Non-negative least squares computation for in vivo myelin mapping using simulated multi-echo spin-echo T2 decay data.

Multi-compartment T2 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 T2 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, B1+ 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 T2 and MWF maps. We generated multi-echo spin-echo T2 decay curves following the Carr-Purcell-Meiboom-Gill approach for various myelin concentrations and myelin T2 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 T2 (gmT2 ). MWF estimates were more stable than myelin water gmT2 time across different settings of the T2 analysis. We observed that the lower limit of the T2 distribution grid should be slightly shorter than TE1 . Both TE1 and the acquisition echo spacing also have to be sufficiently short to capture the rapidly decaying myelin water T2 signal. Among all parameters of interest, the estimated MWF and intra-/extracellular water gmT2 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 B1+ inhomogeneities and at lower signal-to-noise ratio. Tailoring acquisition strategies may allow us to better characterize the T2 distribution, including the myelin water, in vivo.

Proton MRS of large multiple sclerosis lesions reveals subtle changes in metabolite T(1) and area.

The T(1) values of metabolites were measured in eight subjects with clinically definite multiple sclerosis (MS) having at least one large brain lesion (2.6 ± 0.7 mL) and in eight age- and sex-matched healthy controls. MRS examinations were conducted at 1.5 T using point-resolved spectroscopy (PRESS) (TE = 30 ms, TR = 530, 750, 1200, 1500, 3500, 5000 ms). Spectra were acquired from a voxel placed in the largest lesion in the subject with MS, and in a corresponding voxel (same size and region) in normal white matter (NWM) in the matched control, and were fitted using LCModel. As there are regional variations in metabolite and water T(1) and metabolite signal areas, careful placement of the control voxel was necessary to measure subtle differences between the lesions and NWM. The T(1) and T(1)-corrected signal areas of creatine were the same in MS lesions as in controls. The T(1) values of choline were significantly shorter in MS lesions located in occipital and parietal, but not in frontal, white matter. N-Acetylaspartate (NAA) and myoinositol T(1) values in MS lesions were similar to those in NWM; however, the area of myoinositol correlated directly with lesion water T(1), and the area of NAA correlated inversely with lesion water T(1). MR spectra acquired at short TR require T(1) correction of choline for accurate quantification. Careful voxel placement in controls to match lesion location in subjects with MS enables a clearer view of the subtle changes in lesions.

Two-year study of cervical cord volume and myelin water in primary progressive multiple sclerosis.

BACKGROUND: Spinal cord involvement in multiple sclerosis (MS) is common and an important element in disability. Previous studies demonstrated smaller cervical cord area at the C2 level in MS compared to controls, and a decrease in cord area over 12 months, most marked in primary progressive MS (PPMS). A subset of subjects participating in a multicentre, double-blind, placebo-controlled clinical trial evaluating the efficacy of glatiramer acetate in PPMS (PROMiSe trial) were followed for 2 years. METHODS: 24 PPMS subjects, randomized to placebo (n = 9) and glatiramer acetate (n = 15), and 24 matched controls were studied. Cervical cord volume (CCV) at C2-3 was determined using a 3D inversion recovery (IR)-prepared spoiled-gradient echo sequence. Myelin water fraction (MWF) at C2-3 was obtained using a 32-echo IR-prepared relaxation sequence. Scans were repeated at baseline, years 1 and 2. RESULTS: Baseline CCV was significantly smaller for PPMS than controls [median (interquartile range) 951 (829-1043) vs. 1072 (1040-1129) mm(3), p = 0.0004] and MWF trended to be lower in PPMS cord [median (interquartile range) 0.225 (0.187-0.267) vs. 0.253 (0.235-0.266), p = 0.12]. Baseline CCV correlated with baseline Expanded Disability Status Scale, disease duration, brain white and grey matter volume. In PPMS, CCV was significantly decreased at year 1 (-0.83%, p = 0.04) and year 2 (-1.65%, p = 0.02). Baseline MWF correlated with baseline CCV and brain white and grey matter volume. MWF was significantly decreased from baseline for PPMS at year 2 (-10.5%, p = 0.01). Treatment effect was not detected on change in CCV nor MWF. CONCLUSIONS: Metrics at the level of the cord, including volume and MWF at C2-3, were lower in PPMS than controls and changed over 2 years only in PPMS.

Magnetite in CI Carbonaceous Meteorites: Origin by Aqueous Activity on a Planetesimal Surface.

