Divya Gupta

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the United States.¹ PD is characterized by a loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and an aggregation of α-synuclein (α-syn).¹ Unfortunately, the majority of PD cases are not due to genetics, limiting the use of genetic biomarkers for PD.¹ By the time distinguishing symptoms such as resting tremor, rigidity, and bradykinesia present, greater than 50% of DA neurons in the SNc have already been lost, making neuroprotective treatment strategies challenging.^{1, 2} For this reason, it is critical to diagnose and treat PD promptly by investigating biomarkers to diagnose PD before the onset of symptoms.³ Because the eye is a window into the brain, it reflects some of the earliest signs of PD such as impaired convergence, loss of visual acuity, and dry eye.⁴ Interestingly, α-syn aggregates thought to cause DA neuron loss in PD have been noted in other areas of the body, including the eye.⁴ As an easily accessible extension of the CNS, the eye may provide great potential for early diagnosis biomarkers and treatment of visual symptoms in PD.⁵

Objective: In this narrative review, we investigate retinal a-syn as a potential biomarker for PD and evidence for an a-syn-induced pathogenic mechanism causing visual dysfunction during PD.

Search Methods: A online investigation using PubMed to search for articles from 2017-2023 was conducted with the following keywords: “Parkinson’s”, “retina”, “eye”, “α-synuclein”, “biomarker”, “pathogenesis”, “early diagnosis”.

Results: Research indicates that phosphorylated α-syn (p-syn) may be present in the eyes of PD patients. One study analyzed postmortem human retinas and found that PD samples stained positive for p-syn within retinal ganglion cells, while control samples stained negative for p-syn.⁶ However, a biopsy of both the retina and the brain are highly invasive procedures, and as such, using p-syn as a biomarker in the retina has the same limitations as α-syn in the substantia nigra. A less invasive technique using a-syn in the eyes was discovered by utilizing tear fluid samples using Schirmer test strips.⁷ Elevated levels of α-syn and neurofilament light chain were present in the tear fluid of patients with PD when compared to controls.⁷ Another technique using OCT-A imaging also found a correlation between retinal vascular density changes and moderate-stage PD.⁷ The study found that vessel density in the deep plexus of the parafoveal region and radial peripapillary capillary layer of the disc region was significantly lower in PD patients with moderate-stage disease in comparison with early-stage disease.⁷ These changes in vessel density were associated with increased risk and symptom progression in PD patients. In addition to serving as a biomarker, α-syn was found to impair the process of ferritinophagy, leading to an increase in iron levels in the retina and contributing to retinal damage and dysfunction in PD.⁸

Conclusion: The eye may be a promising tool for early diagnosis of PD, monitoring the progression of the disease.⁵ In addition, targeting ferritin biology within retinal cells may provide an avenue for addressing visual dysfunction during PD.⁸

Works Cited:

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2. Sarkar S, Raymick J, Imam S. Neuroprotective and Therapeutic Strategies against Parkinson’s Disease: Recent Perspectives. Int J Mol Sci. 2016;17(6).
3. Rees RN, Acharya AP, Schrag A, Noyce AJ. An early diagnosis is not the same as a timely diagnosis of Parkinson’s disease. F1000Res. 2018;7.
4. Veys L, Vandenabeele M, Ortuno-Lizaran I, Baekelandt V, Cuenca N, Moons L, et al. Retinal alpha-synuclein deposits in Parkinson’s disease patients and animal models. Acta Neuropathol. 2019;137(3):379-95.
5. Mohana Devi S, Mahalaxmi I, Aswathy NP, Dhivya V, Balachandar V. Does retina play a role in Parkinson’s Disease? Acta Neurol Belg. 2020;120(2):257-65.
6. Ortuno-Lizaran I, Beach TG, Serrano GE, Walker DG, Adler CH, Cuenca N. Phosphorylated alpha-synuclein in the retina is a biomarker of Parkinson’s disease pathology severity. Mov Disord. 2018;33(8):1315-24.
7. Lin CW, Lai TT, Chen SJ, Lin CH. Elevated alpha-synuclein and NfL levels in tear fluids and decreased retinal microvascular densities in patients with Parkinson’s disease. Geroscience. 2022;44(3):1551-62.
8. Baksi S, Singh N. alpha-Synuclein impairs ferritinophagy in the retinal pigment epithelium: Implications for retinal iron dyshomeostasis in Parkinson’s disease. Sci Rep. 2017;7(1):12843.