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Background and Purpose: Neuromyelitis optica spectrum disorder (NMOSD) affects the optic nerves and spinal cord but can also cause focal brain inflammation. Subcortical pathology may contribute to the etiology of cognitive deficits in NMOSD. Using myelin water imaging, we investigated cerebral normal-appearing white matter (NAWM) and thalamic metrics and their association with cognition in NMOSD participants compared to healthy controls (HC)., Methods: Seventeen NMOSD participants and 21 HC were scanned on a 3.0-Tesla MRI scanner using a multicomponent driven-equilibrium single-pulse observation of T 1 and T 2 protocol. Tissue compartment and thalamic volumes (normalized to intracranial volume), T 1 relaxation time, and myelin water fraction (MWF) were reported. Eleven NMOSD participants underwent the Symbol Digit Modalities Test (SDMT) for cognitive evaluation. Group comparisons were performed using Student's t-test. The association between thalamic metrics and SDMT score was assessed using multiple regression analysis with age as a covariate., Results: Compared to HC, NMOSD participants had reduced white matter volume (-14.2%, p < .0001), increased T 1 relaxation time (+2.29%, p = .022), and lower MWF (-3.64%, p = .024) in NAWM. NMOSD group had a trend for smaller thalamic volumes than HC (-5.52%, p = .082) and no differences in thalamic MWF (p = .258) or T 1 (p = .714). Thalamic T 1 predicted SDMT score (adjusted R 2  = .51, p = .04) when controlling for age., Conclusions: NAWM in NMOSD demonstrates diffuse abnormalities with increased water content and demyelination, suggesting a diffuse disease process overlooked by focal inflammation measures. Increased water content, as a biomarker for diffuse thalamic pathology, may partially explain cognitive impairment in NMOSD., (© 2024 The Author(s). Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)

Purpose of Review: To review recent clinical uses of low-field magnetic resonance imaging (MRI) to guide incorporation into neurological practice., Recent Findings: Use of low-field MRI has been demonstrated in applications including tumours, vascular pathologies, multiple sclerosis, brain injury, and paediatrics. Safety, workflow, and image quality have also been evaluated., Summary: Low-field MRI has the potential to increase access to critical brain imaging for patients who otherwise may not obtain imaging in a timely manner. This includes areas such as the intensive care unit and emergency room, where patients could be imaged at the point of care rather than be transported to the MRI scanner. Such systems are often more affordable than conventional systems, allowing them to be more easily deployed in resource constrained settings. A variety of systems are available on the market or in a research setting and are currently being used to determine clinical uses for these devices. The utility of such devices must be fully evaluated in clinical scenarios before adoption into standard practice can be achieved. This review summarizes recent clinical uses of low-field MR as well as safety, workflows, and image quality to aid practitioners in assessing this new technology., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Quantitative magnetic resonance imaging (MRI) techniques are powerful tools for the study of human tissue, but, in practice, their utility has been limited by lengthy acquisition times. Here, we introduce the Constrained, Adaptive, Low-dimensional, Intrinsically Precise Reconstruction (CALIPR) framework in the context of myelin water imaging (MWI); a quantitative MRI technique generally regarded as the most rigorous approach for noninvasive, in vivo measurement of myelin content. The CALIPR framework exploits data redundancy to recover high-quality images from a small fraction of an imaging dataset, which allowed MWI to be acquired with a previously unattainable sequence (fully sampled acquisition 2 hours:57 min:20 s) in 7 min:26 s (4.2% of the dataset, acceleration factor 23.9). CALIPR quantitative metrics had excellent precision (myelin water fraction mean coefficient of variation 3.2% for the brain and 3.0% for the spinal cord) and markedly increased sensitivity to demyelinating disease pathology compared to a current, widely used technique. The CALIPR framework facilitates drastically improved MWI and could be similarly transformative for other quantitative MRI applications.

Background and Purpose: Conventional MRI measures of multiple sclerosis (MS) disease severity, such as lesion volume and brain atrophy, do not provide information about microstructural tissue changes, which may be driving physical and cognitive progression. Myelin damage in normal-appearing white matter (NAWM) is likely an important contributor to MS disability. Myelin water fraction (MWF) provides quantitative measurements of myelin. Mean MWF reflects average myelin content, while MWF standard deviation (SD) describes variation in myelin within regions. The myelin heterogeneity index (MHI = SD/mean MWF) is a composite metric of myelin content and myelin variability. We investigated how mean MWF, SD, and MHI compare in differentiating MS from controls and their associations with physical and cognitive disability., Methods: Myelin water imaging data were acquired from 91 MS participants and 31 healthy controls (HC). Segmented whole-brain NAWM and corpus callosum (CC) NAWM, mean MWF, SD, and MHI were compared between groups. Associations of mean MWF, SD, and MHI with Expanded Disability Status Scale and Symbol Digit Modalities Test were assessed., Results: NAWM and CC MHI had the highest area under the curve: .78 (95% confidence interval [CI]: .69, .86) and .84 (95% CI: .76, .91), respectively, distinguishing MS from HC., Conclusions: Mean MWF, SD, and MHI provide complementary information when assessing regional and global NAWM abnormalities in MS and associations with clinical outcome measures. Examining all three metrics (mean MWF, SD, and MHI) enables a more detailed interpretation of results, depending on whether regions of interest include areas that are more heterogeneous, earlier in the demyelination process, or uniformly injured., (© 2022 American Society of Neuroimaging.)

Purpose of Review: Myelin water imaging (MWI) is generally regarded as the most rigorous approach for noninvasive, in-vivo measurement of myelin content, which has been histopathologically validated. As such, it has been increasingly applied to neurological diseases with white matter involvement, especially those affecting myelin. This review provides an overview of the most recent research applying MWI in neurological syndromes., Recent Findings: Myelin water imaging has been applied in neurological syndromes including multiple sclerosis, Alzheimer's disease, Huntington's disease, traumatic brain injury, Parkinson's disease, cerebral small vessel disease, leukodystrophies and HIV. These syndromes generally showed alterations observable with MWI, with decreased myelin content tending to correlate with lower cognitive scores and worse clinical presentation. MWI has also been correlated with genetic variation in the APOE and PLP1 genes, demonstrating genetic factors related to myelin health., Summary: MWI can detect and quantify changes not observable with conventional imaging, thereby providing insight into the pathophysiology and disease mechanisms of a diverse range of neurological syndromes., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Advanced magnetic resonance imaging (MRI) methods can provide more specific information about various microstructural tissue changes in multiple sclerosis (MS) brain. Quantitative measurement of T 1 and T 2 relaxation, and diffusion basis spectrum imaging (DBSI) yield metrics related to the pathology of neuroinflammation and neurodegeneration that occurs across the spectrum of MS., Objective: To use relaxation and DBSI MRI metrics to describe measures of neuroinflammation, myelin and axons in different MS subtypes., Methods: 103 participants (20 clinically isolated syndrome (CIS), 33 relapsing-remitting MS (RRMS), 30 secondary progressive MS and 20 primary progressive MS) underwent quantitative T 1 , T 2 , DBSI and conventional 3T MRI. Whole brain, normal-appearing white matter, lesion and corpus callosum MRI metrics were compared across MS subtypes., Results: A gradation of MRI metric values was seen from CIS to RRMS to progressive MS. RRMS demonstrated large oedema-related differences, while progressive MS had the most extensive abnormalities in myelin and axonal measures., Conclusion: Relaxation and DBSI-derived MRI measures show differences between MS subtypes related to the severity and composition of underlying tissue damage. RRMS showed oedema, demyelination and axonal loss compared with CIS. Progressive MS had even more evidence of increased oedema, demyelination and axonal loss compared with CIS and RRMS.

