Elsevier

NeuroImage

Volume 56, Issue 1, 1 May 2011, Pages 21-26
NeuroImage

Magnetisation transfer ratio in optic neuritis is associated with axonal loss, but not with demyelination

https://doi.org/10.1016/j.neuroimage.2011.02.041Get rights and content

Abstract

Background

Pathophysiological basis of Magnetisation Transfer Ratio (MTR) reduction in multiple sclerosis still remains a matter of controversy. Optic nerve represents an ideal model to study the consequences of axonal loss and demyelination on MTR since effects of disease on the optic nerve are clinically apparent and potentially quantifiable by objective means. By measuring the latency of multifocal visual evoked potentials (mfVEP) (measure of optic nerve conduction) and Retinal Nerve Fiber Layer (RNFL) thickness (measure of axonal damage) we investigated the effect of neurodegeneration and demyelination on MTR after an episode of optic neuritis (ON).

Methods

23 patients with a single unilateral episode of ON and 10 healthy volunteers were enrolled. Orbital MRI including MTR protocol, Optical Coherence Tomography and Multifocal VEP were performed at post-acute stage of ON.

Results

Average MTR of affected eye was significantly reduced as compared to the fellow eye and normal controls. There was a highly significant correlation between MTR and measures of axonal loss (RNFL thickness and mfVEP amplitude), which was independent on the level of demyelination. While latency delay also correlated significantly with MTR, correlation became non-significant when adjusted for the degree of axonal loss. There was a significant reduction of MTR in a group of patients with extensive axonal damage, while MTR remained normal in a group of patients with extensive demyelination, but little or no axonal loss.

Conclusion

Results of this study indicate that reduction of optic nerve MTR after an episode of ON has a strong association with the degree of axonal damage, but not with demyelination.

Research highlights

► Pathophysiological basis of Magnetisation Transfer Ratio reduction in MS uncertain. ► Optic neuritis is an ideal model to study MTR, axonal loss and demyelination in MS. ► Latency delay of multifocal VEP is a marker of optic nerve demyelination. ► RNFL thinning is a marker of optic nerve axonal loss. ► MTR reduction is related to RNFL thinning, but not to latency delay of multifocal VEP.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system (CNS). It is a leading cause of non traumatic neurological disability in young adults in developed countries. Approximately 1 million people worldwide suffer from the disease (Weinshenker, 1991). While MRI is proven to be a very sensitive tool in confirming the diagnosis of multiple sclerosis (MS) and monitoring of treatment trials, it is pathologically non specific. Although MRI provides some insight into temporal characteristic of MS lesions (i.e. gadolinium-enhanced T1 imaging (Katz et al., 1993)), it cannot distinguish between oedema, inflammation, demyelination and axonal loss (Blumhardt et al., 1977, Zivadinov and Cox, 2007).

It has been suggested that non-conventional MRI techniques such as Magnetisation Transfer Ratio (MTR) may provide a more specific characterisation of underlying pathological processes. MTR imaging is a measure of the exchange of protons between free water and macromolecules in membranes. It is believed to be affected by either dilution of protons caused by oedema or loss of tissue structure, in particular structure of myelin. While animal research has demonstrated a strong relationship between the level of myelination and MTR (Deloire-Grassin et al., 2000, Zaaraoui et al., 2008), the situation is more complicated in human studies which are primarily based on post-mortem examination. Some studies have found a strong correlation between MTR reduction and the level of demyelination (Barkhof et al., 2003, Deloire-Grassin et al., 2000, Dousset et al., 1992, Schmierer et al., 2004), while others demonstrated correlation between MTR with axonal density(Gass et al., 1994, van Waesberghe et al., 1999) or both (Mottershead et al., 2003). As new methods for precise tracking of MTR changes in MS brains are now becoming available (Chen et al., 2008, Dwyer et al., 2009) it is important to verify the true nature of its underlying pathophysiology.

