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Retinal Imaging May Detect Pathologic Changes in Early Stages of Parkinson's Disease

ARTICLE IN BRIEF

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DR. VICTORIA S. PELAK: “This study confirms prior research, including a January 2014 metanalysis in PLOS One, showing that patients with PD have more thinning of their inner retinas than healthy controls. However, it is the first study to also look at the relationship between changes in the brain and the retina in Parkinsons and find a significant correlation between thinning in the left retina and dopamine loss in the left substantia nigra.”

Retinal thinning was associated with nigral dopaminergic loss in de novo Parkinson disease, investigators reported.

Retinal thinning, which is present in the early stages of Parkinson's disease (PD), may be associated with dopamine loss in the left substantia nigral area of the midbrain, according to a paper published online August 15 in Neurology. In addition, retinal imaging may be useful to detect pathologic changes occurring in the early stages of PD, the study authors said.

“We were surprised to find significant relationships between retinal thinning and dopamine transporter loss. We also discovered that the retinal thinning occurred in the neuronal type of cell layers of the retina, in particular the inner plexiform and ganglion cell layers,” principal investigator Jee-Young Lee, MD, PhD, associate professor of neurology at Seoul Metropolitan Government-Seoul National University Boramae Medical Center, South Korea, told Neurology Today.

Although numerous studies have consistently reported retinal thinning in patients with PD, Dr. Lee cautioned that more research is needed before retinal thinning can be used as a biomarker. “We need a longitudinal study to confirm the relationship between retinal thinning and dopamine loss as the disease progresses.”

The study was supported by the Seoul Metropolitan Government Seoul National University Boramae Medical Center and the National Research Foundation funded by the Ministry of Education, Science, and Technology in Korea.

STUDY DESIGN

The researchers wanted to investigate the relationship between retinal thinning and dopaminergic deterioration in patients who were newly diagnosed with PD and not taking medications.

Forty-nine patients with PD who visited the movement disorder clinic at Boramae Medical Center between 2013 and 2014 participated in the study. Fifty-eight healthy volunteers who visited the Boramae Medical Center for routine health check-up or were participants in the Korean Longitudinal Study on Health and Aging cohort study, also participated in the study. People with ophthalmic conditions that could affect retinal thickness were excluded such as age-related macular degeneration, glaucoma diabetic retinopathy, and retinal vein or artery occlusion.

A movement disorders specialist diagnosed patients with PD based on the clinical diagnostic criteria of the UK PD Brain Bank Society. At the time of diagnosis, researchers collected clinical information on age, sex, age of PD onset, Hoehn and Yahr staging for PD, and ophthalmologic parameters that could affect retinal thickness. They matched them with controls based on age (69-70) and sex.

Ophthalmologists conducted complete eye examinations of all participants. In patients with PD, the researchers used optical coherence tomography (OCT) of the macula to measure retinal layer thickness and volume and examined the functional implications of retinal anatomical change by correlating inner retinal layer thinning with a special form of visual field testing called microperimetry. To study the relationship between retinal thickness and dopamine transporter densities, PET and MRI scans were also performed in patients with PD.

Patients with PD showed a significant association between retinal thickness and dopamine transporter density in the left substantia nigra (p < 0.001). There was no association (p > 0.05 for all) in other brain regions.

Researchers saw retinal thinning in the inner retinal layers corresponding with the plexiform and ganglion cells. The thinning was correlated (FDR-adjusted p < 0.05) with the loss of dopamine transporter in the substantia nigra, “suggesting a pathological connection between the retinal and nigral dopaminergic cell degeneration in patients with PD,” said Dr. Lee.

Using a high-resolution OCT scanning device with built-in automated segmentation software made the analysis of each retinal layer more accurate and reliable and was a major strength of the study.

However, a potential limitation of using the OCT device and software is the lack of specificity to detect early retinal changes in PD. “We hope that emerging technologies will enable us in the future to look more specifically at neuronal loss in the retinas of patients with PD,” co-investigator Jeeyun Ahn, MD, PhD, associate professor of ophthalmology at Seoul Metropolitan Government-Seoul National University Boramae Medical Center, told Neurology Today.

EXPERT COMMENTARY

“This study confirms prior research, including a January 2014 metanalysis in PLOS One, showing that patients with PD have more thinning of their inner retinas than healthy controls. However, it is the first study to also look at the relationship between changes in the brain and the retina in Parkinson's and find a significant correlation between thinning in the left retina and dopamine loss in the left substantia nigra,” said Victoria S. Pelak, MD, professor of neurology and ophthalmology at the University of Colorado School of Medicine in Denver, who was not involved with the study.

