Alex L. MacKay

Quantitative interpretation of NMR relaxation data

Abstract Least-squares and linear programming algorithms for the interpretation of NMR relaxation data in terms of a spectrum of relaxation times are presented. These stable methods are noniterative and avoid all of the difficulties associated with nonlinear optimization schemes. Moreover, they are not restricted by any assumptions which limit the number of possible relaxation times. The inherent nonuniqueness due to the finite number of inaccurate measurements means that a variety of discrete and continuous spectra exist which fit the data equally well. For a complete interpretation the range of possible solutions must be examined. The algorithms discussed explore the space of acceptable solutions by constructing relaxation spectra from a continuum of models ranging from a few isolated delta functions to a continuous distribution. Alternatively, the interpreter can choose that class of spectrum (discrete or continuous) which best represents the physical system under investigation and so enhance the reliability of the interpretation. This flexibility is essential in order to avoid the pitfalls of interpreting a single spectrum returned by a single algorithm. In addition, the linear programming approach reduces the non-uniqueness by constructing unique information in the form of bounds on all spectra which satisfy the observations. These bounds and the corresponding extreme models are necessary for any quantitative determination of how spectral peaks change in amplitude or position with a change in the physical system.0 1989 Academic Press, Inc.

Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins.

Schizophrenia unfolds during the late period of brain maturation, while myelination is still continuing. In the present study, we used MRI and T2 relaxation analysis to measure the myelin water fraction in schizophrenia. In schizophrenia (n=30) compared with healthy subjects (n=27), overall white matter showed 12% lower myelin water fraction (P=0.031), with the most prominent effects on the left genu of the corpus callosum (36% lower, P=0.002). The left anterior genu was affected in both first-episode (P=0.035) and chronic patients (P=0.011). In healthy subjects, myelin water fraction in total white matter and in frontal white matter increased with age, and with years of education, indicating ongoing maturation. In patients with schizophrenia, neither relation was statistically significant. Post-mortem studies of anterior frontal cortex demonstrated less immunoreactivity of two oligodendrocyte-associated proteins in schizophrenia (2′,3′-cyclic nucleotide 3′-phosphodiesterase by 33%, P=0.05; myelin-associated glycoprotein by 27%, P=0.14). Impaired myelination in schizophrenia could contribute to abnormalities of neural connectivity and persistent functional impairment in the illness.

Water content and myelin water fraction in multiple sclerosis

Abstract.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.

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.

De-pake-ing of NMR spectra

A procedure suggested elsewhere (Bloom, Davis, and MacKay, Chem. Phys. Lett.80, 198 (1981)) for extracting the nuclear magnetic resonance spectrum of an oriented system from the spectrum consisting of a superposition of contributions from randomly oriented domains (“powder spectrum”) is modified to enable its application to a wider range of systems. The method works well for the spectra associated with quadrupolar, dipolar, and anisotropic chemical or Knight shift interactions whose secular components have axial symmetry and scale as 3 cos2 θ − 1, where θ is the angle between the symmetry axis and the external magnetic field. Simulated spectra are used to explore the applicability of the method to lineshapes with different types of broadening and to lineshapes arising from nonaxially symmetric systems.

Direct determination of the oriented sample nmr spectrum from the powder spectrum for systems with local axial symmetry

Abstract A procedure is described for extracting the nuclear magnetic resonance spectrum of an oriented system from the spectrum of a superposition of randomly oriented domains. The procedure is applicable to dipolar, quadrupolar and anisotropic chemical shift interactions in systems having local axial symmetry and is illustrated using simulated and experimental spectra.

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 diffusion anisotropy an accurate monitor of myelination? Correlation of multicomponent T2 relaxation and diffusion tensor anisotropy in human brain.

We compare T2-relaxation and diffusion tensor data from normal human brain. The relationships between myelin-water fraction (MWF) and various diffusion tensor measures [e.g., fractional anisotropy (FA), perpendicular diffusivity (ADC perpendicular) and mean diffusivity ] in white matter (WM) and gray matter (GM) structures in the brain were examined in 16 normal volunteers at 1.5 T and 6 normal subjects at 3.0 T and mean diffusivity. We found some degree of linear correlation between these measurements, but by using region of interest (ROI)-based analysis, we also observed several structures which seemed to deviate significantly from a linear relationship. From all investigated relationships between various diffusion tensor measures and myelin-water content, FA and ADC perpendicular yielded the highest correlation coefficients with MWF. However, diffusion anisotropy was also significantly influenced by factors other than myelin-water content. The less operator-dependent voxel-based analysis (VBA) between myelin-water and diffusional anisotropy measures is proposed as an innovative alternative to ROI-based analysis. We confirmed that WM structures, in general, have higher diffusional anisotropy than GM structures and also have higher myelin-water content. However, our findings suggest that in the highly organized fibre arrangement of compact WM structures such as the genu of the corpus callosum, elevated degrees of diffusional anisotropies are measured, which do not necessarily correspond to an elevated myelin content but more likely reflect the highly organized directionality of fibre bundles in these areas (low microscopic and macroscopic tortuosity) as well as strongly restricted diffusion in the interstitial space between the myelinated axons. Conversely, in structures with disorganized fibre bundles and multiple fibre crossings, such as the minor and major forceps, low FA values were measured, which does not necessarily reflect a decrease myelin-water content.

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