Maximum spherical mean value filtering for whole-brain QSM.

PURPOSE: To develop a tissue field-filtering algorithm, called maximum spherical mean value (mSMV), for reducing shadow artifacts in QSM of the brain without requiring brain-tissue erosion. THEORY AND METHODS: Residual background field is a major source of shadow artifacts in QSM. The mSMV algorithm filters large field-magnitude values near the border, where the maximum value of the harmonic background field is located. The effectiveness of mSMV for artifact removal was evaluated by comparing existing QSM algorithms in numerical brain simulation as well as using in vivo human data acquired from 11 healthy volunteers and 93 patients. RESULTS: Numerical simulation showed that mSMV reduces shadow artifacts and improves QSM accuracy. Better shadow reduction, as demonstrated by lower QSM variation in the gray matter and higher QSM image quality score, was also observed in healthy subjects and in patients with hemorrhages, stroke, and multiple sclerosis. CONCLUSION: The mSMV algorithm allows QSM maps that are substantially equivalent to those obtained using SMV-filtered dipole inversion without eroding the volume of interest.

QSM Throughout the Body.

Magnetic materials in tissue, such as iron, calcium, or collagen, can be studied using quantitative susceptibility mapping (QSM). To date, QSM has been overwhelmingly applied in the brain, but is increasingly utilized outside the brain. QSM relies on the effect of tissue magnetic susceptibility sources on the MR signal phase obtained with gradient echo sequence. However, in the body, the chemical shift of fat present within the region of interest contributes to the MR signal phase as well. Therefore, correcting for the chemical shift effect by means of water-fat separation is essential for body QSM. By employing techniques to compensate for cardiac and respiratory motion artifacts, body QSM has been applied to study liver iron and fibrosis, heart chamber blood and placenta oxygenation, myocardial hemorrhage, atherosclerotic plaque, cartilage, bone, prostate, breast calcification, and kidney stone.

QQ-NET - using deep learning to solve quantitative susceptibility mapping and quantitative blood oxygen level dependent magnitude (QSM+qBOLD or QQ) based oxygen extraction fraction (OEF) mapping.

PURPOSE: To improve accuracy and speed of quantitative susceptibility mapping plus quantitative blood oxygen level-dependent magnitude (QSM+qBOLD or QQ) -based oxygen extraction fraction (OEF) mapping using a deep neural network (QQ-NET). METHODS: The 3D multi-echo gradient echo images were acquired in 34 ischemic stroke patients and 4 healthy subjects. Arterial spin labeling and diffusion weighted imaging (DWI) were also performed in the patients. NET was developed to solve the QQ model inversion problem based on Unet. QQ-based OEF maps were reconstructed with previously introduced temporal clustering, tissue composition, and total variation (CCTV) and NET. The results were compared in simulation, ischemic stroke patients, and healthy subjects using a two-sample Kolmogorov-Smirnov test. RESULTS: In the simulation, QQ-NET provided more accurate and precise OEF maps than QQ-CCTV with 150 times faster reconstruction speed. In the subacute stroke patients, OEF from QQ-NET had greater contrast-to-noise ratio (CNR) between DWI-defined lesions and their unaffected contralateral normal tissue than with QQ-CCTV: 1.9 ± 1.3 vs 6.6 ± 10.7 (p = 0.03). In healthy subjects, both QQ-CCTV and QQ-NET provided uniform OEF maps. CONCLUSION: QQ-NET improves the accuracy of QQ-based OEF with faster reconstruction.

QSM in canine model of acute cerebral ischemia: A pilot study.

PURPOSE: In the present study, we investigated the potential of QSM to assess the physiological state of cortical tissue in the middle cerebral artery occlusion canine model of a cerebral ischemia. METHODS: Experiments were performed in 8 anesthetized canines. Gradient echo, perfusion, and DWI data of brains at normal and ischemic states were acquired. In the postprocessed susceptibility and quantitative cerebral blood flow maps, changes in values within the middle cerebral artery-fed cortical territories were quantified both on the ischemic and normal contralateral hemisphere side. RESULTS: QSM values in critically ischemic tissue were significantly different from contralateral values-namely, susceptibility increase was observed in the cases in which cerebral perfusion was maintained above the threshold of neuronal death. Furthermore, the data indicates presence of a significant correlation between the changes in susceptibility values, cerebral perfusion, and the infarct volume and pial collateral scores. Additionally, our data suggests that difference in cortical susceptibility is prospectively indicative of the infarct growth rate. CONCLUSION: In an experimental permanent middle cerebral artery occlusion model, QSM was shown to correlate with the functional parameters characterizing viability of ischemic tissue, thus warranting further research on its ability to provide complementary information during acute stroke MRI examinations in humans.

