned using a 7-T animal MRI system to measure the transverse relaxation rates of R2 and R2* before and after the injection of the monocrystalline iron oxide nanoparticle contrast agent. After calculating ΔR2* and ΔR2, the vessel size index (VSI), mean vessel diameter (mVD), mean vessel density, mean vessel-weighted image (MvWI) and blood volume fraction (BVf) were mapped. Voxel-based analyses and region of interest (ROI)-based analyses were performed to compare the indices of the non-Tg and Tg groups. Voxel comparisons showed that BVf, mVD, VSI and MvWI were greater in the Tg group than in the non-Tg group. Additionally, the ROI-based analysis showed that ΔR2*, BVf, mVD, MvWI and VSI increased in several brain regions of the Tg group compared with those in the non-Tg group. VSI and mVD increased in Tg mice; these findings indicated microvascular disruption in the brain that could be related to damage to the neurovascular unit in AD caused by cerebral amyloid angiopathy.

MRI T2 and T2* relaxometry to visualize neuromelanin in the dorsal substantia nigra pars compacta.

Visualizing gradual changes in neuromelanin distribution within the substantia nigra is an important metric used to monitor the progression of Parkinsonism. This study aimed to identify the origin of the mismatch region between magnetic resonance transverse relaxation times (T2 and T2*) in the substantia nigra and investigate its feasibility and implications for in vivo detection of neuromelanin as a clinical biomarker. The relationships between neuromelanin distribution assessed by histological staining and the area of T2 and T2* mismatch determined by high- and low-resolution magnetic resonance relaxometry at 7T were directly compared in two normal and one depigmented substantia nigra collected at postmortem. In vivo feasibility of assessing T2 and T2* mismatch, clinically, was investigated using 3T magnetic resonance imaging. In the normal postmortem substantia nigra tissue, the T2 and T2* mismatch region exhibiting a linear pattern was strongly colocalized with neuromelanin distribution along the dorsal substantia nigra pars compacta, but a negligible amount of dorsal mismatch was observed in the depigmented brain. The regions of T2 and T2* mismatch from MRI, neuromelanin pigments from histology, and elevated iron signals from mass spectrometry were spatially overlapped for a normal postmortem brain. In preliminary in vivo studies, a similar, linear T2 and T2* mismatch region was observed in the dorsal area of the substantia nigra in eight normal subjects; this mismatch was significantly obscured in eight Parkinson's disease patients. The length of the dorsal linear mismatch line based on the T2*-T2 mask was significantly shorter in the Parkinson's disease patients compared to normal controls; this result was corroborated by reduced striatal uptake of [18F] FP-CIT dopamine transporters assessed by positron emission tomography scans. In conclusion, the measurement of T2 and T2* mismatch could serve as a complementary imaging biomarker to visualize the dorsal region of the substantia nigra pars compacta, which contains large amounts of neuromelanin.

Pattern recognition analysis of directional intravoxel incoherent motion MRI in ischemic rodent brains.

This study aimed to demonstrate a reliable automatic segmentation method for independently separating reduced diffusion and decreased perfusion areas in ischemic stroke brains using constrained nonnegative matrix factorization (cNMF) pattern recognition in directional intravoxel incoherent motion MRI (IVIM-MRI). First, the feasibility of cNMF-based segmentation of IVIM signals was investigated in both simulations and in vivo experiments. The cNMF analysis was independently performed for S0 -normalized and scaled (by the difference between the maximum and minimum) IVIM signals, respectively. Segmentations of reduced diffusion (from S0 -normalized IVIM signals) and decreased perfusion (from scaled IVIM signals) areas were performed using the corresponding cNMF pattern weight maps. Second, Monte Carlo simulations were performed for directional IVIM signals to investigate the relationship between the degree of vessel alignment and the direction of the diffusion gradient. Third, directional IVIM-MRI experiments (x, y and z diffusion-gradient directions, 20 b values at 7 T) were performed for normal (n = 4), sacrificed (n = 1, no flow) and ischemic stroke models (n = 4, locally reduced flow). The results showed that automatic segmentation of the hypoperfused lesion using cNMF analysis was more accurate than segmentation using the conventional double-exponential fitting. Consistent with the simulation, the double-exponential pattern of the IVIM signals was particularly strong in white matter and ventricle regions when the directional flows were aligned with the applied diffusion-gradient directions. cNMF analysis of directional IVIM signals allowed robust automated segmentation of white matter, ventricle, vascular and hypoperfused regions in the ischemic brain. In conclusion, directional IVIM signals were simultaneously sensitive to diffusion and aligned flow and were particularly useful for automatically segmenting ischemic lesions via cNMF-based pattern recognition.

