Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS

Zivadinov, Robert; Rudick, Richard A.; Masi, Roberto De; Nasuelli, Davide; Ukmar, Maja; Mucelli, Roberto Pozzi; Grop, Attilio; Cazzato, Giuseppe; Zorzon, Marino

doi:10.1212/wnl.57.7.1239

Cited by 327 publications

(255 citation statements)

References 48 publications

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“…T2-lesion volume was calculated by using a reliable semiautomated edge-detection contouring/thresholding technique previously described. 28 With FMRIB's Linear Image Registration Tool software (FMRIB; http://www.fmrib.ox. ac.uk/), 29 all follow-up FLAIR images for a given subject were coregistered to his or her baseline FLAIR image by using a 6 df rigid-body model.…”

Section: Methodsmentioning

confidence: 99%

Evolution of Cortical and Thalamus Atrophy and Disability Progression in Early Relapsing-Remitting MS during 5 Years

Zivadinov

Bergsland

Doležal³

et al. 2013

AJNR Am J Neuroradiol

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Section: Methodsmentioning

confidence: 99%

Evolution of Cortical and Thalamus Atrophy and Disability Progression in Early Relapsing-Remitting MS during 5 Years

Zivadinov

Bergsland

Doležal³

et al. 2013

AJNR Am J Neuroradiol

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“…T2 and gadolinium lesion volumes were calculated for both the CIS and RRMS groups by using a reliable contouring-thresholding technique, as previously described. 22,23,25 T2 and gadolinium lesion numbers were also obtained in the CIS group only. Before we used the T1-weighted 3D spoiled gradient-recalled for subsequent analysis, it was modified by using an in-house-developed in-painting technique to avoid the impact of WM lesions on GM volume measurements 26 as previously described.…”

Section: Mr Imaging Methodsmentioning

confidence: 99%

Subcortical and Cortical Gray Matter Atrophy in a Large Sample of Patients with Clinically Isolated Syndrome and Early Relapsing-Remitting Multiple Sclerosis

Bergsland

Horáková²,

Dwyer

et al. 2012

AJNR Am J Neuroradiol

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141

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BACKGROUND AND PURPOSE:Recent studies have shown that selective regional, but not global, GM atrophy occurs from clinical onset to conversion to clinically definite MS. Our aim was to investigate the difference in the extent of SDGM and cortical atrophy in a large sample of patients with CIS and early RRMS and to explore the relationship between SDGM and cortical atrophy and other MR imaging and clinical outcomes. MATERIALS AND METHODS:Two hundred twelve patients with CIS recruited at the first clinical event (mean age, 29.3 years; median EDSS, 1.5; median disease duration, 3 months) and 177 patients with early RRMS (mean age, 30.7 years; median EDSS, 2.0; median disease duration, 47 months) were imaged on a 1.5T scanner by using a high-resolution 3D T1 spoiled gradient-recalled sequence. Volumetric data for SDGM structures were obtained by using FSL FIRST, while whole-brain, GM, white matter, cortical, and lateral ventricle volumes were estimated by using SIENAX software. Comparisons between the groups were adjusted for age and sex. RESULTS:Patients with early RRMS showed significantly lower SDGM but not cortical volumes compared with patients with CIS. The most apparent SDGM differences were evident in the caudate and thalamus (P Ͻ .0001), total SDGM (P ϭ .0001), and globus pallidus (P ϭ .01). Patients with CIS with a median T2 lesion volume Ͼ4.49 mL showed lower total SDGM, caudate, thalamus (P Ͻ .001), globus pallidus (P ϭ .007), hippocampus (P ϭ .004), and putamen (P ϭ .01) volumes and higher lateral ventricle volume (P ϭ .001) than those with a median T2 lesion volume Ͻ4.49 mL. Decreased thalamic volume showed the most consistent relationship with MR imaging outcomes (P Ͻ .0001) in patients with CIS.CONCLUSIONS: Significant SDGM, but not cortical, atrophy develops during the first 4 years of the RRMS. GM atrophy is relevant for disease progression from the earliest clinical stages.ABBREVIATIONS: ASA ϭ Avonex-Steroid-Azathioprine; CIS ϭ clinically isolated syndrome; EDSS ϭ Expanded Disease Status Scale; FSL ϭ FMRIB Software Library; GM ϭ gray matter; NBV ϭ normalized brain volume; NCV ϭ normalized cortical volume; NGMV ϭ normalized gray matter volume; NLVV ϭ normalized lateral ventricle volume; NWMV ϭ normalized white matter volume; RRMS ϭ relapsing remitting MS; SDGM ϭ subcortical deep gray matter; SET ϭ Study of Early Interferon ␤ 1a Treatment in High Risk Subjects after CIS M R imaging is a vital tool enabling clinicians to diagnose, monitor, and predict the progression of MS. Conventional MR imaging has proved to be very sensitive for detecting focal changes in the WM, yet it is relatively insensitive to involvement of the GM in MS. GM pathology in MS is quite different from that in WM, with only mild blood-brain barrier disruption and little-to-no inflammation due to minimal Tcell infiltration.1 Hence, the difference between lesion and normal GM relaxation times on MR imaging is less than that seen between lesion and normal white matter. 2In the past decade, continuous effort has been made to develop n...