Background: Spinal cord atrophy provides a clinically relevant metric for monitoring MS. However, the spinal cord is imaged far less frequently than brain due to artefacts and acquisition time, whereas MRI of the brain is routinely performed., Objective: To validate spinal cord cross-sectional area measurements from routine 3DT1 whole-brain MRI versus those from dedicated cord MRI in healthy controls and people with MS., Methods: We calculated cross-sectional area at C1 and C2/3 using T2*-weighted spinal cord images and 3DT1 brain images, for 28 healthy controls and 73 people with MS. Correlations for both groups were assessed between: (1) C1 and C2/3 using cord images; (2) C1 from brain and C1 from cord; and (3) C1 from brain and C2/3 from cord., Results and Conclusion: C1 and C2/3 from cord were strongly correlated in controls ( r  = 0.94, p <0.0001) and MS ( r  = 0.85, p <0.0001). There was strong agreement between C1 from brain and C2/3 from cord in controls ( r  = 0.84, p <0.0001) and MS ( r  = 0.81, p <0.0001). This supports the use of C1 cross-sectional area calculated from brain imaging as a surrogate for the traditional C2/3 cross-sectional area measure for spinal cord atrophy., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Background: Neurofilaments are cytoskeletal proteins that are detectable in the blood after neuroaxonal injury. Multiple sclerosis (MS) disease progression, greater lesion volume, and brain atrophy are associated with higher levels of serum neurofilament light chain (NfL), but few studies have examined the relationship between NfL and advanced magnetic resonance imaging (MRI) measures related to myelin and axons. We assessed the relationship between serum NfL and brain MRI measures in a diverse group of MS participants., Methods and Materials: 103 participants (20 clinically isolated syndrome, 33 relapsing-remitting, 30 secondary progressive, 20 primary progressive) underwent 3T MRI to obtain myelin water fraction (MWF), geometric mean T 2 (GMT 2 ), water content, T 1 ; high angular resolution diffusion imaging (HARDI)-derived axial diffusivity (AD), radial diffusivity (RD), fractional anisotropy (FA); diffusion basis spectrum imaging (DBSI)-derived AD, RD, FA; restricted, hindered, water and fiber fractions; and volume measurements of normalized brain, lesion, thalamic, deep gray matter (GM), and cortical thickness. Multiple linear regressions assessed the strength of association between serum NfL (dependent variable) and each MRI measure in whole brain (WB), normal appearing white matter (NAWM) and T 2 lesions (independent variables), while controlling for age, expanded disability status scale, and disease duration., Results: Serum NfL levels were significantly associated with metrics of axonal damage (FA: R 2 WB-HARDI  = 0.29, R 2 NAWM-HARDI  = 0.31, R 2 NAWM-DBSI  = 0.30, R 2 Lesion-DBSI  = 0.31; AD: R 2 WB-HARDI =0.31), myelin damage (MWF: R 2 WB  = 0.29, R 2 NAWM  = 0.30, RD: R 2 WB-HARDI  = 0.32, R 2 NAWM-HARDI  = 0.34, R 2 Lesion-DBSI  = 0.30), edema and inflammation (T 1 : R 2 Lesion  = 0.32; GMT 2 : R 2 WB  = 0.31, R 2 Lesion  = 0.31), and cellularity (restricted fraction R 2 WB  = 0.30, R 2 NAWM  = 0.32) across the entire MS cohort. Higher serum NfL levels were associated with significantly higher T 2 lesion volume (R 2  = 0.35), lower brain structure volumes (thalamus R 2  = 0.31; deep GM R 2  = 0.33; normalized brain R 2  = 0.31), and smaller cortical thickness R 2  = 0.31)., Conclusion: The association between NfL and myelin MRI markers suggest that elevated serum NfL is a useful biomarker that reflects not only acute axonal damage, but also damage to myelin and inflammation, likely due to the known synergistic myelin-axon coupling relationship., (Copyright © 2021 Elsevier B.V. All rights reserved.)

MRI enables detailed in vivo depiction of multiple sclerosis (MS) pathology. Localized areas of MS damage, commonly referred to as lesions, or plaques, have been a focus of clinical and research MRI studies for over four decades. A nonplaque MRI abnormality which is present in at least 25% of MS patients but has received far less attention is diffusely abnormal white matter (DAWM). DAWM has poorly defined boundaries and a signal intensity that is between normal-appearing white matter and classic lesions on proton density and T 2 -weighted images. All clinical phenotypes of MS demonstrate DAWM, including clinically isolated syndrome, where DAWM is associated with higher lesion volume, reduced brain volume, and earlier conversion to MS. Advanced MRI metric abnormalities in DAWM tend to be greater than those in NAWM, but not as severe as focal lesions, with myelin, axons, and water-related changes commonly reported. Histological studies demonstrate a primary lipid abnormality in DAWM, with some axonal damage and lesser involvement of myelin proteins. This review provides an overview of DAWM identification, summarizes in vivo and postmortem observations, and comments on potential pathophysiological mechanisms, which may underlie DAWM in MS. Given the prevalence and potential clinical impact of DAWM, the number of imaging studies focusing on DAWM is insufficient. Characterization of DAWM significance and microstructure would benefit from larger longitudinal and additional quantitative imaging efforts. Revisiting data from previous studies that included proton density and T 2 imaging would enable retrospective DAWM identification and analysis., (© 2021 American Society of Neuroimaging.)

We characterized the frequency of diffusely abnormal white matter (DAWM) across a broad spectrum of multiple sclerosis (MS) participants. 35% of clinically isolated syndrome (CIS), 57% of relapsing remitting and 64% of secondary progressive MS participants demonstrated DAWM. CIS with DAWM had decreased cortical thickness, higher lesion load and a higher concentration of serum neurofilament light chain compared to CIS without DAWM. DAWM may be useful in identifying CIS patients with greater injury to their brains. Larger and longitudinal studies are warranted., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Purpose: Myelin water fraction (MWF) is a histopathologically validated in vivo myelin marker. As MWF is the proportion of water with a short T 2 relative to the total water, increases in water from edema and inflammation may confound MWF determination in multiple sclerosis (MS) lesions. Total water content (TWC) measurement enables calculation of absolute myelin water content (MWC) and can be used to distinguish edema/inflammation from demyelination. We assessed what influence changes in total water might have on MWF by calculating MWC values in new MS lesions., Methods: 3T 32-echo T 2 relaxation data were collected monthly for 6 months from six relapsing-remitting MS participants. TWC was determined and multiplied with MWF images to calculate corrected MWC images. The effect of this water content correction was examined in 20 new lesions by comparing mean MWF and MWC over time., Results: On average, at lesion first appearance, lesion TWC increased by 6.4% (p = .003; range: -1% to +21%), MWF decreased by 24% (p = .006; range: -70% to +12%), and MWC decreased by 20% (p = .026; range: -68% to +21%), relative to prelesion values. Average TWC in lesions then gradually decreased, whereas MWF and MWC remained low. The shape of the MWF and MWC lesion evolution curves was nearly identical, differing only by an offset., Conclusion: MWF mirrors MWC and is able to monitor myelin in new lesions. Even after taking into account water content increases, MWC still decreased at lesion first appearance attributed to demyelination., (© 2021 American Society of Neuroimaging.)

The traditional approach for measuring myelin-associated water with quantitative magnetic resonance imaging (MRI) uses multi-echo T 2 relaxation data to calculate the myelin water fraction (MWF). A fundamentally different approach, abbreviated "mcDESPOT", uses a more efficient steady-state acquisition to generate an equivalent metric (f M ). Although previous studies have demonstrated inherent instability and bias in the complex mcDESPOT analysis procedure, f M has often been used as a surrogate for MWF. We produced and compared multivariate atlases of MWF and f M in healthy human brain and cervical spinal cord (available online) and compared their ability to detect multiple sclerosis pathology. A significant bias was found in all regions (p < 10 -5 ), albeit reversed for spinal cord (f M -MWF =  - 3.4%) compared to brain (+ 6.2%). MWF and f M followed an approximately linear relationship for regions with MWF <  ~ 10%. For MWF >  ~ 10%, the relationship broke down and f M no longer increased in tandem with MWF. For multiple sclerosis patients, MWF and f M Z score maps showed overlapping areas of low Z score and similar trends between patients and brain regions, although those of f M generally had greater spatial extent and magnitude of severity. These results will guide future choice of myelin-sensitive quantitative MRI and improve interpretation of studies using either myelin imaging approach.

