16 Aug 2018

Retinal thinning crops up early in Parkinson’s. Could it herald disease? A paper published August 15 in Neurology hints that it might. Scientists led by Beomseok Jeon, Seoul National University College of Medicine, South Korea, report that in people with early Parkinson’s, thinning of the retina correlated with loss of dopaminergic neurons in the substantia nigra. The findings raise the possibility that a simple eye exam could provide an early indicator of the disease.

“The findings are interesting in that they show a possible relationship between inner retinal thinning and nigral dopaminergic neuronal loss,” wrote Benjamin Kim, Hospital of the University of Pennsylvania, Philadelphia, to Alzforum. However, he cautioned that since retinal thinning has been reported in other neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia, it probably couldn’t be a diagnostic biomarker for PD (Ferrari et al., 2017; Mukherjee et al., 2017). Whether retinal thinning can track disease will require longitudinal data showing a significant rate of change in retinal layer thickness over time, he said.

Previous studies found that certain areas of the retina deteriorated in PD patients, though they differed on exactly where in the retina that thinning took place (Albrecht et al., 2012; Garcia-Martin et al., 2014). Scientists also reported α-synuclein in the cells of the eye (Bodis-Wollner et al., 2014; Beach et al., 2014). However, until now, no one had correlated retinal thinning with loss of dopaminergic neurons in the substantia nigra, a hallmark of PD pathology. Could cells in the eye provide a window into what is going on in the brain?

Look Into My Eyes. The researchers looked at scans showing individual layers of the retina (A). They narrowed their focus to concentric circles surrounding the fovea (B and C).

Co-first authors Jeeyun Ahn and Jee-Young Lee analyzed retinas of 49 patients just diagnosed with PD who had not started on medication, and 54 age-matched controls, using a type of optical coherence tomography (OCT) that has only been available in recent years. High-resolution, spectral-domain OCT allows layer-by-layer scanning of the retina, including the inner plexiform layer, which contains projections from dopaminergic amacrine cells in the inner nuclear layer. The researchers focused on concentric circles centered on the fovea, the dimple in the central retina that receives light from the middle of the visual field (see image above). A random selection of 30 PD patients also underwent positron emission tomography scanning with N-(3-[18F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane (18F-FP-CIT) to measure dopamine transporter binding in the brain.

In PD patients, the researchers saw retinal thinning in the outer and lower quadrants of the middle circle, especially in the inner plexiform and ganglion cell layers. The more thinning in that lower quadrant, the worse people scored on the Hoehn and Yahr scale, a measure of PD progression. Thinning in this section also correlated with decreased dopamine transporter activity in the left substantia nigra. This could mean there is a pathological link between the retina and nigral dopaminergic cell degeneration in PD, the authors wrote. It remains to be determined whether the specific areas of retinal deterioration identified here are unique, as other PD studies have found thinning in other focal parts of the retina, they added.

Complex Layers. The retina is made up of individual layers. Parkinson’s patients have thinning especially in the ganglion cell and inner plexiform layers.

“Ultimately, if retinal thinning is pathologically linked to nigral dopaminergic loss, retinal imaging could be used for making an early diagnosis, monitoring disease progression, and measuring the efficacy of neuroprotective therapies in PD,” wrote Jamie Adams, University of Rochester Medical Center, New York, and Chiara La Morgia, University of Bologna, Italy, in an accompanying editorial. They agreed with the authors that longitudinal data from a larger sample would be needed, perhaps examining a larger area of the retina. If this did pan out, it is likely that retinal thickness might be one of several biomarkers used in combination for PD, implied Adams and La Morgia.

Kim was more cautious, wondering if these focal thin spots might occur more randomly across the retina. “Then it could be challenging to use mild retinal thinning as a biomarker for early diagnosis,” he wrote to Alzforum. “Some ophthalmic diseases or insults to the retina can come and go leaving little trace except for a focal thinning,” he added.—Gwyneth Dickey Zakaib

Comments

1. • Reem Deeb
     SUNY Downstate Medical Center
   • Ivan Bodis-Wollner
     SUNY Downstate Medical Center
   • Posted: 20 Aug 2018

   This study is important as it strengthens previous suggestions of the applicability of optical coherence tomography (OCT) as a biomarker tool to investigate the structural changes in the retina in the early stage of PD. The segmentation algorithm of OCT is consistent with dopaminergic cells loss in the inner plexiform layer and in the ganglion cell layer of the retina in PD. Most importantly this study detected dysfunction of dopaminergic neurons in the basal ganglia and correlated it with retinal pathology in PD. Retinal ganglion cells, whose axons form the retinal nerve fiber layer, are non-dopaminergic, yet this study reported a correlation between thinning of the GCL and dopaminergic cell loss in the substantia nigra. While both dopamine and serotonin deficiency are found in PD, this study did not address whether there is alteration in serotonin or other neurotransmitter uptake in the early stage of PD.

   View all comments by Reem Deeb View all comments by Ivan Bodis-Wollner

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References

Paper Citations

1. Ferrari L, Huang SC, Magnani G, Ambrosi A, Comi G, Leocani L. Optical Coherence Tomography Reveals Retinal Neuroaxonal Thinning in Frontotemporal Dementia as in Alzheimer's Disease. J Alzheimers Dis. 2017;56(3):1101-1107. PubMed.
2. Mukherjee N, McBurney-Lin S, Kuo A, Bedlack R, Tseng H. Retinal thinning in amyotrophic lateral sclerosis patients without ophthalmic disease. PLoS One. 2017;12(9):e0185242. Epub 2017 Sep 25 PubMed.
3. Albrecht P, Müller AK, Südmeyer M, Ferrea S, Ringelstein M, Cohn E, Aktas O, Dietlein T, Lappas A, Foerster A, Hartung HP, Schnitzler A, Methner A. Optical coherence tomography in parkinsonian syndromes. PLoS One. 2012;7(4):e34891. Epub 2012 Apr 13 PubMed.
4. Garcia-Martin E, Rodriguez-Mena D, Satue M, Almarcegui C, Dolz I, Alarcia R, Seral M, Polo V, Larrosa JM, Pablo LE. Electrophysiology and optical coherence tomography to evaluate Parkinson disease severity. Invest Ophthalmol Vis Sci. 2014 Feb 4;55(2):696-705. PubMed.
5. Bodis-Wollner I, Kozlowski PB, Glazman S, Miri S. α-synuclein in the inner retina in parkinson disease. Ann Neurol. 2014 Jun;75(6):964-6. Epub 2014 Jun 13 PubMed.
6. Beach TG, Carew J, Serrano G, Adler CH, Shill HA, Sue LI, Sabbagh MN, Akiyama H, Cuenca N, Arizona Parkinson's Disease Consortium. Phosphorylated α-synuclein-immunoreactive retinal neuronal elements in Parkinson's disease subjects. Neurosci Lett. 2014 Jun 13;571:34-8. Epub 2014 Apr 28 PubMed.

Further Reading

Papers

1. Matlach J, Wagner M, Malzahn U, Schmidtmann I, Steigerwald F, Musacchio T, Volkmann J, Grehn F, Göbel W, Klebe S. Retinal changes in Parkinson's disease and glaucoma. Parkinsonism Relat Disord. 2018 Jun 21; PubMed.
2. Ortuño-Lizarán I, Beach TG, Serrano GE, Walker DG, Adler CH, Cuenca N. Phosphorylated α-synuclein in the retina is a biomarker of Parkinson's disease pathology severity. Mov Disord. 2018 Aug;33(8):1315-1324. Epub 2018 May 8 PubMed.

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