Cornelia Laule

Water content and myelin water fraction in multiple sclerosis

Abstract.Background:Measurements of the T2 decay curvenprovide estimates of total water content and myelin waternfraction in white matter in-vivo, which may help innunderstanding the pathological progression of multiple sclerosisn(MS).Methods:Thirty-three MS patients (24 relapsing remitting, 8nsecondary progressive, 1 primary progressive) and 18 controlsnunderwent MR examinations. T2 relaxationndata were acquired using a 32-echo measurement. All controls andn18 of the 33 MS patients were scanned in the transverse planenthrough the genu and splenium of the corpus callosum. Five whitenmatter and 6 grey matter structures were outlined in each ofnthese subjects. The remaining 15 MS patients were scanned innother transverse planes. A total of 189 lesions were outlined innthe MS patients. Water content and myelin water fraction werencalculated for all regions of interest and all lesions.Results:The normal appearing white matter (NAWM) water contentnwas, on average, 2.2% greater than that from controls, withnsignificant differences occurring in the posterior internalncapsules, genu and splenium of the corpus callosum, minornforceps and major forceps (p < 0.0006). On average, MS lesionsnhad 6.3% higher water content than contralateral NAWM (p <n0.0001). Myelin water fraction was 16% lower in NAWM than forncontrols, with significant differences in the major and minornforceps, internal capsules, and splenium (p < 0.05). Thenmyelin water fraction of MS lesions averaged 52 % that ofnNAWM.Conclusions:NAWM in MS has a higher water content and lower myelinnwater fraction than control white matter. The cause of thenmyelin water fraction decrease in NAWM could potentially be duento either diffuse edema, inflammation, demyelination or anyncombination of these features. We present a simple model whichnsuggests that myelin loss is the dominant feature of NAWMnpathology.

Myelin water imaging in multiple sclerosis: quantitative correlations with histopathology

Various magnetic resonance (MR) techniques are used to study the pathological evolution of demyelinating diseases, such as multiple sclerosis (MS). However, few studies have validated MR derived measurements with histopathology. Here, we determine the correlation of myelin water imaging, an MR measure of myelin content, with quantitative histopathologic measures of myelin density. The multi-component T2 distribution of water was determined from 25 formalin-fixed MS brain samples using a multi-echo T2 relaxation MR experiment. The myelin water fraction (MWF), defined as T2 signal below 30 milliseconds divided by the total signal, was determined for various regions of interest and compared to Luxol fast blue (myelin stain) mean optical density (OD) for each sample. MWF had a strong correlation with myelin stain [mean (range) R2-/0.67 (0.45+ 0.92)], validating MWF as a measure of myelin density. This quantitative technique has many practical applications for the in vivo monitoring of demyelination and remyelination in a variety of disorders of myelin.

Myelin water imaging of multiple sclerosis at 7 T: Correlations with histopathology

Myelin water imaging (MWI) promises to be invaluable in understanding neurological diseases like MS. However, a limitation of MWI is signal to noise ratio. Recently, a number of investigators have performed MWI at field strengths higher than 1.5 T. Our goal was to determine if myelin water imaging at increased SNR, arising from the use of a small bore 7 T MR system with optimized coil geometry, enables the production of superior myelin water maps with increased spatial detail and enables better correlations with histology. Ten formalin-fixed MS brain samples underwent a 32-echo T(2) relaxation experiment which measured myelin water fraction (MWF) on a 7-T animal MRI scanner. MWF correlated strongly qualitatively and quantitatively with luxol fast blue staining for myelin [mean (range): R(2)=0.78 (0.56-0.95), p<0.0001]. The quality and detail of 7 T myelin water maps were far superior to that previously seen at 1.5 T, allowing for visualization of fine structures such as the normal prominent myelination of the deeper cortical layers, the alveus of the hippocampus and rings of preserved myelin in a concentric Balos lesion. 7 T imaging will allow detailed assessment of myelin pathology to a degree not possible with lower field strengths.

Magnetic resonance imaging of myelin.

