This edition has been revised to include new data on genetics, molecular biology, and the role of cellular structures on one side and the growing experience with MR patterns of less common myelin disorders on the other. In addition, chapters have been added on disorders of which the white matter involvement was previously unclear.

Magnetic Resonance of Myelin, Myelination, and Myelin Disorders

We attempted to define the role of subtle changes in the normal-appearing white matter (NAWM) in the development of disability in multiple sclerosis (MS). Twenty-seven clinically definite MS patients with either relapsing-remitting or chronic-progressive courses and 10 sex- and age-matched controls entered the study. For each patient and control, we studied two NAWM areas in the frontal lobe with magnetization transfer imaging (MTI). For patients, we also calculated the MT ratios (MTRs) for three contiguous areas of NAWM progressively further from "isolated" lesions visible on conventional MRI. Frontal NAWM in MS patients had lower mean MTRs than the frontal white matter of the controls (p = 0.02). MTRs in the NAWM adjacent to isolated lesions increased with distance from them to the cortical gray matter (p = 0.04). This pattern was typical for patients with chronic-progressive MS whose MTRs in the first two regions of NAWM adjacent to lesions were lower than those of the same regions of patients with relapsing-remitting MS. This study confirms that there are alterations in the NAWM of MS patients and suggests that such changes might be relevant to the disability in MS.

A Magnetization Transfer Imaging Study of Normal-Appearing White Matter in Multiple Sclerosis

A histological, histochemical and biochemical study of the macroscopically normal white matter in multiple sclerosis.

Chapter 15 – docosahexaenoic acid: membrane function and metabolism

Recently reported contrast in phase images of human and animal brains obtained with gradient-recalled echo MRI holds great promise for the in vivo study of biological tissue structure with substantially improved resolution. Herein we investigate the origins of this contrast and demonstrate that it depends on the tissue “magnetic architecture” at the subcellular and cellular levels. This architecture is mostly determined by the structural arrangements of proteins, lipids, non-heme tissue iron, deoxyhemoglobin, and their magnetic susceptibilities. Such magnetic environment affects/shifts magnetic resonance (MR) frequencies of the water molecules moving/diffusing in the tissue. A theoretical framework allowing quantitative evaluation of the corresponding frequency shifts is developed based on the introduced concept of a generalized Lorentzian approximation. It takes into account both tissue architecture and its orientation with respect to the external magnetic field. Theoretical results quantitatively explain frequency contrast between GM, WM, and CSF previously reported in motor cortex area, including the absence of the contrast between WM and CSF. Comparison of theory and experiment also suggests that in a normal human brain, proteins, lipids, and non-heme iron provide comparable contributions to tissue phase contrast; however, the sign of iron and lipid contributions is opposite to the sign of contribution from proteins. These effects of cellular composition and architecture are important for quantification of tissue microstructure based on MRI phase measurements. Also theory predicts the dependence of the signal phase on the orientation of WM fibers, holding promise as additional information for fiber tracking applications.

https://www.pnas.org/content/pnas/106/32/13558.full.pdf

Biophysical mechanisms of phase contrast in gradient echo MRI

— Quantitative analyses of white matter from four brains of patients with multiple sclerosis (MS) and four control brains were carried out for total and soluble proteins, individual lipid fractions, and their corresponding fatty acids. In three specimens from two of the MS brains there were reductions of cerebrosides and of the C20:1 acid in the ethanolamine glycerophosphatide (EGP) fraction and a slight increase of tetraenes and trienes, while all other components were present in concentrations similar to those in the controls. In three other samples from two of the MS brains, galactolipids were deficient to a greater extent than cholesterol, EGP or CGP (choline glycerophosphatide), while proteins were within the control range. In samples where thinning of myelin was observed in Luxol-blue stained sections, there were proportional decreases of all components. The percentage of C20:1 acid in the EGP fraction was reduced in two of three myelin preparations from corresponding samples of MS white matter, and that of C24:1 acid in the cerebroside fraction was reduced in all three MS myelin preparations when compared with the two controls. The data suggest that inadequacy of the fatty acid elongation process together with deficits of cerebrosides represent one of the early biochemical lesions in the white matter of the MS brain.

Lipids and proteins in multiple sclerosis white matter.

The many attempts to elucidate the pathogenesis of multiple sclerosis (MS) by chemical analysis of brain, blood and spinal fluid have been amply reviewed recently by Scheinberg and Korey.' The present studies have been directed toward the alteration of lipids that precede visible demyelination. Their results, in conjunction with findings of other authors, might permit tentative conclusions or, at least, conjecture about the biochemical pathway of demyelination in MS. In addition, the relevance of the early chemical lesions to function and to clinical remission merits attention. Supplementary to the lipid analyses done earlier,2 the 2-hydroxy fatty acids (HFA) were studied in detail to see whether further evidence for selective removal of lipids3 could be obtained. It has not been established that the lipid deficits found in grossly intact white matter of MS bra inP5 are all located in myelin proper. In fact, there is a paucity of data on the lipid composition of this structure. Consequently, a comprehensive analysis of purified myelin fractions was undertaken.

Alterations in myelin fatty acids and plasmalogens in multiple sclerosis.

In view of the deficits of sphingolipids and of nervonic acid in presence of normal quantities of cholesterol and total proteins in MS white matter reported earlier, the fatty acids of these lipids and of their possible precursors were analyzed. Small quantities of ceramides were present in all specimens. These, as well as the cerebrosides of 2 MS gray matters showed decreased ratios of long chain monounsaturated fatty acids. Reduction of the ratio of nervonic acid was succinct in the sphingomyelins and ceramides of several MS white matters and of the plaques, and was noted, to a lesser degree, in their cerebrosides and sulfatides. This was associated with an increase of the stearic acid ratio. Free fatty acids of both gray and white matter contained large proportions of C 16:0, 18:0, 18:1 and 20:4, and only minimal ones of C 24:0 acids. These findings in addition to absence of C 26:1 acid in ceramides suggest that elongation and desaturation are taking place during in vivo biosynthesis of cerebrosides and sphingomyelins. These processes appear to be deficient in MS and are discussed in context with biochemical and immunologic findings by other authors. Psychosine was not found in any of the adult or in one infants brain and its role as an in vivo precursor for sphingolipids is questionable.

M. G. Tavaststjerna

Papers

Lipids and proteins in multiple sclerosis white matter.

Alterations in myelin fatty acids and plasmalogens in multiple sclerosis.

Sphingolipids and their precursors in human brain (normal and MS).

Lipids of malignant tumors.