Myelin Water Fraction Imaging Research Articles

Dietary supplementation of 3'-sialyllactose or 6'-sialyllactose elicits minimal influence on cognitive and brain development in growing pigs.

Sialylated human milk oligosaccharides (HMO), such as 3'-sialyllactose (3'-SL) and 6'-sialyllactose (6'-SL), are abundant throughout lactation and at much higher concentrations than are present in bovine milk or infant formulas. Previous studies have suggested that sialylated HMO may have neurocognitive benefits in early life. Recent research has focused on infant formula supplementation with key nutrients and bioactives to narrow the developmental gap between formula-fed and breastfed infants. Herein, we investigated the impact of supplemental 3'-SL or 6'-SL on cognitive and brain development at two time-points [postnatal days (PND) 33 and 61]. Two-day-old piglets (N = 75) were randomly assigned to commercial milk replacer ad libitum without or with 3'-SL or 6'-SL (added in a powdered form at a rate of 0.2673% on an as-is weight basis). Cognitive development was assessed via novel object recognition and results were not significant at both time-points (p > 0.05). Magnetic resonance imaging was used to assess structural brain development. Results varied between scan type, diet, and time-point. A main effect of diet was observed for absolute volume of white matter and 9 other regions of interest (ROI), as well as for relative volume of the pons on PND 30 (p < 0.05). Similar effects were observed on PND 58. Diffusion tensor imaging indicated minimal differences on PND 30 (p > 0.05). However, several dietary differences across the diffusion outcomes were observed on PND 58 (p < 0.05) indicating dietary impacts on brain microstructure. Minimal dietary differences were observed from myelin water fraction imaging at either time-point. Overall, sialyllactose supplementation had no effects on learning and memory as assessed by novel object recognition, but may influence temporally-dependent aspects of brain development.

MWF of the corpus callosum is a robust measure of remyelination: Results from the ReBUILD trial

Myelin repair is an unrealized therapeutic goal in the treatment of multiple sclerosis (MS). Uncertainty remains about the optimal techniques for assessing therapeutic efficacy and imaging biomarkers are required to measure and corroborate myelin restoration. We analyzed myelin water fraction imaging from ReBUILD, a double-blind, randomized placebo-controlled (delayed treatment) remyelination trial, that showed a significant reduction in VEP latency in patients with MS. We focused on brain regions rich in myelin. Fifty MS subjects in two arms underwent 3T MRI at baseline and months 3 and 5. Half of the cohort was randomly assigned to receive treatment from baseline through 3mo, whereas the other half received treatment from 3mo to 5mo post-baseline. We computed myelin water fraction changes occurring in normal-appearing white matter of corpus callosum, optic radiations, and corticospinal tracts. An increase in myelin water fraction was documented in the normal-appearing white matter of the corpus callosum, in correspondence with the administration of the remyelinating treatment clemastine. This study provides direct, biologically validated imaging-based evidence of medically induced myelin repair. Moreover, our work strongly suggests that significant myelin repair occurs outside of lesions. We therefore propose myelin water fraction within the normal-appearing white matter of the corpus callosum as a biomarker for clinical trials looking at remyelination.

Exploring in vivo lesion myelination dynamics: Longitudinal Myelin Water Imaging in early Multiple Sclerosis