Phantom validation of quantitative susceptibility and dynamic contrast-enhanced permeability MR sequences across instruments and sites.

BACKGROUND: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative permeability (DCEQP) on magnetic resonance (MR) have been shown to correlate with neurovascular disease progression as markers of vascular leakage and hemosiderin deposition. Applying these techniques as monitoring biomarkers in clinical trials will be necessary; however, their validation across multiple MR platforms and institutions has not been rigorously verified. PURPOSE: To validate quantitative measurement of MR biomarkers on multiple instruments at different institutions. STUDY TYPE: Phantom validation between platforms and institutions. PHANTOM MODEL: T1 /susceptibility phantom, two-compartment dynamic flow phantom. FIELD STRENGTH/SEQUENCE: 3T/QSM, T1 mapping, dynamic 2D SPGR. ASSESSMENT: Philips Ingenia, Siemens Prisma, and Siemens Skyra at three different institutions were assessed. A QSM phantom with concentrations of gadolinium, corresponding to magnetic susceptibilities of 0, 0.1, 0.2, 0.4, and 0.8 ppm was assayed. DCEQP was assessed by measuring a MultiHance bolus as the consistency of the width ratio of the curves at the input and outputs over a range of flow ratios between outputs. STATISTICAL TESTS: Each biomarker was assessed by measures of accuracy (Pearson correlation), precision (paired t-test between repeated measurements), and reproducibility (analysis of covariance [ANCOVA] between instruments). RESULTS: QSM accuracy of r2 > 0.997 on all three platforms was measured. Precision (P = 0.66 Achieva, P = 0.76 Prisma, P = 0.69 Skyra) and reproducibility (P = 0.89) were good. T1 mapping of accuracy was r2 > 0.98. No significant difference between width ratio regression slopes at site 2 (P = 0.669) or site 3 (P = 0.305), and no significant difference between width ratio regression slopes between sites was detected by ANCOVA (P = 0.48). DATA CONCLUSION: The phantom performed as expected and determined that MR measures of QSM and DCEQP are accurate and consistent across repeated measurements and between platforms. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1192-1199.

Bone quantitative susceptibility mapping using a chemical species-specific R2* signal model with ultrashort and conventional echo data.

PURPOSE: To develop quantitative susceptibility mapping (QSM) of bone using an ultrashort echo time (UTE) gradient echo (GRE) sequence for signal acquisition and a bone-specific effective transverse relaxation rate ( R2*) to model water-fat MR signals for field mapping. METHODS: Three-dimensional radial UTE data (echo times ≥ 40 µs) was acquired on a 3 Tesla scanner and fitted with a bone-specific signal model to map the chemical species and susceptibility field. Experiments were performed ex vivo on a porcine hoof and in vivo on healthy human subjects (n = 7). For water-fat separation, a bone-specific model assigning R2* decay mostly to water was compared with the standard models that assigned the same decay for both fat and water. In the ex vivo experiment, bone QSM was correlated with CT. RESULTS: Compared with standard models, the bone-specific R2* method significantly reduced errors in the fat fraction within the cortical bone in all tested data sets, leading to reduced artifacts in QSM. Good correlation was found between bone CT and QSM values in the porcine hoof (R2 = 0.77). Bone QSM was successfully generated in all subjects. CONCLUSIONS: The QSM of bone is feasible using UTE with a conventional echo time GRE acquisition and a bone-specific R2* signal model. Magn Reson Med 79:121-128, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Cardiac quantitative susceptibility mapping (QSM) for heart chamber oxygenation.

