Pathway to Independence Awards (K99/R00): Funding Dynamics and Prediction of Future National Institutes of Health Research Project Funding.

PURPOSE: The authors used the National Institutes of Health (NIH) RePORTER (Research Portfolio Online Reporting Tools) to evaluate funding trends and historic NIH investment increase in the K99 award pathway and examine whether R00 to R01 or R21 achievement time correlated with the future success of an early-stage NIH-funded investigator. METHOD: All K99 awards and funding data in this study were limited to all clinical departments. The authors identified all researchers and awards through a K99 search from fiscal years (FYs) 2007 to 2022 across all clinical departments and investigated trends in K99 awards and funding from NIH FYs 2007 to 2022. They generated an R00 data set and analyzed the K99 to R00 achievement statistics from FYs 2007 to 2022. The authors aggregated NIH annual data files for FYs 2007 to 2021 to generate a master data file of all R01 and R21 awards. They linked R01 and R21 award data to the researcher previously identified through the K99 search and focused on the connection between K99/R00 awardees and subsequent R01 or R21 awards. RESULTS: From FY 2008 to FY 2022, the NIH K99 budget increased 127.0%, whereas the NIH program-level budget increased 17.3%. A principal investigator's mean funding per year significantly decreased as time from R00 to R01 or R21 increased ( P < .001); 7 of 15 comparisons differed significantly (2 at P < .01 and 5 at P < .001). CONCLUSIONS: NIH investment in the K99 award pathway has substantially outpaced the NIH program-level budget increase, and there is a strong association between mean funding per year since the start of the R00 phase and time from R00 to R01 or R21. This analysis may be useful to clinical departments as they evaluate selecting new and retaining current biomedical scientists for independent research positions.

National Institutes of Health Funding Gaps for Principal Investigators.

Importance: Early-stage and established investigators compete for a limited supply of funds from the National Institutes of Health (NIH). Regardless of their previous funding success, many principal investigators (PIs) encounter a funding gap in which they no longer receive ongoing funding from the NIH. Objective: To determine incidence rates of PI-level funding gaps, the mean funding gap length, and whether these 2 metrics are associated with previous funding success. Design, Setting, and Participants: This study was conducted using data from NIH RePORTER. Historical datafiles for fiscal year (FY) 2011 to FY 2021 were aggregated to generate 2 master datafiles for this period: all NIH awards and only R01 awards. PIs with no funding in FY 2011 or FY 2021 were removed. PIs were sorted by FY 2011 total funding amounts and grouped by quarter of amount. Results: A total of 39 944 unique researchers were awarded 220 131 NIH awards, of which 103 753 were R01 awards. For all NIH awards, there was an overall linear increase from top quarter to bottom quarter in the percentage of PIs who had at least 1 year without funding (from 27% to 75%), percentage of these gap PIs who had at least 2 consecutive years without funding (from 56% to 68%), and mean maximum consecutive years without funding for gap PIs (2.2 years to 3.1 years). For only R01 awards, there was an overall linear increase from top quarter to bottom quarter in the percentage of PIs who had at least 1 year without funding (50% to 74%), percentage of gap PIs who had at least 2 consecutive years without funding (59% to 71%), and mean maximum consecutive years without funding for gap PIs (2.4 years to 3.1 years). Conclusions and Relevance: In this cohort study of NIH-funded investigators, PIs with higher NIH funding were less likely to experience a funding gap. Additionally, when these PIs encountered a funding gap, this period without funding was shorter; however, among all PIs, funding gaps typically lasted 2 to 3 years. These associations were found inclusive of all NIH awards and when analysis was limited to only R01 awards. These findings may be useful to PIs and academic institutions as they prepare, structure, and project research resource allocations.

Age-dependent changes in brain iron deposition and volume in deep gray matter nuclei using quantitative susceptibility mapping.