BackgroundMultiple Sclerosis (MS) lesions are pathologically heterogeneous and the temporal behavior in terms of growth and myelination status of individual lesions is highly variable, especially in the early phase of the disease. Thus, monitoring the development of individual lesion myelination by using quantitative magnetic resonance myelin water imaging (MWI) could be valuable to capture the variability of disease pathology and get an individual insight into the subclinical disease activity. ObjectiveThe goal of this work was (1) to observe the variation and longitudinal change of in vivo lesion myelination by means of MWI and its parameter Myelin Water Fraction (MWF), and, (2) to identify individual lesion myelination patterns in early MS. MethodsIn this study n = 12 patients obtained conventional MRI and quantitative MWI derived from multi-component driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) within four weeks after presenting a clinically isolated syndrome and remained within the study if clinically definitive MS was diagnosed within the 12 months study period. Four MRI sessions were acquired at baseline, 3, 6, and 12 months. The short-term and long-term variability of MWF maps was evaluated by scan-rescan measures and the coefficient of variation was determined in four healthy controls. Tracking of individual lesions was performed using the Automatic Follow-up of Individual Lesions (AFIL) algorithm. Lesion volume and MWF were evaluated for every individual lesion in all patients. Median lesion MWF change was used to define lesion categories as decreasing, varying, increasing and invariant for MWF variation. ResultsIn total n = 386 T2 lesions were detected with a subset of n = 225 permanent lesions present at all four time-points. Among those, a heterogeneous lesion MWF reduction was found, with the majority of lesions bearing only mild MWF reduction, approximately a third with an intermediate MWF decrease and highest MWF reduction in acute-inflammatory active lesions. A moderate negative correlation was determined between individual lesion volumes and median MWF consistent across all time-points. Permanent lesions featured variable temporal dynamics with the majority of varying MWF (58 %), however decreasing (16 %), increasing (15 %) and invariant (11 %) subgroups could be identified resembling demyelinating activity and post-demyelinating inactivity known from histopathology studies. Inflammatory-active enhancing lesions showed a distinct pattern of MWF reduction followed by partial recovery after 3 months. This was similar in new enhancing lesions and those with a non-enhancing precursor lesion. ConclusionThis work provides in vivo evidence for an individual evolution of early demyelinated MS lesions measured by means of MWF imaging. Our results support the hypothesis, that MS lesions undergo multiple demyelination and remyelination episodes in the early acute phase. The in vivo MRI surrogate of myelin turnover bears capacity as a novel biomarker to select and potentially monitor personalized MS treatment.

Brain myelin water fraction is associated with APOE4 allele status in patients with cognitive impairment.

Apolipoprotein E4 (APOE4) is a major genetic risk factor for Alzheimer's disease. However, the effect of APOE4 status on myelin remains unclear. This study investigated the effect of APOE4 on myelin content in cognitively impaired individuals using T2* gradient echo (GRE)-based myelin water fraction (MWF) imaging. Between August 2017 and January 2019, we evaluated 39 cognitively impaired patients (median age, 75 years; male:female = 8:31; Alzheimer's disease: mild cognitive impairment = 11:28). We obtained brain MWF values from white matter hyperintensities (WMHs) and normal-appearing white matter (NAWM). Linear regression analysis was performed to investigate the relationship between the APOE4 status and MWF and cognitive function and MWF. Among the 39 cognitively impaired patients, nine (23.1%) were APOE4 carriers and 30 (76.9%) were noncarriers. APOE4 carriers had a lower hippocampal volume than noncarriers (p = .045), but other brain volume parameters were not differed. After age adjustment, the APOE4 status was significantly associated with reduced MWF in NAWM (β = -0.310 per allele; p = .049) but not in WMH (β = -0.258 per allele; p = .113). After age adjustment, MWF in NAWM was significantly associated with Mini-Mental State Examination score (β = 0.313, p = .031). T2* GRE-based MWF imaging can reveal myelin loss, particularly in NAWM, in cognitively impaired patients among APOE4 carriers. In vivo MWF in NAWM might be a novel imaging marker of Alzheimer's disease, for clarifying the interactions between the white matter and cognitive dysfunction with respect to the APOE4 status.

Imaging in X-Linked Adrenoleukodystrophy

Magnetic resonance imaging (MRI) is the gold standard for the detection of cerebral lesions in X-linked adrenoleukodystrophy (ALD). ALD is one of the most common peroxisomal disorders and is characterized by a defect in degradation of very long chain fatty acids (VLCFA), resulting in accumulation of VLCFA in plasma and tissues. The clinical spectrum of ALD is wide and includes adrenocortical insufficiency, a slowly progressive myelopathy in adulthood, and cerebral demyelination in a subset of male patients. Cerebral demyelination (cerebral ALD) can be treated with hematopoietic cell transplantation (HCT) but only in an early (pre- or early symptomatic) stage and therefore active MRI surveillance is recommended for male patients, both pediatric and adult. Although structural MRI of the brain can detect the presence and extent of cerebral lesions, it does not predict if and when cerebral demyelination will occur. There is a great need for imaging techniques that predict onset of cerebral ALD before lesions appear. Also, imaging markers for severity of myelopathy as surrogate outcome measure in clinical trials would facilitate drug development. New quantitative MRI techniques are promising in that respect. This review focuses on structural and quantitative imaging techniques-including magnetic resonance spectroscopy, diffusion tensor imaging, MR perfusion imaging, magnetization transfer (MT) imaging, neurite orientation dispersion and density imaging (NODDI), and myelin water fraction imaging-used in ALD and their role in clinical practice and research opportunities for the future.

