MRI T2 hypointensity of the dentate nucleus is related to ambulatory impairment in multiple sclerosis

https://doi.org/10.1016/j.jns.2005.02.009Get rights and content

Abstract

Objectives

MRI T2 hypointensity in multiple sclerosis (MS) gray matter, suggesting iron deposition, is associated with physical disability, disease course, lesion load, and brain atrophy. Ambulatory dysfunction limits quality of life; however correlation with conventional MRI remains poor.

Methods

Normalized intensity on T2-weighted images was obtained in the basal ganglia, thalamus, red nucleus, and dentate nucleus in 47 MS patients and 15 healthy controls. Brain T1-hypointense and FLAIR-hyperintense lesion volume, third ventricle width, brain parenchymal fraction and timed 25 foot walk (T25FW) were measured in the MS group.

Results

T2 hypointensity was present throughout gray matter in MS vs. controls (all p < 0.01). Dentate T2 hypointensity was the only MRI variable significantly correlated with T25FW (Pearson r = −0.355, p = 0.007) and was also the best MRI correlate of physical disability (EDSS) score in regression modeling (r = −0.463, R2 = 0.223, p = 0.004).

Conclusions

T2 hypointensity is present in subcortical gray matter nuclei in patients with MS vs. normal controls. Dentate nucleus T2 hypointensity is independently related to ambulatory impairment and disability, accounting for more variance than conventional lesion and atrophy measures. This study adds more weight to the notion that T2 hypointensity is a clinically relevant marker of tissue damage in MS.

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

References (60)

  • F. Barkhof

    MRI in multiple sclerosis: correlation with expanded disability status scale (EDSS)

    Mult Scler

    (1999)
  • R. Zivadinov et al.

    Role of MRI in multiple sclerosis I: inflammation and lesions

    Front Biosci

    (2004)
  • A.J. Fabiano et al.

    Thalamic involvement in multiple sclerosis: a diffusion MRI study

    J Neuroimaging

    (2003)
  • J.S. Wolinsky et al.

    Magnetic resonance spectroscopy in multiple sclerosis: window into the diseased brain

    Curr Opin Neurol

    (2002)
  • M. Filippi et al.

    Magnetization transfer magnetic resonance imaging in the assessment of neurological diseases

    J Neuroimaging

    (2004)
  • R. Zivadinov et al.

    Central nervous system atrophy and clinical status in multiple sclerosis

    J Neuroimaging

    (2004)
  • R. Bakshi et al.

    T2 hypointensity in the deep gray matter of patients with multiple sclerosis: a quantitative magnetic resonance imaging study

    Arch Neurol

    (2002)
  • R. Bakshi et al.

    MRI T2 shortening (“black T2”) in multiple sclerosis: frequency, location, and clinical correlation

    NeuroReport

    (2000)
  • B.P. Drayer et al.

    Reduced signal intensity on MR images of the thalamus and putamen in multiple sclerosis: increased iron content?

    AJR Am J Roentgenol

    (1987)
  • T. Nishii et al.

    Reduced signal intensity of T2 weighted MR imaging of thalamus and putamen in multiple sclerosis in Japan

    Rinsho Shinkeigaku

    (2000)
  • Bermel RA, Puli SR, Rudick RA, Weinstock-Guttman B, Fisher E, Munschauer FE, et al., Gray matter MRI T2 hypointensity...
  • J.F. Kurtze

    Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS)

    Neurology

    (1983)
  • J.S. Fischer et al.

    The Multiple Sclerosis Functional Composite Measure (MSFC): an integrated approach to MS clinical outcome assessment. National MS Society Clinical Outcomes Assessment Task Force

    Mult Scler

    (1999)
  • S.R. Schwid et al.

    Quantitative functional measures in MS: what is a reliable change?

    Neurology

    (2002)
  • B.G. Vickrey et al.

    A health-related quality of life measure for multiple sclerosis

    Qual Life Res

    (1995)
  • S.L. Hauser et al.

    Intensive immunosuppression in progressive multiple sclerosis: a randomized three-arm study of high-dose cyclophosphamide, plasma exchange, and ACTH

    N Engl J Med

    (1983)
  • R.A. Rudick et al.

    The multiple sclerosis functional composite: a new clinical outcome measure for multiple sclerosis trials

    Mult Scler

    (2002)
  • D.E. Goodkin et al.

    Comparing the ability of various compositive outcomes to discriminate treatment effects in MS clinical trials. The Multiple Sclerosis Collaborative Research Group (MSCRG)

    Mult Scler

    (1998)
  • N.F. Kalkers et al.

    Concurrent validity of the MS Functional Composite using MRI as a biological disease marker

    Neurology

    (2001)
  • N.F. Kalkers et al.

    Optimizing the association between disability and biological markers in MS

    Neurology

    (2001)
  • Cited by (101)

    • Chemical Elements and Oxidative Status in Neuroinflammation

      2017, Biometals in Neurodegenerative Diseases: Mechanisms and Therapeutics
    View all citing articles on Scopus
    View full text