This scientific commentary refers to ‘Demyelination precedes axonal loss in the transneuronal spread of human neurodegenerative disease’, by You et al. (doi:).
Although the study of neurodegenerative disease has traditionally focused on neuronal damage, over the past decade there has been an explosion of interest in glial cells, among them the oligodendrocytes that produce the myelin sheath. Myelin, in addition to its role in increasing action potential conduction velocity, is critical for establishing proper connections within neural circuits. It also provides trophic support to the axon—as part of the axon-myelin unit (Stassart et al., 2018)—and contributes to brain plasticity and learning (Nave and Werner, 2014). However, myelin is highly susceptible to damage as a result of ischaemic, toxic and inflammatory insults, or secondary to axonal damage (Ferrer, 2018). In this issue of Brain, You and co-workers provide further evidence of demyelination in patients with glaucoma or multiple sclerosis, as well as evidence to support the role of trans-synaptic degeneration as a mechanism driving neurodegeneration, both concepts with strong therapeutic implications (You et al., 2019).
You et al. conducted quantitative brain MRI and visual evoked potential (VEP) studies to assess the integrity of the posterior visual pathway (optic radiations) by monitoring the presence of demyelination (defined by the combination of delayed VEP latencies and increased radial diffusivity on MRI) and/or axonal loss (amplitude reduction of VEP or increased axial diffusivity on MRI). They analysed the contribution of trans-synaptic axonal degeneration to the degenerative process and the balance between myelin and axonal damage. Trans-synaptic degeneration is a process that spreads damage from the site of injury to the projecting neurons, in a domino-like cascade (Gabilondo et al., 2014). It contributes to the damage to the visual pathway observed in association with various aetiologies, including multiple sclerosis and glaucoma. By focusing on the visual pathway, You et al. were able to take advantage of its retinotopic organization and of its close, monosynaptic, relationship to the retina, which allowed them to disentangle the different biological processes. They reported the presence of demyelination prior to trans-synaptic degeneration in the visual pathway, and validated this finding in a longitudinal cohort of patients with multiple sclerosis using diffusion tensor imaging (DTI). Finally, in a rodent model of traumatic optic neuropathy, they revealed demyelination and the presence of macrophages phagocytizing myelin in the optic radiations, again before axonal degeneration—as revealed by accumulation of axonal amyloid precursor protein—was established.
You et al. propose that myelin is sensitive to axonal degeneration, and that when the axon-myelin unit is disturbed by the spread of neurodegeneration, damage to myelin occurs before the axons are entirely disrupted. This sequence of events has long been anticipated in multiple sclerosis, a prototypical demyelinating disease, but it was unexpected in a neurodegenerative disease like glaucoma (although the extension of damage from the retina to the cortex has been recognized for years). Moreover, demyelination has also been observed in neurodegenerative diseases such as Alzheimer’s disease, in the form of diffuse white matter damage, and in multiple system atrophy as revealed by the accumulation of toxic α-synuclein deposits in oligodendrocytes (Ferrer, 2018).
Demyelination is a dynamic process, which can be efficiently reversed—at least in young adults—through remyelination by surviving oligodendrocytes or by new oligodendrocytes formed by the differentiation of oligodendrocyte precursors (Kutzelnigg and Lassmann, 2014; Plemel et al., 2017). Therefore, the critical question for neurology is whether preventing demyelination or promoting remyelination might be a feasible neuroprotective strategy to limit axonal damage and neurodegeneration in conditions ranging from chronic ischaemia or trauma brain injury to neurodegenerative diseases such as Parkinson’s or Alzheimer’s disease or glaucoma.
Remyelinating therapies are being pursued as a repair strategy for multiple sclerosis, potentially within a paradigm of combination therapy for brain diseases (Plemel et al., 2017). Remyelination is seen as a promising therapeutic strategy because of the existence of efficient natural repair mechanisms that promote remyelination to achieve plasticity. These include the capacity of the numerous oligodendrocyte precursors (5% and 10% of total cells in grey and white matter, respectively) to migrate to the site of damage, the ability of such precursors to differentiate and to wrap myelin around axons, and the ability of newly formed myelin to restore saltatory conduction and provide trophic support to the axon (Nave and Werner, 2014). However, this natural repair process is not without obstacles. Oligodendrocytes and their precursors decrease in number, migratory capacity and myelinating ability with age and as a result of tissue damage, and chronically denuded axons are refractory to remyelination (Kutzelnigg and Lassmann, 2014; Plemel et al., 2017). For this reason, the efficacy of remyelinating therapies would be highly dependent on the time window since injury, and would be influenced by age and the degree of axonal abnormalities.
The spread of neurodegeneration and demyelination in the visual pathway. The cartoon illustrates demyelination and trans-synaptic degeneration of the visual pathway in patients with damage to the anterior visual pathway that spreads to the posterior visual pathway. (A) The visual pathway in healthy controls consists of retinal ganglion cells (RGC, first neuron), lateral geniculate nucleus (LGN, second neuron) and the projection to the visual cortex via the optic radiations. VEPs are measured over visual cortex and reflect the transmission of the impulse along the whole visual pathway. (B) Anterograde degeneration of damaged RGCs (as a result of glaucoma or multiple sclerosis) is followed by demyelination of LGN neurons and subsequent visual cortex atrophy according to the You et al. model. (C) Trans-synaptic degeneration of first (RGC) and second (LGN) neurons leads to atrophy of cortical neurons as the endpoint of the neurodegenerative process.