The composition and morphology of magnetite in CI carbonaceous meteorites appear incompatible with a nebular origin. Mineralization on the meteorite parent body is a more plausible mode of formation. The iodine-xenon age of this material therefore dates an episode of secondary mineralization on a planetesimal rather than the epoch of condensation in the primitive solar nebula.

Longitudinal changes in myelin water fraction in two MS patients with active disease.

Multiple sclerosis (MS) is characterised by focal areas that undergo cycles of demyelination and remyelination. Although conventional magnetic resonance imaging is very effective in localising areas of damage, these techniques are not pathology specific. A newer technique, T(2) relaxation, can separate water from brain into three compartments: (1) a long T(2) component (>2 s) arising from CSF, (2) an intermediate T(2) component (~80 ms) attributed to intra- and extra-cellular water and (3) a short T(2) component (~20 ms) assigned to water trapped in between the myelin bilayers (termed myelin water). Histological evidence shows that myelin water is a specific marker of myelination. The goal of this work was to follow changes in total water content (WC) and myelin water fraction (MWF) in evolving MS lesions over one year. Multi-echo T(2) relaxation data was collected and used to measure water content and myelin water fraction from three new MS lesions in two patients. WC increased in the three large (>1 cm(3)) lesions at lesion appearance and remained elevated in the central core. Two lesions showed low MWF in the core suggesting demyelination upon first appearance. At later time points, one lesion showed a decrease in volume of low MWF, reflecting remyelination whereas the volume of low MWF in the other lesion core remained constant. This work provides evidence that MWF and WC can monitor demyelination and remyelination in MS.

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.

Multi-parametric MR assessment of T(1) black holes in multiple sclerosis : evidence that myelin loss is not greater in hypointense versus isointense T(1) lesions.

BACKGROUND: Chronic T(1) hypointense lesions in multiple sclerosis (MS) are areas of severe tissue destruction. The purpose of this study was to compare total water content (WC),myelin water content (MWC), magnetization transfer ratio (MTR), T(1) relaxation time (T(1)), mean T(2) relaxation time (GMT(2)) between stable MS lesions that are hypointense and isointense on T(1)-weighted images. METHODS: Six MS patients were scanned five times over one year. WC, MWC, MTR, T(1) and GMT(2) were calculated for 15 isointense and 15 hypointense chronically stable T(1) lesions, as well as contralateral normal appearing white matter (NAWM). RESULTS: All MR measurements from both iso- and hypointense stable lesion types were significantly different from NAWM. WC, T(1) and GMT(2) were significantly higher and MTR significantly lower in hypointense T(1) lesions compared to isointense lesions. MWC was not significantly different between iso- and hypointense lesions. CONCLUSIONS: This work suggests that myelin loss occurs equally in both the chronic isointense and hypointense lesions but hypointense lesions are distinguished by increased extracellular water.

Multiple measures of corticospinal excitability are associated with clinical features of multiple sclerosis.

In individuals with multiple sclerosis (MS), transcranial magnetic stimulation (TMS) may be employed to assess the integrity of corticospinal system and provides a potential surrogate biomarker of disability. The purpose of this study was to provide a comprehensive examination of the relationship between multiple measures corticospinal excitability and clinical disability in MS (expanded disability status scale (EDSS)). Bilateral corticospinal excitability was assessed using motor evoked potential (MEP) input-output (IO) curves, cortical silent period (CSP), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and transcallosal inhibition (TCI) in 26 individuals with MS and 11 healthy controls. Measures of corticospinal excitability were compared between individuals with MS and controls. We evaluated the relationship(s) between age and clinical demographics such as age at MS onset (AO), disease duration (DD) and clinical disability (EDSS) with measures of corticospinal excitability. Corticospinal excitability thresholds were higher, MEP latency and CSP onset delayed and MEP durations prolonged in individuals with MS compared to controls. Age, DD and EDSS correlated with corticospinal excitability thresholds. Also, TCI duration and the linear slope of the MEP amplitude IO curve correlated with EDSS. Hierarchical regression modeling demonstrated that combining multiple TMS-based measures of corticospinal excitability accounted for unique variance in clinical disability (EDSS) beyond that of clinical demographics (AO, DD). Our results indicate that multiple TMS-based measures of corticospinal and interhemispheric excitability provide insights into the potential neural mechanisms associated with clinical disability in MS. These findings may aid in the clinical evaluation, disease monitoring and prediction of disability in MS.

2H- and 31P-NMR studies of cholesteryl palmitate in sphingomyelin dispersions.

