Enhanced Axonal Metabolism during Early Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis

Wiebenga, Oliver T.; Klauser, Antoine; Schoonheim, Menno M.; Nagtegaal, G. J. A.; Steenwijk, Martijn D.; Rossum, J.A. van; Polman, Chris H.; Barkhof, Frederik; Pouwels, Petra J. W.; Geurts, Jeroen J. G.

doi:10.3174/ajnr.a4252

Cited by 16 publications

(22 citation statements)

References 35 publications

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“…While this was the only statistically significant metabolite change, there was also a statistical trend for NAA increase in moderately hypointense lesions. With this caveat, we note that findings of increasing NAA in lesions and NAWM can be attributed to medication [Khan et al, ; Narayanan et al, ; Wiebenga et al, ], and therefore it can be speculated that our results suggest such an effect, but only in moderately hypointense lesions.…”

Section: Discussionsupporting

confidence: 86%

Proton MR spectroscopy of lesion evolution in multiple sclerosis: Steady‐state metabolism and its relationship to conventional imaging

Kirov

Liu

Tal

et al. 2017

Human Brain Mapping

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Although MRI assessment of white matter lesions is essential for the clinical management of multiple sclerosis, the processes leading to the formation of lesions and underlying their subsequent MRI appearance are incompletely understood. We used proton MR spectroscopy to study the evolution of N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho) and myo-inositol (mI) in pre-lesional tissue, persistent and transient new lesions, as well as in chronic lesions, and related the results to quantitative MRI measures of T1-hypointensity and T2-volume. Within 10 patients with relapsing-remitting course, there were 180 regions-of-interest consisting of up to seven semi-annual follow-ups of normal-appearing white matter (NAWM, n=10), pre-lesional tissue giving rise to acute lesions which resolved (n=3) or persisted (n=3), and of moderately (n=9) and severely hypointense (n=6) chronic lesions. Compared to NAWM, pre-lesional tissue had higher Cr and Cho, while compared to lesions, pre-lesional tissue had higher NAA. Resolving acute lesions showed similar NAA levels pre- and post-formation, suggesting no long-term axonal damage. In chronic lesions, there was an increase in mI, suggesting accumulating astrogliosis. Lesion volume was a better predictor of axonal health than T1-hypointensity, with lesions larger than 1.5 cm3 uniformly exhibiting very low (<4.5 millimolar) NAA concentrations. A positive correlation between longitudinal changes in Cho and in lesion volume in moderately hypointense lesions implied that lesion size is mediated by chronic inflammation. These and other results are integrated in a discussion on the steady state metabolism of lesion evolution in multiple sclerosis, viewed in the context of conventional MRI measures.

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Section: Discussionsupporting

confidence: 86%

Proton MR spectroscopy of lesion evolution in multiple sclerosis: Steady‐state metabolism and its relationship to conventional imaging

Kirov

Liu

Tal

et al. 2017

Human Brain Mapping

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“…Whether the observed stabilization of GM damage is due to a neuroprotective effect of natalizumab deserves further investigation in appropriately designed studies. Some studies have already pointed to this hypothesis using MRI 32,33 , with recent studies using spectroscopy showing that natalizumab increases the levels of N-acetylaspartate, creatine and phosphocreatine, maybe indicating an enhanced axonal metabolism in natalizumabtreated patients 34 and reduction of WM damage during the first year of treatment using diffusion tensor imaging 35 . Finally, body fluid biomarkers in a progressive MS study with patients treated with natalizumab also showed a reduction in intrathecal inflammation (decreased levels of osteopontin) accompanied by decreases in other markers of neurodegeneration (neurofilament light chain) and tissue damage (increases in MTR in cortical GM and normal-appearing WM) 36 .…”

Section: Discussionmentioning

confidence: 99%

Grey matter atrophy is associated with disability increase in natalizumab-treated patients

et al. 2016

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“…In addition to the clinical benefits of natalizumab therapy seen in phase III studies of patients with relapsing forms of MS [Polman et al 2006;Rudick et al 2006], other studies have revealed evidence of enhanced tissue integrity and improved axonal metabolism in some natalizumab-treated RRMS patients, suggesting that reducing inflammation may enable endogenous repair mechanisms to take place during natalizumab therapy [Fox et al 2011;Wiebenga et al 2015]. While it is unclear whether or to what extent this may be pertinent in SPMS, it is encouraging that natalizumab treatment improved magnetization transfer ratios in the cerebral cortex and normal-appearing white matter of SPMS/ PPMS patients [Romme Christensen et al 2014].…”

Section: Discussionmentioning

confidence: 99%

Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis

Sellebjerg

Cadavid

Steiner

et al. 2015

Ther Adv Neurol Disord

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Multiple sclerosis (MS) is a common and chronic central nervous system (CNS) demyelinating disease and a leading cause of permanent disability. Patients most often present with a relapsing-remitting disease course, typically progressing over time to a phase of relentless advancement in secondary progressive MS (SPMS), for which approved disease-modifying therapies are limited. In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS. In both forms of MS, active brain-tissue injury is associated with inflammation; but in SPMS, the inflammatory response occurs at least partly behind the blood-brain barrier and is followed by a cascade of events, including persistent microglial activation that may lead to chronic demyelination and neurodegeneration associated with irreversible disability. In patients with relapsing forms of MS, natalizumab therapy is known to significantly reduce intrathecal inflammatory responses which results in reductions in brain lesions and brain atrophy as well as beneficial effects on clinical measures, such as reduced frequency and severity of relapse and reduced accumulation of disability. Natalizumab treatment also reduces levels of cerebrospinal fluid chemokines and other biomarkers of intrathecal inflammation, axonal damage and demyelination, and has demonstrated the ability to reduce innate immune activation and intrathecal immunoglobulin synthesis in patients with MS. The efficacy of natalizumab therapy in SPMS is currently being investigated in a randomized, double-blind, placebo-controlled trial.

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Enhanced Axonal Metabolism during Early Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis

Cited by 16 publications

References 35 publications

Proton MR spectroscopy of lesion evolution in multiple sclerosis: Steady‐state metabolism and its relationship to conventional imaging

Proton MR spectroscopy of lesion evolution in multiple sclerosis: Steady‐state metabolism and its relationship to conventional imaging

Grey matter atrophy is associated with disability increase in natalizumab-treated patients

Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis

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