Myelin Water Imaging Demonstrates Lower Brain Myelination in Children and Adolescents With Poor Reading Ability.

Magnetic resonance imaging (MRI) provides a means to non-invasively investigate the neurological links with dyslexia, a learning disability that affects one’s ability to read. Most previous brain MRI studies of dyslexia and reading skill have used structural or diffusion imaging to reveal regional brain abnormalities. However, volumetric and diffusion MRI lack specificity in their interpretation at the microstructural level. Myelin is a critical neural component for brain function and plasticity, and as such, deficits in myelin may impact reading ability. MRI can estimate myelin using myelin water fraction (MWF) imaging, which is based on evaluation of the proportion of short T2 myelin-associated water from multi-exponential T2 relaxation analysis, but has not yet been applied to the study of reading or dyslexia. In this study, MWF MRI, intelligence, and reading assessments were acquired in 20 participants aged 10–18 years with a wide range of reading ability to investigate the relationship between reading ability and myelination. Group comparisons showed markedly lower MWF by 16–69% in poor readers relative to good readers in the left and right thalamus, as well as the left posterior limb of the internal capsule, left/right anterior limb of the internal capsule, left/right centrum semiovale, and splenium of the corpus callosum. MWF over the entire group also correlated positively with three different reading scores in the bilateral thalamus as well as white matter, including the splenium of the corpus callosum, left posterior limb of the internal capsule, left anterior limb of the internal capsule, and left centrum semiovale. MWF imaging from T2 relaxation suggests that myelination, particularly in the bilateral thalamus, splenium, and left hemisphere white matter, plays a role in reading abilities. Myelin water imaging thus provides a potentially valuable in vivo imaging tool for the study of dyslexia and its remediation.

Myelin water imaging from multi-echo [formula omitted] MR relaxometry data using a joint sparsity constraint

Demyelination is the key pathological process in multiple sclerosis (MS). The extent of demyelination can be quantified with magnetic resonance imaging by assessing the myelin water fraction (MWF). However, long computation times and high noise sensitivity hinder the translation of MWF imaging to clinical practice. In this work, we introduce a more efficient and noise robust method to determine the MWF using a joint sparsity constraint and a pre-computed B1+-T2 dictionary.A single component analysis with this dictionary is used in an initial step to obtain a B1+ map. The T2 distribution is then determined from a reduced dictionary corresponding to the estimated B1+ map using a combination of a non-negativity and a joint sparsity constraint.The non-negativity constraint ensures that a feasible solution with non-negative contribution of each T2 component is obtained. The joint sparsity constraint restricts the T2 distribution to a small set of T2 relaxation times shared between all voxels and reduces the noise sensitivity.The applied Sparsity Promoting Iterative Joint NNLS (SPIJN) algorithm can be implemented efficiently, reducing the computation time by a factor of 50 compared to the commonly used regularized non-negative least squares algorithm. The proposed method was validated in simulations and in 8 healthy subjects with a 3D multi-echo gradient- and spin echo scan at 3 ​T. In simulations, the absolute error in the MWF decreased from 0.031 to 0.013 compared to the regularized NNLS algorithm for SNR ​= ​250. The in vivo results were consistent with values reported in literature and improved MWF-quantification was obtained especially in the frontal white matter. The maximum standard deviation in mean MWF in different regions of interest between subjects was smaller for the proposed method (0.0193) compared to the regularized NNLS algorithm (0.0266). In conclusion, the proposed method for MWF estimation is less computationally expensive and less susceptible to noise compared to state of the art methods. These improvements might be an important step towards clinical translation of MWF measurements.