Retinal thinning may be explained by degeneration due to the presence of proteins such as alpha-synuclein in the retina or loss of retinal dopamine, but this is not yet known, said Dr. Pelak.

She noted three strengths of the study, which contribute to the body of knowledge regarding PD and retinal changes: first, that changes in dopamine transporter imaging correlate with changes in the retina; next, the functional parameters of the retina based on microperimetry correlate with retinal thickness in PD; and lastly, enrolling patients with early stage PD before they are treated with dopamine, shows retinal changes that can be detected by OCT.

Another positive aspect was that the researchers included both eyes of each subject in their evaluations. “We know that there are differences between the right and left brain in neurodegenerative diseases. It's time that we start thinking of the retina in the same way,” said Dr. Pelak.

The small sample size was in line with similar imaging studies of retina OCT in patients with PD. “Ideally, we would have large databases and/or registries similar to the Alzheimer's Disease Neuroimaging Initiative where everyone would contribute data on PD to facilitate this type of analysis.”

Several studies have looked at retinal thickness in patients with PD with OCT scans. However, this is purely a structural imaging technique compared to using positron emission tomography or magnetic resonance imaging with a dopamine ligand to look at the dopamine transporter, said Ali Hamedani, MD, MHS, an attending neuro-ophthalmologist in the department of neurology at the University of Pennsylvania School of Medicine in Philadelphia.

“That is new and introduces an element of functionality. By linking OCT retinal scans with dopamine transporter scans in this study, researchers found an association between retinal thickness and dopamine receptor density,” Dr. Hamedani said.

PD typically affects one side of the body before the other, he noted. “This study had more individuals with early PD with right-sided motor symptoms, which was consistent with reduced dopamine transporter binding in the left substantia nigra. The retinal findings mirror this asymmetry, suggesting that retinal thinning in PD may also occur on one side before the other.”

A limitation of using OCT for clinical purposes in PD is that most measurements fall within the normal range. “The differences in retinal thickness between people with PD and people without the disease are so small and subtle that it is impossible to differentiate them using a single cutoff,” said Dr. Hamedani.

In the past decade, papers have been published on the correlation of retinal thinning using OCT with motor signs of PD. “The findings have suggested that the retina is a good place to monitor pathology related to PD both for early diagnosis and disease progression,” said Ivan Bodis-Wollner, MD, DSc, professor of neurology and professor of ophthalmology at the State University of New York– Downstate Medical Center in Brooklyn.

The benefits of OCT are that it is not time-consuming, invasive, or expensive, and it's available in most ophthalmologists' and optometrists' offices. “OCT is an ideal tool to monitor the progression of PD and screen for the disease in people age 45 and older,” said Dr. Bodis-Wollner.

Nonetheless, a major barrier to using OCT has been that “most neurologists do not consider the retina a visible part of brain.” Dr. Bodis-Wollner referred to the influential work of retinal physiology and anatomy pioneer John Dowling, who wrote The Retina: An Approachable Part of the Brain. Dowling states that “the retina is an integral and readily accessible part of the central nervous system.”

To evaluate data from the OCT scans, professionals need to use the proper analytical tools such as pixel by pixel analysis rather than volume averaging, and a mathematical model for the foveal resin to define changes in the model variables. The software for that, however, is limited, noted Dr. Bodis-Wollner.

Another limitation is that the resolution of the OCT matrix is set at only 2.5 to 3 microns. Dr. Bodis-Wollner suggested that OCT companies increase the resolution to home in on the nerve cells of the retina and detect changes.

LINK UP FOR MORE INFORMATION:

• Ahn J, Le J-Y, Kim TW, et al. Retinal thinning associated with nigral dopaminergic loss in de novo Parkinson disease http://n.neurology.org/content/early/2018/08/15/WNL.0000000000006157. Neurology 2018; Epub 2018 August 15.
    • Beach TG, Carew J, Serrano G, Adler CH, et al. Phosphorylated α-synuclein-immunoreactive retinal neuronal elements in PD subjects https://www.sciencedirect.com/science/article/abs/pii/S0304394014003309. Neurosci Lett 2014; 571:34–38.
      • Bodis-Wollner I, Kozlowski PB, Glazman S, et al. Alpha-synuclein in the inner retina in PD https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.24182. Ann Neurol 2014; 75(6):964–966.
        • Ding Y, Spund B, Glazman S, et al. Application of an OCT data-based mathematical model of the foveal pit in Parkinson disease https://link.springer.com/article/10.1007%2Fs00702-014-1214-2. J Neural Transm (Vienna) 2014;121(11):1367–1376.
          • Yu JG, Feng YF, Xiang Y, et al. Retinal nerve fiber layer thickness changes in Parkinson disease: A meta-analysis https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085718. PLoS One 2014;9(1):e85718.