Recommended implementation of quantitative susceptibility mapping for clinical research in the brain: A consensus of the ISMRM electro-magnetic tissue properties study group.

This article provides recommendations for implementing QSM for clinical brain research. It is a consensus of the International Society of Magnetic Resonance in Medicine, Electro-Magnetic Tissue Properties Study Group. While QSM technical development continues to advance rapidly, the current QSM methods have been demonstrated to be repeatable and reproducible for generating quantitative tissue magnetic susceptibility maps in the brain. However, the many QSM approaches available have generated a need in the neuroimaging community for guidelines on implementation. This article outlines considerations and implementation recommendations for QSM data acquisition, processing, analysis, and publication. We recommend that data be acquired using a monopolar 3D multi-echo gradient echo (GRE) sequence and that phase images be saved and exported in Digital Imaging and Communications in Medicine (DICOM) format and unwrapped using an exact unwrapping approach. Multi-echo images should be combined before background field removal, and a brain mask created using a brain extraction tool with the incorporation of phase-quality-based masking. Background fields within the brain mask should be removed using a technique based on SHARP or PDF, and the optimization approach to dipole inversion should be employed with a sparsity-based regularization. Susceptibility values should be measured relative to a specified reference, including the common reference region of the whole brain as a region of interest in the analysis. The minimum acquisition and processing details required when reporting QSM results are also provided. These recommendations should facilitate clinical QSM research and promote harmonized data acquisition, analysis, and reporting.

Paramagnetic rim lesions predict greater long-term relapse rates and clinical progression over 10 years.

BACKGROUND: Paramagnetic rim lesions (PRLs) have been linked to higher clinical disease severity and relapse frequency. However, it remains unclear whether PRLs predict future, long-term disease progression. OBJECTIVES: The study aimed to assess whether baseline PRLs were associated with subsequent long-term (10 years) Expanded Disability Status Scale (EDSS) increase and relapse frequency and, if so, whether PRL-associated EDSS increase was mediated by relapse. METHODS: This retrospective analysis included 172 people with multiple sclerosis (pwMS) with 1868 yearly clinical visits over a mean follow-up time of 10.2 years. 3T magnetic resonance imaging (MRI) was acquired at baseline and PRLs were assessed on quantitative susceptibility mapping (QSM) images. The associations between PRLs, relapse, and rate of EDSS change were assessed using linear models. RESULTS: PRL+ pwMS had greater overall annual relapse rate (ß = 0.068; p = 0.010), three times greater overall odds of relapse (exp(ß) = 3.472; p = 0.009), and greater rate of yearly EDSS change (ß = 0.045; p = 0.010) than PRL- pwMS. Greater PRL number was associated with greater odds of at least one progression independent of relapse activity (PIRA) episode over follow-up (exp(ß) = 1.171, p = 0.009). Mediation analysis showed that the association between PRL presence (yes/no) and EDSS increase was 96.7% independent of relapse number. CONCLUSION: PRLs are a marker of aggressive ongoing disease inflammatory activity, including more frequent future clinical relapses and greater long-term, relapse-independent disability progression.

Paramagnetic rim lesions are associated with greater incidence of relapse and worse cognitive recovery following relapse.

BACKGROUND: Paramagnetic rim lesions (PRL) may be linked to relapse risk of people with relapsing-remitting multiple sclerosis (pwRRMS). OBJECTIVE: To determine the relationship between presence of PRL lesions and cognitive recovery after relapse. METHODS: PRL load was compared between acutely relapsing pwRRMS and matched stable pwRRMS controls (each group n = 21). In addition, cognitive recovery was compared between acutely relapsing pwRRMS with at least one PRL (PRL+) and those without any PRL (PRL-). RESULTS: Acutely relapsing pwRRMS had significantly greater prevalence and number of PRL (p = 0.004 and p = 0.003) compared with stable controls. These findings remained significant after adjusting for global neuroinflammatory burden (enhancing and non-enhancing lesions). In addition, acutely relapsing PRL + pwRRMS (n = 10) had worse recovery of verbal memory following relapse compared with acutely relapsing PRL - pwRRMS (n = 7; p = 0.027). CONCLUSION: These findings may partially explain previously suggested associations between presence of PRL with more severe disease course.

