Quantitative myelin imaging with MRI and PET: an overview of techniques and their validation status.

Myelin is the protective sheath wrapped around axons, consisting of a phospholipid bilayer with water between the wraps. The measurement of damage to the myelin sheaths, the evaluation of the efficacy of therapies aiming to promote remyelination and monitoring the degree of brain maturation in children all require non-invasive quantitative myelin imaging methods. To date, various myelin imaging techniques have been developed. Five different MRI approaches can be distinguished based on their biophysical principles: (i) imaging of the water between the lipid bilayers directly (e.g. myelin water imaging); (ii) imaging the non-aqueous protons of the phospholipid bilayer directly with ultra-short echo-time techniques; (iii) indirect imaging of the macromolecular content (e.g. magnetization transfer; inhomogeneous magnetization transfer); (iv) mapping of the effects of the myelin sheath's magnetic susceptibility on the MRI signal (e.g. quantitative susceptibility mapping); and (v) mapping of the effects of the myelin sheath on water diffusion. Myelin imaging with PET uses radioactive molecules with high affinity to specific myelin components, in particular myelin basic protein. This review aims to give an overview of the various myelin imaging techniques, their biophysical principles, image acquisition, data analysis and their validation status.

Multi-echo dipole inversion for magnetic susceptibility mapping.

PURPOSE: Reconstructing tissue magnetic susceptibility (QSM) from MRI phase data involves solving multiple consecutive ill-posed inverse problems such as phase unwrapping, background field removal, and field-to-source inversion. Multi-echo acquisitions present an additional challenge, as the magnetization field is typically computed from the multiple phase data prior to reconstructing the susceptibility map. Processing the multiple phase data introduces errors during the field estimation, violating assumptions of the subsequent inverse problems, manifesting as streaking artifacts in the susceptibility map. To address this challenge, we propose a multi-echo field-to-source forward model that forgoes the field estimation step. Moreover, we propose a fully general underestimation correction step to recover susceptibility sources that were regularized away during the field-to-source inversion. METHODS: The multi-echo forward model and correction step were validated on the QSM Challenge 2.0 datasets and compared to the standard single field-to-source model in in vivo human brains using different types of deconvolution algorithms. RESULTS: On the QSM Challenge 2.0 datasets the multi-echo forward model and correction step attain state-of-the-art results on all metrics by a wide margin. Experiments in in vivo brains show that the multi-echo model is in agreement with the single field-to-source model and that the proposed forward model and correction step can be used with any available dipole inversion method. CONCLUSION: A multi-echo field-to-source forward model forgoes the need to fit multi-echo phase data and achieves state-of-the-art results on the QSM Challenge 2.0 data. Underestimated low-frequency susceptibility distributions can be partially recovered using a correction step.

The Effects of Wearing a 3-Ply or KN95 Face Mask on Cerebral Blood Flow and Oxygenation.

BACKGROUND: The SARS-CoV-2 virus has impacted life in many ways, one change being the use of face masks. Their effect on MRI-based measurements of cerebral oxygen levels with quantitative susceptibility mapping (QSM) and cerebral blood flow (CBF) is not known. PURPOSE: This study investigated whether wearing a face mask leads to changes in CBF and cerebral venous oxygen saturation measured with MRI. STUDY TYPE: Repeated-measures cohort study. POPULATION: A total of 16 healthy volunteers (eight male, eight female; 22-36 years) were recruited for the 3-ply study. Ten of the 16 participants (five male, five female; 23-36 years) took part in the KN95 study. FIELD STRENGTH/SEQUENCE: A 3 T, single-delay 3D gradient-and spin-echo pseudo-continuous arterial spin labeling (pCASL) scan for CBF quantification, and gradient-echo for QSM and oxygenation quantification. ASSESSMENT: Gray matter CBF and magnetic susceptibility were assessed by masking the pCASL CBF map and the QSM map to the T1 -weighted gray matter tissue segmentation. Venous oxygenation was determined from venous segmentation of QSM maximum intensity projections. STATISTICAL TESTS: Paired Student's t-tests and Cohen's d effect sizes were used to compare the face mask and no face mask scans for gray matter CBF, gray matter magnetic susceptibility, and cerebral venous oxygen saturation. Standard t-tests were used to assess whether the order of scanning with and without a mask had any impact. A statistical cut off of P < 0.05 was used. RESULTS: The 3-ply masks increased gray matter CBF from an average of 43.99 mL/(100 g*min) to 46.81 mL/(100 g*min). There were no significant changes in gray matter magnetic susceptibility (P = 0.07), or cerebral venous oxygen saturation (P = 0.36) for the 3-ply data set. The KN95 masks data set showed no statistically significant changes in gray matter CBF (P = 0.52) and magnetic susceptibility (P = 0.97), or cerebral venous oxygen saturation (P = 0.93). DATA CONCLUSION: The changes in blood flow and oxygenation due to face masks are small. Only CBF increased significantly due to wearing a 3-ply mask. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Brain Imaging Abnormalities in Mixed Alzheimer's and Subcortical Vascular Dementia.