BACKGROUND: Microstructural changes in deep gray matter (DGM) nuclei are related to physiological behavior, cognition, and memory. Therefore, it is critical to study age-dependent trajectories of biomarkers in DGM nuclei for understanding brain development and aging, as well as predicting cognitive or neurodegenerative diseases. OBJECTIVES: We aimed to (1) characterize age-dependent trajectories of mean susceptibility, adjusted volume, and total iron content simultaneously in DGM nuclei using quantitative susceptibility mapping (QSM); (2) examine potential contributions of sex related effects to the different age-dependence trajectories of volume and iron deposition; and (3) evaluate the ability of brain age prediction by combining mean magnetic susceptibility and volume of DGM nuclei. METHODS: Magnetic susceptibilities and volumetric values of DGM nuclei were obtained from 220 healthy participants (aged 10-70 years) scanned on a 3T MRI system. Regions of interest (ROIs) were drawn manually on the QSM images. Univariate regression analysis between age and each of the MRI measurements in a single ROI was performed. Pearson correlation coefficients were calculated between magnetic susceptibility and adjusted volume in a single ROI. The statistical significance of sex differences in age-dependent trajectories of magnetic susceptibilities and adjusted volumes were determined using one-way ANCOVA. Multiple regression analysis was used to evaluate the ability to estimate brain age using a combination of the mean susceptibilities and adjusted volumes in multiple DGM nuclei. RESULTS: Mean susceptibility and total iron content increased linearly, quadratically, or exponentially with age in all six DGM nuclei. Negative linear correlation was observed between adjusted volume and age in the head of the caudate nucleus (CN; R2 = 0.196, p < 0.001). Quadratic relationships were found between adjusted volume and age in the putamen (PUT; R2 = 0.335, p < 0.001), globus pallidus (GP; R2 = 0.062, p = 0.001), and dentate nucleus (DN; R2 = 0.077, p < 0.001). Males had higher mean magnetic susceptibility than females in the PUT (p = 0.001), red nucleus (RN; p = 0.002), and substantia nigra (SN; p < 0.001). Adjusted volumes of the CN (p < 0.001), PUT (p = 0.030), GP (p = 0.007), SN (p = 0.021), and DN (p < 0.001) were higher in females than those in males throughout the entire age range (10-70 years old). The total iron content of females was higher than that of males in the CN (p < 0.001), but lower than that of males in the PUT (p = 0.014) and RN (p = 0.043) throughout the entire age range (10-70 years old). Multiple regression analyses revealed that the combination of the mean susceptibility value of the PUT, and the volumes of the CN and PUT had the strongest associations with brain age (R2 = 0.586). CONCLUSIONS: QSM can be used to simultaneously investigate age- and sex- dependent changes in magnetic susceptibility and volume of DGM nuclei, thus enabling a comprehensive understanding of the developmental trajectories of iron accumulation and volume in DGM nuclei during brain development and aging.

Relationship Between Iron Distribution in Deep Gray Matter Nuclei Measured by Quantitative Susceptibility Mapping and Motor Outcome After Deep Brain Stimulation in Patients With Parkinson's Disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor deficits in advanced Parkinson's disease (PD) patients, but the degree of motor improvement varies across individuals. PD pathology involves the changes of iron spatial distribution in the deep gray matter nuclei. PURPOSE: To explore the relationship between the iron spatial distribution and motor improvement among PD patients who underwent STN-DBS surgery in three regions: substantia nigra (SN), STN, and dentate nucleus (DN). STUDY TYPE: Prospective. SUBJECTS: Forty PD patients (49.7 ± 8.8 years, 22 males/18 females) who underwent bilateral STN-DBS. FIELD STRENGTH/SEQUENCE: A 3 T preoperative three-dimensional spoiled bipolar-readout multi-echo gradient recalled echo and two-dimensional fast spin echo sequences. ASSESSMENT: Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) scores were assessed 2-3 days before and 6 months after STN-DBS. The first- and second-order texture features in regions of interest were measured on susceptibility maps. STATISTICAL TESTS: Intraclass correlation coefficient was used to determine the consistency of the region of interest volumes delineated by the two raters. Pearson or Spearman's correlation coefficients were used to assess the relationship between motor improvement after DBS and texture features. A P-value <0.05 was considered statistically significant. RESULTS: MDS-UPDRS III scores were reduced by 59.9% after STN-DBS in 40 PD patients. Motor improvement correlated with second-order texture parameters in the SN including angular second moment (r = -0.449), correlation (rho = 0.326), sum of squares (r = 0.402), sum of entropy (rho = 0.421), and entropy (r = 0.410). Additionally, DBS outcome negatively correlated with mean susceptibility values in the DN (r = -0.400). DATA CONCLUSION: PD patients with a more homogeneous iron distribution throughout the SN or a higher iron concentration in the DN responded worse to STN-DBS. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

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.

