Cerebral blood perfusion deficits using dynamic susceptibility contrast MRI with gadolinium chelates in rats with post-ischemic reperfusion without significant dynamic contrast-enhanced MRI-derived vessel permeabilities: A cautionary note

In this study, we quantified perfusion deficits using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) with an extravasating contrast agent (CA). We also investigated the efficacy of leakage compensation from CA pre-load in brains from post-ischemic rat models without significant dynamic contrast-enhanced MRI (DCE-MRI)-derived vessel wall permeability. DSC measurements were obtained using fast (0.3 s) echo-planar imaging in both normal rats and rats with transient middle carotid artery occlusion (MCAO) (1-h MCAO, 24-h reperfusion) after successive administrations of gadoterate meglumine (Dotarem) and intravascular superparamagnetic iron oxide nanoparticles (SPION). The relative cerebral blood volume (CBV) and cerebral blood flow (CBF) values acquired using Dotarem were significantly underestimated (~20%) when compared to those acquired using SPION in ipsilesional post-ischemic brain regions. A slight overestimation of relative mean transit time was observed. Areas with underestimated CBV and CBF values from the corresponding error maps encompassed the area of infarcted tissue (apparent diffusion coefficient < 500 ??m2/s) and mostly coincided with the area wherein conspicuous longitudinal relaxation time differences were observed pre- vs. post-injection of Dotarem. The DSC measurements with significant pre-load (0.3 mmol??kg-1) of Dotarem displayed minimal perfusion deficits when compared to those determined using the reference intravascular SPION

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Department of Biomedical Engineering (Biomedical Engineering)Cerebrovascular permeability has been considered a standard biomarker for brain tumors or multiple sclerosis that causes severe blood-brain-barrier (BBB) disruption. In addition, as dementia or aging has been reported to damage the BBB, interest in cerebrovascular permeability as a biomarker of degenerative brain disease is increasing. Dynamic contrast enhanced (DCE)-MRI is a standard technique to evaluate cerebrovascular permeability and widely used in clinics. However, DCE-MRI is less sensitive to subtle BBB damaged diseases such as early stage of ischemic stroke and degenerative brain disease, so it sometimes fails to evaluate cerebrovascular permeability. Therefore, improving the sensitivity of cerebrovascular permeability imaging technique is essential. Generally, T2* contrast is more sensitive to MR contrast agent (CA) than T1 contrast. For CA effects on T1, proton should be physically contact to metal ion in CA. However, CA effect on T2* relaxation is based on inhomogeneity of local magnetic field, which means that protons do not need to contact the metal ions of CA. Therefore, T2*-weighted signal may be more sensitive to CA extravasation than T1-weighted signal. DCE-MRI use T1-weighted signal, but there is another MRI technique called dynamic susceptibility contrast (DSC)-MRI that use a T2*-weighted signal In this thesis, firstly, the feasibility of improving sensitivity using DSC-MRI has been studied with temporal middle carotid artery occlusion (tMCAO) rat model. To study the extravasated CA effect on DSC-MRI, two different types of CAs were used, which are Gd-DOTA and monocrystalline iron oxide nanoparticle (MION). MION is one of the blood pool CA and it is too large to leak out of the blood. Therefore, by comparing MION and Gd-DOTA, the extravasated CA effects on DSC-MRI systematically were studied. The results showed that Gd-DOTA injected DSC-MRI of infarction underestimated cerebral blood volume and cerebral blood flow, and contralateral hemisphere did not. Also, the difference between Gd-DOTA and MION of DSC-MRI was strong correlated with the damaged level of BBB. Therefore, DSC-MRI has enough contrast to evaluate vascular permeability for subtle BBB damaged region. Secondly, the sensitivity of DCE-MRI and DSC-MRI was compared with tMCAO model. Also, the risk of incorrect segmentation of normal tissue was reduced through pattern recognition analysis. The results showed that DSC-MRI is more sensitive to CA extravasation than DCE-MRI, and that pattern recognition guided DSC-MRI has advantages in automatically segmenting normal tissue areas without pre-knowledge of the level of BBB damage. Therefore, pattern recognition guided DSC-MRI is suitable for evaluating vascular permeability of subtle BBB damaged region. Lastly, the quantification process of DSC-MRI was improved by using sequentially injected DSC-MRI data. To evaluate vascular permeability, pharmacokinetic model of DSC-MRI forces to define the normal tissue region. However, errors arise due to the ROI dependence and mismatch between the pharmacokinetic model and the DSC-MRI signal. To reduce the errors, vascular permeability was calculated through model-free analysis using additional DSC-MRI data. The results showed that dual DSC-MRI is robust to ROI dependence and reduces errors due to pharmacokinetic models. Therefore, dual DSC-MRI has an advantage in quantifying vascular permeability. In conclusion, vascular permeability of subtle BBB damaged region was successfully evaluated by DSC-MRI and showed that DSC-MRI is sensitive to CA extravasation than DCE-MRI. Although most studies focus on improving sensitivity of DCE-MRI, it is difficult due to the fundamental limitations of T1-weighted signal, and T2*-weighted signal can be a good alternative. The potential of T2*-weighted signal was shown in this thesis but still it is unclear why T2*-weighted signal is more sensitive to CA extravasation than T1-weighted signal. The T2* effects on CA extravasation is so complex that it has not been well studied, but if the T2* effects are deeply understood in further studies, DSC-MRI could be further improved.ope