BACKGROUND: A large proportion of Alzheimer's disease (AD) patients have coexisting subcortical vascular dementia (SVaD), a condition referred to as mixed dementia (MixD). Brain imaging features of MixD presumably include those of cerebrovascular disease and AD pathology, but are difficult to characterize due to their heterogeneity. OBJECTIVE: To perform an exploratory analysis of conventional and non-conventional structural magnetic resonance imaging (MRI) abnormalities in MixD and to compare them to those observed in AD and SVaD. METHODS: We conducted a cross-sectional, region-of-interest-based analysis of 1) hyperintense white-matter signal abnormalities (WMSA) on T2-FLAIR and hypointense WMSA on T1-weighted MRI; 2) diffusion tensor imaging; 3) quantitative susceptibility mapping; and 4) effective transverse relaxation rate (R2*) in N = 17 participants (AD:5, SVaD:5, MixD:7). General linear model was used to explore group differences in these brain imaging measures. RESULTS: Model findings suggested imaging characteristics specific to our MixD group, including 1) higher burden of WMSAs on T1-weighted MRI (versus both AD and SVaD); 2) frontal lobar preponderance of WMSAs on both T2-FLAIR and T1-weighted MRI; 3) higher fractional anisotropy values within normal-appear white-matter tissues (versus SVaD, but not AD); and 4) lower R2* values within the T2-FLAIR WMSA areas (versus both AD and SVaD). CONCLUSION: These findings suggest a preliminary picture of the location and type of brain imaging characteristics associated with MixD. Future imaging studies may employ region-specific hypotheses to distinguish MixD more rigorously from AD or SVaD.

Orientation dependence of R2 relaxation in the newborn brain.

In MRI the transverse relaxation rate, R2 = 1/T2, shows dependence on the orientation of ordered tissue relative to the main magnetic field. In previous studies, orientation effects of R2 relaxation in the mature brain's white matter have been found to be described by a susceptibility-based model of diffusion through local magnetic field inhomogeneities created by the diamagnetic myelin sheaths. Orientation effects in human newborn white matter have not yet been investigated. The newborn brain is known to contain very little myelin and is therefore expected to exhibit a decrease in orientation dependence driven by susceptibility-based effects. We measured R2 orientation dependence in the white matter of human newborns. R2 data were acquired with a 3D Gradient and Spin Echo (GRASE) sequence and fiber orientation was mapped with diffusion tensor imaging (DTI). We found orientation dependence in newborn white matter that is not consistent with the susceptibility-based model and is best described by a model of residual dipolar coupling. In the near absence of myelin in the newborn brain, these findings suggest the presence of residual dipolar coupling between rotationally restricted water molecules. This has important implications for quantitative imaging methods such as myelin water imaging, and suggests orientation dependence of R2 as a potential marker in early brain development.

Risk factors for hippocampal cavities in a marginally housed population.

