MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS

Miller, David H.; Soon, Derek; Fernando, Kryshani; MacManus, David; Barker, Gareth J.; Yousry, Tarek; Fisher, Elizabeth; O’Connor, Paul; Phillips, J. Theodore; Polman, Chris H.; Kappos, Ludwig; Hutchinson, Michael; Havrdová, Eva; Lublin, Fred; Giovannoni, Gavin; Wajgt, A; Rudick, Richard A.; Lynn, F; Panzara, Michael A.; Sandrock, Alfred

doi:10.1212/01.wnl.0000260064.77700.fd

Cited by 310 publications

(235 citation statements)

References 23 publications

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“…In the patients receiving natalizumab, this finding might be caused by the well-known pseudoatrophy effect, in which the anti-inflammatory effect of natalizumab reduces the edema during the first 12 months of treatment. 9,29,30 Clinically, natalizumab appeared to stabilize EDSS scores and reduce symptoms of depression, as observed in our data. No effect on cognitive functioning was found in this study.…”

Section: Discussionsupporting

confidence: 86%

White Matter Diffusion Changes during the First Year of Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis

Wiebenga¹,

Schoonheim²,

Hulst³

et al. 2016

AJNR Am J Neuroradiol

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Section: Discussionsupporting

confidence: 86%

White Matter Diffusion Changes during the First Year of Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis

Wiebenga¹,

Schoonheim²,

Hulst³

et al. 2016

AJNR Am J Neuroradiol

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“…149 In the phase III placebo-controlled natalizumab trial in patients with RRMS, the patients receiving active therapy had a higher rate of brain volume loss in the first year than patients receiving a placebo, whereas the opposite was seen in the second year. 146 Similarly, in patients receiving autologous hematopoietic stem cell transplantation, a faster rate of brain volume loss was observed in the first few months than in the pre-treatment period. 147 However, subsequently, the treatment appears to slow the rate of atrophy.…”

Section: Brain Atrophymentioning

confidence: 96%

“…145 Atrophy measures are being incorporated into studies that explore the efficacy and safety of novel MS therapies. New data have emerged from natalizumab, 146 autologous hematopoietic stem cell transplantation, 147,148 and testosterone. 149 In the phase III placebo-controlled natalizumab trial in patients with RRMS, the patients receiving active therapy had a higher rate of brain volume loss in the first year than patients receiving a placebo, whereas the opposite was seen in the second year.…”

Section: Brain Atrophymentioning

confidence: 99%

MRI in Multiple Sclerosis: What’s Inside the Toolbox?

et al. 2007

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Summary: Magnetic resonance imaging (MRI) has played a central role in the diagnosis and management of multiple sclerosis (MS). In addition, MRI metrics have become key supportive outcome measures to explore drug efficacy in clinical trials. Conventional MRI measures have contributed to the understanding of MS pathophysiology at the macroscopic level yet have failed to provide a complete picture of underlying MS pathology. They also show relatively weak relationships to clinical status such as predictive strength for clinical progression. Advanced quantitative MRI measures such as magnetization transfer, spectroscopy, diffusion imaging, and relaxometry techniques are somewhat more specific and sensitive for underlying pathology. These measures are particularly useful in revealing diffuse damage in cerebral white and gray matter and therefore may help resolve the dissociation between clinical and conventional MRI findings. In this article, we provide an overview of the array of tools available with brain and spinal cord MRI technology as it is applied to MS. We review the most recent data regarding the role of conventional and advanced MRI techniques in the assessment of MS. We focus on the most relevant pathologic and clinical correlation studies relevant to these measures.

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“…Some studies have reported no significant, or conflicting, effects of DMTs on brain atrophy (Bermel & Bakshi, 2006; Calabrese et al., 2012; Lublin et al., 2016; Tiberio et al., 2005). Others have reported statistically significant slowing of brain atrophy, but only after 24 months or more (Cohen et al., 2012; Coles et al., 2012; Kappos et al., 2010; Mattioli, Stampatori, Bellomi, Scarpazza, & Capra, 2015; Miller et al., 2007; Rinaldi et al., 2012). Brain atrophy is considered predictive of progression in cognitive and/or motor disability (Bermel & Bakshi, 2006; Deloire et al., 2011; Morgen et al., 2006), emphasizing a need for early intervention to prevent brain atrophy and forestall the advance of disability.…”

Section: Introductionmentioning

confidence: 99%

Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

et al. 2018

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IntroductionProgressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairment has been observed in 40%–70% of MS patients and has been linked to GM atrophy. In a phase 2 trial of estriol treatment in women with relapsing–remitting MS (RRMS), higher estriol levels correlated with greater improvement on the paced auditory serial addition test (PASAT) and imaging revealed sparing of localized GM in estriol‐treated compared to placebo‐treated patients. To better understand the significance of this GM sparing, the current study explored the relationships between the GM sparing and traditional MRI measures and clinical outcomes.MethodsSixty‐two estriol‐ and forty‐nine placebo‐treated RRMS patients underwent clinical evaluations and brain MRI. Voxel‐based morphometry (VBM) was used to evaluate voxelwise GM sparing from high‐resolution T1‐weighted scans.ResultsA region of treatment‐induced sparing (TIS) was defined as the areas where GM was spared in estriol‐ as compared to placebo‐treated groups, localized primarily within the frontal and parietal cortices. We observed that TIS volume was directly correlated with improvement on the PASAT. Next, a longitudinal cognitive disability‐specific atlas (DSA) was defined by correlating voxelwise GM volumes with PASAT scores, that is, areas where less GM correlated with less improvement in PASAT scores. Finally, overlap between the TIS and the longitudinal cognitive DSA revealed a specific region of cortical GM that was preserved in estriol‐treated subjects that was associated with better performance on the PASAT.ConclusionsDiscovery of this region of overlap was biology driven, not based on an a priori structure of interest. It included the medial frontal cortex, an area previously implicated in problem solving and attention. These findings indicate that localized GM sparing during estriol treatment was associated with improvement in cognitive testing, suggesting a clinically relevant, disability‐specific biomarker for clinical trials of candidate neuroprotective treatments in MS.

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MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS

Abstract: Natalizumab has a sustained effect in preventing the formation of new lesions in patients with relapsing multiple sclerosis.

Cited by 310 publications

References 23 publications

White Matter Diffusion Changes during the First Year of Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis

White Matter Diffusion Changes during the First Year of Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis

MRI in Multiple Sclerosis: What’s Inside the Toolbox?

Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

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