Time is myelin: early cortical myelin repair prevents atrophy and clinical progression in multiple sclerosis.

Cortical myelin loss and repair in multiple sclerosis (MS) have been explored in neuropathological studies, but the impact of these processes on neurodegeneration and the irreversible clinical progression of the disease remains unknown. Here, we evaluated in vivo cortical demyelination and remyelination in a large cohort of people with all clinical phenotypes of MS followed up for 5 years using magnetization transfer imaging (MTI), a technique that has been shown to be sensitive to myelin content changes in the cortex. We investigated 140 people with MS (37 clinically isolated syndrome, 71 relapsing-MS, 32 progressive-MS), who were clinically assessed at baseline and after 5 years and, along with 84 healthy controls, underwent a 3 T-MRI protocol including MTI at baseline and after 1 year. Changes in cortical volume over the radiological follow-up were computed with a Jacobian integration method. Magnetization transfer ratio was employed to calculate for each patient an index of cortical demyelination at baseline and of dynamic cortical demyelination and remyelination over the follow-up period. The three indices of cortical myelin content change were heterogeneous across patients but did not significantly differ across clinical phenotypes or treatment groups. Cortical remyelination, which tended to fail in the regions closer to CSF (-11%, P < 0.001), was extensive in half of the cohort and occurred independently of age, disease duration and clinical phenotype. Higher indices of cortical dynamic demyelination (ß = 0.23, P = 0.024) and lower indices of cortical remyelination (ß = -0.18, P = 0.03) were significantly associated with greater cortical atrophy after 1 year, independently of age and MS phenotype. While the extent of cortical demyelination predicted a higher probability of clinical progression after 5 years in the entire cohort [odds ratio (OR) = 1.2; P = 0.043], the impact of cortical remyelination in reducing the risk of accumulating clinical disability after 5 years was significant only in the subgroup of patients with shorter disease duration and limited extent of demyelination in cortical regions (OR = 0.86, P = 0.015, area under the curve = 0.93). In this subgroup, a 30% increase in cortical remyelination nearly halved the risk of clinical progression at 5 years, independently of clinical relapses. Overall, our results highlight the critical role of cortical myelin dynamics in the cascade of events leading to neurodegeneration and to the subsequent accumulation of irreversible disability in MS. Our findings suggest that early-stage myelin repair compensating for cortical myelin loss has the potential to prevent neuro-axonal loss and its long-term irreversible clinical consequences in people with MS.

Three-dimensional EPI with shot-selective CAIPIRIHANA for rapid high-resolution quantitative susceptibility mapping at 3 T.

PURPOSE: QSM provides insight into healthy brain aging and neuropathologies such as multiple sclerosis (MS), traumatic brain injuries, brain tumors, and neurodegenerative diseases. Phase data for QSM are usually acquired from 3D gradient-echo (3D GRE) scans with long acquisition times that are detrimental to patient comfort and susceptible to patient motion. This is particularly true for scans requiring whole-brain coverage and submillimeter resolutions. In this work, we use a multishot 3D echo plannar imaging (3D EPI) sequence with shot-selective 2D CAIPIRIHANA to acquire high-resolution, whole-brain data for QSM with minimal distortion and blurring. METHODS: To test clinical viability, the 3D EPI sequence was used to image a cohort of MS patients at 1-mm isotropic resolution at 3 T. Additionally, 3D EPI data of healthy subjects were acquired at 1-mm, 0.78-mm, and 0.65-mm isotropic resolution with varying echo train lengths (ETLs) and compared with a reference 3D GRE acquisition. RESULTS: The appearance of the susceptibility maps and the susceptibility values for segmented regions of interest were comparable between 3D EPI and 3D GRE acquisitions for both healthy and MS participants. Additionally, all lesions visible in the MS patients on the 3D GRE susceptibility maps were also visible on the 3D EPI susceptibility maps. The interplay among acquisition time, resolution, echo train length, and the effect of distortion on the calculated susceptibility maps was investigated. CONCLUSION: We demonstrate that the 3D EPI sequence is capable of rapidly acquiring submillimeter resolutions and providing high-quality, clinically relevant susceptibility maps.