Cavities in the hippocampus are morphological variants of uncertain significance. Aberrant neurodevelopment along with vascular and inflammatory etiologies have been proposed. We sought to characterize these cavities and their potential risk factors in a marginally housed population, with high rates of viral infection, addiction, and mental illness. (1) The volume of hippocampal cavities (HCavs) is greater in this highly multimorbid population compared to the general population. (2) Conventional vascular risk factors such as greater age and systolic blood pressure are associated with higher HCav volume. (3) Nonprescribed substance-related risk factors such as stimulant use or dependence, and smoking are associated with increased HCav volume independent of vascular risk factors. This is a retrospective analysis of an ongoing prospective study. We analyzed baseline data, including medical history, physical exam, psychiatric diagnosis, and MRI from a total of 375 participants. Hippocampal cavities were defined as spaces isointense to CSF on T1 MRI sequences, bounded on all sides by hippocampal tissue, with a volume of at least 1 mm3 . Risk factors were evaluated using negative binomial multiple regression. Stimulant use was reported by 87.3% of participants, with stimulant dependence diagnosed in 83.3% of participants. Prevalence of cavities was 71.6%, with a mean total bilateral HCav volume of 13.89 mm3 . On average, a 1 mmHg greater systolic blood pressure was associated with a 2.17% greater total HCav volume (95% CI = [0.57%, 3.79%], p = .0076), while each cigarette smoked per day trended toward a 2.69% greater total HCav volume (95% CI = [-0.87%, 5.54%], p = .058). A diagnosis of stimulant dependence was associated with a 95.6% greater total HCav volume (95% CI = [5.39%, 263.19%], p = .0335). Hypertension and diagnosis of stimulant dependence were associated with a greater total volume of HCav.

Recovering SWI-filtered phase data using deep learning.

PURPOSE: To develop a deep neural network to recover filtered phase from clinical MR phase images to enable the computation of QSMs. METHODS: Eighteen deep learning networks were trained to recover combinations of 13 SWI phase-filtering pipelines. SWI-filtered data were computed offline from five multiorientation, multiecho MRI scans yielding 132 3D volumes (118/7/7 training/validation/testing). Two experiments were conducted to show the efficacy of the networks. First, using QSM processing, local fields were computed from the raw phase and subsequently filtered using the SWI-filtering pipelines. The networks were then trained to invert the filtering operation. Second, the trained networks were fine-tuned to recover unfiltered local fields from filtered local fields computed by applying QSM processing to the SWI-filtered phase. Susceptibility maps were computed from the recovered fields and compared with gold standard multiple orientation sampling reconstructions. RESULTS: Susceptibility maps computed from the raw phase using standard QSM processing have a normalized root mean square error (NRMSE) of 0.732 ± 0.095. Susceptibility maps computed from the recovered phase obtained NRMSEs of 0.725 ± 0.095. The network trained using all 13 processing methods generalized well, obtaining NRMSEs of 0.725 ± 0.89 on filters it has not seen, while matching the reconstruction accuracy of networks trained to recover a single filter. CONCLUSION: It is feasible to recover SWI-filtered phase using deep learning. QSM can be computed from the recovered phase from SWI acquisition with comparable accuracy to standard QSM processing.

Deep grey matter injury in multiple sclerosis: a NAIMS consensus statement.

Although multiple sclerosis has traditionally been considered a white matter disease, extensive research documents the presence and importance of grey matter injury including cortical and deep regions. The deep grey matter exhibits a broad range of pathology and is uniquely suited to study the mechanisms and clinical relevance of tissue injury in multiple sclerosis using magnetic resonance techniques. Deep grey matter injury has been associated with clinical and cognitive disability. Recently, MRI characterization of deep grey matter properties, such as thalamic volume, have been tested as potential clinical trial end points associated with neurodegenerative aspects of multiple sclerosis. Given this emerging area of interest and its potential clinical trial relevance, the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative held a workshop and reached consensus on imaging topics related to deep grey matter. Herein, we review current knowledge regarding deep grey matter injury in multiple sclerosis from an imaging perspective, including insights from histopathology, image acquisition and post-processing for deep grey matter. We discuss the clinical relevance of deep grey matter injury and specific regions of interest within the deep grey matter. We highlight unanswered questions and propose future directions, with the aim of focusing research priorities towards better methods, analysis, and interpretation of results.

Characterizing Traumatic Brain Injury and Its Association with Losing Stable Housing in a Community-based Sample.