A further challenge in moving remyelinating therapies from the laboratory to the clinic, in addition to efficacy, is how to design clinical trials and which surrogate endpoints to use (Plemel et al., 2017). The CNS can cope with substantial levels of demyelination, probably above 50–70%, without a significant clinical phenotype, as observed in patients with extensive peripheral nerve demyelination in Charcot-Marie-Tooth disease or central demyelination in multiple sclerosis. This means that therapies that achieve 30–50% efficacy in remyelinating white matter tracts may not exceed the threshold to detect a clinical benefit. In addition, assessing the neuroprotective effects of remyelination in chronically damaged axons may require long periods of observation, which are beyond the duration that would be reasonable for clinical trials. Including appropriate surrogate endpoints to probe whether a therapy is inducing remyelination will therefore be critical, as will selection of the right clinical model and therapeutic window.
You et al. address some of these issues in their current study, in which they applied advanced imaging and electrophysiological tools to the analysis of one of the best understood and eloquent CNS pathways, the visual pathway. The most sensitive and specific method for assessing demyelination and remyelination is to measure the latency of the VEP; VEP latencies were thus used as primary endpoints in two recent phase II trials of candidate remyelinating drugs (Cadavid et al., 2017; Green et al., 2017). Moreover, the use of multifocal VEPs increases the sensitivity of the technique by allowing detection of small changes affecting specific sectors of the visual pathway. Second, imaging techniques can complement, but not substitute for, the information obtained from a functional test such as the VEP. Optical coherence tomography (OCT) provides highly accurate measurements of retinal atrophy. It is therefore used to quantify neuroaxonal damage within the visual pathway and to measure the efficacy of neuroprotective therapies, as in phase II trials in acute optic neuritis (Suhs et al., 2012; Raftopoulos et al., 2016). Retinal atrophy may not be sensitive in the short term to the effects of de/remyelination, but it will reflect the long-term effects of neurodegeneration of chronically demyelinated axons as observed with the assessment of trans-synaptic degeneration (Gabilondo et al., 2014). Moreover, PET using radioligands that bind to myelin, such as amyloid tracers, can be used to refine the search for therapies in phase II trials.
A number of MRI techniques have been developed to assess de/remyelination, such as use of the magnetization transfer ratio, texture analysis, and measurement of the myelin-water fraction or radial diffusivity (Plemel et al., 2017). Although none of these imaging methods is specific to the demyelinating process (for instance, radial diffusivity abnormalities are the result of damage to both myelin and axons), they can make a significant contribution to the assessment of demyelination when combined with VEP measures, as shown by You et al. However, despite all their efforts to segment optic radiations into different sectors to avoid the limitations associated with DTI in non-parallel fibres (crossing fibres), You et al. were still faced with limitations related to spatial resolution. First, crossing fibres usually occurs at 100 μm and voxel size in the study was 1000 μm (1 mm3 isometric). More importantly, the authors relied on the specificity of axial and radial diffusivity as markers of axonal and myelin damage, respectively, which is not entirely true. Axial diffusivity measures the preferential movement of water molecules in the primary direction in the elliptical-based DTI model and radial diffusivity measures movement perpendicular to the primary direction. The primary movement direction is dictated by various structures including the myelin sheet, axonal membrane, neurofilaments, and microtubules. Spatial resolutions lower than 10 μm would be required to discriminate between different layers. Considering all of the above, conclusions based on DTI metrics should be treated with caution.
In summary, multimodal analysis of the visual pathway is proposed as a model for assessing CNS damage and evaluating the efficacy of reparatory therapies. At the level of clinical outcomes, recent studies promoted by the IMSVISUAL consortium have shown that low contrast visual acuity is highly correlated with retinal thickness and VEP, providing an excellent structure-function model for evaluating remyelinating and neuroprotective therapies. Demyelination is increasingly recognized as a pathological mechanism common to many brain diseases, and remyelination as a potential therapeutic strategy to prevent neurodegeneration. Even if demyelination is not the main driver of damage, it will probably be a feasible therapeutic target. Recent advances in the neurobiology of myelination, and the availability of clinical models for testing remyelinating therapies based on analysis of the visual pathway using multimodal surrogate endpoints, are promising new avenues for achieving neuroprotection.
Multimodal assessment of axonal loss: Biomarkers of axonal loss include a decrease in axial diffusivity, a reduction in the volume of visual cortex (calcarine cortex) or thalamus (lateral geniculate nucleus), a decrease in N-acetyl-aspartate upon brain MRI, a reduction in the thickness of the retinal nerve fibre layer or the ganglion cell plus inner plexiform layer upon OCT, and a decrease in VEP amplitude.
Multimodal assessment of demyelination: Biomarkers of demyelination and remyelination include a decrease in VEP latencies, abnormalities in radial diffusivity, magnetization transfer ratio, myelin-water fraction or texture analysis upon brain MRI, and a decrease in the signal from myelin ligands upon PET.
Trans-synaptic degeneration: The spread of degeneration from a neuron to its projecting neuron due to the absence of neurotransmission.
Visual pathway: The pathway from retinal ganglion cells (first neuron) to the lateral geniculate nucleus (second neuron) via the optic nerve and optic tract, to the visual cortex (calcarine cortex, third neuron) via the optic radiations.
Competing interests
P.V. has received consultancy fees and has stocks in Bionure Farma, Spiral Therapeutix, Health Engineering, and QMenta.
