MRI T2 hypointensity of the dentate nucleus is related to ambulatory impairment in multiple sclerosis
Introduction
While conventional MRI measures have demonstrated efficacy in the diagnosis and longitudinal monitoring of patients with multiple sclerosis (MS), these conventional measures, primarily white matter lesion assays, correlate poorly with clinical measures of physical disability, disease activity and disease progression [1], [2]. As neuroimaging technology matures, improvements to both scanning and analysis platforms have produced advanced MRI-based measures with improved sensitivity and specificity relative to conventional measures [2], [3], [4], [5], [6], [7]. These advanced measures, which include diffusion weighted imaging [2], [4], [5], magnetic resonance spectroscopy [2], [6], and magnetization transfer imaging [2], [7] have revealed a more widespread disease process extending beyond overt white matter lesions and, in turn, improved clinical-imaging correlation [2]. MRI measurement of CNS atrophy has also emerged as a particularly powerful tool to assess the continuously destructive disease process in MS, showing better clinical predictive value than conventional lesion assessments [2], [8].
T2 hypointensity in the gray matter is another innovative MRI measure of disease that is related to physical disability, disease course, and brain atrophy in cross-sectional MS studies [9], [10], [11], [12], [13] and is predictive of atrophy that will occur subsequently [14]. Abnormal T2 hypointensity, thought to represent iron deposition [12], can be found in the cerebral cortex, basal ganglia, and thalamus of MS patients [9], [10], [11], [12], [13]. While abnormal in MS patients in comparison to age-matched controls [9], [10], [11], it is not as yet clear whether T2 hypointensity is a disease epiphenomenon, contributes to pathogenesis or whether it has a role as a surrogate marker of disease progression.
Advances in structural imaging have been paralleled by development of more sensitive clinical measures of disease progression. In addition to the standard ordinal rating system of Kurtzke—the Expanded Disability Status Scale (EDSS) [15], newer measures of neurologic disability, such as the MS Functional Composite (MSFC), have been proposed as advantageous due their continuous and quantitative nature [16], [17]. Both of these measures incorporate assessment of ambulatory dysfunction, perhaps the most debilitating aspect of MS regarding quality of life [18]. The MSFC directly measures ambulatory function with the timed 25 foot walk (T25FW). The T25FW is an evolved version of the ambulatory index (AI) [19], using a continuous rather than ordinal scale. T25FW has efficacy in distinguishing treatment effects in MS [20], but correlates poorly with conventional MRI findings [21], [22]. T25FW has been shown to correlate weakly with MRI calculated brain atrophy [23]. A stronger clinical-MRI correlation has been seen with the parent MSFC [22].
The purpose of this study was to: (1) determine if the dentate nucleus is a site of T2 hypointensity in patients with MS vs. age-matched normal controls. This seemed plausible due to the avidity of the dentate nucleus for iron in normal aging [24] and our suspicion that this process is accelerated in MS, (2) evaluate the relationship between T2 hypointensity in the dentate and clinical impairment—we focused on the dentate given its anatomic relationship with ambulation [25], (3) parcel out the independent contribution of T2 hypointensity towards explaining the variance in clinical impairment by adjusting for the effect of conventional MRI lesion and atrophy measurements.
Section snippets
Patients
Forty-seven patients with MS meeting McDonald criteria [26] were consecutively imaged on the same MRI scanner using the same pulse sequences. Patient characteristics are summarized in Table 1. Patients were clinically evaluated at a University-affiliated MS clinic for this cross-sectional study. The cohort was limited to patients with age between 20 and 60 years old (mean ± S.D. age 42.39 ± 8.49 years, 32 females or 68%). Patients were excluded if they had other major medical illnesses,
Results
T2 hypointensity was more prominent in MS vs. controls in all of the gray matter ROIs (Fig. 2), as follows: caudate nucleus (MS: 0.390 ± 0.05; NL: 0.470 ± 0.085; 18% decrease in MS vs. controls; p < 0.001), dentate nucleus (MS: 0.295 ± 0.036; NL: 0.351 ± 0.068; 16% decrease; p < 0.001), globus pallidus (MS: 0.260 ± 0.034; NL: 0.306 ± 0.056; 15% decrease; p = 0.001), putamen (MS: 0.328 ± 0.043; NL: 0.389 ± 0.071; 16% decrease; p < 0.01), red nucleus (MS: 0.271 ± 0.035; NL: 0.314 ± 0.054; 13% decrease; p = 0.002), and
Discussion
Dentate T2 hypointensity was present in MS patients as compared to normal controls. As pathological iron deposition has been implicated as a cause of gray matter T2 hypointensity in MS [12], this study suggests that iron deposition occurs in the gray matter nuclei of the cerebellum. Dentate T2 hypointensity was also found to be most closely associated with ambulatory dysfunction and EDSS score, independent of all other MRI measures. Thus, T2 hypointensity in the dentate nucleus may reflect
Acknowledgments
Supported by research grants from the National Institutes of Health (NIH-NINDS 1 K23 NS42379-01, R. Bakshi), National Multiple Sclerosis Society (RG 3258A2/1, B. Weinstock-Guttman, R. Bakshi), and National Science Foundation (DBI-0234895, B. Weinstock-Guttman, R. Bakshi). We thank Jin Kuwata, Robert Bermel and Jitendra Sharma for technician support and Mark Horsfield, PhD for developing and installing neuroimaging analysis software. This work was presented in preliminary form at the 2003 annual
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