OBJECTIVE: Traumatic brain injury (TBI) is increasingly recognized as a common and impactful health determinant in homeless and precariously housed populations. We sought to describe the history of TBI in a precariously housed sample and evaluate how TBI was associated with the initial loss and lifetime duration of homelessness and precarious housing. METHOD: We characterized the prevalence, mechanisms, and sex difference of lifetime TBI in a precariously housed sample. We also examined the impact of TBI severity and timing on becoming and staying homeless or precariously housed; 285 precariously housed participants completed the Brain Injury Screening Questionnaire in addition to other health assessments. RESULTS: A history of TBI was reported in 82.1% of the sample, with 64.6% reporting > 1 TBI, and 21.4% reporting a moderate or severe TBI. Assault was the most common mechanism of injury overall, and females reported significantly more traumatic brain injuries due to physical abuse than males (adjusted OR = 1.26, 95% CI = 1.14 to 1.39, P < 0.0001). The first moderate or severe TBI was significantly closer to the first experience of homelessness (b = 2.79, P = 0.003) and precarious housing (b = 2.69, P < 0.0001) than was the first mild TBI. In participants who received their first TBI prior to becoming homeless or precariously housed, traumatic brain injuries more proximal to the initial loss of stable housing were associated with a longer lifetime duration of homelessness (RR = 1.04, 95% CI = 1.02 to 1.06, P < 0.0001) and precarious housing (RR = 1.03, 95% CI = 1.01 to 1.04, P < 0.0001). CONCLUSIONS: These findings demonstrate the high prevalence of TBI in this vulnerable population, and that aspects of TBI severity and timing are associated with the loss and lifetime duration of stable housing.

Myelin water imaging depends on white matter fiber orientation in the human brain.

PURPOSE: The multi-exponential T2 decay of the MRI signal from cerebral white matter can be separated into short T2 components related to myelin water and long T2 components related to intracellular and extracellular water. In this study, we investigated to what degree the apparent myelin water fraction (MWF) depends on the angle between white matter fibers and the main magnetic field. METHODS: Maps of the apparent MWF were acquired using multi-echo Carr-Purcell-Meiboom-Gill and gradient-echo spin-echo sequences. The Carr-Purcell-Meiboom-Gill sequence was acquired with a TR of 1073 ms, 1500 ms, and 2000 ms. The fiber orientation was mapped with DTI. By angle-wise pooling the voxels across the brain's white matter, orientation-dependent apparent MWF curves were generated. RESULTS: We found that the apparent MWF varied between 25% and 35% across different fiber orientations. Furthermore, the selection of the TR influences the apparent MWF. CONCLUSION: White matter fiber orientation induces a strong systematic bias on the estimation of the apparent MWF. This finding has implications for future research and the interpretation of MWI results in previously published studies.

In vivo investigation of the multi-exponential T2 decay in human white matter at 7 T: Implications for myelin water imaging at UHF.

INTRODUCTION: Multi-component T2 mapping using a gradient- and spin-echo (GraSE) acquisition has become standard for myelin water imaging at 3 T. Higher magnetic field strengths promise signal-to-noise ratio benefits but face specific absorption rate limits and shortened T2 times. This study investigates compartmental T2 times in vivo and addresses advantages and challenges of multi-component T2 mapping at 7 T. METHODS: We acquired 3D multi-echo GraSE data in seven healthy adults at 7 T, with three subjects also scanned at 3 T. Stimulated echoes arising from B1+ inhomogeneities were accounted for by the extended phase graph (EPG) algorithm. We used the computed T2 distributions to determine T2 times that identify different water pools and assessed signal-to-noise and fit-to-noise characteristics of the signal estimation. We compared short T2 fractions and T2 properties of the intermediate water pool at 3 T and 7 T. RESULTS: Flip angle mapping confirmed that EPG accurately determined the larger B1+ inhomogeneity at 7 T. Multi-component T2 analysis demonstrated shortened T2 times at 7 T compared with 3 T. Fit-to-noise and signal-to-noise ratios were improved at 7 T but depended on B1+ homogeneity. Adjusting the shortest T2 to 8 ms and the T2 threshold that separates different water compartments to 20 ms yielded short T2 fractions at 7 T that conformed to 3 T data. Short T2 fractions in myelin-rich white matter regions were lower at 7 T than at 3 T, and higher in iron-rich structures. DISCUSSION: Adjusting the T2 compartment boundaries was required due to the shorter T2 relaxation times at 7 T. Shorter echo spacing would better sample the fast decaying signal but would increase peripheral nerve stimulation. Multi-channel transmission will improve T2 measurements at 7 T. CONCLUSION: We used a multi-echo 3D GraSE sequence to characterize the multi-exponential T2 decay at 7 T. We adapted T2 parameters for evaluation of the short T2 fraction. Obtained 7 T multi-component T2 maps were in good agreement with 3 T data.

White matter but not grey matter predicts change in reading skills after intervention.