Model-free leakage index estimation of the blood-brain barrier using dual dynamic susceptibility contrast MRI acquisition

Pharmacokinetic K-2 mapping from dynamic susceptibility contrast (DSC)-MRI can be a sensitive technique for evaluating the vascular permeability of the subtly damaged blood-brain barrier (BBB) in ischemic regions. However, the K-2 values of ischemic lesions depend upon the selection of the intact BBB reference region. As previous observations suggest that the Delta R-2* curve of pre-loaded DSC-MRI is not significantly affected by the extravasation of contrast agent, dual DSC-MRI acquisitions can be performed to derive the BBB leakage index from the voxel-wise reference input function for ischemic regions. This study aims to demonstrate the robustness of such model-free leakage index estimation in ischemic brains. By configuring the relationship between dual Delta R-2* curves of the intact contralateral brain, the deviation of the measured Delta R-2* curve from the unloaded DSC-MRI with respect to the non-deviated Delta R-2* curve in the pre-loaded DSC-MRI can be quantified as the BBB leakage index. Such model-free leakage index values from rats with transient middle carotid artery occlusion (tMCAO) (n = 17) and normal controls (n = 3) were evaluated and compared with conventional K-2 values with multiple reference regions. Inter-subject leakage index values were also compared with the corresponding Delta T-1 map. Evans-blue-stained images were used to validate the leakage index. For the tMCAO group, leakage index values correlated well with Delta T-1 (Pearson's r = 0.828). The hyperintense area on the leakage index map matched well with the corresponding Evans-blue-stained area (Dice correlation = 0.626). The slopes of the scatter-plot from the leakage index (0.97-1.00) were observed to be more robust against changes in the reference region than those from conventional K-2 values (0.94-1.07). In a subtly damaged BBB tMCAO model, model-free evaluation of vascular permeability using dual DSC-MRIs would provide a consistent measure of inter-subject vascular permeability

MRI investigation of vascular remodeling for heterogeneous edema lesions in subacute ischemic stroke rat models: Correspondence between cerebral vessel structure and function