Adult brain aging investigated using BMC-mcDESPOT–based myelin water fraction imaging

The relationship between regional brain myelination and aging has been the subject of intense study, with magnetic resonance imaging perhaps the most effective modality for elucidating this. However, most of these studies have used nonspecific methods to probe myelin content, including diffusion tensor imaging, magnetization transfer ratio, and relaxation times. In the present study, we used the BMC-mcDESPOT analysis, a direct and specific method for imaging of myelin water fraction (MWF), a surrogate of myelin content. We investigated age-related differences in MWF in several brain regions in a large cohort of cognitively unimpaired participants, spanning a wide age range. Our results indicate a quadratic, inverted U-shape, relationship between MWF and age in all brain regions investigated, suggesting that myelination continues until middle age followed by decreases at older ages. We also observed that these age-related differences vary across different brain regions, as expected. Our results provide evidence for nonlinear associations between age and myelin in a large sample of well-characterized adults, using a direct myelin content imaging method.

Multi-Exponential Relaxometry Using l1 -Regularized Iterative NNLS (MERLIN) With Application to Myelin Water Fraction Imaging.

A new parameter estimation algorithm, MERLIN, is presented for accurate and robust multi-exponential relaxometry using magnetic resonance imaging, a tool that can provide valuable insight into the tissue microstructure of the brain. Multi-exponential relaxometry is used to analyze the myelin water fraction and can help to detect related diseases. However, the underlying problem is ill-conditioned, and as such, is extremely sensitive to noise and measurement imperfections, which can lead to less precise and more biased parameter estimates. MERLIN is a fully automated, multi-voxel approach that incorporates state-of-the-art l1 -regularization to enforce sparsity and spatial consistency of the estimated distributions. The proposed method is validated in simulations and in vivo experiments, using a multi-echo gradient-echo (MEGE) sequence at 3 T. MERLIN is compared to the conventional single-voxel l2 -regularized NNLS (rNNLS) and a multi-voxel extension with spatial priors (rNNLS + SP), where it consistently showed lower root mean squared errors of up to 70 percent for all parameters of interest in these simulations.

Myelin Water Fraction Imaging of the Brain in Children with Prenatal Alcohol Exposure.

Prenatal alcohol exposure (PAE) is linked to alterations of cerebral white matter, including volume and nonspecific diffusion magnetic resonance imaging (MRI) indices of microstructure in humans. Some animal models of PAE have demonstrated myelination deficiencies, but myelin levels have not yet been evaluated in individuals with PAE. Multiecho T2 MRI offers a quantitative method to estimate myelin water fraction (MWF; related to myelin content) noninvasively, which was used here to evaluate brain myelination in children with PAE. Participants with PAE (n=10, 6 females, mean age 13.9years, range 7 to 18years) and controls (n=14, 11 females, mean age 13.2years, range 9 to 16years) underwent 3T MRI of the brain. T2 images (15minutes acquisition for 32 echoes) were used to create MWF maps from which mean MWF was measured in 12 regions of interest (ROIs) including 8 in white matter and 4 in deep gray matter. As expected, across the combined sample, MWF was highest for major white matter tracts such as the internal capsule and genu/splenium of the corpus callosum (10 to 18%) while the caudate and putamen had MWF less than 5%. Mean MWF was similar across 11/12 brain white and gray matter regions for the PAE and control groups (L/R internal capsule, major forceps, putamen, caudate nucleus, L minor forceps, genu and splenium of corpus callosum). In the PAE group, MWF was positively correlated with age in the genu of corpus callosum and right minor forceps, notably 2 frontal tracts. Given comparable MRI-derived myelination fraction measures in PAE relative to controls, white matter alterations shown in other imaging studies, such as diffusion tensor imaging, may reflect microstructural anomalies related to axon caliber and density.

Cesarean Delivery Impacts Infant Brain Development.

