Mri In Monitoring Treatment Efficacy In Ms Trials

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cMRI-derived end-points have been used as primary and secondary outcome measures for monitoring MS clinical trials (Table 4) (3,4,238-240). In this context, the

Average lesion MD (10"3 mm2/sec) NABT MD (10"3 mm2/sec)

Figure 17 (A) Scatterplot of the correlation between the relative activation of the contralateral primary sensorimotor cortex and average lesion mean diffusivity in nondisabled relap-sing-remitting multiple sclerosis patients during a simple motor task. (B) Scatterplot of the correlation between the relative activation of the contralateral infraparietal sulcus and normal appearing brain tissue average mean diffusivity in nondisabled relapsing-remitting multiple sclerosis patients during a simple motor task.

Average lesion MD (10"3 mm2/sec) NABT MD (10"3 mm2/sec)

Figure 17 (A) Scatterplot of the correlation between the relative activation of the contralateral primary sensorimotor cortex and average lesion mean diffusivity in nondisabled relap-sing-remitting multiple sclerosis patients during a simple motor task. (B) Scatterplot of the correlation between the relative activation of the contralateral infraparietal sulcus and normal appearing brain tissue average mean diffusivity in nondisabled relapsing-remitting multiple sclerosis patients during a simple motor task.

most widely used cMRI measures are those reflecting disease activity (new or enlarged T2 lesion counts, enhancing and new enhancing lesion counts, enhancing lesion volume measurement) and accumulated disease burden (T2 lesion load assessment). Over the past decade, a large number of parallel group, placebo-controlled and baseline versus treatment trials have unambiguously shown the ability of several immunomodulating and immunosuppressive treatments to reduce both MRI-measured inflammation and the consequent increase of accumulated lesion burden in patients with CIS, RRMS, and SPMS (241).

Some trials have also investigated the effect of treatment in preventing the accumulation of T1 black holes (242-245) or the development of brain atrophy (87,115,246-252). In RRMS and SPMS, these studies have consistently shown that the effect, if any, of all the tested treatments in reducing the rate of accumulation of black holes or the rate of development of brain atrophy was moderate at best, even when the same treatment was highly effective on MRI measures of MS activity (253). The situation seems to be different in patients at the earliest clinical stage of MS, where a low dose of IFN beta-1a given subcutaneously once a week has shown to be able to reduce accumulation of brain atrophy by about 30% in two years (87). Nevertheless, even in such patients, as it is the case for those with RRMS and SPMS, the magnitude of the correlation between MRI-detectable inflammation and neurodegeneration remains poor (253), suggesting a mismatch between the two major pathological aspects of the disease since its onset onwards. Two studies have evaluated the effect of glatiramer acetate (GA) (254) and interferon (IFN) beta-1b (255) on the probability of newly formed MS lesions to evolve into chronically T1 hypoin-tense lesions. Although this approach is highly time consuming, it sounds promising for assessing in a relatively short time the ability of a given treatment to alter

Figure 18 Relative cortical activations of the contralateral thalamus and ipsilateral rolandic operculum in right-handed nonfatigued multiple sclerosis patients during the performance of a simple motor task with their clinically unimpaired and fully normal functioning upper right hands in comparison to right-handed fatigued multiple sclerosis patients performing the same task (A). In (B), the correlation between relative activation of the contralateral thalamus and FSS scores in patients is shown. Note that the values of some subjects are negative because they have been scaled to the mean value of the functional magnetic resonance imaging scans of each individual (i.e., values are mean centered). Abbreviation: FSS, Fatigue Severity Scale.

Figure 18 Relative cortical activations of the contralateral thalamus and ipsilateral rolandic operculum in right-handed nonfatigued multiple sclerosis patients during the performance of a simple motor task with their clinically unimpaired and fully normal functioning upper right hands in comparison to right-handed fatigued multiple sclerosis patients performing the same task (A). In (B), the correlation between relative activation of the contralateral thalamus and FSS scores in patients is shown. Note that the values of some subjects are negative because they have been scaled to the mean value of the functional magnetic resonance imaging scans of each individual (i.e., values are mean centered). Abbreviation: FSS, Fatigue Severity Scale.

favorably the mechanisms leading to irreversible tissue loss. New approaches have been suggested to improve the sensitivity of cMRI in detecting disease activity (108) or irreversible tissue loss (3,4,111). TD MRI might be useful to grade the efficacy of experimental treatment on MRI-detectable inflammation (256-258) and to reduce the sample sizes and follow-up periods needed to achieve a given study power (108,259). Although the optimization and standardization across multiple sites and over time of MT sequences might be challenging and long-term longitudinal studies using MT MRI are lacking, MT MRI holds substantial promise to provide good surrogate measures for MS evolution. An International consensus conference of the

Table 4 Schematic Characterization of Magnetic Resonance Imaging-Monitored Trials of Multiple Sclerosis

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