Editors Selection IGR 20-3

Pathogenesis: Demyelination and Neurodegeneration

Kevin Chan

Comment by Kevin Chan on:

79922 Demyelination precedes axonal loss in the transneuronal spread of human neurodegenerative disease, You Y; Joseph C; Wang C et al., Brain, 2019; 142: 426-442

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Increasing evidence indicates that glaucoma involves transneuronal degeneration in the brain's visual system and beyond.1,2 However, the underlying mechanisms remain unclear.3 In this cross-sectional, case-control study, You et al. used diffusion tensor imaging (DTI) and multifocal visual evoked potential (VEP) recordings on 25 and 16 glaucoma patients respectively, and suggested that demyelination precedes axonal loss in the transneuronal spread of human neurodegenerative diseases including glaucoma. Specifically, they showed that radial diffusivity in the optic radiation of glaucoma patients increased with visual field deficits and cortical thinning in a retinotopic manner.

Radial diffusivity in the optic radiation of glaucoma patients increased with visual field deficits and cortical thinning in a retinotopic manner

In addition, the extent of radial diffusivity increase appeared more widespread throughout the optic radiation than that of axial diffusivity decrease. They also observed significant associations between increased radial diffusivity in optic radiation and delay of VEP latency, which is a potential functional measure of demyelination as authors demonstrated previously in a rat model of optic neuritis.4 To confirm histologically their hypothesis, authors used a mouse model of optic nerve axotomy and observed early glial activation and demyelination in the posterior visual projections prior to amyloid precursor protein accumulation in the axons.

While glaucoma is often considered not a demyelinating disease, the hypothesis of early demyelination in glaucoma, if proven to be true, may be impactful to improving strategies for glaucoma neuroprotective treatment. However, cautions should be taken when interpreting the findings of this study. In particular, in vivo directional diffusivities in conventional DTI are known to be sensitive but not specific to individual pathophysiological events. For example, while axonal injury and demyelination are demonstrated to be associated with axial and radial diffusivities, observations of axial and radial diffusivity changes do not necessarily imply axonal and myelin damages, as other events such as cell infiltration, vasogenic edema, and tissue loss can also contribute to directional diffusivity changes concurrently.5 To improve the specificity of biophysical measurements, higher- order diffusion MRI such as diffusion basis spectrum imaging, diffusion kurtosis imaging and the standard model of white matter tract integrity may be used5,6 and are now available at clinically feasible scanning durations. Since diffusion-based measurements cannot directly assess myelin content, more extensive imaging modalities such as magnetization transfer imaging and myelin water imaging may also be employed with diffusion MRI alongside longitudinal investigations and larger samples to validate these claims in terms of myelin integrity. As the optic nerve axotomy model is typically regarded as an acute, severe traumatic optic neuropathy model, more relevant mild chronic glaucoma models may also be considered for histopathology in parallel with in vivo preclinical multiparametric MRI.7,8 Cautions may also be noted when deriving regional visual field sensitivity thresholds given the log units used in standard automated perimetry test reports.9

More detailed comments on glaucoma imaging and other aspects of this paper: see ref. 10


  1. Gupta N, Ang LC, Noel de Tilly L, Bidaisee L, Yucel YH. Human glaucoma and neural degeneration in intracranial optic nerve, lateral geniculate nucleus, and visual cortex. Br J Ophthalmol. 2006;90(6):674-678
  2. Lawlor M, Danesh-Meyer H, Levin LA, et al. Glaucoma and the brain: Trans-synaptic degeneration, structural change, and implications for neuroprotection. Surv Ophthalmol. 2018;63(3):296-306
  3. Faiq MA, Wollstein G, Schuman JS, Chan KC. Cholinergic nervous system and glaucoma: From basic science to clinical applications. Prog Retin Eye Res. 2019;72:100767
  4. You Y, Klistorner A, Thie J, Graham SL. Latency delay of visual evoked potential is a real measurement of demyelination in a rat model of optic neuritis. Invest Ophthalmol Vis Sci. 2011;52(9):6911-6918
  5. Wang Y, Wang Q, Haldar JP, et al. Quantification of increased cellularity during inflammatory demyelination. Brain. 2011;134(Pt 12):3590-3601
  6. Fieremans E, Jensen JH, Helpern JA. White matter characterization with diffusional kurtosis imaging. Neuroimage. 2011;58(1):177-188
  7. Chan KC, Yu Y, Ng SH, et al. Intracameral injection of a chemically cross-linked hydrogel to study chronic neurodegeneration in glaucoma. Acta Biomater. 2019;94:219-231
  8. Yang XL, van der Merwe Y, Sims J, et al. Age-related Changes in Eye, Brain and Visuomotor Behavior in the DBA/2J Mouse Model of Chronic Glaucoma. Sci Rep. 2018;8(1):4643
  9. Hood DC, Kardon RH. A framework for comparing structural and functional measures of glaucomatous damage. Prog Retin Eye Res. 2007;26(6):688-710.
  10. Villoslada P, Martinez-Lapiscina EH. Remyelination: A good neuroprotective strategy for preventing axonal degeneration? Brain. 2019;142(2):233-236

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