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.

Oxygen extraction fraction (OEF) assesses cerebral oxygen metabolism of deep gray matter in patients with pre-eclampsia.

OBJECTIVES: The objective of this study was to compare oxygen extraction fraction (OEF) values in the deep gray matter (GM) of pre-eclampsia (PE) patients, pregnant healthy controls (PHCs), and non-pregnant healthy controls (NPHCs) to explore their brain oxygen metabolism differences in GM. METHODS: Forty-seven PE patients, forty NPHCs, and twenty-one PHCs were included. Brain OEF values were computed from quantitative susceptibility mapping (QSM) plus quantitative blood oxygen level-dependent magnitude (QSM + qBOLD = QQ)-based mapping. One-way ANOVA was used to compare mean OEF values in the three groups. The area under the curve of the mean OEF value in each region of interest was estimated using a receiver operating characteristic curve analysis. RESULTS: We found that the mean OEF values in the thalamus, putamen, caudate nucleus, pallidum, and substantia nigra were significantly different in these three groups (F = 5.867, p = 0.004; F = 5.142, p = 0007; F = 6.158, p = 0.003; F = 6.319, p = 0.003; F = 5.491, p = 0.005). The mean OEF values for these 5 regions were higher in PE patients than in NPHCs and in PHCs (p < 0.05). The AUC of these ROIs ranged from 0.673 to 0.692 (p < 0.01) and cutoff values varied from 35.1 to 36.6%, indicating that the OEF values could discriminate patients with and without PE. Stepwise multivariate analysis revealed that the OEF values correlated with hematocrit in pregnant women (r = 0.353, p = 0.003). CONCLUSION: OEF values in the brains of pregnant women can be measured in clinical practice using QQ-based OEF mapping for noninvasive assessment of hypertensive disorders. KEY POINTS: • Pre-eclampsia is a hypertensive disorder associated with abnormalities in brain oxygen extraction. • Oxygen extraction fraction (OEF) is an indicator of brain tissue viability and function. QQ-based mapping of OEF is a new MRI technique that can noninvasively quantify brain oxygen metabolism. • OEF values in the brains of pregnant women can be measured for noninvasive assessment of hypertensive disorders in clinical practice.

Automated Segmentation of Midbrain Structures in High-Resolution Susceptibility Maps Based on Convolutional Neural Network and Transfer Learning.

BACKGROUND: Accurate delineation of the midbrain nuclei, the red nucleus (RN), substantia nigra (SN) and subthalamic nucleus (STN), is important in neuroimaging studies of neurodegenerative and other diseases. This study aims to segment midbrain structures in high-resolution susceptibility maps using a method based on a convolutional neural network (CNN). METHODS: The susceptibility maps of 75 subjects were acquired with a voxel size of 0.83 × 0.83 × 0.80 mm3 on a 3T MRI system to distinguish the RN, SN, and STN. A deeply supervised attention U-net was pre-trained with a dataset of 100 subjects containing susceptibility maps with a voxel size of 0.63 × 0.63 × 2.00 mm3 to provide initial weights for the target network. Five-fold cross-validation over the training cohort was used for all the models' training and selection. The same test cohort was used for the final evaluation of all the models. Dice coefficients were used to assess spatial overlap agreement between manual delineations (ground truth) and automated segmentation. Volume and magnetic susceptibility values in the nuclei extracted with automated CNN delineation were compared to those extracted by manual tracing. Consistencies of volume and magnetic susceptibility values by different extraction strategies were assessed by Pearson correlation coefficients and Bland-Altman analyses. RESULTS: The automated CNN segmentation method achieved mean Dice scores of 0.903, 0.864, and 0.777 for the RN, SN, and STN, respectively. There were no significant differences between the achieved Dice scores and the inter-rater Dice scores (p > 0.05 for each nucleus). The overall volume and magnetic susceptibility values of the nuclei extracted by the automatic CNN method were significantly correlated with those by manual delineation (p < 0.01). CONCLUSION: Midbrain structures can be precisely segmented in high-resolution susceptibility maps using a CNN-based method.