Super-resolution QSM in little or no additional time for imaging (NATIve) using 2D EPI imaging in 3 orthogonal planes.

Quantitative Susceptibility Mapping has the potential to provide additional insights into neurological diseases but is typically based on a quite long (5-10 min) 3D gradient-echo scan which is highly sensitive to motion. We propose an ultra-fast acquisition based on three orthogonal (sagittal, coronal and axial) 2D simultaneous multi-slice EPI scans with 1 mm in-plane resolution and 3 mm thick slices. Images in each orientation are corrected for susceptibility-related distortions and co-registered with an iterative non-linear Minimum Deformation Averaging (Volgenmodel) approach to generate a high SNR, super-resolution data set with an isotropic resolution of close to 1 mm. The net acquisition time is 3 times the volume acquisition time of EPI or about 12 s, but the three volumes could also replace "dummy scans" in fMRI, making it feasible to acquire QSM in little or No Additional Time for Imaging (NATIve). NATIve QSM values agreed well with reference 3D GRE QSM in the basal ganglia in healthy subjects. In patients with multiple sclerosis, there was also a good agreement between the susceptibility values within lesions and control ROIs and all lesions which could be seen on 3D GRE QSMs could also be visualized on NATIve QSMs. The approach is faster than conventional 3D GRE by a factor of 25-50 and faster than 3D EPI by a factor of 3-5. As a 2D technique, NATIve QSM was shown to be much more robust to motion than the 3D GRE and 3D EPI, opening up the possibility of studying neurological diseases involving iron accumulation and demyelination in patients who find it difficult to lie still for long enough to acquire QSM data with conventional methods.

The relevance of rich club regions for functional outcome post-stroke is enhanced in women.

This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. In spatial specificity analyses, we randomized the split into "rich club" and "non-rich club" regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long-term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women.

Autolysis Affects the Iron Cargo of Ferritins in Neurons and Glial Cells at Different Rates in the Human Brain.

Iron is known to accumulate in neurological disorders, so a careful balance of the iron concentration is essential for healthy brain functioning. An imbalance in iron homeostasis could arise due to the dysfunction of proteins involved in iron homeostasis. Here, we focus on ferritin-the primary iron storage protein of the brain. In this study, we aimed to improve a method to measure ferritin-bound iron in the human post-mortem brain, and to discern its distribution in particular cell types and brain regions. Though it is known that glial cells and neurons differ in their ferritin concentration, the change in the number and distribution of iron-filled ferritin cores between different cell types during autolysis has not been revealed yet. Here, we show the cellular and region-wide distribution of ferritin in the human brain using state-of-the-art analytical electron microscopy. We validated the concentration of iron-filled ferritin cores to the absolute iron concentration measured by quantitative MRI and inductively coupled plasma mass spectrometry. We show that ferritins lose iron from their cores with the progression of autolysis whereas the overall iron concentrations were unaffected. Although the highest concentration of ferritin was found in glial cells, as the total ferritin concentration increased in a patient, ferritin accumulated more in neurons than in glial cells. Summed up, our findings point out the unique behaviour of neurons in storing iron during autolysis and explain the differences between the absolute iron concentrations and iron-filled ferritin in a cell-type-dependent manner in the human brain. The rate of loss of the iron-filled ferritin cores during autolysis is higher in neurons than in glial cells.

High serum neurofilament light chain levels correlate with brain atrophy and physical disability in multiple sclerosis.