Myelin water imaging is a quantitative neuroimaging technique that provides the myelin water fraction (MWF), a metric highly specific to myelin content, and the intra-/extra-cellular T 2 (IET2), which is related to water and iron content. We coupled high-resolution data from 100 adults with gold-standard methodology to create an optimized anatomical brain template and accompanying MWF and IET2 atlases. We then used the MWF atlas to characterize how myelin content relates to demographic factors. In most brain regions, myelin content followed a quadratic pattern of increase during the third decade of life, plateau at a maximum around the fifth decade, then decrease during later decades. The ranking of mean myelin content between brain regions remained consistent across age groups. These openly available normative atlases can facilitate evaluation of myelin imaging results on an individual basis and elucidate the distribution of myelin content between brain regions and in the context of aging.

Multi-compartment T 2 mapping has gained particular relevance for the study of myelin water in the brain. As a facilitator of rapid saltatory axonal signal transmission, myelin is a cornerstone indicator of white matter development and function. Regularized non-negative least squares fitting of multi-echo T 2 data has been widely employed for the computation of the myelin water fraction (MWF), and the obtained MWF maps have been histopathologically validated. MWF measurements depend upon the quality of the data acquisition, B 1 + homogeneity and a range of fitting parameters. In this special issue article, we discuss the relevance of these factors for the accurate computation of multi-compartment T 2 and MWF maps. We generated multi-echo spin-echo T 2 decay curves following the Carr-Purcell-Meiboom-Gill approach for various myelin concentrations and myelin T 2 scenarios by simulating the evolution of the magnetization vector between echoes based on the Bloch equations. We demonstrated that noise and imperfect refocusing flip angles yield systematic underestimations in MWF and intra-/extracellular water geometric mean T 2 (gmT 2 ). MWF estimates were more stable than myelin water gmT 2 time across different settings of the T 2 analysis. We observed that the lower limit of the T 2 distribution grid should be slightly shorter than TE 1 . Both TE 1 and the acquisition echo spacing also have to be sufficiently short to capture the rapidly decaying myelin water T 2 signal. Among all parameters of interest, the estimated MWF and intra-/extracellular water gmT 2 differed by approximately 0.13-4 percentage points and 3-4 ms, respectively, from the true values, with larger deviations observed in the presence of greater B 1 + inhomogeneities and at lower signal-to-noise ratio. Tailoring acquisition strategies may allow us to better characterize the T 2 distribution, including the myelin water, in vivo., (© 2020 John Wiley & Sons, Ltd.)

Purpose: Myelin water imaging (MWI) provides a valuable biomarker for myelin, but clinical application has been restricted by long acquisition times. Accelerating the standard multi-echo T 2 acquisition with gradient echoes (GRASE) or by 2D multi-slice data collection results in image blurring, contrast changes, and other issues. Compressed sensing (CS) can vastly accelerate conventional MRI. In this work, we assessed the use of CS for in vivo human MWI, using a 3D multi spin-echo sequence., Methods: We implemented multi-echo T 2 relaxation imaging with compressed sensing (METRICS) and METRICS with partial Fourier acceleration (METRICS-PF). Scan-rescan data were acquired from 12 healthy controls for assessment of repeatability. MWI data were acquired for METRICS in 9 m:58 s and for METRICS-PF in 7 m:25 s, both with 1.5 × 2 × 3 mm 3 voxels, 56 echoes, 7 ms ΔTE, and 240 × 240 × 170 mm 3 FOV. METRICS was compared with a novel multi-echo spin-echo gold-standard (MSE-GS) MWI acquisition, acquired for a single additional subject in 2 h:2 m:40 s., Results: METRICS/METRICS-PF myelin water fraction had mean: repeatability coefficient 1.5/1.1, coefficient of variation 6.2/4.5%, and intra-class correlation coefficient 0.79/0.84. Repeatability metrics comparing METRICS with METRICS-PF were similar, and both sequences agreed with reference values from literature. METRICS images and quantitative maps showed excellent qualitative agreement with those of MSE-GS., Conclusion: METRICS and METRICS-PF provided highly repeatable MWI data without the inherent disadvantages of GRASE or 2D multi-slice acquisition. CS acceleration allows MWI data to be acquired rapidly with larger FOV, higher estimated SNR, more isotropic voxels and more echoes than with previous techniques. The approach introduced here generalizes to any multi-component T 2 mapping application., (© 2020 International Society for Magnetic Resonance in Medicine.)

Importance: Cognitive impairment is a debilitating symptom of multiple sclerosis (MS) that affects up to 70% of patients. An improved understanding of the underlying pathology of MS-related cognitive impairment would provide considerable benefit to patients and clinicians., Objective: To determine whether there is an association between myelin damage in tissue that appears completely normal on standard clinical imaging, but can be detected by myelin water imaging (MWI), with cognitive performance in MS., Design, Setting, and Participants: In this cross-sectional study, participants with MS and controls underwent cognitive testing and magnetic resonance imaging (MRI) from August 23, 2017, to February 20, 2019. Participants were recruited through the University of British Columbia Hospital MS clinic and via online recruitment advertisements on local health authority websites. Cognitive testing was performed in the MS clinic, and MRI was performed at the adjacent academic research neuroimaging center. Seventy-three participants with clinically definite MS fulfilling the 2017 revised McDonald criteria for diagnosis and 22 age-, sex-, and education-matched healthy volunteers without neurological disease were included in the study. Data analysis was performed from March to November 2019., Exposures: MWI was performed at 3 T with a 48-echo, 3-dimensional, gradient and spin-echo (GRASE) sequence. Cognitive testing was performed with assessments drawn from cognitive batteries validated for use in MS., Main Outcomes and Measures: The association between myelin water measures, a measurement of the T2 relaxation signal from water in the myelin bilayers providing a specific marker for myelin, and cognitive test scores was assessed using Pearson correlation. Three white matter regions of interest-the cingulum, superior longitudinal fasciculus (SLF), and corpus callosum-were selected a priori according to their known involvement in MS-related cognitive impairment., Results: For the 95 total participants, the mean (SD) age was 49.33 (11.44) years. The mean (SD) age was 50.2 (10.7) years for the 73 participants with MS and 46.4 (13.5) for the 22 controls. Forty-eight participants with MS (66%) and 14 controls (64%) were women. The mean (SD) years of education were 14.7 (2.2) for patients and 15.8 (2.5) years for controls. In MS, significant associations were observed between myelin water measures and scores on the Symbol Digit Modalities Test (SLF, r = -0.490; 95% CI, -0.697 to -0.284; P < .001; corpus callosum, r = -0.471; 95% CI, -0.680 to -0.262; P < .001; and cingulum, r = -0.419; 95% CI, -0.634 to -0.205; P < .001), Selective Reminding Test (SLF, r = -0.444; 95% CI, -0.660 to -0.217; P < .001; corpus callosum, r = -0.411; 95% CI, -0.630 to -0.181; P = .001; and cingulum, r = -0.361; 95% CI, -0.602 to -0.130; P = .003), and Controlled Oral Word Association Test (SLF, r = -0.317; 95% CI, -0.549 to -0.078; P = .01; and cingulum, r = -0.335; 95% CI, -0.658 to -0.113; P = .006). No significant associations were found in controls., Conclusions and Relevance: This study used MWI to demonstrate that otherwise normal-appearing brain tissue is diffusely damaged in MS, and the findings suggest that myelin water measures are associated with cognitive performance. MWI offers an in vivo biomarker feasible for use in clinical trials investigating cognition, providing a means for monitoring changes in myelination and its association with symptom worsening or improvement.