PURPOSE: To demonstrate the feasibility of in vivo quantitative susceptibility mapping (QSM) in cardiac MRI and to show that mixed-venous oxygen saturation (SvO2 ) can be measured non-invasively using QSM. METHODS: Electrocardiographic-gated multi-echo 2D gradient echo data were collected at 1.5 T from 14 healthy volunteers during successive breath-holds. Phase wraps and fat chemical shift were removed using a graph-cut-based phase analysis and IDEAL in an iterative approach. The large susceptibility range from air in the lungs to blood in the heart was addressed by using the preconditioning approach in the dipole field inversion. SvO2 was calculated based on the difference in blood susceptibility between the right ventricle (RV) and left ventricle (LV). Cardiac QSM quality was assessed by two independent readers. RESULTS: Nine out of fourteen volunteers (64%) yielded interpretable cardiac QSM. QSM maps showed strong differential contrast between RV and LV blood with RV blood having higher susceptibility values (291.5 ± 32.4 ppb), which correspond to 78.3 ± 2.3% SvO2 . CONCLUSION: In vivo cardiac QSM is feasible and can be used to measure SvO2 , but improvements in data acquisition are needed. Magn Reson Med 79:1545-1552, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

In Situ and Real-Time Studies, via Synchrotron X-ray Scattering, of the Orientational Order of Cellulose Nanocrystals during Solution Shearing.

In this manuscript, we report on the ordering of the cellulose nanocrystals (CNCs) as they experience shear forces during the casting process. To achieve these measurements, in situ and in real time, we used synchrotron-based grazing incidence wide-angle X-ray scattering (GIWAX). We believe that the GIWAX technique, although not commonly used to probe these types of phenomena, can open new avenues to gain deeper insights into film formation processes and surface-driven phenomena. In particular, we investigated the influence of solution concentration, shear-cast velocity, and drying temperature on the ordering of cellulose nanocrystals (CNCs) using GIWAXS. The films were prepared from aqueous suspensions of cellulose nanocrystals at two concentration values (7 and 9 wt %). As the films were cast, the X-ray beam was focused on a fixed position and GIWAXS patterns were recorded at regular time intervals. Structural characterization of the dry films was carried out via polarized optical microscopy and scanning electron microscopy. In addition, a rheological study of the CNC suspensions was performed. Our results show that the morphology of the CNC films was significantly influenced by shear velocity, concentration of the precursor suspension, and evaporation temperature. In contrast, we observed that the orientation parameter of the films was not significantly affected. The scattering intensity of the peak (200) was analyzed as a function of time, following a sigmoidal profile, hence indicating short- and long-range interactions within the anisotropic domains as they reached their final orientation state. A model capable of describing the resulting film morphologies is also proposed. The results and analysis presented in this manuscript provide new insights into the controlled alignment of cellulose nanocrystals under shear. This controlled alignment has significant implications in the development of advanced coatings and films currently used in a myriad of applications, such as catalysis, optics, electronics, and biomedicine.

Primal-dual and forward gradient implementation for quantitative susceptibility mapping.

PURPOSE: To investigate the computational aspects of the prior term in quantitative susceptibility mapping (QSM) by (i) comparing the Gauss-Newton conjugate gradient (GNCG) algorithm that uses numerical conditioning (ie, modifies the prior term) with a primal-dual (PD) formulation that avoids this, and (ii) carrying out a comparison between a central and forward difference scheme for the discretization of the prior term. THEORY AND METHODS: A spatially continuous formulation of the regularized QSM inversion problem and its PD formulation were derived. The Chambolle-Pock algorithm for PD was implemented and its convergence behavior was compared with that of GNCG for the original QSM. Forward and central difference schemes were compared in terms of the presence of checkerboard artifacts. All methods were tested and validated on a gadolinium phantom, ex vivo brain blocks, and in vivo brain MRI data with respect to COSMOS. RESULTS: The PD approach provided a faster convergence rate than GNCG. The GNCG convergence rate slowed considerably with smaller (more accurate) values of the conditioning parameter. Using a forward difference suppressed the checkerboard artifacts in QSM, as compared with the central difference. The accuracy of PD and GNCG were validated based on excellent correlation with COSMOS. CONCLUSIONS: The PD approach with forward difference for the gradient showed improved convergence and accuracy over the GNCG method using central difference. Magn Reson Med 78:2416-2427, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

The clinical utility of QSM: disease diagnosis, medical management, and surgical planning.