Pattern recognition analysis of dynamic susceptibility contrast (DSC)-MRI curves automatically segments tissue areas with intact blood-brain barrier in a rat stroke model: A feasibility and comparison study.

BACKGROUND: The manual segmentation of intact blood-brain barrier (BBB) regions in the stroke brain is cumbersome, due to the coexistence of infarction, large blood vessels, ventricles, and intact BBB regions, specifically in areas with weak signal enhancement following contrast agent injection. HYPOTHESIS: That from dynamic susceptibility contrast (DSC)-MRI alone, without user intervention, regions of weak BBB damage can be segmented based on the leakage-related parameter K 2 and the extent of intact BBB regions, needed to estimate K 2 values, determined. STUDY TYPE: Feasibility. ANIMAL MODEL: Ten female Sprague-Dawley rats (SD, 200-250g) underwent 1-hour middle carotid artery occlusion (MCAO) and 1-day reperfusion. Two SD rats underwent 1-hour MCAO with 3-day and 5-day reperfusion. FIELD STRENGTH/SEQUENCE: 7T; ADC and T1 maps using diffusion-weighted echo planar imaging (EPI) and relaxation enhancement (RARE) with variable repetition time (TR), respectively. dynamic contrast-enhanced (DCE)-MRI using FLASH. DSC-MRI using gradient-echo EPI. ASSESSMENT: Constrained nonnegative matrix factorization (cNMF) was applied to the dynamic ΔR2* -curves of DSC-MRI (<4 min) in a BBB-disrupted rat model. Areas of voxels with intact BBB, classified by automated cNMF analyses, were then used in estimating K 1 and K 2 values, and compared with corresponding values from manually-derived areas. STATISTICAL TESTS: Mean ± standard deviation of ΔT1 -differences between ischemic and healthy areas were displayed with unpaired Student's t-tests. Scatterplots were displayed with slopes and intercepts and Pearson's r values were evaluated between K 2 maps obtained with automatic (cNMF)- and manually-derived regions of interest (ROIs) of the intact BBB region. RESULTS: Mildly BBB-damaged areas (indistinguishable from DCE-MRI (10 min) parameters) were automatically segmented. Areas of voxels with intact BBB, classified by automated cNMF, matched closely the corresponding, manually-derived areas when respective areas were used in estimating K 2 maps (Pearson's r = 0.97, 12 slices). DATA CONCLUSION: Automatic segmentation of short DSC-MRI data alone successfully identified areas with intact and compromised BBB in the stroke brain and compared favorably with manual segmentation. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:1369-1381.

Netrin-1/DCC-mediated PLCγ1 activation is required for axon guidance and brain structure development.