BACKGROUND AND PURPOSE: Serum neurofilament light chain (sNfL) is a promising biomarker of neuroaxonal damage in persons with multiple sclerosis (pwMS). In cross-sectional studies, sNfL has been associated with disease activity and brain magnetic resonance imaging (MRI) changes; however, it is still unclear to what extent in particular high sNfL levels impact on subsequent disease evolution. METHODS: sNfL was quantified by an ultrasensitive single molecule array (Simoa) in 199 pwMS (median age = 34.2 years, 64.3% female) and 49 controls. All pwMS underwent 3-T MRI to assess global and compartmental normalized brain volumes, T2-lesion load, and cortical mean thickness. Follow-up data and serum samples were available in 144 pwMS (median follow-up time = 3.8 years). Linear and binary logistic models were used to estimate the independent contribution of sNfL for changes in MRI and Expanded Disability Status Scale (EDSS). Age-corrected sNfL z-scores from a normative database of healthy controls were used for sensitivity analyses. RESULTS: High sNfL levels at baseline were associated with atrophy measures of the whole brain (standardized beta coefficient ßj = -0.352, p < 0.001), white matter (ßj = -0.229, p = 0.007), thalamus (ßj = -0.372, p = 0.004), and putamen (ßj = -1.687, p = 0.012). pwMS with high levels of sNfL at baseline and follow-up had a greater risk of EDSS worsening (p = 0.007). CONCLUSIONS: Already single time point elevation of sNfL has a distinct effect on brain volume changes over a short-term period, and repeated high levels of sNfL indicate accumulating physical disability. Serial assessment of sNfL may provide added value in the clinical management of pwMS.

Long-term risk of recurrent vascular events and mortality in young stroke patients: Insights from a multicenter study.

BACKGROUND: Although the incidence of stroke in the young is rising, data on long-term outcomes in these patients are scarce. We thus aimed to investigate the long-term risk of recurrent vascular events and mortality in a multicenter study. METHODS: We followed 396 consecutive patients aged 18-55 years with ischemic stroke (IS) or transient ischemic attack (TIA) enrolled in three European centers during the period 2007-2010. A detailed outpatient clinical follow-up assessment was performed between 2018 and 2020. When an in-person follow-up visit was not possible, outcome events were assessed using electronic records and registry data. RESULTS: During a median follow-up of 11.8 (IQR 10.4-12.7) years, 89 (22.5%) patients experienced any recurrent vascular event, 62 (15.7%) had any cerebrovascular event, 34 (8.6%) had other vascular events, and 27 (6.8%) patients died. Cumulative 10-year incidence rate per 1000 person-years was 21.6 (95% CI 17.1-26.9) for any recurrent vascular event and 14.9 (95% CI 11.3-19.3) for any cerebrovascular event. The prevalence of cardiovascular risk factors increased over time, and 22 (13.5%) patients lacked any secondary preventive medication at the in-person follow-up. After adjustment for demographics and comorbidities, atrial fibrillation at baseline was found to be significantly associated with recurrent vascular events. CONCLUSIONS: This multicenter study shows a considerable risk of recurrent vascular events in young IS and TIA patients. Further studies should investigate whether detailed individual risk assessment, modern secondary preventive strategies, and better patient adherence may reduce recurrence risk.

Free water diffusion MRI and executive function with a speed component in healthy aging.

Extracellular free water (FW) increases are suggested to better provide pathophysiological information in brain aging than conventional biomarkers such as fractional anisotropy. The aim of the present study was to determine the relationship between conventional biomarkers, FW in white matter hyperintensities (WMH), FW in normal appearing white matter (NAWM) and in white matter tracts and executive functions (EF) with a speed component in elderly persons. We examined 226 healthy elderly participants (median age 69.83 years, IQR: 56.99-74.42) who underwent brain MRI and neuropsychological examination. FW in WMH and in NAWM as well as FW corrected diffusion metrics and measures derived from conventional MRI (white matter hyperintensities, brain volume, lacunes) were used in partial correlation (adjusted for age) to assess their correlation with EF with a speed component. Random forest analysis was used to assess the relative importance of these variables as determinants. Lastly, linear regression analyses of FW in white matter tracts corrected for risk factors of cognitive and white matter deterioration, were used to examine the role of specific tracts on EF with a speed component, which were then ranked with random forest regression. Partial correlation analyses revealed that almost all imaging metrics showed a significant association with EF with a speed component (r = -0.213 - 0.266). Random forest regression highlighted FW in WMH and in NAWM as most important among all diffusion and structural MRI metrics. The fornix (R2=0.421, p = 0.018) and the corpus callosum (genu (R2 = 0.418, p = 0.021), prefrontal (R2 = 0.416, p = 0.026), premotor (R2 = 0.418, p = 0.021)) were associated with EF with a speed component in tract based regression analyses and had highest variables importance. In a normal aging population FW in WMH and NAWM is more closely related to EF with a speed component than standard DTI and brain structural measures. Higher amounts of FW in the fornix and the frontal part of the corpus callosum leads to deteriorating EF with a speed component.