Dispersions (50 wt% in water) of sphingomyelin/cholesteryl palmitate (95 : 5 mol%) have been studied by 2H- and 31P-NMR spectroscopy between 25 and 60 degrees C. The deuterated esters, cholesteryl palmitate-d31 and cholesteryl palmitate-16, 16, 16-d3, were used for 2H-NMR studies. Of the 5 mol% cholesteryl palmitate added, 1.5 mol% was found to incorporate in the sphingomyelin and this amount remained constant throughout the temperature range studied. The remainder of the cholesteryl palmitate was present as regions of solid. At temperatures above the gel-to-liquid crystalline phase transition of sphingomyelin the NMR spectra indicate that a fraction of the cholesteryl palmitate and sphingomyelin is undergoing rapid isotropic motions. This fraction, which increases with increasing temperature above the phase transition, is probably composed of small bilayer structures. When 50 mol% cholesterol (relative to sphingomyelin) was added to the sphingomyelin/cholesteryl palmitate dispersion, the isotropic component in the NMR spectral was no longer present, the gel-to-liquid crystalline phase transition was removed, and the incorporation of ester in the membrane decreased by more than an order of magnitude.

Deuterium magnetic resonance of selectively deuterated cholesteryl esters in dipalmitoyl phosphatidylcholine dispersions.

Dispersions (50 wt% water) containing 95 mol% dipalmitoyl phosphatidylcholine/5 mol% deuterated cholesteryl palmitate (or stearate) were studied using 2H-NMR. Incorporation of ester into the phospholipid bilayer was found to be 0.5 mol% at 50 degrees C. From the profile of 2H quadrupolar splitting vs. chain position, support for an average conformation resembling a 'horseshoe' within the bilayer is obtained. Quadrupolar relaxation times T2e of approx. 250 microseconds and approx. 850 microseconds are measured for cholesteryl palmitate-2,2-d2 and cholesteryl palmitate-16,16,16-d3, respectively, which are less than one-half those obtained for the corresponding positions in dipalmitoyl-d62 phosphatidylcholine. This is ascribed to a slower rate of motion of the ester chain and/or an extra, slow motion of the molecule.

Modeling T(1) and T(2) relaxation in bovine white matter.

The fundamental basis of T1 and T2 contrast in brain MRI is not well understood; recent literature contains conflicting views on the nature of relaxation in white matter (WM). We investigated the effects of inversion pulse bandwidth on measurements of T1 and T2 in WM. Hybrid inversion-recovery/Carr-Purcell-Meiboom-Gill experiments with broad or narrow bandwidth inversion pulses were applied to bovine WM in vitro. Data were analysed with the commonly used 1D-non-negative least squares (NNLS) algorithm, a 2D-NNLS algorithm, and a four-pool model which was based upon microscopically distinguishable WM compartments (myelin non-aqueous protons, myelin water, non-myelin non-aqueous protons and intra/extracellular water) and incorporated magnetization exchange between adjacent compartments. 1D-NNLS showed that different T2 components had different T1 behaviours and yielded dissimilar results for the two inversion conditions. 2D-NNLS revealed significantly more complicated T1/T2 distributions for narrow bandwidth than for broad bandwidth inversion pulses. The four-pool model fits allow physical interpretation of the parameters, fit better than the NNLS techniques, and fits results from both inversion conditions using the same parameters. The results demonstrate that exchange cannot be neglected when analysing experimental inversion recovery data from WM, in part because it can introduce exponential components having negative amplitude coefficients that cannot be correctly modeled with nonnegative fitting techniques. While assignment of an individual T1 to one particular pool is not possible, the results suggest that under carefully controlled experimental conditions the amplitude of an apparent short T1 component might be used to quantify myelin water.

A pathology-MRI study of the short-T2 component in formalin-fixed multiple sclerosis brain.

OBJECTIVE: To determine the pathologic basis of areas not exhibiting signal of the short-T2 component of the T2 relaxation distribution in MS, as studied in formalin-fixed brain. BACKGROUND: A myelin-specific MRI signal would be of great importance in assessing demyelination in patients with MS. Evidence indicates that the short-T2 (10 to 50 millisecond) component of the T2 relaxation distribution originates from water in myelin sheaths. The authors present two cases of MS in which the anatomic distribution of the short-T2 component was correlated with the pathologic findings in postmortem formalin-fixed brain. METHOD: One half of the formalin-fixed brain was suspended in a gelatin-albumin mixture cross-linked with glutaraldehyde, and scanned with a 32-echo MRI sequence. The brain was then cut along the center of the 5-mm slices scanned, photographed, dehydrated, and embedded in paraffin. Paraffin sections, stained with Luxol fast blue and immunocytochemically for 2',3'-cyclic nucleotide 3'-phosphohydrolase for myelin and by the Bielschowsky technique for axons, were compared with the distribution of the amplitude of the short-T2 component of the comparable image slices. RESULTS: The anatomic distribution of the short-T2 component signal corresponded to the myelin distribution. Chronic, silent MS plaques with myelin loss correlated with areas of absence of short-T2 signal. The numbers of axons within lesions were reduced, but many surviving axons were also seen in these areas of complete loss of myelin. CONCLUSION: In formalin-fixed MS brains the short-T2 component of the T2 relaxation distribution corresponds to the anatomic distribution of myelin. Chronic, silent demyelinated MS plaques show absence of the short-T2 component signal. These results support the hypothesis that the short-T2 component originates from water related to myelin.-1510