Coordinated expression of guidance molecules and their signal transduction are critical for correct brain wiring. Previous studies have shown that phospholipase C gamma1 (PLCγ1), a signal transducer of receptor tyrosine kinases, plays a specific role in the regulation of neuronal cell morphology and motility in vitro However, several questions remain regarding the extracellular stimulus that triggers PLCγ1 signaling and the exact role PLCγ1 plays in nervous system development. Here, we demonstrate that PLCγ1 mediates axonal guidance through a netrin-1/deleted in colorectal cancer (DCC) complex. Netrin-1/DCC activates PLCγ1 through Src kinase to induce actin cytoskeleton rearrangement. Neuronal progenitor-specific knockout of Plcg1 in mice causes axon guidance defects in the dorsal part of the mesencephalon during embryogenesis. Adult Plcg1-deficient mice exhibit structural alterations in the corpus callosum, substantia innominata, and olfactory tubercle. These results suggest that PLCγ1 plays an important role in the correct development of white matter structure by mediating netrin-1/DCC signaling.

Gradient-echo and spin-echo blood oxygenation level-dependent functional MRI at ultrahigh fields of 9.4 and 15.2 Tesla.

PURPOSE: Sensitivity and specificity of blood oxygenation level-dependent (BOLD) functional MRI (fMRI) is sensitive to magnetic field strength and acquisition methods. We have investigated gradient-echo (GE)- and spin-echo (SE)-BOLD fMRI at ultrahigh fields of 9.4 and 15.2  Tesla. METHODS: BOLD fMRI experiments responding to forepaw stimulation were performed with 3 echo times (TE) at each echo type and B0 in α-chloralose-anesthetized rats. The contralateral forelimb somatosensory region was selected for quantitative analyses. RESULTS: At 9.4 T and 15.2 T, average baseline T2* (n = 9) was 26.6 and 17.1 msec, whereas baseline T2 value (n = 9) was 35.7 and 24.5 msec, respectively. Averaged stimulation-induced ΔR2* was -1.72 s-1 at 9.4 T and -3.09 s-1 at 15.2 T, whereas ΔR2 was -1.19 s-1 at 9.4 T and -1.97 s-1 at 15.2 T. At the optimal TE of tissue T2* or T2 , BOLD percent changes were slightly higher at 15.2 T than at 9.4 T (GE: 7.4% versus 6.4% and SE: 5.7% versus 5.4%). The ΔR2* and ΔR2 ratio of 15.2 T to 9.4 T was 1.8 and 1.66, respectively. The ratio of the macrovessel-containing superficial to microvessel-dominant parenchymal BOLD signal was 1.73 to 1.76 for GE-BOLD versus 1.13 to 1.19 for SE-BOLD, indicating that the SE-BOLD contrast is less sensitive to macrovessels than GE-BOLD. CONCLUSION: SE-BOLD fMRI improves spatial specificity to microvessels compared to GE-BOLD at both fields. BOLD sensitivity is similar at the both fields and can be improved at ultrahigh fields only for thermal-noise-dominant ultrahigh-resolution fMRI.

Paramagnetic Carbon Nanosheets with Random Hole Defects and Oxygenated Functional Groups.

Ordered graphitic carbon nanosheets (GCNs) were, for the first time, synthesized by the direct condensation of multifunctional phenylacetyl building blocks (monomers) in the presence of phosphorous pentoxide. The GCNs had highly ordered structures with random hole defects and oxygenated functional groups, showing paramagnetism. The results of combined structural and magnetic analyses indicate that the hole defects and functional groups are associated with the appearance and stabilization of unpaired spins. DFT calculations further suggest that the emergence of stabilized spin moments near the edge groups necessitates the presence of functionalized carbon atoms around the hole defects. That is, both hole defects and oxygenated functional groups are essential ingredients for the generation and stabilization of spins in GCNs.

Specific visualization of neuromelanin-iron complex and ferric iron in the human post-mortem substantia nigra using MR relaxometry at 7T.