Effect of Siponimod on Brain and Spinal Cord Imaging Markers of Neurodegeneration in the Theiler's Murine Encephalomyelitis Virus Model of Demyelination.

Siponimod (Sp) is a Sphingosine 1-phosphate (S1P) receptor modulator, and it suppresses S1P- mediated autoimmune lymphocyte transport and inflammation. Theiler's murine encephalomyelitis virus (TMEV) infection mouse model of multiple sclerosis (MS) exhibits inflammation-driven acute and chronic phases, spinal cord lesions, brain and spinal cord atrophy, and white matter injury. The objective of the study was to investigate whether Sp treatment could attenuate inflammation-induced pathology in the TMEV model by inhibiting microglial activation and preventing the atrophy of central nervous tissue associated with neurodegeneration. Clinical disability score (CDS), body weight (BW), and rotarod retention time measures were used to assess Sp's impact on neurodegeneration and disease progression in 4 study groups of 102 animals, including 44 Sp-treated (SpT), 44 vehicle-treated, 6 saline-injected, and 8 age-matched healthy controls (HC). Next, 58 (22 SpT, 22 vehicle, 6 saline injected, and 8 HC) out of the 102 animals were further evaluated to assess the effect of Sp on brain region-specific and spinal cord volume changes, as well as microglial activation. Sp increased CDS and decreased BW and rotarod retention time in TMEV mice, but did not significantly affect most brain region volumes, except for lateral ventricle volume. Sp suppressed ventricular enlargement, suggesting reduced TMEV-induced inflammation in LV. No significant differences in spine volume changes were observed between Sp- and vehicle-treated animals, but there were differences between HC and TMEV groups, indicating TMEV-induced inflammation contributed to increased spine volume. Spine histology revealed no significant microglial density differences between groups in gray matter, but HC animals had higher type 1 morphology and lower type 2 morphology percentages in gray and white matter regions. This suggests that Sp did not significantly affect microglial density but may have modulated neuroinflammation in the spinal cord. Sp may have some effects on neuroinflammation and ventricular enlargement. However, it did not demonstrate a significant impact on neurodegeneration, spinal volume, or lesion volume in the TMEV mouse model. Further investigation is required to fully understand Sp's effect on microglial activation and its relevance to the pathophysiology of MS. The differences between the current study and previous research using other MS models, such as EAE, highlight the differences in pathological processes in these two disease models.

Susceptibility networks reveal independent patterns of brain iron abnormalities in multiple sclerosis.

Brain iron homeostasis is necessary for healthy brain function. MRI and histological studies have shown altered brain iron levels in the brains of patients with multiple sclerosis (MS), particularly in the deep gray matter (DGM). Previous studies were able to only partially separate iron-modifying effects because of incomplete knowledge of iron-modifying processes and influencing factors. It is therefore unclear to what extent and at which stages of the disease different processes contribute to brain iron changes. We postulate that spatially covarying magnetic susceptibility networks determined with Independent Component Analysis (ICA) reflect, and allow for the study of, independent processes regulating iron levels. We applied ICA to quantitative susceptibility maps for 170 individuals aged 9-81 years without neurological disease ("Healthy Aging" (HA) cohort), and for a cohort of 120 patients with MS and 120 age- and sex-matched healthy controls (HC; together the "MS/HC" cohort). Two DGM-associated "susceptibility networks" identified in the HA cohort (the Dorsal Striatum and Globus Pallidus Interna Networks) were highly internally reproducible (i.e. "robust") across multiple ICA repetitions on cohort subsets. DGM areas overlapping both robust networks had higher susceptibility levels than DGM areas overlapping only a single robust network, suggesting that these networks were caused by independent processes of increasing iron concentration. Because MS is thought to accelerate brain aging, we hypothesized that associations between age and the two robust DGM-associated networks would be enhanced in patients with MS. However, only one of these networks was altered in patients with MS, and it had a null age association in patients with MS rather than a stronger association. Further analysis of the MS/HC cohort revealed three additional disease-related networks (the Pulvinar, Mesencephalon, and Caudate Networks) that were differentially altered between patients with MS and HCs and between MS subtypes. Exploratory regression analyses of the disease-related networks revealed differential associations with disease duration and T2 lesion volume. Finally, analysis of ROI-based disease effects in the MS/HC cohort revealed an effect of disease status only in the putamen ROI and exploratory regression analysis did not show associations between the caudate and pulvinar ROIs and disease duration or T2 lesion volume, showing the ICA-based approach was more sensitive to disease effects. These results suggest that the ICA network framework increases sensitivity for studying patterns of brain iron change, opening a new avenue for understanding brain iron physiology under normal and disease conditions.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging for the Prediction of Monoclonal Antibody Tumor Disposition.

