Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy

Abstract

Background and purpose: The mechanisms behind the demyelination that is characteristic of multiple sclerosis (MS) are still poorly understood. The purpose of this study was to compare immunopathologic findings in demyelinating lesions of three patients with in vivo assessments obtained by quantitative proton MR spectroscopy (MRS).

Methods: Between four and seven stereotactic needle brain biopsies were performed in three young adults with diagnostically equivocal findings for MS. Axonal density, gliosis, blood brain-barrier breakdown, and demyelinating activity of lesions were determined. Combined MR/MRS studies were performed (T1-weighted fast low-angle shot and single-voxel stimulated-echo acquisition mode), and absolute metabolite levels were obtained with a user-independent fitting routine. Metabolite control values were obtained from a group of age-matched healthy volunteers (n = 40, age range, 20-25 years old). Alterations of metabolite levels of control subjects were considered significant when exceeding two standard deviations.

Results: There were parallel decreases of N-acetylaspartate (21%-82%) and reductions of axonal density (44%-74%) in demyelinating plaques. Concomitant increases of choline (75%-152%) and myo-inositol (84%-160%) corresponded to glial proliferation. Elevated lactate was associated with inflammation.

Conclusion: The present data suggest that in vivo MRS indicates key pathologic features of demyelinating lesions.

fig 1.

Bielschowsky's silver impregnation shows axonal density in the normal periplaque white matter (patient 1) (A), a reduction by 45% (patient 3) (B), and a reduction by 75% (patient 1) (C) within the plaques (magnification for all, ×166). Prominent protoplasmic gliosis with large astrocytes (D) is seen by immunocytochemistry for GFAP (patient 1). Numerous GFAP-positive cell processes (E) indicate fibrillary gliosis (patient 3). Immunocytochemistry for MOG (F) shows an early active demyelinating lesion (patient 2). Macrophages carry MOG-positive degradation products in their cytoplasm. Dense macrophage infiltrate (G) is seen in the same lesion as shown in F (immunocytochemistry for Ki-MlP)

fig 2.

T1-weighted gradient-echo MR images (3D fast low-angle shot, 4-mm partitions, 15/6 TR/TE, 20° flip angle) of patient 1 indicating VOIs selected for MRS. A, Transverse section with VOIs centered at the left parieto-occipital lesion (20 × 20 × 20 mm³) and in a contralateral control region (16 × 30 × 16 mm³). B, Sagittal section with a smaller VOI (16 × 16 × 16 mm³) encompassing the same lesion (note small defect in the skull and corresponding biopsy canal), C, Coronal section depicting an ipsilateral VOI (20 × 20 × 20 mm³) in left frontoparietal cortex unsuspicious at MR imaging.

fig 3.

Localized proton MR spectra (stimulated-echo acquisition mode, 3000/20/30 [TR/TE/TM]) of patient 1 from locations indicated in figure 2. Left occipitoparietal lesion (top) image using a 4-mL VOI and (second row) 8-mL VOI, an ipsilateral 8-mL VOI in unsuspicious left frontoparietal cortex (third row), and contralateral control (bottom). Major resonances are due to N-acetylaspartate (NAA), creatine and phosphocreatine (Cr), choline-containing compounds (Cho), myo-inositol (Ins), and lactate (Lac). Spectra are normalized for comparison