Neuromelanin (NM) is an endogenous iron chelating molecule of pigmented neurons in the human substantia nigra (SN). Along with the increase in iron deposition, the reduction in NM-containing dopaminergic neurons and the variation of iron load on NM are generally considered to be important factors participating to pathogenesis of Parkinson's disease (PD). The aim of this study was to non-invasively delineate the spatial distributions of paramagnetic magnetic susceptibility perturbers, such as NM-iron complex and ferric iron in SN. Multiple quantitative MR parameters of T1, T2, T2*, susceptibility weighted image (SWI), quantitative susceptibility map (QSM), and T1 weighted image with magnetization transfer (MT) effects were acquired for six post-mortem SN samples without a history of neurological disease. Co-registered quantitative histological validations were performed to identify and correlate NM pigments, iron deposits, and myelin distributions with respect to associated MR parameters. The regions with NM pigments and iron deposits showed positive magnetic susceptibility (paramagnetic) values, while myelinated areas showed negative magnetic susceptibility (diamagnetic) values from the QSM. The region of reduced T2 values in SN mostly coincided with high iron deposits, but not necessarily with the NM pigments. The correlations between T2*/T2 (or T2*/T22) values and NM pigments were higher than those between T2* values and NM pigments, due to the effective size differences between NM-iron complex and ferric iron. Consequently, separate segmentations of ferric iron from the T2 map and NM-iron complex from the T2*/T2 map (or T2*/T22 map) were possible with the boundary of the SN determined from the T1 weighted image.

Automation of pattern recognition analysis of dynamic contrast-enhanced MRI data to characterize intratumoral vascular heterogeneity.

PURPOSE: To automate dynamic contrast-enhanced MRI (DCE-MRI) data analysis by unsupervised pattern recognition (PR) to enable spatial mapping of intratumoral vascular heterogeneity. METHODS: Three steps were automated. First, the arrival time of the contrast agent at the tumor was determined, including a calculation of the precontrast signal. Second, four criteria-based algorithms for the slice-specific selection of number of patterns (NP) were validated using 109 tumor slices from subcutaneous flank tumors of five different tumor models. The criteria were: half area under the curve, standard deviation thresholding, percent signal enhancement, and signal-to-noise ratio (SNR). The performance of these criteria was assessed by comparing the calculated NP with the visually determined NP. Third, spatial assignment of single patterns and/or pattern mixtures was obtained by way of constrained nonnegative matrix factorization. RESULTS: The determination of the contrast agent arrival time at the tumor slice was successfully automated. For the determination of NP, the SNR-based approach outperformed other selection criteria by agreeing >97% with visual assessment. The spatial localization of single patterns and pattern mixtures, the latter inferring tumor vascular heterogeneity at subpixel spatial resolution, was established successfully by automated assignment from DCE-MRI signal-versus-time curves. CONCLUSION: The PR-based DCE-MRI analysis was successfully automated to spatially map intratumoral vascular heterogeneity. Magn Reson Med 79:1736-1744, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Covalent Conjugation of Small-Molecule Adjuvants to Nanoparticles Induces Robust Cytotoxic T Cell Responses via DC Activation.

Specific recognitions of pathogen associated molecular patterns by Toll-like receptors (TLRs) initiate dendritic cell (DC) activation, which is critical for coordinating innate and adaptive immune responses. Imidazoquinolines as small-molecule TLR7 agonists often suffer from prompt dissemination and short half-life in the bloodstream, preventing their localization to the corresponding receptors and effective DC activation. We postulated that covalent incorporation of imidazoquinoline moieties onto the surface of biocompatible nanoparticles (∼30 nm size) would enhance their chemical stability, cellular uptake efficiency, and adjuvanticity. The fully synthetic adjuvant-nanocomplexes led to successful DC activation at lower nanomolar doses compared with free small-molecule agonists. Once a model antigen such as ovalbumin was used for immunization, we found that the nanocomplexes promoted an unusually strong cytotoxic T lymphocyte response, revealing their unique immunostimulatory capacity benefiting from multivalency and efficient transport to endosomal TLR7.

Temporal resolution improvement of calibration-free dynamic contrast-enhanced MRI with compressed sensing optimized turbo spin echo: The effects of replacing turbo factor with compressed sensing accelerations.

