Researchers from the Université Laval in Québec have shown in a recent study that a noninvasive eye exam analyzing the retina could diagnose early signs of Parkinson’s disease (PD) years in advance before motor symptoms appear. The research, published in Neurobiology of Disease, details how the retina in people with PD responds differently to light than it does in healthy people, suggesting it could be used as an early biomarker of PD development.
As there is currently no single test for PD, it is currently diagnosed clinically through a combination of observable symptoms, medical history, and a neurological examination.
“By then, the disease has been present for several years, and the affected neurons are already engaged in an irreversible degenerative process. That’s why it’s important to find biomarkers that detect Parkinson’s at an early stage of the disease,” said study leader Martin Lévesque, professor at Université Laval’s Faculty of Medicine and researcher at the CERVO Brain Research Centre.
For this study, the researchers used electroretinography (ERG), a method that measures electrical activity in the retina in response to light, to compare retinal function between individuals with early-stage Parkinson’s and healthy controls. They found distinct differences in the b-wave, photopic negative response (PhNR) b-wave, and PhNR-wave amplitudes, which might indicate α-synuclein pathology occurring in outer retinal layers.
“The retina is a direct extension of the central nervous system and, consequently, offers a noninvasive way of exploring the brain,” Lévesque said. “An unusual response of the retina to light stimuli could be indicative of a pathology affecting the brain.”
To explore this, the team conducted both human and mouse model experiments. Twenty patients diagnosed with Parkinson’s within the last five years underwent ERG tests using electrodes placed on the lower eyelid to record retinal responses to various light flashes. Similar ERG tests were conducted in a transgenic mouse model that overexpresses the human A53T α-synuclein protein implicated in Parkinson’s pathology. These mice, tested before any motor symptoms were evident, also showed abnormal retinal responses.
“Our cohorts exhibited both sex-specific and general ERG anomalies, with the most significant changes occurring in the b-wave, PhNR b-wave, and PhNR-wave, which appear to reflect early disease stages,” the researchers wrote. In both mice and human participants, reductions in these waveforms suggest functional impairment of key retinal cells prior to overt neurodegeneration. The study also noted stronger effects in female participants, possibly due to sex-based differences in retinal physiology and disease progression.
This research builds on earlier studies that showed dopamine dysfunction in the retina may underlie visual abnormalities in Parkinson’s. However, the current study is among the first to demonstrate specific ERG anomalies in early-stage PD patients and to link them to retinal alpha-synuclein pathology and dopamine-related dysfunction in animal models.
“The results we obtained for people with Parkinson’s had a distinct signature from those in the control group,” said Lévesque. In mice, similar ERG differences were found even before the appearance of motor symptoms. “This suggests that the functional manifestations of Parkinson’s could be detected at an early stage of the disease by retinal examination,” he added.
The implications for clinical care could be significant. Currently, PD is diagnosed based on motor symptoms, by which time substantial dopaminergic neuron loss has already occurred. A simple, noninvasive ERG test could allow for earlier intervention, potentially slowing disease progression.
“We could offer a functional retinal exam from the age of 50,” said Lévesque. “By detecting the disease early, we could offer interventions that prevent the degeneration of the neurons involved in Parkinson’s. This approach could also be used to monitor the progression of the disease, as well as the effectiveness of interventions offered to patients.”
While the researchers showed that these observable changes of how the retina responds to light can determine early signs of PD, the exact mechanisms of these changes are not yet known. The investigators also noted that the specificity of the retinal signature needs to be confirmed with additional studies, as well as comparative studies with other disorders such as Lewy body dementia, to validate this testing method.
Nonetheless, the research provides a promising direction for future studies and the development of a retinal biomarker for PD. “To our knowledge, this is the earliest recorded instance of ERG anomalies in diagnosed PD patients, supporting the development of a diagnostic tool for early detection and monitoring, with the potential to improve interventions and patient management,” the researchers wrote.
Next steps for the researchers include testing larger and more diverse cohorts, refining the ERG protocol, and examining how retinal responses change with disease progression and treatment. The team will also further investigate the mechanistic role of dopamine and alpha-synuclein in the retina.