SummaryThe ability to measure myelin in vivo has great consequences for furthering our knowledge of normal development, as well as for understanding a wide range of neurological disorders. The following review summarizes the current state of myelin imaging using MR. We consider five MR techniques that have been used to study myelin: 1) conventional MR, 2) MR spectroscopy, 3) diffusion, 4) magnetization transfer, and 5) T2 relaxation. Fundamental studies involving peripheral nerve and MR/histology comparisons have aided in the interpretation and validation of MR data. We highlight a number of important findings related to myelin development, damage, and repair, and we conclude with a critical summary of the current techniques available and their potential to image myelin in vivo.

Is the magnetization transfer ratio a marker for myelin in multiple sclerosis

To investigate the correlation between water content (WC) and magnetization transfer ratio (MTR) in normal and multiple sclerosis (MS) brain. The MTR has been proposed as a marker for myelin in central nervous system tissue. However, changes in WC due to inflammation and edema may also affect the MTR.

MR relaxation in multiple sclerosis.

This article provides an overview of relaxation times and their application to normal brain and brain and cord affected by multiple sclerosis. The goal is to provide readers with an intuitive understanding of what influences relaxation times, how relaxation times can be accurately measured, and how they provide specific information about the pathology of MS. The article summarizes significant results from relaxation time studies in the normal human brain and cord and from people who have multiple sclerosis. It also reports on studies that have compared relaxation time results with results from other MR techniques.

Dirty-appearing white matter in multiple sclerosis: preliminary observations of myelin phospholipid and axonal loss.

Abstract“Dirty-appearing white matter” (DAWM) in multiple sclerosis (MS) is defined as a region(s) with ill-defined borders of intermediate signal intensity between that of normal-appearing white matter (NAWM) and that of plaque on T2-weighted and proton density imaging. To delineate the histopathology of DAWM, four formalin-fixed cerebral hemisphere slices of three MS patients with DAWM were scanned with T2- weighted and proton density sequences. The myelin water fraction (MWF) was obtained by expressing the short T2 component as a fraction of the total T2 distribution. Hemispheric sections were then stained with Luxol fast blue (LFB) for myelin phospholipids, for myelin basic protein (MBP) and 2’,3’-cyclic nucleotide 3’-phosphohydrolase (CNP) for myelin; Bielschowsky silver impregnation for axons; and for glial fibrillary acidic protein (GFAP) for astrocytes. Compared to NAWM, DAWM showed reduction in MWF, corresponding to a reduction of LFB staining. DAWM also showed reduced Bielschowsky staining. Quantitatively, the change in MWF in DAWM most consistently correlated with the change in LFB staining. The findings of this preliminary study suggest that DAWM is characterized by loss of myelin phospholipids, detected by the short T2 component, and axonal reduction.

Reproducibility of myelin water fraction analysis: a comparison of region of interest and voxel-based analysis methods

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.

Evolution of focal and diffuse magnetisation transfer abnormalities in multiple sclerosis

Abstract.nMagnetisation transfern(MT) imaging provides indirect informationnon tissue structure abnormalitiesnin areas that otherwisenmay appear normal on conventionalnMRI. We determined thenevolution of MT changes in normalnappearing white matter (NAWM)nand lesion on serial examination ofn9 multiple sclerosis (MS) patientsnand age matched controls. Thenmean NAWM MT ratio (MTR) wasnfound to correlate stronglyn(R = 0.93) with the length of timensince the patient’s first clinical presentationnand was well characterizednby a linear decrease ofn-0.16%/year (p < 0.0001). The timenzero intercept of the NAWM MTRnregression was 30.7 ± 0.2%, notndifferent from the average MTRnof white matter from controlsn(30.4 ± 0.2 %). An additional gradualndecrease in NAWM MTR wasnobserved 6 to 12 months before thenappearance of a new lesion on conventionalnMRI, while a more precipitousndecrease in MTR was seenn2 to 6 months before the lesion appeared.nThose lesions that exhibitednpre-lesion MTR decreasesnshowed less MTR recovery than lesionsnwhich had no pre-lesion MTRndecrease. The data suggest that thenMTR of NAWM in MS undergoes anslow progressive decrease thatnstarts at disease onset and acceleratesnrapidly in focal areas just priornto lesion appearance on conventionalnMRI.

Comparison of myelin water fraction from multiecho T2 decay curve and steady-state methods.

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.