Purpose: Based on a deep learning neural network (NN) algorithm, a super fast and easy to implement data analysis method was proposed for myelin water imaging (MWI) to calculate the myelin water fraction (MWF)., Methods: A NN was constructed and trained on MWI data acquired by a 32-echo 3D gradient and spin echo (GRASE) sequence. Ground truth labels were created by regularized non-negative least squares (NNLS) with stimulated echo corrections. Voxel-wise GRASE data from 5 brains (4 healthy, 1 multiple sclerosis (MS)) were used for NN training. The trained NN was tested on 2 healthy brains, 1 MS brain with segmented lesions, 1 healthy spinal cord, and 1 healthy brain acquired from a different scanner., Results: Production of whole brain MWF maps in approximately 33 ​s can be achieved by a trained NN without graphics card acceleration. For all testing regions, no visual differences between NN and NNLS MWF maps were observed, and no obvious regional biases were found. Quantitatively, all voxels exhibited excellent agreement between NN and NNLS (all R 2 >0.98, p ​< ​0.001, mean absolute error <0.01)., Conclusion: The time for accurate MWF calculation can be dramatically reduced to less than 1 ​min by the proposed NN, addressing one of the barriers facing future clinical feasibility of MWI., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Myelin water fraction (MWF) images in brain tend to be spatially noisy with unknown or no apparent spatial patterns structure, so values are therefore typically averaged over large white matter (WM) volumes. We investigated the existence of an inherent spatial structure in MWF maps and explored the benefits of examining MWF values along diffusion tensor imaging (DTI)-derived white matter tracts. We compared spatial anisotropy between MWF and the more widely-used fractional anisotropy (FA) measure. Sixteen major white matter fibre bundles were extracted based on DTI data from 41 healthy subjects. MWF coefficients of variation (CoV) were computed in sub-segments along each fibre tract and compared to MWF CoVs from the surrounding "tubes" - i.e. voxels just exterior to the tract - of each segment. We further assessed the consistency of the MWF along fibre bundles across subjects and investigated the benefit of examining MWF values in sections along each fibre bundle rather than integrating over the whole tract. CoVs of MWF and FA were lower in fibre bundles compared to their enclosing tubes in all investigated tracts. Both measures possessed a spatial gradient of CoV that was smaller aligned along, compared to perpendicular to, the fibre bundles. All WM tracts showed MWF profiles along their trajectory that were consistent across subjects and were more accurate than the mean overall fibre MWF value in estimating ages of the subjects. We conclude that, although less obvious visually, the spatial MWF distribution in white matter consistently follows a distinct pattern along underlying fibre bundles across subjects. Assessing MWF in sections along white matter tracts may provide a sensitive and robust way to assess myelin across subjects., Competing Interests: Declaration of competing interest None., (Copyright © 2019. Published by Elsevier Inc.)

Background and Purpose: Myelin water imaging (MWI) and diffusion tensor imaging (DTI) provide information about myelin and axon-related brain microstructure, which can be useful for investigating normal brain development and many childhood brain disorders. While pediatric DTI atlases exist, there are no pediatric MWI atlases available for the 9-10 years old age group. As myelination and structural development occurs throughout childhood and adolescence, studies of pediatric brain pathologies must use age-specific MWI and DTI healthy control data. We created atlases of myelin water fraction (MWF) and DTI metrics for healthy children aged 9-10 years for use as normative data in pediatric neuroimaging studies., Methods: 3D-T 1 , DTI, and MWI scans were acquired from 20 healthy children (mean age: 9.6 years, range: 9.2-10.3 years, 4 females). ANTs and FSL registration were used to create quantitative MWF and DTI atlases. Region of interest (ROI) analysis in nine white matter regions was used to compare pediatric MWF with adult MWF values from a recent study and to investigate the correlation between pediatric MWF and DTI metrics., Results: Adults had significantly higher MWF than the pediatric cohort in seven of the nine white matter ROIs, but not in the genu of the corpus callosum or the cingulum. In the pediatric data, MWF correlated significantly with mean diffusivity, but not with axial diffusivity, radial diffusivity, or fractional anisotropy., Conclusions: Normative MWF and DTI metrics from a group of 9-10 year old healthy children provide a resource for comparison to pathologies. The age-specific atlases are ready for use in pediatric neuroimaging research and can be accessed: https://sourceforge.net/projects/pediatric-mri-myelin-diffusion/., (© 2020 by the American Society of Neuroimaging.)

Background and Purpose: Cognitive impairment is a core symptom in multiple sclerosis (MS). Damage to normal appearing white matter (NAWM) is likely involved. We sought to determine if greater myelin heterogeneity in NAWM is associated with decreased cognitive performance in MS., Methods: A total of 27 participants with MS and 13 controls matched for age, sex, and education underwent myelin water imaging (MWI) from which the myelin water fraction (MWF) was calculated. Corpus callosum, superior longitudinal fasciculus, and cingulum were chosen as regions of interest (ROIs) a priori based on their involvement in MS-related cognitive impairment. Cognitive performance was assessed using the Symbol Digit Modalities Test (SDMT). Pearson ́s product moment correlations were performed to assess relationships between cognitive performance and myelin heterogeneity (variance of MWF within an ROI)., Results: In MS, myelin heterogeneity in all three ROIs was significantly associated with performance on the SDMT. These correlations ranged from moderate (r = -.561) to moderately strong (r = -.654) and were highly significant (P values ranged from .001 to .0002). Conversely, myelin heterogeneity was not associated with SDMT performance in controls in any ROI (P > .108)., Conclusion: Increased myelin heterogeneity in NAWM is associated with decreased cognitive processing speed performance in MS., (© 2019 by the American Society of Neuroimaging.)

Background and Purpose: Acquiring and interpreting quantitative myelin-specific MRI data at an individual level is challenging because of technical difficulties and natural myelin variation in the population. To overcome these challenges, we used multiecho T 2 myelin water imaging (MWI) to create T 2 metric healthy population atlases that depict the mean and variation of myelin water fraction (MWF), and intra- and extracellular water mobility as described by geometric mean T 2 (IEGMT 2 )., Methods: Cervical cord MWI was performed at 3T on 20 healthy individuals (10M/10F, mean age: 36 years) and 3 relapsing remitting multiple sclerosis (RRMS) participants (1M/2F, age: 39/42/37 years). Anatomical data were collected for the purpose of image segmentation and registration. Atlases were created by coregistering and averaging T 2 metrics from all controls. Voxel-wise z-score maps from 3 RRMS participants were produced to demonstrate the preliminary utility of the MWF and IEGMT 2 atlases., Results: The average MWF atlas provides a representation of myelin in the spinal cord consistent with well-known spinal cord anatomical characteristics. The IEGMT 2 atlas also depicted structural variations in the spinal cord. Z-score analysis illustrated distinct abnormalities in MWF and IEGMT 2 in the 3 RRMS cases., Conclusions: Our findings highlight the potential for using a quantitative T 2 relaxation metric atlas to visualize and detect pathology in spinal cord. Our MWF and IEGMT 2 atlases (URL: https://sourceforge.net/projects/mwi-spinal-cord-atlases/) can serve as normative references in the cervical spinal cord for other studies., (© 2019 by the American Society of Neuroimaging.)

Background: Enhanced prediction of progression in secondary progressive multiple sclerosis (SPMS) could improve clinical trial design. Machine learning (ML) algorithms are methods for training predictive models with minimal human intervention., Objective: To evaluate individual and ensemble model performance built using decision tree (DT)-based algorithms compared to logistic regression (LR) and support vector machines (SVMs) for predicting SPMS disability progression., Methods: SPMS participants ( n  = 485) enrolled in a 2-year placebo-controlled (negative) trial assessing the efficacy of MBP8298 were classified as progressors if a 6-month sustained increase in Expanded Disability Status Scale (EDSS) (≥1.0 or ≥0.5 for a baseline of ≤5.5 or ≥6.0 respectively) was observed. Variables included EDSS, Multiple Sclerosis Functional Composite component scores, T2 lesion volume, brain parenchymal fraction, disease duration, age, and sex. Area under the receiver operating characteristic curve (AUC) was the primary outcome for model evaluation., Results: Three DT-based models had greater AUCs (61.8%, 60.7%, and 60.2%) than independent and ensemble SVM (52.4% and 51.0%) and LR (49.5% and 51.1%)., Conclusion: SPMS disability progression was best predicted by non-parametric ML. If confirmed, ML could select those with highest progression risk for inclusion in SPMS trial cohorts and reduce the number of low-risk individuals exposed to experimental therapies., (© The Author(s) 2019.)