The optic nerve represents an ideal model to study MS due to the fact that it subserves a single class of functions which are easily identifiable and measurable in vivo. Thus axonal loss in post-acute period can be assessed by measuring the thinning of RNFL, which is caused by retrograde degeneration subsequent to inflammatory-mediated axonal transection (Costello et al., 2006, Frohman et al., 2008, Trip et al., 2005) and amplitude of the VEP, while latency of the VEP provides a measure of demyelination. Conduction block in acute optic neuritis normally recovers within a few weeks, during which inflammation subsides, ion channels are reconstructed and conduction resumes, although often in a slower, continuous mode (Smith and Waxman, 2005). Therefore, the degree of conductivity delay through the lesion, as detected by the VEP latency and found in a high proportion of patients with optic neuritis, is most likely a manifestation of the extent of inflammatory demyelination (Davies et al., 1998, Halliday et al., 1972, McDonald, 1977). This direct association between latency delay and degree of optic nerve myelination was recently confirmed using an animal model (Martin et al., 2006).

While a number of studies have use optic nerve inflammation in an attempt to clarify the relationship of MTR with demyelination and axonal loss, this still remains uncertain. In some studies MTR was shown to correlate with a presumed measure of demyelination (VEP latency) and not correlate with a measure of axonal loss (visual acuity or VEP amplitude)(Hickman et al., 2004, Thorpe et al., 1995); in others the opposite results were obtained(Inglese et al., 2002, Melzi et al., 2007). This may relate to the heterogeneous nature of the pathological changes after optic neuritis, which at different times may result in varying degrees of axonal loss and demyelination or a combination of both.

In an attempt to resolve the problem of heterogeneity seen in previous studies, the aim of current investigation was to examine the relationship between MTR and each of the pathological conditions (axonal loss and demyelination) by minimising the effect of each factor on another one. This was achieved by separating optic neuritis patients into two groups: one with significant axonal loss and another with no axonal loss, but extensive chronic demyelination using Optical Coherence Tomography and visual evoked potentials.

Section snippets

Subjects

Twenty three consecutive patients who had suffered a single clinical episode of ON and no previous clinical demyelinating events were recruited specifically for this study. ON was diagnosed by a neuro-ophthalmologist based on clinical findings. Exclusion criteria were atypical presentation, bilateral and/or recurrent ON and a history of other ocular or neurological diseases. No other data from these patients presented in other publications.

Ten age-matched healthy volunteers were also examined

Result

Demographic data is presented in Table 1.

In normal controls MTR inter-subject coefficient of variability was 14.3% and intra-subject coefficient of variability was 6.7%.

Average MTR of affected eye of ON patients was significantly reduced as compared to the fellow eye and normal controls (19.9 (5.6), 23.6 (4.9) μ and 25.9 (3.1) μ respectively (p = 0.005, one-way ANOVA). Post-hoc analysis revealed a significant difference between MTR of affected and fellow eyes (p = 0.033) and between MTR of affected

Discussion

Combined MRI and histopathological studies in animals and human postmortem MS studies have demonstrated correlations in MTR with inflammation, axonal loss, gliosis and demyelination but it is difficult to separate these components in the brain. Although assessment of optic neuritis is a good model to clarify this, previous studies have led to conflicting results.

Thorpe et al. (1995) in a study of 20 patients with optic neuritis observed a reduction of MTR in affected eyes, which correlated

Conclusion

Results of this study indicate that the reduction of optic nerve MTR after an episode of ON has a strong association with the degree of axonal damage, but not with demyelination.

Acknowledgment

The work was supported by grants from Novartis and Sydney Medical Foundation [grant number E34].

References (35)

  • E.M. Frohman et al.

    Modeling axonal degeneration within the anterior visual system

    Ann. Neurol.

    (2008)
  • P.J. Gareau et al.

    Magnetization transfer and multicomponent T2 relaxation measurements with histopathologic correlation in an experimental model of MS

    J. Magn. Reson. Imaging

    (2000)
  • A. Gass et al.