The prediction of monoclonal antibody (mAb) disposition within solid tumors for individual patients is difficult due to inter-patient variability in tumor physiology. Improved a priori prediction of mAb pharmacokinetics in tumors may facilitate the development of patient-specific dosing protocols and facilitate improved selection of patients for treatment with anti-cancer mAb. Here, we report the use of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), with tumor penetration of the contrast agent gadobutrol used as a surrogate, to improve physiologically based pharmacokinetic model (PBPK) predictions of cetuximab pharmacokinetics in epidermal growth factor receptor (EGFR) positive xenografts. In the initial investigations, mice bearing Panc-1, NCI-N87, and LS174T xenografts underwent DCE-MRI imaging with the contrast agent gadobutrol, followed by intravenous dosing of an 125Iodine-labeled, non-binding mAb (8C2). Tumor concentrations of 8C2 were determined following the euthanasia of mice (3 h-6 days after 8C2 dosing). Potential predictor relationships between DCE-MRI kinetic parameters and 8C2 PBPK parameters were evaluated through covariate modeling. The addition of the DCE-MRI parameter Ktrans alone or Ktrans in combination with the DCE-MRI parameter Vp on the PBPK parameters for tumor blood flow (QTU) and tumor vasculature permeability (σTUV) led to the most significant improvement in the characterization of 8C2 pharmacokinetics in individual tumors. To test the utility of the DCE-MRI covariates on a priori prediction of the disposition of mAb with high-affinity tumor binding, a second group of tumor-bearing mice underwent DCE-MRI imaging with gadobutrol, followed by the administration of 125Iodine-labeled cetuximab (a high-affinity anti-EGFR mAb). The MRI-PBPK covariate relationships, which were established with the untargeted antibody 8C2, were implemented into the PBPK model with considerations for EGFR expression and cetuximab-EGFR interaction to predict the disposition of cetuximab in individual tumors (a priori). The incorporation of the Ktrans MRI parameter as a covariate on the PBPK parameters QTU and σTUV decreased the PBPK model prediction error for cetuximab tumor pharmacokinetics from 223.71 to 65.02%. DCE-MRI may be a useful clinical tool in improving the prediction of antibody pharmacokinetics in solid tumors. Further studies are warranted to evaluate the utility of the DCE-MRI approach to additional mAbs and additional drug modalities.

Decreasing brain iron in multiple sclerosis: The difference between concentration and content in iron MRI.

Increased brain iron concentration is often reported concurrently with disease development in multiple sclerosis (MS) and other neurodegenerative diseases. However, it is unclear whether the higher iron concentration in patients stems from an influx of iron into the tissue or a relative reduction in tissue compartments without much iron. By taking into account structural volume, we investigated tissue iron content in the deep gray matter (DGM) over 2 years, and compared findings to previously reported changes in iron concentration. 120 MS patients and 40 age- and sex-matched healthy controls were included. Clinical testing and MRI were performed both at baseline and after 2 years. Overall, iron content was calculated from structural MRI and quantitative susceptibility mapping in the thalamus, caudate, putamen, and globus pallidus. MS patients had significantly lower iron content than controls in the thalamus, with progressive MS patients demonstrating lower iron content than relapsing-remitting patients. Over 2 years, iron content decreased in the DGM of patients with MS, while it tended to increase or remain stable among controls. In the thalamus, decreasing iron content over 2 years was associated with disability progression. Our study showed that temporally increasing magnetic susceptibility in MS should not be considered as evidence for iron influx because it may be explained, at least partially, by disease-related atrophy. Declining DGM iron content suggests that, contrary to the current understanding, iron is being removed from the DGM in patients with MS.

