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Interferon-beta-1a used in SPMS showed significant effects on all MRI measures, particularly in patients with relapses in the 2 years before the study.

Although multiple sclerosis (MS) lesions have been studied extensively using histology and magnetic resonance imaging (MRI), little is known about diffusely abnormal white matter (DAWM). Diffusely abnormal white matter, regions with reduced mild MRI hyperintensity and ill-defined boundaries, show reduced myelin water fraction, and decreased Luxol fast blue staining of myelin phospholipids, with relative preservation of myelin basic protein and 2',3'-cyclic-nucleotide 3'-phosphohydrolase. Because DAWM may be important in MS disability and progression, further histologic characterization is warranted. The MRI data were collected on 14 formalin-fixed MS brain samples that were then stained for myelin phospholipids, myelin proteins, astrocytes and axons. Diffusely abnormal white matter showed reduced myelin water fraction (-30%, p < 0.05 for 13 samples). Myelin phospholipids showed the most dramatic and consistent histologic reductions in staining optical density (-29% Luxol fast blue and -24% Weil's, p < 0.05 for 13 and 14 samples,respectively) with lesser myelin protein involvement (-11% myelin-associated glycoprotein, -10% myelin basic protein, -8% myelin-oligodendrocyte glycoprotein, -7% proteolipid protein, -5% 2',3'-cyclic-nucleotide 3'-phosphohydrolase, p < 0.05 for 3, 3, 1, 2, and 3 samples, respectively). Axonal involvement was intermediate. Diffusely abnormal white matter lipid and protein reductions occurred independently. These findings suggest a primary lipid abnormality in DAWM that exceeds protein loss and is accompanied by axonal degeneration. These phenomena may be important in MS pathogenesis and disease progression, which is prominent in individuals with DAWM.

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BACKGROUND AND PURPOSE Multiple sclerosis (MS) diffusely abnormal white matter (DAWM) is a mildly hyperintense magnetic resonance imaging abnormality distinct from typical lesions. Our goal was to investigate the prevalence and natural history of DAWM in a large cohort (n = 348) of relapsing–remitting MS (RRMS) patients. METHODS The presence of DAWM and relationship to changes in T2 burden of disease (BOD), brain volume (brain fractional ratio, BFR), and disability (Expanded Disability Status Scale, EDSS) were investigated at baseline and year 7–8 (long‐term follow‐up, LTF). RESULTS DAWM was present in 25.3% (88 of 348) of patients at baseline. At LTF, DAWM was unchanged in 69.3% (61 of 88), decreased in 28.4% (25 of 88), and increased in 2.3% (2 of 88) of patients. Baseline BOD and change in BOD did not significantly differ between patients with and without DAWM. DAWM was associated with greater reduction in BFR at LTF (P = .038). DAWM and DAWM change did not predict EDSS or EDSS progression. CONCLUSIONS DAWM is present in a quarter of RRMS patients, and rarely increases or develops de novo. DAWM predicts brain atrophy but does not predict physical disability. Because of its posterior periventricular location, further investigation is warranted to evaluate its relationship to other measures of disability, including visual spatial processing and cognitive function.

"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 T(2)-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 T(2)- weighted and proton density sequences. The myelin water fraction (MWF) was obtained by expressing the short T(2) component as a fraction of the total T(2) 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 T(2) component, and axonal reduction.

In the multicenter, randomized, placebo-controlled trial of alternate-day injections of recombinant interferon beta-1b in relapsing-remitting multiple sclerosis (MS), urine specimens were collected periodically from all patients (n = 64) in two of the clinical test sites over the 2 years of the study. Urine specimens were also collected over two consecutive 24-hour periods from 43 patients from a third center. Urine samples were assayed for their content of myelin basic protein-like material (MBPLM), the level of which was correlated with clinical changes, cranial magnetic resonance imaging results, and the development of progressive disease. Concordant changes in creatinine values affected some of the relationships of MBPLM. The level of urinary MBPLM correlated with a chronic progressive course and with the number of lesions and the total lesion area on cranial magnetic resonance images. A rise in the level of urinary MBPLM appeared to antedate the clinical transition from a relapsing-remitting to a chronic progressive course. By chance, the randomized entry of patients led to significant differences in urinary MBPLM levels among the three treatment groups, thus precluding correlation studies of treatment effects. However, the patient group from which 24-hour specimens were collected showed that the patients with relapsing-remitting MS changing to a chronic progressive course, and more specifically, those patients with chronic progressive MS receiving placebo, had the highest values of urinary MBPLM. These findings indicate that urinary MBPLM may offer an objective test and possibly serve as a surrogate marker for detecting or predicting the failure of remission or the transition to a progressive phase of MS.