Water content and myelin water fraction in multiple sclerosis. A T2 relaxation study.

BACKGROUND: Measurements of the T2 decay curve provide estimates of total water content and myelin water fraction in white matter in-vivo, which may help in understanding the pathological progression of multiple sclerosis (MS). METHODS: Thirty-three MS patients (24 relapsing remitting, 8 secondary progressive, 1 primary progressive) and 18 controls underwent MR examinations. T2 relaxation data were acquired using a 32-echo measurement. All controls and 18 of the 33 MS patients were scanned in the transverse plane through the genu and splenium of the corpus callosum. Five white matter and 6 grey matter structures were outlined in each of these subjects. The remaining 15 MS patients were scanned in other transverse planes. A total of 189 lesions were outlined in the MS patients. Water content and myelin water fraction were calculated for all regions of interest and all lesions. RESULTS: The normal appearing white matter (NAWM) water content was, on average, 2.2% greater than that from controls, with significant differences occurring in the posterior internal capsules, genu and splenium of the corpus callosum, minor forceps and major forceps (p<0.0006). On average, MS lesions had 6.3% higher water content than contralateral NAWM (p<0.0001). Myelin water fraction was 16% lower in NAWM than for controls, with significant differences in the major and minor forceps, internal capsules, and splenium (p<0.05). The myelin water fraction of MS lesions averaged 52 % that of NAWM. CONCLUSIONS: NAWM in MS has a higher water content and lower myelin water fraction than control white matter. The cause of the myelin water fraction decrease in NAWM could potentially be due to either diffuse edema, inflammation, demyelination or any combination of these features. We present a simple model which suggests that myelin loss is the dominant feature of NAWM pathology.

Measurement of lung water content and pleural pressure gradient with magnetic resonance imaging.

The aim of this study was to develop a magnetic resonance (MR) sequence capable of measuring water content and the gravity-dependent gradient in lung density in normal lung. First, the MR signal from excised normal pig lung was characterized using a 2.1 T nuclear magnetic resonance (NMR) spectrometer. A multiecho sequence was then developed on a 0.15 T Picker MR scanner. This sequence was validated in excised normal pig lung by comparison with gravimetric lung water content. Finally, this sequence was used in five normal volunteers in the prone and supine positions during quiet breathing and in the supine position at total lung capacity (TLC). The ratio of lung water measured by MR and gravimetric techniques was 0.95 +/- 0.03. There was no significant difference in average lung density in the prone (0.21 +/- 0.03 g/ml) and in the supine (0.20 +/- 0.03 g/ml) positions. Lung density decreased at TLC (0.12 +/- 0.01 g/ml) (p < 0.01). Gradients in lung density were visible in all prone and supine scans at functional residual capacity (FRC), and on average the gradients were decreased by 90% at TLC. The average estimated pleural pressure gradient in the prone position was 0.13 +/- 0.08 cm H2O/cm lung and in the supine position was 0.38 +/- 0.23 cm H2O/cm lung. MRI allows measurement of lung water content and pleural pressure gradient.

Bovine granular vulvitis associated with ureaplasma infection.

A granular vulvitis syndrome associated with ureaplasma infection was first recognized in Ontario dairy herds in 1972. The acute form of the disease was characterized by a purulent vulvar discharge, an inflamed hyperemic vulvar mucosa and varying degrees of granularity. In the chronic form, there was an absence of a purulent discharge and a gradual decline in the severity of the hyperemia and granularity. Epithelial inclusion cysts were observed in the vulvar epithelium of approximately 10% of affected cows.A seasonal variation in the incidence of the disease was observed. Herd morbidities during the summer months reached a low of 37% and increased to 75% during the winter months with constant housing.When widespread in herds, the acute form of the disease had a significant effect on fertility. In four herds examined, first service conceptions dropped on average by 27%. The chronic form of the disease had a less detrimental effect on fertility with first service conceptions being reduced on average by 13%. Intrauterine infusions of a tetracycline 24 hours postbreeding were found to be of value in improving conception rates in acutely affected herds.