QSM reconstruction challenge 2.0: Design and report of results.

PURPOSE: The aim of the second quantitative susceptibility mapping (QSM) reconstruction challenge (Oct 2019, Seoul, Korea) was to test the accuracy of QSM dipole inversion algorithms in simulated brain data. METHODS: A two-stage design was chosen for this challenge. The participants were provided with datasets of multi-echo gradient echo images synthesized from two realistic in silico head phantoms using an MR simulator. At the first stage, participants optimized QSM reconstructions without ground truth data available to mimic the clinical setting. At the second stage, ground truth data were provided for parameter optimization. Submissions were evaluated using eight numerical metrics and visual ratings. RESULTS: A total of 98 reconstructions were submitted for stage 1 and 47 submissions for stage 2. Iterative methods had the best quantitative metric scores, followed by deep learning and direct inversion methods. Priors derived from magnitude data improved the metric scores. Algorithms based on iterative approaches and total variation (and its derivatives) produced the best overall results. The reported results and analysis pipelines have been made public to allow researchers to compare new methods to the current state of the art. CONCLUSION: The synthetic data provide a consistent framework to test the accuracy and robustness of QSM algorithms in the presence of noise, calcifications and minor voxel dephasing effects. Total Variation-based algorithms produced the best results among all metrics. Future QSM challenges should assess whether this good performance with synthetic datasets translates to more realistic scenarios, where background fields and dipole-incompatible phase contributions are included.

QSM reconstruction challenge 2.0: A realistic in silico head phantom for MRI data simulation and evaluation of susceptibility mapping procedures.

PURPOSE: To create a realistic in silico head phantom for the second QSM reconstruction challenge and for future evaluations of processing algorithms for QSM. METHODS: We created a digital whole-head tissue property phantom by segmenting and postprocessing high-resolution (0.64 mm isotropic), multiparametric MRI data acquired at 7 T from a healthy volunteer. We simulated the steady-state magnetization at 7 T using a Bloch simulator and mimicked a Cartesian sampling scheme through Fourier-based processing. Computer code for generating the phantom and performing the MR simulation was designed to facilitate flexible modifications of the phantom in the future, such as the inclusion of pathologies as well as the simulation of a wide range of acquisition protocols. Specifically, the following parameters and effects were implemented: TR and TE, voxel size, background fields, and RF phase biases. Diffusion-weighted imaging phantom data are provided, allowing future investigations of tissue-microstructure effects in phase and QSM algorithms. RESULTS: The brain part of the phantom featured realistic morphology with spatial variations in relaxation and susceptibility values similar to the in vivo setting. We demonstrated some of the phantom's properties, including the possibility of generating phase data with nonlinear evolution over TE due to partial-volume effects or complex distributions of frequency shifts within the voxel. CONCLUSION: The presented phantom and computer programs are publicly available and may serve as a ground truth in future assessments of the faithfulness of quantitative susceptibility reconstruction algorithms.

Thalamic Nuclei Volumes and Their Relationships to Neuroperformance in Multiple Sclerosis: A Cross-Sectional Structural MRI Study.