Brain oxygen extraction fraction mapping in patients with multiple sclerosis.

We aimed to demonstrate the feasibility of whole brain oxygen extraction fraction (OEF) mapping for measuring lesion specific and regional OEF abnormalities in multiple sclerosis (MS) patients. In 22 MS patients and 11 healthy controls (HC), OEF and neural tissue susceptibility (χn) maps were computed from MRI multi-echo gradient echo data. In MS patients, 80 chronic active lesions with hyperintense rim on quantitative susceptibility mapping were identified, and the mean OEF and χn within the rim and core were compared using linear mixed-effect model analysis. The rim showed higher OEF and χn than the core: relative to their adjacent normal appearing white matter, OEF contrast = -6.6 ± 7.0% vs. -9.8 ± 7.8% (p < 0.001) and χn contrast = 33.9 ± 20.3 ppb vs. 25.7 ± 20.5 ppb (p = 0.017). Between MS and HC, OEF and χn were compared using a linear regression model in subject-based regions of interest. In the whole brain, compared to HC, MS had lower OEF, 30.4 ± 3.3% vs. 21.4 ± 4.4% (p < 0.001), and higher χn, -23.7 ± 7.0 ppb vs. -11.3 ± 7.7 ppb (p = 0.018). Our feasibility study suggests that OEF may serve as a useful quantitative marker of tissue oxygen utilization in MS.

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.

QSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions.

BACKGROUND: Inflammation in chronic active lesions occurs behind a closed blood-brain barrier and cannot be detected with MRI. Activated microglia are highly enriched for iron and can be visualized with quantitative susceptibility mapping (QSM), an MRI technique used to delineate iron. OBJECTIVE: To characterize the histopathological correlates of different QSM hyperintensity patterns in MS lesions. METHODS: MS brain slabs were imaged with MRI and QSM, and processed for histology. Immunolabeled cells were quantified in the lesion rim, center, and adjacent normal-appearing white matter (NAWM). Iron+ myeloid cell densities at the rims were correlated with susceptibilities. Human-induced pluripotent stem cell (iPSC)-derived microglia were used to determine the effect of iron on the production of reactive oxygen species (ROS) and pro-inflammatory cytokines. RESULTS: QSM hyperintensity at the lesion perimeter correlated with activated iron+ myeloid cells in the rim and NAWM. Lesions with high punctate or homogenous QSM signal contained no or minimally activated iron- myeloid cells. In vitro, iron accumulation was highest in M1-polarized human iPSC-derived microglia, but it did not enhance ROS or cytokine production. CONCLUSION: A high QSM signal outlining the lesion rim but not punctate signal in the center is a biomarker for chronic inflammation in white matter lesions.

Quantitative Measurement of Metal Accumulation in Brain of Patients With Wilson's Disease.

BACKGROUND: Currently, no study has evaluated metal accumulation in the brains of patients with Wilson's disease by using quantitative susceptibility mapping at 3T MRI. The objectives of this study were to qualitatively and quantitatively evaluate changes in magnetic susceptibility and R2* maps in deep gray matter nuclei to discriminate Wilson's disease patients from healthy controls and to evaluate their sensitivities in diagnosing Wilson's disease. METHODS: Magnetic susceptibility and R2* maps and conventional T1-weighted, T2-weighted, and T2-weighted fluid-attenuated inversion recovery images were obtained from 17 Wilson's disease patients and 14 age-matched healthy controls on a 3T MRI scanner. Differences between Wilson's disease and healthy control groups in susceptibility and R2* values in multiple deep nuclei were evaluated using a Mann-Whitney U test and receiver operating characteristic curves. The correlations of susceptibility and R2* values with Unified Wilson's Disease Rating Scale score were also performed. RESULTS: Magnetic susceptibility and R2* can effectively distinguish different types of signal abnormalities. Magnetic susceptibility and R2* values in multiple deep nuclei of Wilson's disease patients were significantly higher than those in healthy controls. Magnetic susceptibility value in the substantia nigra had the highest area under the curve (0.888). There were positive correlations of the Unified Wilson's Disease Rating Scale score with susceptibility values in the caudate nucleus (r = 0.757, P = 0.011), putamen (r = 0.679, P = 0.031), and red nucleus (r = 0.638, P = 0.047), as well as R2* values in the caudate nucleus (r = 0.754, P = 0.012). CONCLUSIONS: Quantitative susceptibility mapping at 3T could be a useful tool to evaluate metal accumulation in deep gray matter nuclei of Wilson's disease patients. © 2020 International Parkinson and Movement Disorder Society.