A study of drug residues in milk following intrauterine infusion of antibacterial drugs in lactating cows.

Intrauterine infusion of nine antibacterial compounds caused detectable drug residues in 17 out of 165 cows or in 25 out of 1110 posttreatment milkings. Four cows treated with pyrolidinomethyl tetracycline suspension had drug residues at the first milking. One cow had residues after oxytetracycline treatment, two after procaine penicillin G, three after acriflavin and after chloramphenicol-dapsone and four after hibitane. Nitrofurazone, nitrofurathiazide and Hibitane Compound(R) did not cause detectable inhibitory residues in any milk sample.

Evaluation of white matter myelin water fraction in chronic stroke.

Multi-component T2 relaxation imaging (MCRI) provides specific in vivo measurement of myelin water content and tissue water environments through myelin water fraction (MWF), intra/extra-cellular water fraction (I/EWF) and intra/extracellular and global geometric mean T2 (GMT2) times. Quantitative MCRI assessment of tissue water environments has provided new insights into the progression and underlying white matter pathology in neural disorders such as multiple sclerosis. It has not previously been applied to investigate changes in white matter in the stroke-affected brain. Thus, the purposes of this study were to 1) use MCRI to index myelin water content and tissue water environments in the brain after stroke 2) evaluate relationships between MWF and diffusion behavior indexed by diffusion tensor imaging-based metrics and 3) examine the relationship between white matter status (MWF and fractional anisotropy) and motor behavior in the chronic phase of stroke recovery. Twenty individuals with ischemic stroke and 12 matched healthy controls participated. Excellent to good test/re-test and inter-rater reliability was observed for region of interest-based voxelwise MWF data. Reduced MWF was observed in whole-cerebrum white matter (p < 0.001) and in the ipsilesional (p = 0.017) and contralesional (p = 0.037) posterior limb of internal capsule (PLIC) after stroke compared to whole-cerebrum and bilateral PLIC MWF in healthy controls. The stroke group also demonstrated increased I/EWF, I/E GMT2 and global GMT2 times for whole-cerebrum white matter. Measures of diffusion behavior were also significantly different in the stroke group across each region investigated (p < 0.001). MWF was not significantly correlated with specific tensor-based measures of diffusion in the PLIC for either group. Fractional anisotropy in the ipsilesional PLIC correlated with motor behavior in chronic stroke. These results provide novel insights into tissue-specific changes within white matter after stroke that may have important applications for the understanding of the neuropathology of stroke.

Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease.

OBJECTIVES: To evaluate in vivo brain metabolite differences in control subjects, individuals with premanifest Huntington disease (pre-HD), and individuals with early HD using ¹H magnetic resonance spectroscopy (MRS) and to assess their relationship with motor performance. METHODS: Eighty-five participants (30 controls, 25 pre-HD, and 30 early HD) were recruited as part of the TRACK-HD study. Eighty-four were scanned at 3 T with single-voxel spectroscopy in the left putamen. Disease burden score was >220 among pre-HD individuals. Subjects underwent TRACK-HD motor assessment including Unified Huntington's Disease Rating Scale (UHDRS) motor scoring and a novel quantitative motor battery. Statistical analyses included linear regression and one-way analysis of variance. RESULTS: Total N-acetylaspartate (tNAA), a neuronal integrity marker, was lower in early HD (∼15%) vs controls (p < 0.001). N-acetylaspartate (NAA), a constituent of tNAA, was lower in pre-HD (∼8%) and early HD (∼17%) vs controls (p < 0.05). The glial cell marker, myo-inositol (mI), was 50% higher in early HD vs pre-HD (p < 0.01). In early HD, mI correlated with UHDRS motor score (R² = 0.23, p < 0.05). Across pre-HD and early HD, tNAA correlated with performance on a tongue pressure task (R² = 0.30, p < 0.0001) and with disease burden score (R² = 0.17, p < 0.005). CONCLUSIONS: We demonstrate lower putaminal tNAA in early HD compared to controls in a cross-section of subjects. A novel biomarker role for mI in early HD was also identified. These findings resolve disagreement in the literature about the role of MRS as an HD biomarker. We conclude that putaminal MRS measurements of NAA and mI are promising potential biomarkers of HD onset and progression.