Parkinson’s Subtypes Detectable by Patterns of Corneal Nerve Damage

The retina is well known to be a rich source of information about systemic disease—can ocular innervation structures offer the same? Researchers in China recently explored the ways that Parkinson’s disease (PD) manifests through changes to the corneal subbasal nerve plexus. Different PD subtypes exist and the condition possesses heterogenous and diverse clinical manifestations. While more research is currently being extended to focus on those experiencing rapid progression and poorer prognoses, subtype classification relies on symptom assessment since no reliable biomarkers currently exist.In new research published in Investigative Ophthalmology & Visual Science, investigators wanted to distinguish if corneal nerves can differentiate between different PD subtypes. Included for analysis were 63 Parkinson’s patients with tremor-dominant (TD), postural instability and gait disturbance (PIGD) and mixed subtypes; another 31 age- and sex-matched controls were included. The corneal subbasal plexus, located about 1mm to 2mm nasal to the inferior corneal apex, provides an ideal anatomical landmark to observe corneal nerve changes due to its fixed location, ease of identification and reproducibility relative to the central corneal area. These images from the study show how researchers used IVCM imaging (digitally enhanced in the bottom row) to identify distinct patterns that can be linked to the three specific subtypes assessed in this study. Photos show (a,e) a healthy control and patients with (b,f) tremor-dominant PD, (c,g) postural instability and gait disturbance PD, and (d,h) mixed disease. Photo: Li D, et al. Invest Ophthalmol Vis Sci. 2025;66(6):21. Click image to enlarge. After undergoing in vivo confocal microscopy (IVCM) and comprehensive assessment of clinical neurological symptoms, researchers determined 23 patients had TD type Parkinson’s, 30 had PIGD type and 10 had mixed type. Most central and whorl-like corneal nerve indicators were found to be significantly lower in the PIGD subgroup compared with the TD group. It was further demonstrated that combined central and inferior whorl-like corneal nerve indicators exhibited high discriminatory power between the TD and PIGD types, with an area under the curve of 0.97.Specifically, the study researchers found that indicators quantifying corneal nerve injury—including corneal nerve fiber fractal dimension, inferior whorl length, inferior whorl fiber area, inferior whorl fiber width and inferior whorl fractal dimension—all significantly decreased in patients with Parkinson’s. Alongside this finding, the newly identified detection area of the inferior whorl-like area was found more sensitive in detecting nerve damage in PD patients.The authors relay that, “moreover, the receiver operating characteristic curve results indicate that IVCM has a high diagnostic efficacy in distinguishing PD from the control group, suggesting that, in addition to the traditionally recognized central nervous system degeneration, there are also peripheral neuropathies affecting small nerve fibers in PD.”In comparison of the subtypes, no significant differences were seen in corneal nerve branch density and corneal total branch density; however, TD subtype patients had significant decreases in corneal nerve fiber length and density. As well, corneal nerve fiber width, area and fractal dimension and inferior whorl length, inferior whorl fiber area, width and fractal dimension were all found to be lower in Parkinson’s patients with the PIGD subtype than TD subtype. This reflects observations in prior literature outlining that TD-type Parkinson’s patients typically have a better prognosis, slower disease progression and overall higher quality of life.The combination of central and whorl-like area corneal nerve parameters differentiated TD and PIGD subtypes with excellent diagnostic use, indicated by the area under the curve (AUC) being 0.97, which passed the combination of central region corneal nerve parameters, with an AUC of 0.83 and also outperforming plasma neurofilament light chain, with an AUC of only 0.66. As the investigators posit, “this indicates that the corneal whorl-like area nerves are also worthy of attention in PD-related peripheral neuropathy.”Taken together, they are hopeful that “in the future, corneal nerves may be used as a sensitivity indicator for observing the progress of patients with PD.”Click here for the journal source. Li D, Zhang X, Yang F, et al. Cornea nerves can identify different types of Parkinson’s disease. Invest Ophthalmol Vis Sci. 2025;66(6):21.