BACKGROUND: Although reduced thalamic volume is associated with multiple sclerosis (MS)-related clinical impairment, the role of individual thalamic nuclei remains poorly understood. PURPOSE/HYPOTHESIS: To test whether individual thalamic nuclei volumes are more strongly associated with clinical disability than the whole thalamic volume. STUDY TYPE: Retrospective analysis of a prospective dataset. SUBJECTS: A total of 108 MS patients and 48 age- and sex-matched healthy controls (HCs) FIELD STRENGTH: 3T. SEQUENCES: 3D T1 -weighted inversion recovery spoiled gradient echo; 2D T2 -weighted fluid-attenuated inversion recovery spin echo; 2D dual-echo proton density-weighted/T2 -weighted spin echo. ASSESSMENTS: Clinical assessments included the Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMTR), and the California Verbal Learning Test (CVLT2). FreeSurfer provided anterior, intralaminar, lateral, medial, ventral, posterior, and total volumes. STATISTICAL TESTS: False discovery rate-corrected partial correlations (controlling for age, sex, and education) to assess the relationships between volumes and neuroperformance. RESULTS: Compared to HCs, MS patients presented with lower thalamic nuclei volumes (P < 0.05) except for the intralaminar nucleus (P = 0.279) and scored worse on all neuroperformance scales (P ≤ 0.05) except for CVLT2 (P = 0.151). All nuclei except intralaminar were associated with EDSS (correlation coefficient range: -0.233 to -0.395), SDMT (range: 0.247-0.423), and 9HPT (range: -0.232 to -0.303) (all P < 0.05). BVMTR was associated with anterior (r = 0.319), lateral (r = 0.31), and medial (r = 0.304) volumes (all P < 0.05). T25FW correlated with ventral (r = -0.392) and total (r = -0.309) volumes (both P < 0.05), with the latter being significantly greater (P < 0.05). DATA CONCLUSION: Assessing individual nuclei volume can aid in unraveling the relationship between thalamic pathology and disparate aspects of MS-related disability. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

Assessment of mesoscopic properties of deep gray matter iron through a model-based simultaneous analysis of magnetic susceptibility and R2* - A pilot study in patients with multiple sclerosis and normal controls.

Most studies of brain iron relied on the effect of the iron on magnetic resonance (MR) relaxation properties, such as R2∗, and bulk tissue magnetic susceptibility, as measured by quantitative susceptibility mapping (QSM). The present study exploited the dependence of R2∗ and magnetic susceptibility on physical interactions at different length-scales to retrieve information about the tissue microenvironment, rather than the iron concentration. We introduce a method for the simultaneous analysis of brain tissue magnetic susceptibility and R2∗ that aims to isolate those biophysical mechanisms of R2∗ -contrast that are associated with the micro- and mesoscopic distribution of iron, referred to as the Iron Microstructure Coefficient (IMC). The present study hypothesized that changes in the deep gray matter (DGM) magnetic microenvironment associated with aging and pathological mechanisms of multiple sclerosis (MS), such as changes of the distribution and chemical form of the iron, manifest in quantifiable contributions to the IMC. To validate this hypothesis, we analyzed the voxel-based association between R2∗ and magnetic susceptibility in different DGM regions of 26 patients with multiple sclerosis and 33 age- and sex-matched normal controls. Values of the IMC varied significantly between anatomical regions, were reduced in the dentate and increased in the caudate of patients compared to controls, and decreased with normal aging, most strongly in caudate, globus pallidus and putamen.

Visualization of thalamic calcium influx with quantitative susceptibility mapping as a potential imaging biomarker for repeated mild traumatic brain injury.

A key event in the pathophysiology of traumatic brain injury (TBI) is the influx of substantial amounts of Ca2+ into neurons, particularly in the thalamus. Detection of this calcium influx in vivo would provide a window into the biochemical mechanisms of TBI with potentially significant clinical implications. In the present work, our central hypothesis was that the Ca2+ influx could be imaged in vivo with the relatively recent MRI technique of quantitative susceptibility mapping (QSM). Wistar rats were divided into five groups: naive controls, sham-operated experimental controls, single mild TBI, repeated mild TBI, and single severe TBI. We employed the lateral fluid percussion injury (FPI) model, which replicates clinical TBI without skull fracture, performed 9.4 Tesla MRI with a 3D multi-echo gradient-echo sequence at weeks 1 and 4 post-injury, computed susceptibility maps using V-SHARP and the QUASAR-HEIDI technique, and performed histology. Sham, experimental controls animals, and injured animals did not demonstrate calcifications at 1 week after the injury. At week 4, calcifications were found in the ipsilateral thalamus of 25-50% of animals after a single TBI and 83% of animals after repeated mild TBI. The location and appearance of calcifications on stained sections was consistent with the appearance on the in vivo susceptibility maps (correlation of volumes: r = 0.7). Our findings suggest that persistent calcium deposits represent a primary pathology of repeated injury and that FPI-QSM has the potential to become a sensitive tool for studying pathophysiology related to mild TBI in vivo.