Background and Purpose: Myelin water imaging (MWI) is a magnetic resonance imaging technique that quantifies myelin in-vivo. Although MWI has been extensively applied to study myelin-related diseases in groups, clinical use in individual patients is challenging mainly due to population heterogeneity. The purpose of this study was twofold: (1) create a normative brain myelin water atlas depicting the population mean and regional variability of myelin content; and (2) apply the myelin atlas to assess the degree of demyelination in individuals with multiple sclerosis (MS)., Methods: 3T MWI was performed on 50 healthy adults (25 M/25 F, mean age 25 years [range 17-42 years]). The myelin water atlas was created by averaging coregistered myelin water fraction (MWF) maps from all healthy individuals. To illustrate the preliminary utility of the atlas, white matter (WM) regional MWF variations were evaluated and voxel-wise z-score maps (z < -1.96) from the MWI of three MS participants were produced to assess individually the degree of demyelination., Results: The myelin water atlas demonstrated significant MWF variation across control WM. No significant MWF differences were found between male and female healthy participants. MS z-score maps revealed diffuse regions of demyelination in the two participants with Expanded Disability Status Scale (EDSS) = 2.0 but not in the participant with EDSS = 0., Conclusions: The myelin water atlas can be used as a reference (URL: https://sourceforge.net/projects/myelin-water-atlas/) to demonstrate areas of demyelination in individual MS participants. Future studies will expand the atlas age range, account for education, and other variables that may affect myelination., (© 2019 by the American Society of Neuroimaging.)

Background: Magnetic resonance spectroscopy quantitatively monitors biomarkers of neuron-myelin coupling (N-acetylaspartate (NAA)), and inflammation (total creatine (tCr), total choline (tCho), myo-inositol (mI)) in the brain., Objective: This study aims to investigate how ocrelizumab and interferon beta-1a differentially affects imaging biomarkers of neuronal-myelin coupling and inflammation in patients with relapsing multiple sclerosis (MS)., Methods: Forty patients with relapsing MS randomized to either treatment were scanned at 3T at baseline and weeks 24, 48, and 96 follow-up. Twenty-four healthy controls were scanned at weeks 0, 48, and 96. NAA, tCr, tCho, mI, and NAA/tCr were measured in a single large supra-ventricular voxel., Results: There was a time × treatment interaction in NAA/tCr ( p  = 0.04), primarily driven by opposing tCr trends between treatment groups after 48 weeks of treatment. Patients treated with ocrelizumab showed a possible decline in mI after week 48 week, and stable tCr and tCho levels. Conversely, the interferon beta-1a treated group showed possible increases in mI, tCr, and tCho over 96 weeks., Conclusions: Results from this exploratory study suggest that over 2 years, ocrelizumab reduces gliosis compared with interferon beta-1a, demonstrated by declining ml, and stable tCr and tCho. Ocrelizumab may improve the physiologic milieu by decreasing neurotoxic factors that are generated by inflammatory processes., (© The Author(s) 2019.)

Background: Tissue damage in both multiple sclerosis (MS) lesions and normal-appearing white matter (NAWM) are important contributors to disability and progression. Specific aspects of MS pathology can be measured using advanced imaging. Alemtuzumab is a humanised monoclonal antibody targeting CD52 developed for MS treatment., Objective: To investigate changes over 2 years of advanced magnetic resonance (MR) metrics in lesions and NAWM of MS patients treated with alemtuzumab., Methods: A total of 42 relapsing-remitting alemtuzumab-treated MS subjects were scanned for 2 years at 3 T. T 1 relaxation, T 2 relaxation, diffusion tensor, MR spectroscopy and volumetric sequences were performed. Mean T 1 and myelin water fraction (MWF) were determined for stable lesions, new lesions and NAWM. Fractional anisotropy was calculated for the corpus callosum (CC) and N-acetylaspartate (NAA) concentration was determined from a large NAWM voxel. Brain parenchymal fraction (BPF), cortical thickness and CC area were also calculated., Results: No change in any MR measurement was found in lesions or NAWM over 24 months. BPF, cortical thickness and CC area all showed decreases in the first year followed by stability in the second year., Conclusion: Advanced MR biomarkers of myelin (MWF) and neuron/axons (NAA) show no change in NAWM over 24 months in alemtuzumab-treated MS participants.

Background: Progressive solitary sclerosis is a unifocal demyelinating disease recently proposed as a possible multiple sclerosis variant., Objective: To compare myelin content and brain metabolite ratio qualitatively in the normal-appearing white matter of progressive solitary sclerosis cases compared to multiple sclerosis and healthy control participants., Methods: Case report., Results: Progressive solitary sclerosis cases showed abnormal myelin in normal-appearing white matter tracts and global normal-appearing white matter as well as lower N-acetyl-aspartate to total creatine ratio compared to multiple sclerosis and healthy control groups., Conclusion: Despite a single demyelinating lesion along the corticospinal tract in progressive solitary sclerosis, we showed evidence of more extensive abnormality within the normal-appearing white matter.

Background: Rapid myelin water imaging (MWI) using a combined gradient and spin echo (GRASE) sequence can produce myelin specific metrics for the human brain. Spinal cord MWI could be similarly useful, but technical challenges have hindered routine application. GRASE rapid MWI was recently successfully implemented for imaging of healthy cervical spinal cord and may complement other advanced imaging methods, such as diffusion tensor imaging (DTI) and quantitative T 1 (qT 1 )., Objective: To demonstrate the feasibility of cervical cord GRASE rapid MWI in multiple sclerosis (MS), primary lateral sclerosis (PLS) and neuromyelitis optica spectrum disorder (NMO), with comparison to DTI and qT 1 metrics., Methods: GRASE MWI, DTI and qT 1 data were acquired in 2 PLS, 1 relapsing-remitting MS (RRMS), 1 primary-progressive MS (PPMS) and 2 NMO subjects, as well as 6 age (±3 yrs) and sex matched healthy controls (HC). Internal cord structure guided template registrations, used for region of interest (ROI) analysis. Z score maps were calculated for the difference between disease subject and mean HC metric values., Results: PLS subjects had low myelin water fraction (MWF) in the lateral funiculi compared to HC. RRMS subject MWF was heterogeneous within the cord. The PPMS subject showed no trends in ROI results but had a region of low MWF Z score corresponding to a focal lesion. The NMO subject with a longitudinally extensive transverse myelitis lesion had low values for whole cord mean MWF of 12.8% compared to 24.3% (standard deviation 2.2%) for HC. The NMO subject without lesions also had low MWF compared to HC. DTI and qT 1 metrics showed similar trends, corroborating the MWF results and providing complementary information., Conclusion: GRASE is sufficiently sensitive to detect decreased myelin within MS spinal cord plaques, NMO lesions, and PLS diffuse spinal cord injury. Decreased MWF in PLS is consistent with demyelination secondary to motor neuron degeneration. GRASE MWI is a feasible method for rapid assessment of myelin content in the cervical spinal cord and provides complementary information to that of DTI and qT 1 measures., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Radiation necrosis mostly occurs in and near the radiation field. We used magnetic resonance imaging to study radiation-induced necrosis of atypical onset, severity, and extent following stereotactic radiosurgery for a symptomatic arteriovenous malformation. Susceptibility-sensitive imaging, T 1 -relaxation, myelin water imaging, and magnetic resonance spectroscopy were acquired three times up to 52 months postradiosurgery. Increasing water content outside the radiation field, contralateral neuronal loss, and gliosis were detected over time. Our findings suggest that radiation-induced vasculopathic changes spread more diffusely than previously described. An autoimmune response to brain antigens could underlie white matter changes outside the initial radiation field., Competing Interests: Vanessa Wiggermann has nothing to disclose. Emmanuelle Lapointe has received consulting fees from Roche, Biogen, and EMD Serono and speaker fees from Genzyme and EMD Serono. Ludmila Litvin, Carina Graf, and Enedino Hernández‐Torres report no disclosures. Michael McKenzie is on the Steering Committee for a randomized trial in prostate cancer sponsored by Janssen R&D. He has received honoraria from Abbott, Bayer, Amgen, and Ferring as well as from Varian. Irene M Vavasour and Cornelia Laule have no disclosures. Erin L. Macmillan is supported by Philips Healthcare Canada. David Li has received research funding from the Canadian Institute of Health Research and Multiple Sclerosis Society of Canada. He is the Emeritus Director of the UBC MS/MRI Research Group, which has been contracted to perform central analysis of MRI scans for therapeutic trials with Novartis, Perceptives, Roche, and Sanofi‐Aventis. The UBC MS/MRI Research Group has also received grant support for investigator‐initiated independent studies from Genzyme, Merck‐Serono, Novartis, and Roche. He has acted as a consultant to Vertex Pharmaceuticals and served on the Data and Safety Advisory Board for Opexa Therapeutics and Scientific Advisory Boards for Adelphi Group, Celgene, Novartis, and Roche. He has also given lectures which have been supported by nonrestricted education grants from Biogen‐Idec, Novartis, Sanofi‐Genzyme, and Teva. Shannon Kolind has consulted for Acorda and Genzyme. She has received research support from Roche. She is grateful for support from the MS Society of Canada and the Milan & Maureen Ilich Foundation. Alexander Rauscher has received funding from NSERC and the National MS Society as well as speaker fees from Philips Medical. Anthony Traboulsee has received grant funding from the MS Society of Canada, Canadian Institute for Health Research, Roche, and Genzyme; he also received honoraria or travel grants from Teva Canada Innovation, Roche, Merck/EMD Serono, Genzyme, Chugai Pharmaceuticals.