    Correlation of magnetisation transfer ratio with clinical disability in multiple sclerosis

    Ann. Neurol.

    (1994)
  • S.L. Graham et al.

    The diagnostic significance of the multifocal pattern visual evoked potential in glaucoma

    Curr. Opin. Ophthalmol.

    (1999)
  • S.J. Hickman et al.

    Serial magnetization transfer imaging in acute optic neuritis

    Brain

    (2004)
  • M. Inglese et al.

    Irreversible disability and tissue loss in multiple sclerosis

    Arch. Neurol.

    (2002)
  • D. Katz et al.

    Correlation between MRI findings and lesion development in chronic, active MS

    Ann. Neurol.

    (1993)
  • Cited by (19)

    • Laboratory biomarkers of Multiple Sclerosis (MS)

      2022, Clinical Biochemistry
      Citation Excerpt :

      MTR is a viable outcome measure for examining the effects of myelinating agents. Thus, it has future potential to be used as a biomarker for axonal damage and a tool for monitoring MS pathogenesis [65,66]. Small noncoding microRNAs (miRNAs) control gene expression—a feature that has resulted in extensive investigations of their use as potential biomarkers [67,68].

    • Multifocal visual evoked potentials in optic neuritis and multiple sclerosis: A review

      2017, Clinical Neurophysiology
      Citation Excerpt :

      No optic tract lesions were shown (Alshowaeir et al., 2014) indicating that in MS retrogeniculate lesions are, at least somewhat, responsible for the latency delay measured on mf-VEP. MTR analysis of monosymptomatic ON patients 6–36 months removed from onset showed association between optic nerve MTR and mf-VEP amplitude but not with mf-VEP latency (when adjusting for OCT and mf-VEP amplitude) indicating that MTR following ON reflects the level of axonal damage and is not directly related to demyelination (Klistorner et al., 2011). However, in another study MTR MRI of the optic nerve at 3, 6 and 12 months did not correlate significantly with mf-VEP amplitude (Wang et al., 2012).

    • Advanced MR Imaging of the Visual Pathway

      2015, Neuroimaging Clinics of North America
      Citation Excerpt :

      These findings suggest that early demyelination occurs, which is then followed by remyelination. However, other studies have demonstrated correlation with measures of axonal damage, such as retinal nerve fiber layer.24 It is possible that MTR reflects a combination of these biological phenomena, which vary with time.

    • Changes in tissue directionality reflect differences in myelin content after demyelination in mice spinal cords

      2014, Journal of Structural Biology
      Citation Excerpt :

      Based on MRI, several measures including magnetization transfer ratio (Chen et al., 2007), myelin water fraction (Laule et al., 2008), and radial diffusivity from DTI (Song et al., 2005) have also shown potential to detect myelin integrity. But these measures are also shown to detect other pathological components except myelin (Klistorner et al., 2011; Schmierer et al., 2004), due to the complexity of demyelinated lesions in patients. In the current study, we confirmed the utility of structure tensor analysis to assess myelin content in simple histological images.

    • Optic neuritis

      2014, The Lancet Neurology
      Citation Excerpt :

      Low axial diffusivities in the acute phase (suggesting greater axonal damage) are associated with worse vision at 6 months.106 Magnetisation transfer imaging distinguishes between free and macromolecular bound protons, and the magnetisation transfer ratio is affected by myelination and axonal loss and is altered from normal in optic neuritis107–109 and MS, decreasing in the initial post-acute phase.110 A time-dependent association between visual evoked potential latency and magnetisation transfer ratio suggests the potential for the lesional magnetisation transfer ratio to be indicative of remyelination after optic neuritis,109 and results of post-mortem pathology–MRI studies have shown higher magnetisation transfer ratio in remyelinated than in demyelinated lesions.111,112

    View all citing articles on Scopus
    View full text