Disability in multiple sclerosis is related to thalamic connectivity and cortical network atrophy.

BACKGROUND: Thalamic atrophy is proposed to be a major predictor of disability progression in multiple sclerosis (MS), while thalamic function remains understudied. OBJECTIVES: To study how thalamic functional connectivity (FC) is related to disability and thalamic or cortical network atrophy in two large MS cohorts. METHODS: Structural and resting-state functional magnetic resonance imaging (fMRI) was obtained in 673 subjects from Amsterdam (MS: N = 332, healthy controls (HC): N = 96) and Graz (MS: N = 180, HC: N = 65) with comparable protocols, including disability measurements in MS (Expanded Disability Status Scale, EDSS). Atrophy was measured for the thalamus and seven well-recognized resting-state networks. Static and dynamic thalamic FC with these networks was correlated with disability. Significant correlates were included in a backward multivariate regression model. RESULTS: Disability was most strongly related (adjusted R2 = 0.57, p < 0.001) to higher age, a progressive phenotype, thalamic atrophy and increased static thalamic FC with the sensorimotor network (SMN). Static thalamus-SMN FC was significantly higher in patients with high disability (EDSS ⩾ 4) and related to network atrophy but not thalamic atrophy or lesion volumes. CONCLUSION: The severity of disability in MS was related to increased static thalamic FC with the SMN. Thalamic FC changes were only related to cortical network atrophy, but not to thalamic atrophy.

Quantitative magnetic resonance imaging towards clinical application in multiple sclerosis.

Quantitative MRI provides biophysical measures of the microstructural integrity of the CNS, which can be compared across CNS regions, patients, and centres. In patients with multiple sclerosis, quantitative MRI techniques such as relaxometry, myelin imaging, magnetization transfer, diffusion MRI, quantitative susceptibility mapping, and perfusion MRI, complement conventional MRI techniques by providing insight into disease mechanisms. These include: (i) presence and extent of diffuse damage in CNS tissue outside lesions (normal-appearing tissue); (ii) heterogeneity of damage and repair in focal lesions; and (iii) specific damage to CNS tissue components. This review summarizes recent technical advances in quantitative MRI, existing pathological validation of quantitative MRI techniques, and emerging applications of quantitative MRI to patients with multiple sclerosis in both research and clinical settings. The current level of clinical maturity of each quantitative MRI technique, especially regarding its integration into clinical routine, is discussed. We aim to provide a better understanding of how quantitative MRI may help clinical practice by improving stratification of patients with multiple sclerosis, and assessment of disease progression, and evaluation of treatment response.

Analysis of deep grey nuclei susceptibility in early childhood: a quantitative susceptibility mapping and R2* study at 3 Tesla.

PURPOSE: Aging is the most significant determinant for brain iron accumulation in the deep grey matter. Data on brain iron evolution during brain maturation in early childhood are limited. The purpose of this study was to investigate age-related iron deposition in the deep grey matter in children using quantitative susceptibility (QSM) and R2* mapping. METHODS: We evaluated brain MRI scans of 74 children (age 6-154 months, mean 40 months). A multi-echo gradient-echo sequence obtained at 3 Tesla was used for the QSM and R2* calculation. Susceptibility of the pallidum, head of caudate nucleus, and putamen was correlated with age and compared between sexes. RESULTS: Susceptibility changes in all three nuclei correlated with age (correlation coefficients for QSM/R2*: globus pallidus 0.955/0.882, caudate nucleus 0.76/0.65, and putamen 0.643/0.611). During the first 2 years, the R2* values increased more rapidly than the QSM values, indicating a combined effect of iron deposition and myelination, followed by a likely dominating effect of iron deposition. There was no significant gender difference. CONCLUSION: QSM and R2* can monitor myelin maturation processes and iron accumulation in the deep grey nuclei of the brain in early life and may be a promising tool for the detection of deviations of this normal process. Susceptibility in the deep nuclei is almost similar early after birth and increases more quickly in the pallidum. The combined use of QSM and R2* analysis is beneficial.

In vivo assessment of anisotropy of apparent magnetic susceptibility in white matter from a single orientation acquisition.