Myelin water imaging can be achieved using multicomponent T 2 relaxation analysis to quantify in vivo measurement of myelin content, termed the myelin water fraction (MWF). Therefore, myelin water imaging can be a valuable tool to better understand the underlying white matter pathology in demyelinating diseases, such as multiple sclerosis. To apply myelin water imaging in multisite studies and clinical applications, it must be acquired in a clinically feasible scan time (less than 15 min) and be reproducible across sites and scanner vendors. Here, we assessed the reproducibility of MWF measurements in regional and global white matter in 10 healthy human brains across two sites with two different 3 T magnetic resonance imaging scanner vendors (Philips and Siemens), using a 32-echo gradient and spin echo (GRASE) sequence. A strong correlation was found between the MWF measurements in the global white matter (Pearson's r = 0.91; p < 0.001) for all participants across the two sites. The mean intersite MWF coefficient of variation across participants was 2.77% in the global white matter and ranged from 4.47% (splenium of the corpus callosum) to 17.89% (genu of the corpus callosum) in white matter regions of interest. Bland-Altman analysis showed a good agreement in MWF measurements between the two sites with small bias of 0.002. Overall, MWF estimates were in good agreement across the two sites and scanner vendors. Our findings support the use of quantitative multi-echo T 2 relaxation metrics, such as the MWF, in multicenter studies and clinical trials to gain deeper understanding about the pathological processes resulting from the underlying disease progression in neurodegenerative diseases.

Background: Reduced myelin water fraction (MWF, a marker for myelin), increased geometric mean T 2 (ieGMT 2 , reflecting intra/extracellular water properties), and increased T 1 (related to total water content) have been observed in cross-sectional studies of multiple sclerosis (MS) normal-appearing white matter (NAWM)., Objective: To assess longitudinal changes of magnetic resonance (MR) measures in relapsing-remitting MS (RRMS) brain NAWM., Methods: A total of 11 subjects with RRMS and 4 controls were scanned on a 3T MRI at baseline and long-term follow-up (LTFU; 3.2-5.8 years) with a 32-echo T 2 relaxation and an inversion recovery T 1 sequence. For every voxel, MWF, ieGMT 2 , and T 1 were obtained. Mean, peak height, and peak location from NAWM mask-based histograms were determined., Results: In MS subjects, NAWM MWF mean decreased by 8% ( p = 0.0016). No longitudinal changes were measured in T 1 or ieGMT 2 . There was no relationship between change in any MR metric and change in EDSS. Control white matter showed no differences over time in any metric., Conclusion: The decreases we observed in MWF suggest that changes in myelin integrity and loss of myelin may be occurring diffusely and over long time periods in the MS brain. The timescale of these changes indicates that chronic, progressive myelin damage is an evolving process occurring over many years.

Purpose: To assess the extent of demyelination in cervical spondylotic myelopathy (CSM) using myelin water imaging (MWI) and electrophysiologic techniques., Methods: Somatosensory evoked potentials (SSEPs) and MWI were acquired in 14 patients with CSM and 18 age-matched healthy controls. MWI was performed on a 3.0T whole body magnetic resonance scanner. Myelin water fraction (MWF) was extracted for the dorsal columns and whole cord. SSEPs and MWF were also compared with conventional MRI outcomes, including T2 signal intensity, compression ratio, maximum spinal cord compression (MSCC), and maximum canal compromise (MCC)., Results: Group analysis showed marked differences in T2 signal intensity, compression ratio, MSCC, and MCC between healthy controls and patients with CSM. There were no group differences in MWF and SSEP latencies. However, patients with CSM with pathologic SSEPs exhibited reduction in MWF ( p < 0.05). MWF was also correlated with SSEP latencies., Conclusion: Our findings provide evidence of decreased myelin content in the spinal cord associated with impaired spinal cord conduction in patients with CSM. While conventional MRI are of great value to define the extent of cord compression, they show a limited correlation with functional deficits (i.e., delayed SSEPs). MWI provides independent and complementary readouts to spinal cord compression, with a high specificity to detect impaired conduction., (© 2017 American Academy of Neurology.)

Purpose: This work demonstrates the in vivo application of a T 2 relaxation based total water content (TWC) measurement technique at 3T in healthy human brain, and evaluates accuracy using simulations that model brain tissue. The benefit of using T 2 relaxation is that it provides simultaneous measurements of myelin water fraction, which correlates to myelin content., Methods: T 2 relaxation data was collected from 10 healthy human subjects with a gradient and spin echo (GRASE) sequence, along with inversion recovery for T 1 mapping. Voxel-wise T 2 distributions were calculated by fitting the T 2 relaxation data with a non-negative least squares algorithm incorporating B 1 + inhomogeneity corrections. TWC was the sum of the signals in the T 2 distribution, corrected for T 1 relaxation and receiver coil inhomogeneity, relative to either an external water standard or cerebrospinal fluid (CSF). Simulations were performed to determine theoretical errors in TWC., Results: TWC values measured in healthy human brain relative to both external and CSF standards agreed with literature values. Simulations demonstrated that TWC could be measured to within 3-4% accuracy., Conclusion: In vivo TWC measurement using T 2 relaxation at 3T works well and provides a valuable tool for studying neurological diseases with both myelin and water changes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To determine whether differences in hydration state, which could arise from routine clinical procedures such as overnight fasting, affect brain total water content (TWC) and brain volume measured with magnetic resonance imaging (MRI)., Materials and Methods: Twenty healthy volunteers were scanned with a 3T MR scanner four times: day 1, baseline scan; day 2, hydrated scan after consuming 3L of water over 12 hours; day 3, dehydrated scan after overnight fasting of 9 hours, followed by another scan 1 hour later for reproducibility. The following MRI data were collected: T2 relaxation (for TWC measurement), inversion recovery (for T1 measurement), and 3D T1 -weighted (for brain volumes). Body weight and urine specific gravity were also measured. TWC was calculated by fitting the T2 relaxation data with a nonnegative least-squares algorithm, with corrections for T1 relaxation and image signal inhomogeneity and normalization to ventricular cerebrospinal fluid. Brain volume changes were measured using SIENA. TWC means were calculated within 14 tissue regions., Results: Despite indications of dehydration as demonstrated by increases in urine specific gravity (P = 0.03) and decreases in body weight (P = 0.001) between hydrated and dehydrated scans, there was no measurable change in TWC (within any brain region) or brain volume between hydration states., Conclusion: We demonstrate that within a range of physiologic conditions commonly encountered in routine clinical scans (no pretreatment with hydration, well hydrated before MRI, and overnight fasting), brain TWC and brain volumes are not substantially affected in a healthy control cohort. J. Magn. Reson. Imaging 2016;44:296-304., (© 2016 Wiley Periodicals, Inc.)