Ventral posterior substantia nigra iron increases over 3 years in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is characterized in part by the progressive accumulation of iron within the substantia nigra (SN); however, its spatial and temporal dynamics remain relatively poorly understood. OBJECTIVES: The objective of this study was to investigate spatial patterns and temporal evolution of SN iron accumulation in PD. METHODS: A total of 18 PD patients (mean disease duration = 6.2 years) receiving dopaminergic therapy and 16 healthy controls were scanned with 3T MRI at baseline and 3 years later using quantitative susceptibility mapping, an indirect marker of iron content. Iron was assessed separately in the posterior SN and anterior SN at the ventral and dorsal levels of the SN. The results were corrected for the false discovery rate. RESULTS: A significant group effect was found for the ventral posterior SN (P < .001) and anterior SN (P = .042) quantitative susceptibility mapping as well as significant group x time interaction effects (P = .02 and P = .043, respectively). In addition, a significant intragroup change during 3 years of follow-up was found only in the ventral posterior SN of PD (P = .012), but not healthy controls. No significant effects were detected for any dorsal SN measures. No associations were identified with clinical measures. CONCLUSIONS: We found both cross-sectional and longitudinal SN iron changes to be confined to its more ventral location in PD. Because pathology studies also show the ventral SN to degenerate early and to the greatest extent in PD, the assessment of iron levels by quantitative susceptibility mapping in this area may potentially represent a disease progression biomarker in PD. © 2019 International Parkinson and Movement Disorder Society.

Reinforcer pathology: Common neural substrates for delay discounting and snack purchasing in prediabetics.

Reinforcer pathology theory stipulates that individuals with both (a) high preference for smaller, immediate over larger, delayed rewards; and (b) high demand for unhealthy commodities are uniquely susceptible to poor health outcomes. Specifically, two behavioral economic tasks (delay discounting, assessing preference for smaller, immediate or larger, delayed rewards; and purchasing, assessing purchases of commodities over changes in price) have been independently associated with conditions such as overweight/obesity and problem substance use. In the present study, we examined possible shared neural regions involved in the processes of delay discounting and demand for snack foods in a prediabetic sample. Fifty-four participants completed both of these tasks. Conjunction between delay discounting and purchasing task results indicates substantial common neural substrates recruited during these two tasks, consistent with interpretations of executive control, interoception, and attention, in the prefrontal cortex, insula, and frontoparietal cortex (superior/middle frontal cortex and superior/inferior parietal lobules), respectively. Collectively, these results suggest possible neural substrates in which the two behavioral risk factors of reinforcer pathology may interact during real-world decision-making in prediabetes.

Mapping of thalamic magnetic susceptibility in multiple sclerosis indicates decreasing iron with disease duration: A proposed mechanistic relationship between inflammation and oligodendrocyte vitality.

Recent advances in susceptibility MRI have dramatically improved the visualization of deep gray matter brain regions and the quantification of their magnetic properties in vivo, providing a novel tool to study the poorly understood iron homeostasis in the human brain. In this study, we used an advanced combination of the recent quantitative susceptibility mapping technique with dedicated analysis methods to study intra-thalamic tissue alterations in patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS). Thalamic pathology is one of the earliest hallmarks of MS and has been shown to correlate with cognitive dysfunction and fatigue, but the mechanisms underlying the thalamic pathology are poorly understood. We enrolled a total of 120 patients, 40 with CIS, 40 with Relapsing Remitting MS (RRMS), and 40 with Secondary Progressive MS (SPMS). For each of the three patient groups, we recruited 40 controls, group matched for age- and sex (120 total). We acquired quantitative susceptibility maps using a single-echo gradient echo MRI pulse sequence at 3 T. Group differences were studied by voxel-based analysis as well as with a custom thalamus atlas. We used threshold-free cluster enhancement (TFCE) and multiple regression analyses, respectively. We found significantly reduced magnetic susceptibility compared to controls in focal thalamic subregions of patients with RRMS (whole thalamus excluding the pulvinar nucleus) and SPMS (primarily pulvinar nucleus), but not in patients with CIS. Susceptibility reduction was significantly associated with disease duration in the pulvinar, the left lateral nuclear region, and the global thalamus. Susceptibility reduction indicates a decrease in tissue iron concentration suggesting an involvement of chronic microglia activation in the depletion of iron from oligodendrocytes in this central and integrative brain region. Not necessarily specific to MS, inflammation-mediated iron release may lead to a vicious circle that reduces the protection of axons and neuronal repair.