The cesarean delivery rate has increased globally in the past few decades. Neurodevelopmental outcomes associated with cesarean delivery are still unclear. This study investigated whether cesarean delivery has any effect on the brain development of offspring. A total of 306 healthy children were studied retrospectively. We included 3 cohorts: 2-week-old neonates (cohort 1, n = 32/11 for vaginal delivery/cesarean delivery) and 8-year-old children (cohort 2, n = 37/23 for vaginal delivery/cesarean delivery) studied at Arkansas Children's Hospital, and a longitudinal cohort of 3-month to 5-year-old children (cohort 3, n = 164/39 for vaginal delivery/cesarean delivery) studied independently at Brown University. Diffusion tensor imaging, myelin water fraction imaging, voxel-based morphometry, and/or resting-state fMRI data were analyzed to evaluate white matter integrity, myelination, gray matter volume, and/or functional connectivity, respectively. While not all MR imaging techniques were shared across the institutions/cohorts, post hoc analyses showed similar results of potential effects of cesarean delivery. The cesarean delivery group in cohort 1 showed significantly lower white matter development in widespread brain regions and significantly lower functional connectivity in the brain default mode network, controlled for a number of potential confounders. No group differences were found in cohort 2 in white matter integrity or gray matter volume. Cohort 3 had significantly different trajectories of white matter myelination between groups, with those born by cesarean delivery having reduced myelin in infancy but normalizing with age. Cesarean delivery may influence infant brain development. The impact may be transient because similar effects were not observed in older children. Further prospective and longitudinal studies may be needed to confirm these novel findings.

Myelin Water Fraction Imaging Reveals Hemispheric Asymmetries in Human White Matter That Are Associated with Genetic Variation in PLP1

Myelination of axons in the central nervous system is critical for human cognition and behavior. The predominant protein in myelin is proteolipid protein-making PLP1, the gene that encodes for proteolipid protein, one of the primary candidate genes for white matter structure in the human brain. Here, we investigated the relation of genetic variation within PLP1 and white matter microstructure as assessed with myelin water fraction imaging, a neuroimaging technique that has the advantage over conventional diffusion tensor imaging in that it allows for a more direct assessment of myelin content. We observed significant asymmetries in myelin water fraction that were strongest and rightward in the parietal lobe. Importantly, these parietal myelin water fraction asymmetries were associated with genetic variation in PLP1. These findings support the assumption that genetic variation in PLP1 affects white matter myelination in the healthy human brain.

Combining Quantitative Susceptibility Mapping with Automatic Zero Reference (QSM0) and Myelin Water Fraction Imaging to Quantify Iron-Related Myelin Damage in Chronic Active MS Lesions.

A hyperintense rim on susceptibility in chronic MS lesions is consistent with iron deposition, and the purpose of this study was to quantify iron-related myelin damage within these lesions as compared with those without rim. Forty-six patients had 2 longitudinal quantitative susceptibility mapping with automatic zero reference scans with a mean interval of 28.9 ± 11.4 months. Myelin water fraction mapping by using fast acquisition with spiral trajectory and T2 prep was obtained at the second time point to measure myelin damage. Mixed-effects models were used to assess lesion quantitative susceptibility mapping and myelin water fraction values. Quantitative susceptibility mapping scans were on average 6.8 parts per billion higher in 116 rim-positive lesions compared with 441 rim-negative lesions (P < .001). All rim-positive lesions retained a hyperintense rim over time, with increasing quantitative susceptibility mapping values of both the rim and core regions (P < .001). Quantitative susceptibility mapping scans and myelin water fraction in rim-positive lesions decreased from rim to core, which is consistent with rim iron deposition. Whole lesion myelin water fractions for rim-positive and rim-negative lesions were 0.055 ± 0.07 and 0.066 ± 0.04, respectively. In the mixed-effects model, rim-positive lesions had on average 0.01 lower myelin water fraction compared with rim-negative lesions (P < .001). The volume of the rim at the initial quantitative susceptibility mapping scan was negatively associated with follow-up myelin water fraction (P < .01). Quantitative susceptibility mapping rim-positive lesions maintained a hyperintense rim, increased in susceptibility, and had more myelin damage compared with rim-negative lesions. Our results are consistent with the identification of chronic active MS lesions and may provide a target for therapeutic interventions to reduce myelin damage.

Multi-gradient-echo myelin water fraction imaging: Comparison to the multi-echo-spin-echo technique.