Multiple studies have reported a significant dependence of the effective transverse relaxation rate constant (R2*) and the phase of gradient-echo based (GRE) signal on the orientation of white matter fibres in the human brain. It has also been hypothesized that magnetic susceptibility, as obtained by single-orientation quantitative susceptibility mapping (QSM), exhibits such a dependence. In this study, we investigated this hypothesized relationship in a cohort of healthy volunteers. We show that R2* follows the predicted orientation dependence consistently across white matter regions, whereas the apparent magnetic susceptibility is related differently to fibre orientation across the brain and often in a complex non-monotonic manner. In addition, we explored the effect of fractional anisotropy measured by diffusion-weighted MRI on the strength of the orientation dependence and observed only a limited influence in many regions. However, with careful consideration of such an impact and the limitations imposed by the ill-posed nature of the dipole inversion process, it is possible to study magnetic susceptibility anisotropy in specific brain regions with a single orientation acquisition.

Adaptive slice-specific z-shimming for 2D spoiled gradient-echo sequences.

PURPOSE: To reduce the misbalance between compensation gradients and macroscopic field gradients, we introduce an adaptive slice-specific z-shimming approach for 2D spoiled multi-echo gradient-echoe sequences in combination with modeling of the signal decay. METHODS: Macroscopic field gradients were estimated for each slice from a fast prescan (15 seconds) and then used to calculate slice-specific compensation moments along the echo train. The coverage of the compensated field gradients was increased by applying three positive and three negative moments. With a forward model, which considered the effect of the slice profile, the z-shim moment, and the field gradient, R2∗ maps were estimated. The method was evaluated in phantom and in vivo measurements at 3 T and compared with a spoiled multi-echo gradient-echo and a global z-shimming approach without slice-specific compensation. RESULTS: The proposed method yielded higher SNR in R2∗ maps due to a broader range of compensated macroscopic field gradients compared with global z-shimming. In global white matter, the mean interquartile range, proxy for SNR, could be decreased to 3.06 s-1 with the proposed approach, compared with 3.37 s-1 for global z-shimming and 3.52 s-1 for uncompensated multi-echo gradient-echo. CONCLUSION: Adaptive slice-specific compensation gradients between echoes substantially improved the SNR of R2∗ maps, and the signal could also be rephased in anatomical areas, where it has already been completely dephased.

Long-term course and morphological MRI correlates of cognitive function in multiple sclerosis.

BACKGROUND: Cognitive impairment frequently occurs in patients with MS (pwMS). Magnetic resonance imaging (MRI) markers could help to identify patients at risk for decline. OBJECTIVE: To characterize the long-term course and morphological MRI correlates of cognitive function in pwMS. METHODS: We invited 116 pwMS who had undergone clinical, cognitive, and MRI evaluations between 2006 and 2012 (baseline, BL) to attend follow-up (FU) testing between 2016 and 2018. Disability (expanded disability status scale (EDSS)), cognition (brief repeatable battery of neuropsychological test (BRB-N)), global and regional T2-lesion load (T2-LL), brain volumes, and cortical thickness were assessed. RESULTS: Sixty-three pwMS were willing to attend the FU (54%; median EDSS = 2, interquartile range (IQR) = 2) and did not differ from non-participating pwMS regarding BL characteristics. At BL, half of the participants showed cognitive deficits in at least one domain. Across the entire group, we observed no relevant changes in physical disability and cognition over 10 years. BL thalamic volume best predicted cognitive function at FU, in addition to age and BL cognition, explaining 67% of variance. Cognitive decliners (23.8%) were older, had longer disease duration, and a tendency for lower thalamic volume at BL. CONCLUSION: Thalamic volume predicted FU cognitive function and distinguished declining from stable pwMS, underlining the potential of MRI to define risk groups.

The influence of iron oxidation state on quantitative MRI parameters in post mortem human brain.