Thalamic white matter in multiple sclerosis: A combined diffusion-tensor imaging and quantitative susceptibility mapping study.

Thalamic white matter (WM) injury in multiple sclerosis (MS) remains relatively poorly understood. Combining multiple imaging modalities, sensitive to different tissue properties, may aid in further characterizing thalamic damage. Forty-five MS patients and 17 demographically-matched healthy controls (HC) were scanned with 3T MRI to obtain quantitative measures of diffusivity and magnetic susceptibility. Participants underwent cognitive evaluation with the Brief International Cognitive Assessment for Multiple Sclerosis battery. Tract-based spatial statistics identified thalamic WM. Non-parametric combination (NPC) analysis was used to perform joint inference on fractional anisotropy (FA), mean diffusivity (MD) and magnetic susceptibility measures. The association of surrounding WM lesions and thalamic WM pathology was investigated with lesion probability mapping. Compared to HCs, the greatest extent of thalamic WM damage was reflected by the combination of increased MD and decreased magnetic susceptibility (63.0% of thalamic WM, peak p = .001). Controlling for thalamic volume resulted in decreased FA and magnetic susceptibility (34.1%, peak p = .004) as showing the greatest extent. In MS patients, the most widespread association with information processing speed was found with the combination of MD and magnetic susceptibility (67.6%, peak p = .0005), although this was not evident after controlling for thalamic volume. For memory measures, MD alone yielded the most widespread associations (45.9%, peak p = .012 or 76.7%, peak p = .001), even after considering thalamic volume, albeit with smaller percentages. White matter lesions were related to decreased FA (peak p = .0063) and increased MD (peak p = .007), but not magnetic susceptibility, of thalamic WM. Our study highlights the complex nature of thalamic pathology in MS.

Brain Iron at Quantitative MRI Is Associated with Disability in Multiple Sclerosis.

Purpose To study deep gray matter susceptibility in multiple sclerosis (MS) by using quantitative susceptibility mapping (QSM) and to assess the relationship between susceptibility and clinical disability. Materials and Methods For this prospective study between March 2009 and November 2013, 600 participants with MS (452 with relapsing-remitting MS and 148 with secondary progressive MS) and 250 age- and sex-matched healthy control participants were imaged with 3.0-T MRI to measure magnetic susceptibility. Deep gray matter susceptibility (in parts per billion) was analyzed by using region of interest and voxelwise methods. QSM and MRI volumetric differences between study groups and associations with clinical outcomes were assessed. Analysis of covariance, multivariable linear regression, and voxelwise analyses, controlling for age and sex, were used to compare study groups and to explore associations between MRI and clinical outcomes. Results Compared with control participants, participants with MS presented with lower thalamic susceptibility (-7.5 ppb vs -1.1 ppb; P < .001) and higher susceptibility of basal ganglia (62 ppb vs 54.8 ppb; P < .001). Lower thalamic susceptibility was associated with longer disease duration (ß = -0.42; P = .002), higher degree of disability (ß = -0.64; P = .03), and secondary-progressive course (ß = -4.3; P = .009). Higher susceptibility of the globus pallidus was associated with higher disability (ß = 2; P = .03). After correcting for each individual structural volume in voxelwise analysis, lower thalamic susceptibility and higher susceptibility of the globus pallidus remained associated with clinical disability (P < .05). Conclusion Quantitative susceptibility mapping (QSM) suggests that altered deep gray matter iron is associated with the evolution of multiple sclerosis (MS) and on disability accrual, independent of tissue atrophy. © RSNA, 2018 Online supplemental material is available for this article.

Quantitative susceptibility mapping: Report from the 2016 reconstruction challenge.

