Magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), and whole brain NAA measurements provide information on the integrity of normal-appearing brain tissue. The relationships between atrophy and whole brain measures of tissue integrity have not been as extensively studied as the relationship between atrophy and lesions. Decreased MTR is mainly due to demyelination, axonal loss, and diffuse abnormalities in the normal-appearing white matter (Brochet and Dousset, 1999), which are the same factors believed to be responsible for atrophy. Various MTR parameters, including mean MTR; histogram peak height; and first, second, and third MTR histogram quar-tiles, have been shown to be significantly correlated to central slab volume (r = 0.4 to 0.5) (Rovaris et al., 1999). Mean MTR in normal-appearing brain tissue is correlated in cross-section with whole brain atrophy (Richert et al., 2001; Traboulsee et al., 2001; Kalkers et al., 2002). These correlations with atrophy are relatively strong (r = 0.6 to 0.7) compared to correlations with lesions, which is consistent with the hypothesis that both MTR and atrophy are sensitive to diffuse damage in normal-appearing tissue and possibly have common pathological substrates.
DTI and whole brain NAA are other MR methods for measurement of damage in normal-appearing brain tissue. Demyelination and damage to axons lead to alterations in the properties of random water diffusion in brain tissue that can be detected with DTI (Werring et al., 1999). Whole brain NAA is a relatively new MR proton spectroscopy technique that provides an estimate of the total amount of the neuronal injury in the brain (Gonen et al., 2002). A few studies have shown that measures of diffuse tissue damage are correlated with atrophy in cross-section (Phillips et al., 1998; Kalkers, 2002), but their predictive value for subsequent tissue loss has not been studied extensively. Lesions only account for a relatively small amount of variance in subsequent atrophy (Fisher et al., 2002; therefore, diffuse tissue damage in the normal-appearing brain tissue measurable with MTR, DTI, and/or whole brain NAA may account for a substantial portion of brain atrophy. Additional longitudinal studies are needed to clarify the relationship between diffuse tissue damage and atrophy in MS patients.
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