Quantitative susceptibility mapping (QSM) is an MR technique that depicts and quantifies magnetic susceptibility sources. Mapping iron, the dominant susceptibility source in the brain, has many important clinical applications. Herein, we review QSM applications in the diagnosis, medical management, and surgical treatment of disease. To assist in early disease diagnosis, QSM can identify elevated iron levels in the motor cortex of amyotrophic lateral sclerosis patients, in the substantia nigra of Parkinson's disease (PD) patients, in the globus pallidus, putamen, and caudate of Huntington's disease patients, and in the basal ganglia of Wilson's disease patients. Additionally, QSM can distinguish between hemorrhage and calcification, which could prove useful in tumor subclassification, and can measure microbleeds in traumatic brain injury patients. In guiding medical management, QSM can be used to monitor iron chelation therapy in PD patients, to monitor smoldering inflammation of multiple sclerosis (MS) lesions after the blood-brain barrier (BBB) seals, to monitor active inflammation of MS lesions before the BBB seals without using gadolinium, and to monitor hematoma volume in intracerebral hemorrhage. QSM can also guide neurosurgical treatment. Neurosurgeons require accurate depiction of the subthalamic nucleus, a tiny deep gray matter nucleus, prior to inserting deep brain stimulation electrodes into the brains of PD patients. QSM is arguably the best imaging tool for depiction of the subthalamic nucleus. Finally, we discuss future directions, including bone QSM, cardiac QSM, and using QSM to map cerebral metabolic rate of oxygen. Copyright © 2016 John Wiley & Sons, Ltd.

Clinical quantitative susceptibility mapping (QSM): Biometal imaging and its emerging roles in patient care.

Quantitative susceptibility mapping (QSM) has enabled magnetic resonance imaging (MRI) of tissue magnetic susceptibility to advance from simple qualitative detection of hypointense blooming artifacts to precise quantitative measurement of spatial biodistributions. QSM technology may be regarded to be sufficiently developed and validated to warrant wide dissemination for clinical applications of imaging isotropic susceptibility, which is dominated by metals in tissue, including iron and calcium. These biometals are highly regulated as vital participants in normal cellular biochemistry, and their dysregulations are manifested in a variety of pathologic processes. Therefore, QSM can be used to assess important tissue functions and disease. To facilitate QSM clinical translation, this review aims to organize pertinent information for implementing a robust automated QSM technique in routine MRI practice and to summarize available knowledge on diseases for which QSM can be used to improve patient care. In brief, QSM can be generated with postprocessing whenever gradient echo MRI is performed. QSM can be useful for diseases that involve neurodegeneration, inflammation, hemorrhage, abnormal oxygen consumption, substantial alterations in highly paramagnetic cellular iron, bone mineralization, or pathologic calcification; and for all disorders in which MRI diagnosis or surveillance requires contrast agent injection. Clinicians may consider integrating QSM into their routine imaging practices by including gradient echo sequences in all relevant MRI protocols. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2017;46:951-971.

Joint estimation of chemical shift and quantitative susceptibility mapping (chemical QSM).

PURPOSE: The purpose of this work is to address the unsolved problem of quantitative susceptibility mapping (QSM) of tissue with fat where both fat and susceptibility change the MR signal phase. THEORY AND METHODS: The chemical shift of fat was treated as an additional unknown and was estimated jointly with susceptibility to provide the best data fitting using an automated and iterative algorithm. A simplified susceptibility model was used to calculate an updated value of the chemical shift based on the local magnetic field in each iteration. Numerical simulation, phantom experiments and in vivo imaging were performed. Artifacts were assessed by measuring the susceptibility variance in uniform regions. Accuracy was assessed by comparison with ground truth in simulation, and using a susceptibility matching approach in phantom. RESULTS: Using the proposed method, artifacts on the QSM image were markedly suppressed in all tested datasets compared with results generated using fixed chemical shifts. Accuracy of the estimated susceptibility was also improved in numerical simulation and phantom experiments. CONCLUSION: A joint estimation of fat content and magnetic susceptibility using an iterative chemical shift update was shown to improve image quality and accuracy on QSM images.

Quantitative susceptibility mapping for detection of kidney stones, hemorrhage differentiation, and cyst classification in ADPKD.