PURPOSE: The aim of the 2016 quantitative susceptibility mapping (QSM) reconstruction challenge was to test the ability of various QSM algorithms to recover the underlying susceptibility from phase data faithfully. METHODS: Gradient-echo images of a healthy volunteer acquired at 3T in a single orientation with 1.06 mm isotropic resolution. A reference susceptibility map was provided, which was computed using the susceptibility tensor imaging algorithm on data acquired at 12 head orientations. Susceptibility maps calculated from the single orientation data were compared against the reference susceptibility map. Deviations were quantified using the following metrics: root mean squared error (RMSE), structure similarity index (SSIM), high-frequency error norm (HFEN), and the error in selected white and gray matter regions. RESULTS: Twenty-seven submissions were evaluated. Most of the best scoring approaches estimated the spatial frequency content in the ill-conditioned domain of the dipole kernel using compressed sensing strategies. The top 10 maps in each category had similar error metrics but substantially different visual appearance. CONCLUSION: Because QSM algorithms were optimized to minimize error metrics, the resulting susceptibility maps suffered from over-smoothing and conspicuity loss in fine features such as vessels. As such, the challenge highlighted the need for better numerical image quality criteria. Magn Reson Med 79:1661-1673, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Quantitative susceptibility mapping (QSM) with an extended physical model for MRI frequency contrast in the brain: a proof-of-concept of quantitative susceptibility and residual (QUASAR) mapping.

Quantitative susceptibility mapping (QSM) aims to calculate the tissue's magnetic susceptibility distribution from its perturbing effect on the MRI static main magnetic field. The method is increasingly being applied to study iron and myelin in clinical and preclinical settings. However, recent experimental and theoretical findings have challenged the fundamental theoretical assumptions that form the basis of current numerical implementations of QSM algorithms. The present work introduces a new class of susceptibility mapping algorithms, termed quantitative susceptibility and residual mapping (QUASAR), which takes into account frequency contributions not related to the spatial variation of bulk magnetic susceptibility in the Lorentz sphere model. We present a simple proof-of-concept QUASAR algorithm that, unlike most of the QSM algorithms currently used widely, results in an improved anatomical accuracy of the susceptibility distribution without any a priori assumptions about the susceptibility distribution during the field-to-source inversion. The algorithm was evaluated both in silico and in vivo in the preclinical setting. Our preliminary application of QUASAR in rodents provides the first in vivo evidence that the susceptibility-field model traditionally used in the QSM field cannot fully explain the frequency contrast in brain tissues. Only when an additional local frequency contribution is added to the physical model can the frequency contrast in the brain be related properly to the underlying anatomy.

Multimodal Imaging of Retired Professional Contact Sport Athletes Does Not Provide Evidence of Structural and Functional Brain Damage.

BACKGROUND: Long-term consequences of playing professional football and hockey on brain function and structural neuronal integrity are unknown. OBJECTIVES: To investigate multimodal metabolic and structural brain magnetic resonance imaging (MRI) differences in retired professional contact sport athletes compared with noncontact sport athletes. METHODS: Twenty-one male contact sport athletes and 21 age-matched noncontact sport athletes were scanned on a 3 tesla (3T) MRI using a multimodal imaging approach. The MRI outcomes included presence, number, and volume of focal white matter signal abnormalities, volumes of global and regional tissue-specific brain structures, diffusion-tensor imaging tract-based spatial statistics measures of mean diffusivity and fractional anisotropy, quantitative susceptibility mapping of deep gray matter, presence, number, and volume of cerebral microbleeds, MR spectroscopy N-acetyl-aspartate, glutamate, and glutamine concentrations relative to creatine and phosphor creatine of the corpus callosum, and perfusion-weighted imaging mean transit time, cerebral blood flow, and cerebral blood volume outcomes. Subjects were also classified as having mild cognitive impairment. RESULTS: No significant differences were found for structural or functional MRI measures between contact sport athletes and noncontact sport athletes. CONCLUSIONS: This multimodal imaging study did not show any microstructural, metabolic brain tissue injury differences in retired contact versus non-contact sport athletes.