This study examined changes in white matter microstructure and grey matter volume, cortical thickness, and cortical surface area before and after reading intervention. Participants included 22 average readers and 13 dyslexic readers (8-9 years old in third grade); the dyslexic readers were enrolled in reading intervention programs at their elementary school. Participants completed scans of diffusion tensor imaging and T1-weighted MRI before and after 3 months of instruction. An a priori region of interest (ROI) analysis was used. Dyslexic readers, compared to average readers, showed higher mean diffusivity in white matter ROIs including bilateral inferior frontal, bilateral insula, left superior temporal, and right supramarginal gyri across time points. Dyslexic readers also had thicker cortex in left fusiform and bilateral supramarginal gyri; whereas, average readers had greater surface area in right fusiform across time. There were no significant changes in white or grey matter following intervention; however, mean diffusivity in the right hemisphere was associated with reading gains over time. White matter organization in the right hemisphere predicts reading changes, and dyslexic readers may have persistent differences in white and grey matter due to ongoing reading deficits.

Cerebral Small Vessel Disease, Risk Factors, and Cognition in Tenants of Precarious Housing.

BACKGROUND AND PURPOSE: We aim to describe the burden, characteristics, and cognitive associations of cerebral small vessel disease in a Canadian sample living with multimorbidity in precarious housing. METHODS: Participants received T1, T2-fluid-attenuated inversion recovery, and susceptibility-weighted imaging 3T magnetic resonance imaging sequences and comprehensive clinical, laboratory, and cognitive assessments. Cerebral small vessel disease burden was characterized using a modified Small Vessel Disease (mSVD) score. One point each was given for moderate-severe white matter hyperintensities, ≥1 cerebral microbleeds, and ≥1 lacune. Multivariable regression explored associations between mSVD score, risk factors, and cognitive performance. RESULTS: Median age of the 228 participants (77% male) was 44.7 years (range, 23.3-63.2). In n=188 participants with consistent good quality magnetic resonance imaging sequences, mSVD scores were 0 (n=127, 68%), 1 (n=50, 27%), and 2 (n=11, 6%). Overall, one-third had an mSVD ≥1 n=61 (32%); this proportion was unchanged when adding participants with missing sequences n=72/228 (32%). The most prevalent feature was white matter hyperintensities 53/218 (24%) then cerebral microbleed 16/191 (8%) and lacunes 16/228 (7%). Older age (odds ratio, 1.10 [95% CI, 1.05-1.15], P<0.001), higher diastolic blood pressure (odds ratio, 1.05 [95% CI, 1.01-1.09], P=0.008), and a history of injection drug use (odds ratio, 3.13 [95% CI, 1.07-9.16], P=0.037) had significant independent associations with a mSVD score of ≥1 in multivariable analysis. mSVD ≥1 was associated with lower performance on tests of verbal memory, sustained attention, and decision-making, contributing 4% to 5% of the variance in each cognitive domain. CONCLUSIONS: The 32% prevalence of cerebral small vessel disease in this young, socially marginalized cohort was higher than expected for age and was associated with poorer cognitive performance.

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.

Multi-spin echo T2 relaxation imaging with compressed sensing (METRICS) for rapid myelin water imaging.

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 T2 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 T2 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 mm3 voxels, 56 echoes, 7 ms ΔTE, and 240 × 240 × 170 mm3 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 T2 mapping application.

Myelin water imaging and R2* mapping in neonates: Investigating R2* dependence on myelin and fibre orientation in whole brain white matter.

R2* relaxation provides a semiquantitative method of detecting myelin, iron and white matter fibre orientation angles. Compared with standard histogram-based analyses, angle-resolved analysis of R2* has previously been shown to substantially improve the detection of subtle differences in the brain between healthy siblings of subjects with multiple sclerosis and unrelated healthy controls. Neonates, who are born with very little myelin and iron, and an underdeveloped connectome, provide researchers with an opportunity to investigate whether R2* is intimately linked with fibre-angle or myelin content as it is in adults, which may in future studies be explored as a potential white matter developmental biomarker. Five healthy adult volunteers (mean age [±SD] = 31.2 [±8.3] years; three males) were recruited from Vancouver, Canada. Eight term neonates (mean age = 38.6 ± 1.2 weeks; five males) were recruited from the Children's Hospital of Chongqing Medical University neonatal ward. All subjects were scanned on identical 3 T Philips Achieva scanners equipped with an eight-channel SENSE head coil and underwent a multiecho gradient echo scan, a 32-direction DTI scan and a myelin water imaging scan. For both neonates and adults, bin-averaged R2* variation across the brain's white matter was found to be best explained by fibre orientation. For adults, this represented a difference in R2* values of 3.5 Hz from parallel to perpendicular fibres with respect to the main magnetic field. In neonates, the fibre orientation dependency displayed a cosine wave shape, with a small R2* range of 0.4 Hz. This minor relationship in neonates provides further evidence for the key role myelin probably plays in creating this fibre orientation dependence later in life, but suggests limited clinical application in newborn populations. Future studies should investigate fibre-orientation dependency in infants in the first 5 years, when substantial myelin development occurs.