PURPOSE: To enhance the temporal resolution of calibration-free dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) by implementing compressed sensing assisted turbo spin echo (CS-TSE) acquisition. MATERIALS AND METHODS: The dynamic sparse sampling variables including acceleration factor, randomized phase encoding distributions, and reconstruction constraints were retrospectively optimized by minimizing the difference from fully sampled dynamic TSE at 7T. The degree of contrast enhancement and the calibration-free quantification of gadolinium (Gd) concentration were evaluated among fast low-angle shot (FLASH), TSE, and CS-TSE acquisitions with multiple phantoms (0.1-6 mM). The kidney-feeding in vivo arterial input function (AIF) was measured at multiple administration doses (0.1-0.3 mmol/kg) to evaluate the benefit of CS-TSE for quantifying rapidly changing high Gd concentrations in C57BL/6 mice (n = 22). RESULTS: In phantom studies, both calibration-free and calibrated conversions estimated equivalent Gd concentrations for CS-TSE (scatterplot slope = 0.9801, r(2) = 0.9998, P < 0.001). In in vivo studies, 4-fold higher temporal resolution (0.96 sec) of CS-TSE over the corresponding TSE enabled robust measurement of AIF first-pass peak and resulting peak enhancement with CS-TSE were observed, with 1.1439- and 2.1258-fold times higher than those with TSE and FLASH acquisitions, respectively, at the 0.1 mmol/kg dose. Calibration-free estimates of AIF peak concentration with CS-TSE were in good agreement with the calibrated approach at multiple administration doses (scatterplot slope = 0.7800, r(2) = 0.8014, P < 0.001). CONCLUSION: Temporal resolution-improved CS-TSE provides practical subsecond (0.96s) calibration-free dynamic MR quantification of high Gd concentration. J. Magn. Reson. Imaging 2016;44:138-147.

Oxygen-induced frequency shifts in hyperoxia: a significant component of BOLD signal.

In comparison to the well-documented significance of intravascular deoxyhemoglobin (deoxyHgb), the effects of dissolved oxygen on the blood-oxygen-level-dependent (BOLD) signal have not been widely reported. Based on the fact that the prolonged inspiration of high oxygen fraction gas can result in up to a sixfold increase of the baseline tissue oxygenation, the current study focused on the influence of dissolved oxygen on the BOLD signal during hyperoxia. As results, our in vitro study revealed that the r1 and r2 (relaxivities) of the oxygen-treated serum were 0.22 mM(-1) · s(-1) and 0.19 mM(-1) · s(-1) , respectively. In an in vivo experiment, hyperoxic respiration induced negative BOLD contrast (i.e. signal decrease) in 18-42% of measured brain regions, voxels with accompanying significant decreases in both the T(*)2 (-12.1% to -19.4%) and T1 (-5.8% to -3.3%) relaxation times. In contrast, the T(*)2 relaxation time significantly increased (11.2% to 14.0%) for the voxels displaying positive BOLD contrast (in 41-50% of the measured brain), which reflected a hyperoxygenation-induced reduction in tissue deoxyHgb concentration. These data imply that hyperoxia-driven BOLD signal changes are primarily determined by the counteracting effects of extravascular oxygen and intravascular deoxyHgb. Oxygen-induced magnetic susceptibility was further demonstrated by the study of 1 min hypoxia, which induced BOLD signal changes opposite to those under hyperoxia. Vasoconstriction was more common in voxels with negative BOLD contrast than in voxels with positive contrast (% change of blood volume, -9.8% to -12.8% versus 2.0% to 2.2%), which further suggests that negative BOLD contrast is mainly evoked by an increase in extravascular oxygen concentration. Conclusively, frequency shifts, which are induced by the accumulation of oxygen molecules and associated magnetic field inhomogeneity, are a significant source of the negative BOLD contrast during hyperoxia.