Parkinson’s disease (PD) is typically diagnosed after significant neurodegeneration has already occurred and early symptoms have been present. The goal is to validate electroretinography (ERG) for detecting early retinal dysfunction biomarkers non-invasively. PD is a neurodegenerative disorder characterized by motor symptoms resulting from neuron loss. This study examined whether specific ERG features indicate early PD in M83 mice and early human patients. M83 homozygous transgenic mice (n = 10 males, 11 females) overexpressing A53T α-synuclein modelled early PD. Male and female mice were tested behaviourally and with ERG at 2 and 4 months.
Post-mortem retinal and brain tissues were collected. Participants aged 40 to 80 years with a ten-year idiopathic PD diagnosis were included in this study and had been on stable medication for at least one month. Participants were asked to abstain from PD medicines overnight to reduce their effects on results, and other medications not listed in the exclusion criteria were carefully recorded.
Three days of behavioural testing were carried out, commencing with data collection on the rotarod, open-field locomotor activity, and hindlimb clasp tests. This was followed by an overnight dark adaptation and habituation period in the ERG room. Three trials with a five-minute rest interval were performed on mice over the course of two training days and a third recording day. Mice were placed in locomotor detection chambers after one hour of habituation, and five-minute samples were recorded using VersaMax version 3.0 software over 60 minutes.
Twenty early-stage idiopathic PD patients and twenty matched healthy controls were recruited. ERG components were recorded under scotopic, photopic, and photopic negative response (PhNR) conditions. b-wave amplitudes and oscillatory potential (OP) were analysed for retinal function. Eyecup dissections were performed using a stereomicroscope, and the canthus and part of the optic nerve were preserved during removal from the optic cavity. Photopic and scotopic intensity curves were used to measure the intensity of mixed and pure responses in human ERG traces.
The statistical methods were chosen based on an initial focus on ERG components from threshold and saturating flash-light stimuli and translational evidence of identified ERG patterns. Despite the absence of α-synuclein disease and preservation of dopaminergic neurons, M83 mice showed early behavioural abnormalities in females. A notable reduction in b-wave amplitude was observed in photopic ERG, which was constant across sexes and time points.
PhNR ERG shows reduced b-wave and PhNR-wave amplitude, and scotopic ERG shows minor b-wave amplitude deficits in females. p-aSyn accumulation in retinal layers indicates early synaptic dysfunction without loss of retinal ganglion cells. The reduced b-wave amplitudes and delayed implicit times suggest rod dysfunction. Reduced b-wave amplitudes and delayed implicit times suggest rod dysfunction. Female-specific b-wave and PhNR wave amplitude reduction indicate functional impairments. Attenuated OP in female PD patients indicates compromised amacrine cell function. This study examines the OPs in humans, which are influenced by amacrine cells, to understand the role of dopaminergic dysfunction.
The cone system (photopic b-wave) was affected in M83 mice, while the rod system (scotopic b-wave and OP) was more impaired in human subjects. Sex-related differences were visible in females, showing greater ERG abnormalities due to hormonal influence, disease progression, baseline retinal response, and medications.
The study indicates retinal signature in PD-related ERG patterns, including dopaminergic amacrine cell dysfunction and rod and cone pathways disturbances. Retinal functional impairments discovered by ERG offer promise as early biomarkers for PD. The abnormalities in b-wave and PhNR-wave amplitudes show potential before the development of central nerve pathology, along with clinical motor symptoms. Large cohort studies and a longitudinal design are required to confirm ERG as a biomarker.
Reference: Soto Linan V, Rioux V, Peralta M, Dupré N, Hébert M, Lévesque M. Early detection of Parkinson’s disease: Retinal functional impairments as potential biomarkers. Neurobiol Dis. 2025;208:106872. doi:10.1016/j.nbd.2025.106872