The influence of brain iron on myelin water imaging.

With myelin playing a vital role in normal brain integrity and function and thus in various neurological disorders, myelin sensitive magnetic resonance imaging (MRI) techniques are of great importance. In particular, multi-exponential T2 relaxation was shown to be highly sensitive to myelin. The myelin water imaging (MWI) technique allows to separate the T2 decay into short components, specific to myelin water, and long components reflecting the intra- and extracellular water. The myelin water fraction (MWF) is the ratio of the short components to all components. In the brain's white matter (WM), myelin and iron are closely linked via the presence of iron in the myelin generating oligodendrocytes. Iron is known to decrease T2 relaxation times and may therefore mimic myelin. In this study, we investigated if variations in WM iron content can lead to apparent MWF changes. We performed MWI in post mortem human brain tissue prior and after chemical iron extraction. Histology for iron and myelin confirmed a decrease in iron content and no change in myelin content after iron extraction. In MRI, iron extraction lead to a decrease in MWF by 26%-28% in WM. Thus, a change in MWF does not necessarily reflect a change in myelin content. This observation has important implications for the interpretation of MWI findings in previously published studies and future research.

Rapid solution of the Bloch-Torrey equation in anisotropic tissue: Application to dynamic susceptibility contrast MRI of cerebral white matter.

Blood vessel related magnetic resonance imaging (MRI) contrast provides a window into the brain's metabolism and function. Here, we show that the spin echo dynamic susceptibility contrast (DSC) MRI signal of the brain's white matter (WM) strongly depends on the angle between WM tracts and the main magnetic field. The apparent cerebral blood flow and volume are 20% larger in fibres perpendicular to the main magnetic field compared to parallel fibres. We present a rapid numerical framework for the solution of the Bloch-Torrey equation that allows us to explore the isotropic and anisotropic components of the vascular tree. By fitting the simulated spin echo DSC signal to the measured data, we show that half of the WM vascular volume is comprised of vessels running in parallel with WM fibre tracts. The WM blood volume corresponding to the best fit to the experimental data was 2.82%, which is close to the PET gold standard of 2.6%.

Quantitative neuroimaging measures of myelin in the healthy brain and in multiple sclerosis.

Quantitative magnetic resonance imaging (MRI) techniques have been developed as imaging biomarkers, aiming to improve the specificity of MRI to underlying pathology compared to conventional weighted MRI. For assessing the integrity of white matter (WM), myelin, in particular, several techniques have been proposed and investigated individually. However, comparisons between these methods are lacking. In this study, we compared four established myelin-sensitive MRI techniques in 56 patients with relapsing-remitting multiple sclerosis (MS) and 38 healthy controls. We used T2-relaxation with combined GRadient And Spin Echoes (GRASE) to measure myelin water fraction (MWF-G), multi-component driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) to measure MWF-D, magnetization-transfer imaging to measure magnetization-transfer ratio (MTR), and T1 relaxation to measure quantitative T1 (qT1 ). Using voxelwise Spearman correlations, we tested the correspondence of methods throughout the brain. All four methods showed associations that varied across tissue types; the highest correlations were found between MWF-D and qT1 (median ρ across tissue classes 0.8) and MWF-G and MWF-D (median ρ = 0.59). In eight WM tracts, all measures showed differences (p < 0.05) between MS normal-appearing WM and healthy control WM, with qT1 showing the highest number of different regions (8), followed by MWF-D and MTR (6), and MWF-G (n = 4). Comparing the methods in terms of their statistical sensitivity to MS lesions in WM, MWF-D demonstrated the best accuracy (p < 0.05, after multiple comparison correction). To aid future power analysis, we provide the average and standard deviation volumes of the four techniques, estimated from the healthy control sample.

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.