The spatial heterogeneity in the temporal occurrence of pseudo-normalization of MR apparent diffusion coefficient values for ischemic lesions may be related to morphological and functional vascular remodeling. As the area of accelerated pseudo-normalization tends to expand faster and more extensively into the chronic stage, detailed vascular characterization of such areas is necessary. During the subacute stage of transient middle cerebral artery occlusion rat models, the morphological size of the macrovasculature, microvascular vessel size index (VSI), and microvessel density (MVD) were quantified along with functional perfusion measurements of the relative cerebral blood flow (rCBF) and mean transit time (rMTT) of the corresponding areas (33 cases for each parameter). When compared with typical pseudo-normalization lesions, early pseudo-normalization lesions exhibited larger VSI and rCBF (p < 0.001) at reperfusion days 4 and 7, along with reduced MVD and elongated rMTT (p < 0.001) at reperfusion days 1, 4, and 7. The group median VSI and rCBF exhibited a strong positive correlation (r = 0.92), and the corresponding MVD and rMTT showed a negative correlation (r = -0.48). Light sheet fluorescence microscopy images were used to quantitatively validate the corresponding MRI-derived microvascular size, density, and cerebral blood volume

User-designed device for personalized drug delivery and local treatment of chronic disease

Three-dimensional printing enables precise and on-demand manufacture of customizable drug delivery systems to advance healthcare toward the goal of personalized medicine. However, major challenges remain in realizing personalized drug delivery that fits a patient-specific drug dosing schedule using local drug delivery systems. In this study, a user-designed device is developed as implantable therapeutics that can realize personalized drug release kinetics by programming the inner structural design on the microscale. The drug release kinetics required for various treatments, including dose-dense therapy and combination therapy, can be implemented by controlling the dosage and combination of drugs along with the rate, duration, initiation time, and time interval of drug release according to the device layer design. After implantation of the capsular device in mice, the in vitro???in vivo and pharmacokinetic evaluation of the device is performed, and the therapeutic effect of the developed device is achieved through the local release of doxorubicin. The developed user-designed device provides a novel platform for developing next-generation drug delivery systems for personalized and localized therapy

Mean and standard variations of ADC and rCBV error values for infarction, peri-infarction, and normal areas for six rats shown in Figs 4, 5 and 6.

<p>Mean and standard variations of ADC and rCBV error values for infarction, peri-infarction, and normal areas for six rats shown in Figs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0201076#pone.0201076.g004" target="_blank">4</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0201076#pone.0201076.g005" target="_blank">5</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0201076#pone.0201076.g006" target="_blank">6</a>.</p

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 T-1 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 Delta R2*-curves of DSC-MRI (&lt;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 Delta T-1-differences between ischemic and healthy areas were displayed with unpaired Student&apos;s t-tests. Scatterplots were displayed with slopes and intercepts and Pearson&apos;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&apos;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. Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019

Cerebral blood perfusion deficits using dynamic susceptibility contrast MRI with gadolinium chelates in rats with post-ischemic reperfusion without significant dynamic contrast-enhanced MRI-derived vessel permeabilities: A cautionary note - Fig 6

<p>(a.1-d.1) rCBV maps from SPION. (a.2-d.2) rCBV maps from DOTAREM (a.3-d.3) rCBV_error map. (a.4-d.4) Scatter plots of rCBV_SPION/rCBV_DOTAREM values in core region normalized to each normal area. (a.5-d.5) <i>T</i>_<i>1</i> difference maps (post 85 mins) with increasing CA pre-load. No <i>T</i>_<i>1</i> difference map was available for no CA pre-load case and not available.</p

Cerebral blood perfusion deficits using dynamic susceptibility contrast MRI with gadolinium chelates in rats with post-ischemic reperfusion without significant dynamic contrast-enhanced MRI-derived vessel permeabilities: A cautionary note - Fig 5

<p>(a.1) <i>T</i>_<i>2</i>-weighted image. (a.2) ADC map. (a.3) <i>T</i>₁ changes were shown for infarction (green) and normal (blue) region as a function of post-injection time, where injection time-points were marked with red lines. No significant <i>T</i>₁ difference between infarction and normal region were observed from (a.4) <i>T</i>₁ difference map (post-10 mins) after the injection of DOTAREM (0.1 mmol·kg^-1). (a.5) <i>K</i>^<i>trans</i> map. (a.6) <i>V</i>_<i>e</i> map. (a.7) <i>V</i>_<i>p</i> map.</p