Myelin water fraction (MWF) mapping based on multi-gradient recalled-echo (MGRE) imaging has been proposed as an alternative to the conventional multi-echo-spin-echo (MESE) approach. In this work, we performed a comparative study of MESE and MGRE-derived MWFs in the same subject group. MESE and MGRE data were acquired in 12 healthy volunteers at 3T. T2* decay curves were corrected for the effects of field inhomogeneities and multicomponent analysis of T2 and T2* signals was performed using non-negative least-squares fitting. When comparing MGRE and MESE-MWFs across volunteers, no significant differences were observed between average values in WM, deep GM (dGM), and cortical GM (cGM) that were (14 ± 3%), (6 ± 2%), and (8 ± 2%) for MGRE, and (13 ± 2%), (6 ± 1%), and (7 ± 1%), respectively, for MESE. The MGRE and MESE-MWFs showed a strong correlation (r2 = 0.84) and Bland-Altman analysis revealed a small positive bias of (0.8 ± 1.6%) (absolute difference) for the MGRE-MWF. Overall, we observed excellent agreement between the two techniques. The small positive bias of the MGRE-MWF is thought to be a consequence of its potentially reduced sensitivity to water exchange effects, compared to the MESE-MWF. This work suggests that with careful correction for the effects of field inhomogeneities, MGRE-MWF imaging is a promising alternative to the MESE approach. Magn Reson Med 79:1439-1446, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Imaging as an Outcome Measure in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Magnetic resonance imaging (MRI) is sensitive to lesion formation both in the brain and spinal cord. Imaging plays a prominent role in the diagnosis and monitoring of MS. Over a dozen anti-inflammatory therapies are approved for MS and the development of many of these medications was made possible through the use of contrast-enhancing lesions on MRI as a phase II outcome. A similar phase II outcome method for the neurodegeneration that underlies progressive courses of the disease is still unavailable. Although magnetic resonance is an invaluable tool for the diagnosis and monitoring of treatment effects in MS, several imaging barriers still exist. In general, MRI is less sensitive to gray matter lesions, lacks pathological specificity, and does not provide quantitative data easily. Several advanced imaging methods including diffusion tensor imaging, magnetization transfer, functional MRI, myelin water fraction imaging, ultra-high field MRI, positron emission tomography, and optical coherence tomography of the retina study promising ways of overcoming the difficulties in MS imaging.

Field inhomogeneity correction for gradient echo myelin water fraction imaging.

Recently, the multi-echo gradient echo (MGRE) sequence has been proposed for multicomponent T2* (MC T2*) based myelin water fraction (MWF) mapping. This approach has appeal because it can provide fast whole-brain coverage, has low specific absorption rate, and short echo spacing. However, the MGRE signal requires correction for accurate MWF mapping, because of its sensitivity to magnetic field inhomogeneities (ΔB0 ). We propose a ΔB0 correction method for 2D MGRE data obtained for MWF mapping. Latter-echo MGRE data were fit to estimate B0 gradients in the slice-select direction ( Gz). The decay signal was corrected for the effects of Gz, and MC T2* analysis was performed using nonnegative least-squares fitting. The method was evaluated using simulations and its performance demonstrated in healthy volunteers. Simulations showed that MWFs are significantly biased in the presence of Gz and that our correction method leads to accurate MWF estimates. In vivo MWF maps obtained from corrected data showed recovery of MWF estimates in areas of high ΔB0, and overall good agreement with literature values obtained with the reference MC T2-based method. A new algorithm was presented for ΔB0 correction of 2D MGRE echo data acquired for MWF imaging. Simulations and in vivo data showed an improvement in MWF estimates. Magn Reson Med 78:49-57, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

48 echo T₂ myelin imaging of white matter in first-episode schizophrenia: evidence for aberrant myelination.

Myelin water imaging provides a novel strategy to assess myelin integrity and corresponding clinical relationships in psychosis, of particular relevance in frontal white matter regions. In the current study, T2 myelin water imaging was used to assess the myelin water fraction (MWF) signal from frontal areas in a sample of 58 individuals experiencing first-episode psychosis (FEP) and 44 healthy volunteers. No differences in frontal MWF were observed between FEP subjects and healthy volunteers; however, differences in normal patterns of associations between frontal MWF and age, education and IQ were seen. Significant positive relationships between frontal MWF and age, North American Adult Reading Test (NAART) IQ, and years of completed education were observed in healthy volunteers. In contrast, only the relationship between frontal MWF and NAART IQ was significant after Bonferroni correction in the FEP group. Additionally, significant positive relationships between age and MWF in the anterior and posterior internal capsules, the genu, and the splenium were observed in healthy volunteers. In FEP subjects, only the relationship between age and MWF in the splenium was statistically significant. Frontal MWF was not associated with local white matter volume. Altered patterns of association between age, years of education, and MWF in FEP suggest that subtle disturbances in myelination may be present early in the course of psychosis.