A variety of Magnetic Resonance Imaging (MRI) techniques are known to be sensitive to brain iron content. In principle, iron sensitive MRI techniques are based on local magnetic field variations caused by iron particles in tissue. The purpose of this study was to investigate the sensitivity of MR relaxation and magnetization transfer parameters to changes in iron oxidation state compared to changes in iron concentration. Therefore, quantitative MRI parameters including R1, R2, R2∗, quantitative susceptibility maps (QSM) and magnetization transfer ratio (MTR) of post mortem human brain tissue were acquired prior and after chemical iron reduction to change the iron oxidation state and chemical iron extraction to decrease the total iron concentration. All assessed parameters were shown to be sensitive to changes in iron concentration whereas only R2, R2∗ and QSM were also sensitive to changes in iron oxidation state. Mass spectrometry confirmed that iron accumulated in the extraction solution but not in the reduction solution. R2∗ and QSM are often used as markers for iron content. Changes in these parameters do not necessarily reflect variations in iron content but may also be a result of changes in the iron's oxygenation state from ferric towards more ferrous iron or vice versa.

Cross-sectional and Longitudinal Assessment of Brain Iron Level in Alzheimer Disease Using 3-T MRI.

Background Deep gray matter structures in patients with Alzheimer disease (AD) contain higher brain iron concentrations. However, few studies have included neocortical areas, which are challenging to assess with MRI. Purpose To investigate baseline and change in brain iron levels using MRI at 3 T with R2* relaxation rate mapping in individuals with AD compared with healthy control (HC) participants. Materials and Methods In this prospective study, participants with AD recruited between 2010 and 2016 and age-matched HC participants selected from 2010 to 2014 were evaluated. Of 100 participants with AD, 56 underwent subsequent neuropsychological testing and brain MRI at a mean follow-up of 17 months. All participants underwent 3-T MRI, including R2* mapping corrected for macroscopic B0 field inhomogeneities. Anatomic structures were segmented, and median R2* values were calculated in the neocortex and cortical lobes, basal ganglia (BG), hippocampi, and thalami. Multivariable linear regression analysis was applied to study the difference in R2* levels between groups and the association between longitudinal changes in R2* values and cognition in the AD group. Results A total of 100 participants with AD (mean age, 73 years ± 9 [standard deviation]; 58 women) and 100 age-matched HC participants (mean age, 73 years ± 9; 60 women) were evaluated. Median R2* levels were higher in the AD group than in the HC group in the BG (HC, 29.0 sec-1; AD, 30.2 sec-1; P = .01) and total neocortex (HC, 17.0 sec-1; AD, 17.4 sec-1; P < .001) and regionally in the occipital (HC, 19.6 sec-1; AD, 20.2 sec-1; P = .007) and temporal (HC, 16.4 sec-1; AD, 18.1 sec-1; P < .001) lobes. R2* values in the temporal lobe were associated with longitudinal changes in Consortium to Establish a Registry for Alzheimer's Disease total score (ß = -3.23 score/sec-1, P = .003) in participants with AD independent of longitudinal changes in brain volume. Conclusion Iron concentration in the deep gray matter and neocortical regions was higher in patients with Alzheimer disease than in healthy control participants. Change in iron levels over time in the temporal lobe was associated with cognitive decline in individuals with Alzheimer disease. © RSNA, 2020 Online supplemental material is available for this article.

Assessment and correction of macroscopic field variations in 2D spoiled gradient-echo sequences.

PURPOSE: To model and correct the dephasing effects in the gradient-echo signal for arbitrary RF excitation pulses with large flip angles in the presence of macroscopic field variations. METHODS: The dephasing of the spoiled 2D gradient-echo signal was modeled using a numerical solution of the Bloch equations to calculate the magnitude and phase of the transverse magnetization across the slice profile. Additionally, regional variations of the transmit RF field and slice profile scaling due to macroscopic field gradients were included. Simulations, phantom, and in vivo measurements at 3 T were conducted for R2∗ and myelin water fraction (MWF) mapping. RESULTS: The influence of macroscopic field gradients on R2∗ and myelin water fraction estimation can be substantially reduced by applying the proposed model. Moreover, it was shown that the dephasing over time for flip angles of 60° or greater also depends on the polarity of the slice-selection gradient because of phase variation along the slice profile. CONCLUSION: Substantial improvements in R2∗ accuracy and myelin water fraction mapping coverage can be achieved using the proposed model if higher flip angles are required. In this context, we demonstrated that the phase along the slice profile and the polarity of the slice-selection gradient are essential for proper modeling of the gradient-echo signal in the presence of macroscopic field variations.

