Measures of atrophy are more closely related to neurological disability in patients with MS than conventional lesion measurements (Table 2). The strength of the correlations depends on the type of atrophy measure, type of disability measure, and possibly, type of MS. In cross-section, correlations between Expanded Disability Status Scale (EDSS) and brain atrophy are typically modest (r = 0.2 to 0.5) (Liu et al., 1999; Kalkers et al., 2001; Rudick et al., 1999; Paolillo et al., 2000; Ge et al., 2000b; Molyneux et al., 2000; Stevenson et al., 1999), while correlations between EDSS and spinal cord atrophy are stronger (r = 0.5 to 0.7) (Losseff et al., 1996b; Lycklama et al., 1998; Stevenson et al., 1999). This may be related to characteristics of the EDSS, which is primarily a measure of ambulation. Correlations between brain atrophy and the MS Functional Composite (MSFC) (Rudick et al., 1997; 2001) are stronger than the atrophy/EDSS correlations (Kalkers et al., 2001; Fisher et al., 2001). The MSFC consists of a walking score (timed 25-meter walk), an arm function score (9-hole peg test), and a cognitive score (paced serial addition test).
By comparison of results across studies, normalized atrophy measures, which correct for head size, appear to be more strongly correlated to disability than absolute volume measurements. Several longitudinal studies indicate that patients with greater rates of atrophy are more likely to worsen clinically (Losseff et al., 1996a; Molyneux et al., 2000; Fisher et al., 2002) and vice versa (Fisher et al., 2000). In an 8-year follow-up study of 172 patients originally enrolled in the Phase III trial of IFNP-1a in RR-MS, 52% of patients in the quartile with the highest rate of atrophy in the first 2 years had reached an EDSS score of 6 or greater at the 8-year follow-up. In contrast, only 12% of patients in the quartile with the lowest rate of atrophy in the first 2 years had reached an EDSS score of 6 or greater at the time of follow-up visit (Fisher et al., 2002). As with the relationships between atrophy and lesions, the relationship between atrophy and disability may be complicated by a possible time lag between when tissue injury occurs and when this injury is detectable as atrophy on MRI. Furthermore, the brain may be able to compensate for tissue injury early in the disease when there is still sufficient functional reserve and capacity for tissue repair, leading to a dissociation between atrophy and disability. Data demonstrating higher atrophy-disability correlations later on in the disease or in SP-MS as compared to RR-MS support this hypothesis (Ge et al., 2000b; Fisher et al., 2000).
Brain atrophy has also been shown to be related to cognitive impairment (Rao et al., 1985; Edwards et al., 2001; Hohol et al., 1997) in MS patients. An early study of patients with chronic progressive MS (Rao et al., 1985) demonstrated that performance on memory and intelligence tests was correlated to degree of ventricle enlargement. In patients monitored for more than 1 year, cognitive change was related to baseline normalized brain atrophy measures (Hohol et al., 1997).
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