BACKGROUND AND PURPOSE: The objective is to demonstrate feasibility of quantitative susceptibility mapping (QSM) in autosomal dominant polycystic kidney disease (ADPKD) patients and to compare imaging findings with traditional T1/T2w magnetic resonance imaging (MRI). METHODS: Thirty-three consecutive patients (11 male, 22 female) diagnosed with ADPKD were initially selected. QSM images were reconstructed from the multiecho gradient echo data and compared to co-registered T2w, T1w, and CT images. Complex cysts were identified and classified into distinct subclasses based on their imaging features. Prevalence of each subclass was estimated. RESULTS: QSM visualized two renal calcifications measuring 9 and 10 mm and three pelvic phleboliths measuring 2 mm but missed 24 calcifications measuring 1 mm or less and 1 larger calcification at the edge of the field of view. A total of 121 complex T1 hyperintense/T2 hypointense renal cysts were detected. 52 (43%) Cysts appeared hyperintense on QSM consistent with hemorrhage; 60 (49%) cysts were isointense with respect to simple cysts and normal kidney parenchyma, while the remaining 9 (7%) were hypointense. The presentation of the latter two complex cyst subtypes is likely indicative of proteinaceous composition without hemorrhage. CONCLUSION: Our results indicate that QSM of ADPKD kidneys is possible and uniquely suited to detect large renal calculi without ionizing radiation and able to identify properties of complex cysts unattainable with traditional approaches.

Microstructure-Informed Myelin Mapping (MIMM) from Gradient Echo MRI using Stochastic Matching Pursuit.

Quantification of the myelin content of the white matter is important for studying demyelination in neurodegenerative diseases such as Multiple Sclerosis (MS), particularly for longitudinal monitoring. A novel noninvasive MRI method, called Microstructure-Informed Myelin Mapping (MIMM), is developed to quantify the myelin volume fraction (MVF) by utilizing a multi gradient echo sequence (mGRE) and a detailed biophysical model of tissue microstructure. Myelin is modeled as anisotropic negative susceptibility source based on the Hollow Cylindrical Fiber Model (HCFM), and iron as isotropic positive susceptibility source in the extracellular region. Voxels with a range of biophysical parameters are simulated to create a dictionary of MR echo time magnitude signals and total susceptibility values. MRI signals measured using a mGRE sequence are then matched voxel-by-voxel to the created dictionary to obtain the spatial distributions of myelin and iron. Three different MIMM versions are presented to deal with the fiber orientation dependent susceptibility effects of the myelin sheaths: a basic variation, which assumes fiber orientation is an unknown to fit, two orientation informed variations, which assume the fiber orientation distribution is available either from a separate diffusion tensor imaging (DTI) acquisition or from a DTI atlas based fiber orientation map. While all showed a significant linear correlation with the reference method based on T2-relaxometry (p < 0.0001), DTI orientation informed and atlas orientation informed variations reduced overestimation at white matter tracts compared to the basic variation. Finally, the implications and usefulness of attaining an additional iron susceptibility distribution map are discussed. Highlights: novel stochastic matching pursuit algorithm called microstructure-informed myelin mapping (MIMM) is developed to quantify Myelin Volume Fraction (MVF) using Magnetic Resonance Imaging (MRI) and microstructural modeling.utilizes a detailed biophysical model to capture the susceptibility effects on both magnitude and phase to quantify myelin and iron.matter fiber orientation effects are considered for the improved MVF quantification in the major fiber tracts.acquired myelin and iron maps may be utilized to monitor longitudinal disease progress.

Susceptibility source separation from gradient echo data using magnitude decay modeling.