Magnetic resonance elastography of the human brain using a multiphase DENSE acquisition.

PURPOSE: In magnetic resonance elastography (MRE), a series of time-shifted images is acquired at specific phase offsets in relation to an induced mechanical excitation. To efficiently gather the set of phase offset images and to overcome limitations due to prolonged TEs and related susceptibility artifacts at low-frequency MRE, we developed an improved displacement encoding with a stimulated echoes (DENSE) method. METHODS: The proposed multiphase DENSE-MRE acquisition scheme allows full sampling of the wave propagation in 1 encoding direction during each TR using multiple readouts at specific phase offsets. With this approach, all phase offsets can be imaged in 1 TR without the need for whole sequence repetitions at time-shifted offsets relative to the excitation motion. We tested this technique in phantom experiments with 60 Hz and in the brain of 4 volunteers using 20-Hz harmonic excitation. RESULTS: Three-dimensional wave propagation could be acquired in 7 minutes 30 seconds. Following background phase elimination, clear wave images were obtained, showing the propagation of the waves over time. Calculated shear modulus maps of the phantom matched well to the maps obtained by conventional gradient-echo MRE. In the brain, low-frequency DENSE-MRE images were free of susceptibility-induced artifacts and the calculated maps showed a median global complex shear modulus magnitude of 0.72 kPa and phase angle of 1.03 rad across volunteers. CONCLUSION: The proposed multiphase DENSE approach allows efficient low-frequency MRE with short TEs and is well-suited for low-frequency MRE of the human brain.

The role of iron and myelin in orientation dependent R2* of white matter.

Brain myelin and iron content are important parameters in neurodegenerative diseases such as multiple sclerosis (MS). Both myelin and iron content influence the brain's R2* relaxation rate. However, their quantification based on R2* maps requires a realistic tissue model that can be fitted to the measured data. In structures with low myelin content, such as deep gray matter, R2* shows a linear increase with increasing iron content. In white matter, R2* is not only affected by iron and myelin but also by the orientation of the myelinated axons with respect to the external magnetic field. Here, we propose a numerical model which incorporates iron and myelin, as well as fibre orientation, to simulate R2* decay in white matter. Applying our model to fibre orientation-dependent in vivo R2* data, we are able to determine a unique solution of myelin and iron content in global white matter. We determine an averaged myelin volume fraction of 16.02 ± 2.07% in non-lesional white matter of patients with MS, 17.32 ± 2.20% in matched healthy controls, and 18.19 ± 2.98% in healthy siblings of patients with MS. Averaged iron content was 35.6 ± 8.9 mg/kg tissue in patients, 43.1 ± 8.3 mg/kg in controls, and 47.8 ± 8.2 mg/kg in siblings. All differences in iron content between groups were significant, while the difference in myelin content between MS patients and the siblings of MS patients was significant. In conclusion, we demonstrate that a model that combines myelin-induced orientation-dependent and iron-induced orientation-independent components is able to fit in vivo R2* data.

Nigral iron deposition in common tremor disorders.

OBJECTIVE: We investigated R2* relaxation rates as a marker of iron content in the substantia nigra in patients with common tremor disorders and explored their diagnostic properties. METHODS: Mean nigral R2* rates were measured in 40 patients with tremor-dominant Parkinson's disease (PD), 15 with tremor in dystonia, 25 with essential tremor, and 25 healthy controls. RESULTS: Tremor-dominant PD patients had significantly higher nigral R2* values (34.1 ± 5.7) than those with tremor in dystonia (30.0 ± 3.9), essential tremor (30.6 ± 4.8), and controls (30.0 ± 2.8). An R2* threshold of 31.15 separated tremor-dominant PD from controls with a sensitivity and specificity of 67.5% and 72%. The sensitivity and specificity for discrimination between PD and non-PD tremor patients was 67.5% and 60%. CONCLUSION: Iron content in the substantia nigra is significantly higher in tremor-dominant PD than in tremor in dystonia, essential tremor, and controls. Because of the considerable overlap, nigral R2* cannot be suggested as a useful diagnostic tool. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.