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“…MP or other GCs are effective in treating white (Zivadinov et al, 2001;Chataway et al, 2006), but not gray (Edwards et al, 2005;Diener et al, 2008), matter diseases. Epo has similar effects in SCI (Gorio et al, 2002;Vitellaro-Zuccarello et al, 2007) and the white matter diseases (Li et al, 2004).…”

Section: Mp Upregulation Of Epo Expression In Olgs But Not Cortical Nmentioning

confidence: 99%

“…Glucocorticoids (GCs), primarily methylprednisolone (MP), are the mainstay in treating patients with diseases affecting the white matter, including MS and SCI (Bracken et al, 1990;Zivadinov et al, 2001;Chataway et al, 2006). GCs regulate transcriptional events by activating glucocorticoid receptor (GR), which binds to glucocorticoid response element (GRE) or interacts with other transcription factors to regulate gene expression (Becker et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid Protection of Oligodendrocytes against Excitotoxin Involving Hypoxia-Inducible Factor-1 in a Cell-Type-Specific Manner

Sun¹,

Wang²,

Hsu³

et al. 2010

Journal of Neuroscience

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Glucocorticoids are commonly used in treating diseases with white matter lesions, including demyelinating diseases and spinal cord injury (SCI). However, glucocorticoids are ineffective in gray matter injuries, such as head injury and stroke. The differential glucocorticoid effects in white and gray matter injuries are unclear. We report here a novel mechanism of methylprednisolone (MP), a synthetic glucocorticoid widely used for treating multiple sclerosis and SCI, in protecting oligodendrocytes (OLGs) against AMPA-induced excitotoxicity, which has been implicated in the white matter injuries and diseases. The cytoprotective action of MP in OLGs is causally related to its upregulation of a neuroprotective cytokine erythropoietin (Epo). MP transactivation of Epo expression involves dual transcription factors: glucocorticoid receptor (GR) and hypoxia-inducible factor-1␣ (HIF-1␣). Coimmunoprecipitation, chromatin immunoprecipitation analysis, yeast two-hybrid analysis, and structure modeling of three-dimensional protein-protein interactions confirm that MP induces interaction between GR DNA binding domain and HIF-1␣ PAS domain, with subsequent recruitment of HIF-1␤ to transactivate Epo expression in OLGs. In contrast, MP activates GR but does not induce GR-HIF-1␣ interaction, HIF-1␣ binding to Epo enhancer/ promoter, or Epo expression in cultured cortical neurons. The OLG-specific GR-HIF-1␣ transactivation of Epo provides novel insights into the development of more effective therapies for diseases affecting the white matter.

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Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS

Abstract: In patients with RR-MS, treatment with pulses of IVMP slows development of T1 black holes, prevents or delays whole-brain atrophy, and prevents or delays disability progression. A phase III study of IVMP pulses is warranted.

Cited by 327 publications

References 48 publications

Evolution of Cortical and Thalamus Atrophy and Disability Progression in Early Relapsing-Remitting MS during 5 Years

Evolution of Cortical and Thalamus Atrophy and Disability Progression in Early Relapsing-Remitting MS during 5 Years

Subcortical and Cortical Gray Matter Atrophy in a Large Sample of Patients with Clinically Isolated Syndrome and Early Relapsing-Remitting Multiple Sclerosis

Glucocorticoid Protection of Oligodendrocytes against Excitotoxin Involving Hypoxia-Inducible Factor-1 in a Cell-Type-Specific Manner

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