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The emerging potential of advanced OCT-based biomarkers

Neuronal loss of ganglion cells in the retina is an established hallmark of a number of diseases.  As such, a number of clinical trials use the ganglion cell layer (GCL) thickness – or a complex thereof –  as measured with optical coherence tomography (OCT) imaging as a biomarker.  For example, a cursory search on clinicaltrials.gov shows studies using the GCL as an imaging marker in the following diseases:

  • Glaucoma
  • Parkinson’s
  • Diabetic retinopathy
  • Intracerebral processes
  • Alzheimer’s
  • Ischemic optic neuropathy
  • Multiple sclerosis
  • Sturge-Weber syndrome

Some of these diseases involve inflammatory attacks to the central nervous system, but unlike some of the more common ocular diseases that are characterized by fluid pockets, edema, or drusen, these pathologies may instead manifest themselves as gradual thinning of specific layers of the neuroretina.  And while the literature supports the use of GCL as a biomarker, new studies are looking at the effect these pathologies have in the deeper retinal layers.  Specifically, if there are compensatory effects to be seen in the outer layers, what is their etiology and can these be used as biomarkers to predict disease course or response to treatment?  Furthermore, if, as is hypothesized by a number of groups,the retina attempts to maintain structural integrity through the course of pathology, a resulting thickening of the deeper retinal layers may mask atrophy occurring elsewhere.  If only crude measures of retinal thickness are used, it will not be possible to measure and understand the nature of the structural change.  Instead, this requires measuring more retinal layers.  Moreover, if more retinal layers are isolated and measured, then increased sensitivity to change, and therefore detection, may be achieved by looking at the ratio of specific layers, rather than simply the thickness of layers in isolation.

So what evidence is there that change in the deeper retinal layers offers new, compelling OCT-based imaging biomarkers?  At this year’s ARVO meeting, [Wilsey et al. 2015] reported significant increase in the outer retina layer thicknesses in non-human primates with experimental glaucoma, although this was unrelated to disease severity.  During discussion it was hypothesized that this was related to changes in the Mueller cells that might be trying to preserve the structural integrity of the retina as a whole.  [Gabilondo 2015] found that, following acute optic neuritis, while the inner layers atrophied, the outer layers thickened slightly.  This was suggestive of damage to the GCL not extending to the bipolar cells or photoreceptors, at least in the early course of the disease.  As discussed, the compensatory thickening might be a response to the initial insult coordinated by microglia or Mueller glial cells, again to perhaps preserve overall integrity.  Alternatively, the authors suggest, it could be an increase in cellular fluid in these layers causing the thickening.
Using our own Orion software, [Keller 2015] also hypothesized that the thickening seen in the outer nuclear layer (ONL) following acute anterior ischemic optic neuropathy, was due to edema.  More interestingly, however, was how the initial ONL thickness had the strongest correlation with visual outcome.  Given the ONL’s relevance to the recovery of the photoreceptors, this supports further the emerging importance of this layer as a clinical end point.
Two final examples, this time in Parkinson’s disease, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA).  [Chorostecki 2015] saw significant outer plexiform layer (OPL) thickening in Parkinson’s that they thought could relate to alpha-synuclein aggregation in the retina, which in their view could have significant clinical implications.  And using custom analysis software developed at the University of Ulm, [Schneider 2014] found the thickening of the ONL in PSP and the OPL in MSA was highly specific for these disease entities, allowing for the differentiation of PSP from MSA with both high sensitivity and specificity.

In summary, we are seeing isolated changes in individual retinal layers in both both ocular and neurodegenerative diseases that would otherwise be masked were retinal thickness simply measured as a whole.  Furthermore, these changes correlate well with disease type, progression and visual outcomes.  We conclude, therefore, that it is of clinical importance to be able to measure these retinal layers in isolation using OCT and are excited by their potential as advanced biomarkers.

References

[Chorostecki 2015] Characterization of retinal architecture in Parkinson’s disease.  Chorostecki J, Seraji-Bozorgzad N, Shah A, Bao F, Bao G, George E, Gorden V, Caon C, Frohman E, Tariq Bhatti M, Khan O.  J Neurol Sci. 2015 Aug 15;355(1-2):44-8.

[Gabilondo 2015] – Dynamics of retinal injury after acute optic neuritis. Gabilondo I, Martínez-Lapiscina EH, Fraga-Pumar E, Ortiz-Perez S, Torres-Torres R, Andorra M, Llufriu S, Zubizarreta I, Saiz A, Sanchez-Dalmau B, Villoslada P.
Ann Neurol. 2015 Mar;77(3):517-28.

[Keller 2015] Changes in macular layers in the early course of non-arteritic ischaemic optic neuropathy.  Keller J, Oakley JD, Russakoff DB, Andorrà-Inglés M, Villoslada P, Sánchez-Dalmau BF.  Graefes Arch Clin Exp Ophthalmol. 2015 May 28.

[Schneider 2014] Schneider M, Müller HP, Lauda F, Tumani H, Ludolph AC, Kassubek J, Pinkhardt EH.  Retinal single-layer analysis in Parkinsonian syndromes: an optical coherence tomography study.  J Neural Transm. 2014 Jan;121(1):41-7.

[Wilsey 2015] – Outer retinal macular changes in non-human primate experimental glaucoma Wilsey L., Reynaud J, Burgoyne C. and Fortune B.  ISIE ARVO abstract, 2015.

 

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