Background: The optic nerve is frequently injured in multiple sclerosis and neuromyelitis optica, resulting in visual dysfunction, which may be reflected by measures distant from the site of injury., Objective: To determine how retinal nerve fiber layer as a measure of axonal health, and macular volume as a measure of neuronal health are related to changes in myelin water fraction in the optic radiations of multiple sclerosis and neuromyelitis optica participants with and without optic neuritis and compared to healthy controls., Methods: 12 healthy controls, 42 multiple sclerosis (16 with optic neuritis), and 10 neuromyelitis optica participants (8 with optic neuritis) were included in this study. Optical coherence tomography assessment involved measurements of the segmented macular layers (total macular, ganglion cell layer, inner plexiform layer, and inner nuclear layer volume) and paripapillary retinal nerve fiber layer thickness. The MRI protocol included a 32-echo T2-relaxation GRASE sequence. Average myelin water fraction values were calculated within the optic radiations as a measure of myelin density., Results: Multiple sclerosis and neuromyelitis optica eyes with optic neuritis history had lower retinal nerve fiber layer thickness, total macular, ganglion cell and inner plexiform layer volumes compared to eyes without optic neuritis history and controls. Inner nuclear layer volume increased in multiple sclerosis with optic neuritis history (mean = 0.99 mm(3), SD = 0.06) compared to those without (mean = 0.97 mm(3), SD = 0.06; p = 0.003). Mean myelin water fraction in the optic radiations was significantly lower in demyelinating diseases (neuromyelitis optica: mean = 0.098, SD = 0.01, multiple sclerosis with optic neuritis history: mean = 0.096, SD = 0.01, multiple sclerosis without optic neuritis history: mean = 0.098, SD = 0.02; F3,55 = 3.35, p = 0.03) compared to controls. Positive correlations between MRI and optical coherence tomography measures were also apparent (retinal nerve fiber layer thickness and ganglion cell layer thickness: r = 0.25, p = 0.05, total macular volume and inner plexiform layer volume: r = 0.27, p = 0.04)., Conclusions: The relationship between reductions in OCT measures of neuro-axonal health in the anterior visual pathway and MRI-based measures of myelin health in the posterior visual pathway suggests that these measures may be linked through bidirectional axonal degeneration.

The hippocampus has been shown to demonstrate a remarkable degree of plasticity in response to a variety of tasks and experiences. For example, the size of the human hippocampus has been shown to increase in response to aerobic exercise. However, it is currently unknown what underlies these changes. Here we scanned sedentary, young to middle-aged human adults before and after a six-week exercise intervention using nine different neuroimaging measures of brain structure, vasculature, and diffusion. We then tested two different hypotheses regarding the nature of the underlying changes in the tissue. Surprisingly, we found no evidence of a vascular change as has been previously reported. Rather, the pattern of changes is better explained by an increase in myelination. Finally, we show that hippocampal volume increase is temporary, returning to baseline after an additional six weeks without aerobic exercise. This is the first demonstration of a change in hippocampal volume in early to middle adulthood suggesting that hippocampal volume is modulated by aerobic exercise throughout the lifespan rather than only in the presence of age related atrophy. It is also the first demonstration of hippocampal volume change over a period of only six weeks, suggesting that gross morphometric hippocampal plasticity occurs faster than previously thought., (Published by Elsevier Inc.)

Purpose: In vivo measurement of water content would be very useful for evaluating microstructural tissue changes, such as edema, that occur in neurological diseases. Careful assessment of the T2 relaxation decay curve can provide simultaneous measurements of total water content (TWC) and myelin water fraction, a marker for myelin which is also relevant in brain pathology. This work validates a T2 relaxation based method for TWC measurement at 3T using phantoms and simulations., Methods: A phantom consisting of tubes with known water concentrations was scanned using 3T MRI. T2 relaxation data was collected with both gradient echo spin-echo (GRASE) and spin echo sequences, while an inversion recovery experiment provided T1 relaxation data. Voxel-wise T2 distributions were calculated by fitting the T2 relaxation data with a non-negative least squares algorithm that incorporated a correction for errors in flip angle due to B1(+) inhomogeneity. TWC was calculated as the sum of the signal in the T2 distribution, corrected for T1 relaxation, relative to that of a tube containing 100% water. TWC from GRASE was compared to that of spin echo in order to test if the accuracy of the TWC measurement was impacted by using additional gradient echoes to fill k-space. Simulations were performed to determine theoretical errors in TWC., Results: Measured TWC strongly correlated to actual TWC (R=0.997, p=9×10(-8), mean discrepancy=1.8%). Accuracy of GRASE and spin echo TWC measurements did not significantly differ. Simulations indicated a mean systematic TWC error of 0.07% and random error of 0.8%, and revealed that the technique performs well in the presence of B1(+) inhomogeneity., Conclusion: This work demonstrates that, using the T2 relaxation decay curve, TWC can be measured to within 3% accuracy at 3T. Given that T2 relaxation can provide accurate estimates of both TWC and myelin water fraction, multi-echo T2 measurement should be considered a multifaceted approach for assessing pathology and evaluating therapy of central nervous system diseases., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Both multiple sclerosis (MS) and neuromyelitis optica (NMO) can present with transverse myelitis; however, NMO symptoms are usually more severe and may present with more extensive axonal loss. Transcranial magnetic stimulation (TMS)-based input-output recruitment curves can quantitatively assess the excitability of corticospinal tract pathways and myelin water imaging can quantify the amount of myelin within this same pathway., Objective: To compare differential effects of MS and NMO on TMS recruitment curves and myelin water imaging., Methods: Ten healthy controls, 10 individuals with MS and 10 individuals with NMO completed clinical assessments, a TMS assessment and magnetic resonance imaging scan to measure recruitment curves and myelin water fraction in the corticospinal tract., Results: Individuals with NMO had lower recruitment curve slopes (mean 13.6±6 μV/%) than MS (23.6±11 μV/%) and controls (21.9±9 μV/%, analysis of variance (ANOVA) P=0.05). Corticospinal tract myelin water fraction was lower in individuals with NMO (mean 0.17±0.02) compared to MS (0.19±0.02) and controls (0.20±0.02, ANOVA P=0.0006)., Conclusion: Corticospinal pathway damage in individuals with NMO was evident by reduced recruitment curve slope and lower myelin water fraction. These specific measures of corticospinal function and structure may be used to obtain a better understanding and monitor brain injury caused by inflammatory central nervous system disorders., (© The Author(s), 2015.)

Background: Few biomarkers of progressive multiple sclerosis (MS) are sensitive to change within the two-year time frame of a clinical trial., Objective: To identify biomarkers of MS disease progression with magnetic resonance spectroscopy (MRS) in secondary progressive MS (SPMS)., Methods: Forty-seven SPMS subjects were scanned at baseline and annually for two years. Concentrations of N-acetylaspartate, total creatine, total choline, myo-inositol, glutamate, glutamine, and the sum glutamate+glutamine were measured in a single white matter voxel., Results: Glutamate and glutamine were the only metabolites to show an effect with time: with annual declines of (95% confidence interval): glutamate -4.2% (-6.2% to -2.2%, p < 10(-4)), glutamine -7.3% (-11.8% to -2.9%, p = 0.003), and glutamate+glutamine -5.2% (-7.6% to -2.8%, p < 10(-4)). Metabolite rates of change were more apparent than changes in clinical scores or brain atrophy measures., Conclusions: The high rates of change of both glutamate and glutamine over two years suggest they are promising new biomarkers of MS disease progression., (© The Author(s), 2015.)

Purpose: A steady-state approach that was termed multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) has recently been proposed for myelin water fraction (fM) mapping in brain development and demyelinating diseases. However, fMs estimated by mcDESPOT are significantly higher than myelin water fraction derived from multiecho spin echo T2-decay curve approaches. Magnetization transfer (MT), enhanced by the use of short, relatively high amplitude radiofrequency (RF) pulses in mcDESPOT, may artifactually influence fM maps. Our goal was to investigate the role of MT in mcDESPOT., Methods: mcDESPOT data was collected twice from three healthy volunteers using short RF pulses with higher MT effect and long RF pulses with lower MT effect. MR parameters from 11 white and gray regions were compared using a paired student t-test. Whole slice difference images were also compared., Results: MT effects had a substantial influence on the signal generated by the balanced steady-state free procession sequences used in mcDESPOT. However, these MT effects were not clearly evident in the fM values determined by the conventional two-pool mcDESPOT analysis., Conclusion: The signal generated from mcDESPOT is sensitive to MT, but the extracted myelin water fractions are relatively insensitive to changes of MT., (© 2014 Wiley Periodicals, Inc.)