Quantitative susceptibility mapping of the spine using in-phase echoes to initialize inhomogeneous field and R2* for the nonconvex optimization problem of fat-water separation.

Quantitative susceptibility mapping (QSM) of human spinal vertebrae from a multi-echo gradient-echo (GRE) sequence is challenging, because comparable amounts of fat and water in the vertebrae make it difficult to solve the nonconvex optimization problem of fat-water separation (R2*-IDEAL) for estimating the magnetic field induced by tissue susceptibility. We present an in-phase (IP) echo initialization of R2*-IDEAL for QSM in the spinal vertebrae. Ten healthy human subjects were recruited for spine MRI. A 3D multi-echo GRE sequence was implemented to acquire out-phase and IP echoes. For the IP method, the R2* and field maps estimated by separately fitting the magnitude and phase of IP echoes were used to initialize gradient search R2*-IDEAL to obtain final R2*, field, water, and fat maps, and the final field map was used to generate QSM. The IP method was compared with the existing Zero method (initializing the field to zero), VARPRO-GC (variable projection using graphcuts but still initializing the field to zero), and SPURS (simultaneous phase unwrapping and removal of chemical shift using graphcuts for initialization) on both simulation and in vivo data. The single peak fat model was also compared with the multi-peak fat model. There was no substantial difference on QSM between the single peak and multi-peak fat models, but there were marked differences among different initialization methods. The simulations demonstrated that IP provided the lowest error in the field map. Compared to Zero, VARPRO-GC and SPURS, the proposed IP method provided substantially improved spine QSM in all 10 subjects.

Clinical feasibility of brain quantitative susceptibility mapping.

PURPOSE: To evaluate the quality of brain quantitative susceptibility mapping (QSM) that is fully automatically reconstructed in clinical MRI of various neurological diseases. METHODS: 393 consecutive patients in one month were recruited for this evaluation study. QSM was reconstructed using Morphology Enabled Dipole Inversion without zero reference regularization (MEDI) and using MEDI with cerebrospinal fluid automatic zero-reference regularization to generate susceptibility values (MEDI+0). Two neuroradiologists independently assessed the image quality of MEDI+0 and MEDI and image concordance between them. Lesion susceptibility values were measured in 20 cases of glioma, 21 cases of ischemic stroke and 43 multiple sclerosis (MS) cases on both MEDI+0 and MEDI images. RESULTS: The two neuroradiologists rated the MEDI+0 image qualities of the 393 cases as 351 (89.3%) and 362 (92.1%) excellent, 29 (7.4%) and 24 (6.1%) diagnostic, and 13 (3.3%) and 7 (1.8%) poor, and scored the concordances between MEDI+0 and MEDI as 364 (92.6%) and 351 (89.3%) excellent, 13 (3.3%) and 31 (7.9%) good, 14 (3.6%) and 9 (2.3%) intermediate, 2 (0.5%) and 2 (0.5%) poor, and 0 (0%) and 0 (0%) none. There was good correlation between MEDI+0 and MEDI in lesion susceptibility contrast of glioma, ischemic stroke, and MS cases (all p < 0.05). The MS lesion susceptibility time course from this patient cohort was found to be similar to the reported pattern: isointense initially for acute enhancing lesions, and hyperintense over the following years for active chronic lesions. CONCLUSION: Brain QSM images of various neurological diseases have reliable diagnostic quality in clinical MRI, with MEDI+0 providing susceptibility values automatically referenced to CSF in longitudinal and cross-center studies.

Quantitative susceptibility mapping identifies inflammation in a subset of chronic multiple sclerosis lesions.