BACKGROUND AND PURPOSE: The objective is to demonstrate feasibility of separating magnetic sources in quantitative susceptibility mapping (QSM) by incorporating magnitude decay rates R 2 ∗ $R_2^{\rm{*}}$ in gradient echo (GRE) MRI. METHODS: Magnetic susceptibility source separation was developed using R 2 ∗ $R_2^{\rm{*}}$ and compared with a prior method using R 2 ' = R 2 ∗ - R 2 ${R^{\prime}_2} = R_2^* - {R_2}$ that required an additional sequence to measure the transverse relaxation rate R2 . Both susceptibility separation methods were compared in multiple sclerosis (MS) patients (n = 17). Susceptibility values of negative sources estimated with R 2 ∗ $R_2^{\rm{*}}$ -based source separation in a set of enhancing MS lesions (n = 44) were correlated against longitudinal myelin water fraction (MWF) changes. RESULTS: In in vivo data, linear regression of the estimated χ + ${\chi}^{+}$ and χ - ${\chi}^{-}$ susceptibility values between the R 2 ∗ $R_2^*$ - and the R 2 ' ${R^{\prime}_2}$ -based separation methods performed across 182 segmented lesions revealed correlation coefficient r = .96 and slope close .99. Correlation analysis in enhancing lesions revealed a significant positive association between the χ - ${\chi}^{-}$ increase at 1-year post-onset relative to 0 year and the MWF increase at 1 year relative to 0 year (ß = -0.144, 95% confidence interval: [-0.199, -0.1], p = .0008) and good agreement between R 2 ' ${R^{\prime}_2}$ and R 2 ∗ $R_2^*$ methods (r = .79, slope = .95). CONCLUSIONS: Separation of magnetic sources based solely on GRE complex data is feasible by combining magnitude decay rate modeling and phase-based QSM and χ - ${\chi}^{-}$ change may serve as a biomarker for myelin recovery or damage in acute MS lesions.

Magnetic Susceptibility Source Separation Solely from Gradient Echo Data: Histological Validation.

Quantitative susceptibility mapping (QSM) facilitates mapping of the bulk magnetic susceptibility of tissue from the phase of complex gradient echo (GRE) MRI data. QSM phase processing combined with an R2* model of magnitude of multiecho gradient echo data (R2*QSM) allows separation of dia- and para-magnetic components (e.g., myelin and iron) that contribute constructively to R2* value but destructively to the QSM value of a voxel. This R2*QSM technique is validated against quantitative histology­optical density of myelin basic protein and Perls' iron histological stains of rim and core of 10 ex vivo multiple sclerosis lesions, as well as neighboring normal appearing white matter. We found that R2*QSM source maps are in good qualitative agreement with histology, e.g., showing increased iron concentration at the edge of the rim+ lesions and myelin loss in the lesions' core. Furthermore, our results indicate statistically significant correlation between paramagnetic and diamagnetic tissue components estimated with R2*QSM and optical densities of Perls' and MPB stains. These findings provide direct support for the use of R2*QSM magnetic source separation based solely on GRE complex data to characterize MS lesion composition.

Global cerebrospinal fluid as a zero-reference regularization for brain quantitative susceptibility mapping.

BACKGROUND AND PURPOSE: The objective ofthis study was to demonstrate a global cerebrospinal fluid (CSF) method for a consistent and automated zero referencing of brain quantitative susceptibility mapping (QSM). METHODS: Whole brain CSF mask was automatically segmented by thresholding the gradient echo transverse relaxation ( R2∗) map, and regularization was employed to enforce uniform susceptibility distribution within the CSF volume in the field-to-susceptibility inversion. This global CSF regularization method was compared with a prior ventricular CSF regularization. Both reconstruction methods were compared in a repeatability study of 12 healthy subjects using t-test on susceptibility measurements, and in patient studies of 17 multiple sclerosis (MS) and 10 Parkinson's disease (PD) patients using Wilcoxon rank-sum test on radiological scores. RESULTS: In scan-rescan experiments, global CSF regularization provided more consistent CSF volume as well as higher repeatability of QSM measurements than ventricular CSF regularization with a smaller bias: -2.7 parts per billion (ppb) versus -0.13 ppb (t-test p<0.05) and a narrower 95% limits of agreement: [-7.25, 6.99] ppb versus [-16.60, 11.19 ppb] (f-test p<0.05). In PD and MS patients, global CSF regularization reduced smoothly varying shadow artifacts and significantly improved the QSM quality score (p<0.001). CONCLUSIONS: The proposed whole brain CSF method for QSM zero referencing improves repeatability and image quality of brain QSM compared to the ventricular CSF method.

Dimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions.