Feasibility of in vivo myelin water imaging using 3D multigradient‐echo pulse sequences

Quantitative myelin water imaging is able to show demyelinating processes and, therefore, provides insight into the pathology of white matter diseases such as multiple sclerosis. So far, mapping of the myelin water fraction most often was performed using single-slice multiecho spin-echo sequences. Recently, a different approach using two-dimensional multigradient-echo pulse sequences was suggested. In this work, a solution to three-dimensional in vivo myelin water fraction imaging is presented that applies multigradient-echo pulse sequences and uses non-negative least squares algorithms to analyze the multicomponent T*(2) decay. The suggested method offers not only whole brain coverage but also clinically practicable acquisition times. The obtained myelin water fraction values are low (6.9% for white matter) but are able to detect demyelination in multiple sclerosis lesions. However, the clinical application of the proposed method remains questionable, because further measurements that clarify the possibility of detecting ongoing processes in lesions are needed.

Myelin water imaging reflects clinical variability in multiple sclerosis

Whilst MRI is routinely used for the assessment and diagnosis of multiple sclerosis, there is poor correspondence between clinical disability in primary progressive multiple sclerosis (PPMS) patients and conventional MRI markers of disease activity (e.g., number of enhancing lesions). As PPMS patients show diffuse and global myelin loss, the aim of this study was to evaluate the efficacy of whole-brain myelin water fraction (MWF) imaging in PPMS. Specifically, we sought to use full-brain analysis techniques to: 1) determine the reproducibility of MWF estimates in PPMS brain; 2) compare MWF values in PPMS brain to healthy controls; and 3) establish the relationship between MWF and clinical disability, regionally and globally throughout the brain. Seventeen PPMS patients and seventeen age-matched controls were imaged using a whole-brain multi-component relaxation imaging technique to measure MWF. Analysis of MWF reduction was performed on three spatial levels: 1) histogram; 2) white matter skeleton; and 3) voxel-wise at the single-subject level. From histogram analysis, PPMS patients had significantly reduced global normal appearing white matter MWF (6%, p=0.04) compared to controls. Focal lesions showed lower MWF values than white matter in controls (61%, p<0.001) and patients (59%, p<0.001). Along the white matter skeleton, MWF was diffusely reduced throughout the PPMS brain, with significant correlations between reduced MWF and increased clinical disability (more severe symptoms), as measured by the Expanded Disability Status Scale, within the corpus callosum and frontal, temporal, parietal and occipital white matter. Correlations with the more specific mental and sensory functional system scores were localized to clinically eloquent locations: reduced MWF was significantly associated with increased mental scores in anterior regions (i.e., frontal lobes and genu of the corpus callosum), and increased sensory scores in more posterior regions closer to the sensory cortex. Individual patient MWF maps were also compared to a normative population atlas, which highlighted areas of statistical difference between the individual patient and the population mean. A significant correlation was found between the volume of significantly reduced MWF and clinical disability (p=0.008, R=0.58). Our results show that clinical disability is reflected in particular regions of cerebral white matter that are consistent between subjects, and illustrates a method to examine tissue alteration throughout the brain of individual patients. These results strongly support the use of MWF imaging to evaluate disease activity in PPMS.

Insight into in vivo magnetization exchange in human white matter regions

Water exchange can play an important role in interpreting compartment-specific magnetic resonance imaging data in brain. For example, an MR method of myelin measurement, known as myelin water fraction imaging, assumes that water exchange processes are slow compared with the measurement time scale. In this article, we examined whether water exchange processes have an effect on myelin water fraction values. A previously established four pool model of white matter was used to simulate the interactions between two aqueous compartments (myelin water and intra/extracellular water) and nonaqueous compartments (myelin and nonmyelin tissues). To extract the water exchange cross relaxation times, the Bloch equations were solved analytically. As the water exchange time scales are dependent on the spin-lattice T(1) relaxation of each of these four pools and due to the current uncertainties regarding the T(1) associated with each pool, exchange cross relaxation times for three different T(1) scenarios were calculated. The corrections that need to be considered in order for myelin water fraction to be an accurate marker for myelin were found to be less than 15%. This work indicates that regional variations in white matter myelin water fraction values are most likely due to variations in myelin content rather than regional differences in exchange rates.