Chronic active multiple sclerosis lesions, characterized by a hyperintense rim of iron-enriched, activated microglia and macrophages, have been linked to greater tissue damage. Post-mortem studies have determined that chronic active lesions are primarily related to the later stages of multiple sclerosis; however, the occurrence of these lesions, and their relationship to earlier disease stages may be greatly underestimated. Detection of chronic active lesions across the patient spectrum of multiple sclerosis requires a validated imaging tool to accurately identify lesions with persistent inflammation. Quantitative susceptibility mapping provides efficient in vivo quantification of susceptibility changes related to iron deposition and the potential to identify lesions harbouring iron-laden inflammatory cells. The PET tracer 11C-PK11195 targets the translocator protein expressed by activated microglia and infiltrating macrophages. Accordingly, this study aimed to validate that lesions with a hyperintense rim on quantitative susceptibility mapping from both relapsing and progressive patients demonstrate a higher level of innate immune activation as measured on 11C-PK11195 PET. Thirty patients were enrolled in this study, 24 patients had relapsing remitting multiple sclerosis, six had progressive multiple sclerosis, and all patients had concomitant MRI with a gradient echo sequence and PET with 11C-PK11195. A total of 406 chronic lesions were detected, and 43 chronic lesions with a hyperintense rim on quantitative susceptibility mapping were identified as rim+ lesions. Susceptibility (relative to CSF) was higher in rim+ (2.42 ± 17.45 ppb) compared to rim- lesions (-14.6 ± 19.3 ppb, P < 0.0001). Among rim+ lesions, susceptibility within the rim (20.04 ± 14.28 ppb) was significantly higher compared to the core (-5.49 ± 14.44 ppb, P < 0.0001), consistent with the presence of iron. In a mixed-effects model, 11C-PK11195 uptake, representing activated microglia/macrophages, was higher in rim+ lesions compared to rim- lesions (P = 0.015). Validating our in vivo imaging results, multiple sclerosis brain slabs were imaged with quantitative susceptibility mapping and processed for immunohistochemistry. These results showed a positive translocator protein signal throughout the expansive hyperintense border of rim+ lesions, which co-localized with iron containing CD68+ microglia and macrophages. In conclusion, this study provides evidence that suggests that a hyperintense rim on quantitative susceptibility measure within a chronic lesion is a correlate for persistent inflammatory activity and that these lesions can be identified in the relapsing patients. Utilizing quantitative susceptibility measure to differentiate chronic multiple sclerosis lesion subtypes, especially chronic active lesions, would provide a method to assess the impact of these lesions on disease progression.

3D texture analyses within the substantia nigra of Parkinson's disease patients on quantitative susceptibility maps and R2∗ maps.

Iron accumulation in the substantia nigra (SN) is spatially heterogeneous, yet no study has quantitatively evaluated how the texture of quantitative susceptibility maps (QSM) and R2∗ might evolve with Parkinson's disease (PD) and healthy controls (HC). The aim of this study was to discriminate between patients with PD and HC using texture analysis in the SN from QSM and R2∗ maps. QSM and R2∗ maps were obtained from 28 PD patients and 28 HC on a clinical 3T MR imaging scanner using 3D multi-echo gradient-echo sequence. The first- and second- order texture features of the QSM and R2∗ images were obtained to evaluate group differences using two-tailed t-test. After correction for multiple comparisons, for the first-order analysis, the susceptibility of SN from patients with PD was significantly greater (p = 0.017) compared with the SN from HC. For the second-order texture analysis, angular second moment, entropy, and sum of entropy showed significant differences in QSM (p < 0.001) and R2∗ maps (p < 0.01). In addition, correlation, contrast, sum of variance and difference of variance, significantly separated the subject groups in QSM maps (p < 0.05) but not in R2∗ images. Receiver operating characteristic analysis showed that entropy and sum of entropy of the QSM maps in the SN yielded the highest performance for differentiating PD patients from HC (area under the curve = 0.89). In conclusion, most first- and second- order QSM texture features successfully distinguished PD patients from HC and significantly outperformed R2∗ texture analysis. The second-order texture features were more accurate and sensitive than first-order texture features for classifying PD patients.

Brain Iron Distribution after Multiple Doses of Ultra-small Superparamagnetic Iron Oxide Particles in Rats.