BACKGROUND AND OBJECTIVES: To determine the effects of dimethyl fumarate (DMF) and glatiramer acetate on iron content in chronic active lesions in patients with multiple sclerosis (MS) and in human microglia in vitro. METHODS: This was a retrospective observational study of 34 patients with relapsing-remitting MS and clinically isolated syndrome treated with DMF or glatiramer acetate. Patients had lesions with hyperintense rims on quantitative susceptibility mapping, were treated with DMF or glatiramer acetate (GA), and had a minimum of 2 on-treatment scans. Changes in susceptibility in rim lesions were compared among treatment groups in a linear mixed effects model. In a separate in vitro study, induced pluripotent stem cell-derived human microglia were treated with DMF or GA, and treatment-induced changes in iron content and activation state of microglia were compared. RESULTS: Rim lesions in patients treated with DMF had on average a 2.77-unit reduction in susceptibility per year over rim lesions in patients treated with GA (bootstrapped 95% CI -5.87 to -0.01), holding all other variables constant. Moreover, DMF but not GA reduced inflammatory activation and concomitantly iron content in human microglia in vitro. DISCUSSION: Together, our data indicate that DMF-induced reduction of susceptibility in MS lesions is associated with a decreased activation state in microglial cells. We have demonstrated that a specific disease modifying therapy, DMF, decreases glial activity in chronic active lesions. Susceptibility changes in rim lesions provide an in vivo biomarker for the effect of DMF on microglial activity. CLASSIFICATION OF EVIDENCE: This study provided Class III evidence that DMF is superior to GA in the presence of iron as a marker of inflammation as measured by MRI quantitative susceptibility mapping.

Quantitative evaluation of brain iron accumulation in different stages of Parkinson's disease.

BACKGROUND AND PURPOSE: Excessive brain iron deposition is involved in Parkinson's disease (PD) pathogenesis. However, the correlation of iron accumulation in various brain nuclei is not well-established in different stages of the disease. This cross-sectional study aims to evaluate quantitative susceptibility mapping (QSM) as an imaging technique to measure brain iron accumulation in PD patients in different stages compared to healthy controls. METHODS: Ninety-six PD patients grouped by their Hoehn and Yahr (H&Y) stages and 31 healthy controls were included in this analysis. The magnetic susceptibility values of the substantia nigra (SN), red nucleus (RN), caudate, putamen, and globus pallidus were obtained and compared. RESULTS: Iron level was increased in the SN of PD patients in all stages versus controls (p < .001), with no significant difference within stages. Iron in the RN was significantly increased in stage II versus controls (p = .013) and combined stages III and IV versus controls (p < .001). The iron levels in caudate, putamen, and globus pallidus were not different between any groups. CONCLUSIONS: Our data suggest iron accumulation occurs early in the disease course and only in the SN and RN of these patients. This is a large cross-sectional study of brain iron deposition in PD patients according to H&Y staging. Prospective studies are warranted to further validate QSM as a method to follow brain iron, which could serve as a disease biomarker and a therapeutic target.

Influence of simultaneous pressor and vasodilatory agents on the evolution of infarct growth in experimental acute middle cerebral artery occlusion.

BACKGROUND: This study sought to test the hypothesis that simultaneous central blood pressure elevation and potent vasodilation can mitigate pial collateral-dependent infarct growth in acute ischemic stroke. METHODS: Twenty mongrel canines (20-30 kg) underwent permanent middle cerebral artery occlusion (MCAO). Eight subjects received continuous infusion of norepinephrine (0.1-1.5200 µg/kg/min; titrated to a median of 34 mmHg above baseline mean arterial pressure) and hydralazine (20 mg) starting 30 min following MCAO. Pial collateral recruitment was scored prior to treatment and used to predict infarct volume based on a previously reported parameterization. Serial diffusion magnetic resonance imaging (MRI) acquisitions tracked infarct volumes over a 4-hour time frame. Infarct volumes and infarct volume growth between treatment and control groups were compared with each other and to predicted values. Fluid-attenuated inversion recovery (FLAIR) MRI, susceptibility weighted imaging (SWI), and necropsy findings were included in the evaluation. RESULTS: Differences between treatment and control group varied by pial collateral recruitment based on indicator-variable regression effects analysis with interaction confirmed by regression model fit. Benefit in treatment group was only in subjects with poor collaterals which had 35.7% less infarct volume growth (P=0.0008; ANOVA) relative to controls. Measured infarct growth was significantly lower than predicted by the model (linear regression partial F-test, slope P<0.001, intercept=0.003). There was no evidence for cerebral hemorrhage or posterior reversible encephalopathy syndrome. CONCLUSION: Our results indicate that a combination of norepinephrine and hydralazine administered in the acute phase of ischemic stroke mitigates infarct evolution in subjects with poor but not good collateral recruitment.