Purpose: Myelin water fraction is conventionally measured from the T2 decay curve. Recently, a steady-state approach entitled multicomponent-driven equilibrium single pulse observation of T1 /T2 (mcDESPOT) was employed for myelin water fraction mapping. However, no direct comparison between the established multiecho T2 relaxation method and mcDESPOT has been performed., Methods: Gradient and spin echo (GRASE) acquired T2 decay curve and mcDESPOT measurements were acquired from 10 healthy volunteers using a 3T MRI. We compared myelin water fraction, transmit radio frequency field (B1 ), and T2 's of intra- and extracellular water obtained from both methods., Results: For all brain regions examined, myelin water fractions from mcDESPOT were significantly higher than those from multiecho GRASE. B1 maps were qualitatively similar between GRASE and mcDESPOT, but multicomponent T2 times were significantly different. To investigate the effect of exchange, mcDESPOT data were analyzed with and without exchange. When exchange was turned off, intra- and extracellular T2 times from mcDESPOT were roughly consistent with GRASE results; however, myelin water fractions derived from mcDESPOT were still significantly higher than those derived from GRASE., Conclusion: Myelin water fraction values derived from mcDESPOT cannot be considered to be equivalent to those derived from T2 decay curve approaches., (© 2014 Wiley Periodicals, Inc.)

Purpose: Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) is an alternative to established multiecho T2 -based approaches for quantifying myelin water fraction, affording increased volumetric coverage and spatial resolution. A concern with mcDESPOT, however, is the large number of model parameters that must be estimated, which may lead to nonunique solutions and sensitivity to fitting constraints. Here we explore mcDESPOT performance under different experimental conditions to better understand the method's sensitivity and reliability., Methods: To obtain parameter estimates, mcDESPOT uses a stochastic region contraction (SRC) approach to iteratively contract a predefined solution search-space around a global optimum. The sensitivity of mcDESPOT estimates to SRC boundary conditions, and tissue parameters, was examined using numerical phantoms and acquired in vivo human data., Results: The SRC approach is described and shown to return robust myelin water estimates in both numerical phantoms and in vivo data under a range of experimental conditions. However, care must be taken in choosing the initial SRC boundary conditions, ensuring they are broad enough to encompass the "true" solution., Conclusion: Results suggest that under the range of conditions examined, mcDESPOT can provide stabile and precise values., (© 2014 Wiley Periodicals, Inc.)

Objective: To evaluate the effect of metal artifact reduction techniques on dGEMRIC T(1) calculation with surgical hardware present., Materials and Methods: We examined the effect of stainless-steel and titanium hardware on dGEMRIC T(1) maps. We tested two strategies to reduce metal artifact in dGEMRIC: (1) saturation recovery (SR) instead of inversion recovery (IR) and (2) applying the metal artifact reduction sequence (MARS), in a gadolinium-doped agarose gel phantom and in vivo with titanium hardware. T(1) maps were obtained using custom curve-fitting software and phantom ROIs were defined to compare conditions (metal, MARS, IR, SR)., Results: A large area of artifact appeared in phantom IR images with metal when T(I) ≤ 700 ms. IR maps with metal had additional artifact both in vivo and in the phantom (shifted null points, increased mean T(1) (+151 % IR ROI(artifact)) and decreased mean inversion efficiency (f; 0.45 ROI(artifact), versus 2 for perfect inversion)) compared to the SR maps (ROI(artifact): +13 % T(1) SR, 0.95 versus 1 for perfect excitation), however, SR produced noisier T(1) maps than IR (phantom SNR: 118 SR, 212 IR). MARS subtly reduced the extent of artifact in the phantom (IR and SR)., Conclusions: dGEMRIC measurement in the presence of surgical hardware at 3T is possible with appropriately applied strategies. Measurements may work best in the presence of titanium and are severely limited with stainless steel. For regions near hardware where IR produces large artifacts making dGEMRIC analysis impossible, SR-MARS may allow dGEMRIC measurements. The position and size of the IR artifact is variable, and must be assessed for each implant/imaging set-up.

Quantitative myelin content imaging provides novel and pertinent information related to underlying pathogenetic mechanisms of myelin-related disease or disorders arising from aberrant connectivity. Multicomponent driven equilibrium single pulse observation of T1 and T2 is a time-efficient multicomponent relaxation analysis technique that provides estimates of the myelin water fraction, a surrogate measure of myelin volume. Unfortunately, multicomponent driven equilibrium single pulse observation of T1 and T2 relies on a two water-pool model (myelin-associated water and intra/extracellular water), which is inadequate within partial volume voxels, i.e., containing brain tissue and ventricle or meninges, resulting in myelin water fraction underestimation. To address this, a third, nonexchanging "free-water" component was introduced to the multicomponent driven equilibrium single pulse observation of T1 and T2 model. Numerical simulations and experimental in vivo data show that the model to perform advantageously within partial volume regions while providing robust and reproducible results. It is concluded that this model is preferable for future studies and analysis., (Copyright © 2012 Wiley Periodicals, Inc.)

Currently, little is known about the pathology of myelin in spinal cord disease due to the technical challenges of specifically measuring myelin content noninvasively. Multicomponent relaxometry allows estimation of the myelin water fraction, which is related to myelin content. However, conventional multiple-echo spin-echo-based multicomponent relaxometry techniques require prohibitively long acquisition times, lack spatial coverage, and are sensitive to artifacts common in spinal cord imaging. Multicomponent driven equilibrium single pulse observation of T(1) and T(2) (mcDESPOT) offers a promising alternative to conventional multicomponent relaxometry techniques. The goal of this pilot study was to assess the efficacy of mcDESPOT for obtaining high spatial resolution spinal cord myelin water fraction data covering the entire cervical spinal cord. Myelin water fraction values were found to be highly reproducible between subjects and over time but varied considerably along the length of the cord. Other relaxation characteristics that relate to tissue structure and health were also reliably measured., (Copyright © 2010 Wiley-Liss, Inc.)

This study compared region of interest (ROI) and voxel-based analysis (VBA) methods to determine the optimal method of myelin water fraction (MWF) analysis. Twenty healthy controls were scanned twice using a multi-echo T(2) relaxation sequence and ROIs were drawn in white and grey matter. MWF was defined as the fractional signal from 15 to 40 ms in the T(2) distribution. For ROI analysis, the mean intensity of voxels within an ROI was fit using non-negative least squares. For VBA, MWF was obtained for each voxel and the mean and median values within an ROI were calculated. There was a slightly higher correlation between Scan 1 and 2 for the VBA method (R(2)=0.98) relative to the ROI method (R(2)=0.95), and the VBA mean square difference between scans was 300% lower, indicating VBA was the most consistent between scans. For the VBA method, mean MWF was found to be more reproducible than median MWF. As the VBA method is more reproducible and gives more options for visualization and analysis of MWF, it is recommended over the ROI method of MWF analysis.

Multicomponent T(2) relaxation imaging can be used to measure signal from water trapped between myelin bilayers; the ratio of myelin water signal to total water is termed the myelin water fraction (MWF). The goal of this study was to implement and develop the single-slice T(2)-imaging technique proposed by Poon and Henkelman. For refinement, scan parameters (gradient crusher height and slew rate, bandwidth, echo spacing, matrix size, repetition time, and phase rewinding) were varied in water-based phantoms and in fixed and in vivo brain. Changes in the standard deviation of the residuals of the multiexponential fit, MWF, T(2), and peak width of the intra/extracellular water were monitored to determine which scan parameters minimized artifacts. Subsequently, we compared multicomponent T(2) measurements at 1.5T and 3.0T for 10 healthy volunteers, and investigated the differences in SNR, fit residuals, MWF, and T(2) and peak width of the intra/extracellular water, at higher magnetic field. MWF maps were found to be qualitatively similar between field strengths. MWFs were found to be significantly higher at 3.0T than at 1.5T, but with a strongly significant correlation between measurements (R(2) > 0.92, P < 0.0005). The signal-to-noise ratio (SNR) was nearly double at 3.0T, but the standard deviation of residuals was increased in most cases., ((c) 2009 Wiley-Liss, Inc.)