The purpose of this study is to determine the effects of high cumulative doses of ultra-small paramagnetic iron oxide (USPIO) used in neuroimaging studies. We intravenously administered 8 mg/kg of 2 USPIO compounds daily for 4 wk to male Sprague-Dawley rats (Crl:SD). Multiecho gradient-echo MRI, serum iron levels, and histology were performed at the end of dosing and after a 7-d washout period. R2* maps and quantitative susceptibility maps (QSM) were generated from multiecho gradient-echo data. R2* maps and QSM showed iron accumulation in brain ventricles on MR images acquired at the 4- and 5-wk time points. Estimates from QSM data showed ventricular iron concentration was equal to or higher than serum iron concentration. Histologic analysis revealed choroid plexus hemosiderosis and midbrain vacuolation, without iron deposition in brain parenchyma. Serum iron levels increased with administration of both compounds, and a 7-d washout period effectively reduced serum iron levels of one but not both of the compounds. High cumulative doses from multiple, frequent administrations of USPIO can lead to iron deposition in brain ventricles, resulting in persistent signal loss on T2*-weighted images. Techniques such as QSM are helpful in quantifying iron biodistribution in this situation.

Significance and In Vivo Detection of Iron-Laden Microglia in White Matter Multiple Sclerosis Lesions.

Microglia are resident immune cells that fulfill protective and homeostatic functions in the central nervous system (CNS) but may also promote neurotoxicity in the aged brain and in chronic disease. In multiple sclerosis (MS), an autoimmune demyelinating disease of the CNS, microglia and macrophages contribute to the development of white matter lesions through myelin phagocytosis, and possibly to disease progression through diffuse activation throughout myelinated white matter. In this review, we discuss an additional compartment of myeloid cell activation in MS, i.e., the rim and normal adjacent white matter of chronic active lesions. In chronic active lesions, microglia and macrophages may contain high amounts of iron, express markers of proinflammatory polarization, are activated for an extended period of time (years), and drive chronic tissue damage. Iron-positive myeloid cells can be visualized and quantified with quantitative susceptibility mapping (QSM), a magnetic resonance imaging technique. Thus, QSM has potential as an in vivo biomarker for chronic inflammatory activity in established white matter MS lesions. Reducing chronic inflammation associated with iron accumulation using existing or novel MS therapies may impact disease severity and progression.

Magnetic susceptibility increases as diamagnetic molecules breakdown: Myelin digestion during multiple sclerosis lesion formation contributes to increase on QSM.

BACKGROUND: The pathological processes in the first weeks of multiple sclerosis (MS) lesion formation include myelin digestion that breaks chemical bonds in myelin lipid layers. This can increase lesion magnetic susceptibility, which is a potentially useful biomarker in MS patient management, but not yet investigated. PURPOSE: To understand and quantify the effects of myelin digestion on quantitative susceptibility mapping (QSM) of MS lesions. STUDY TYPE: Histological and QSM analyses on in vitro models of myelin breakdown and MS lesion formation in vivo. POPULATION/SPECIMENS: Acutely demyelinating white matter lesions from MS autopsy tissue were stained with the lipid dye oil red O. Myelin basic protein (MBP), a major membrane protein of myelin, was digested with trypsin. Purified human myelin was denatured with sodium dodecyl sulfate (SDS). QSM was performed on phantoms containing digestion products and untreated controls. In vivo QSM was performed on five MS patients with newly enhancing lesions, and then repeated within 2 weeks. FIELD STRENGTH/SEQUENCE: 3D T 2 * -weighted spoiled multiecho gradient echo scans performed at 3T. ASSESSMENT: Region of interest analyses were performed by a biochemist and a neuroradiologist to determine susceptibility changes on in vitro and in vivo QSM images. STATISTICAL TESTS: Not applicable. RESULTS: MBP degradation by trypsin increased the QSM measurement by an average of 112 ± 37 ppb, in excellent agreement with a theoretical estimate of 111 ppb. Degradation of human myelin by SDS increased the QSM measurement by 23 ppb. As MS lesions changed from gadolinium enhancing to nonenhancing over an average of 15.8 ± 3.7 days, their susceptibility increased by an average of 7.5 ± 6.3 ppb. DATA CONCLUSION: Myelin digestion in the early stages of MS lesion formation contributes to an increase in tissue susceptibility, detectable by QSM, as a lesion evolves from gadolinium enhancing to nonenhancing. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1281-1287.

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.