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Could retinal thinning be a biomarker for the detection of early Parkinson‘s disease?

Retinal thinning appears to a consistent finding in patients with Parkinson‘s disease and questions have arisen over whether this serves as an early biomarker for the subsequent onset of the disease. Clinical writer Rod Tucker delves into the evidence.

Parkinson’s disease (PD) is estimated to affect at least 1% of people over the age of 60. The neurodegenerative condition affects both movement and cognition and is linked with the loss of dopaminergic neurons in the substantia nigra together with the presence of Lewy bodies.

Symptoms and progression of PD depend on the subtype, but patients with PD commonly experience tremor, bradykinesia and muscle stiffness, and up to 70% also have recurrent visual complaints and visual hallucinations.

But what is responsible for the visual dysfunction, and is it somehow linked to direct dopaminergic impairment within the eyes?

The fact that dopaminergic neurotransmission occurs within retina has been known since 1982, and the first evidence that patients with PD could experience visual problems emerged in 1987. Researchers observed a loss in both flicker sensitivity and near the peak of the spatial contrast sensitivity in those with the disease. But whether these visual deficits was causally related to PD remained unknown.

Definitive proof linking visual dysfunction with PD finally arrived, but from a rather unusual source. Canadian researchers decided to measure the level of dopamine in the retinas of eight patients with PD who died.

They stratified their findings based on each individual‘s last dose of levodopa therapy. While the retinal dopamine content in five patients who received levodopa therapy before death was similar to that in the controls, the levels were significantly lower in those who had not received the drug within the last five days before death.

Retinal thinning in Parkinson‘s disease

As it became widely acknowledged that retinal levels of dopamine were often reduced in patients with PD, whether this was also associated with a concurrent loss of retinal tissue was less clear. Establishing such a relationship became much easier in 1994, following the introduction of optical coherence tomography (OCT).

This technique, which uses near-infrared light, enabled an assessment of nerve fibre thickness in the eye. In 2004, using OCT, researchers were able to show there was reduced thickness of the circumpapillary retinal nerve fibre layer in patients with PD.

Later work quantified this reduction in comparison to healthy controls and established that retinal thinning of the inner retinal layer was significantly greater in those with PD.

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Although there was an emerging consensus that retinal thinning was a hallmark of PD, it wasn‘t actually a universal finding. For instance, other work was unable to detect a difference in comparison to healthy controls. A second study, which also failed to detect differences with PD and healthy controls, called for further work to define the role of OCT as a diagnostic biomarker.

Nevertheless, in a 2018 study, Korean researchers not only re-affirmed the presence of retinal thinning in patients with PD but provided the first evidence that there was a correlation between retinal thinning and nigral dopaminergic neuronal loss within the brains of patients who were at an early stage of their disease.

The relationship between retinal changes and PD was further strengthened in a 2021 meta-analysis of 27 studies that included 1,470 patients. The authors concluded that whole thickness – the thickness of the combination of ganglion cell layer and inner plexiform layer – and nerve fibre layer of central retina are significantly reduced in PD patients.

Retinal changes prior to disease onset

With confirmation of the relationship between retinal thinning and nigral dopaminergic neuronal loss, researchers sought to address a further pertinent question. If retinal thinning could be detectable in those without overt PD, could it serve as a prognostic marker for the disease?

This was the question posed in a recent study in the journal Neurology. Researchers assessed retinal thinning in two separate cohorts: one in patients with established PD and one in a second prospective cohort where retinal imaging had been performed.

The team looked at several aspects of retinal tissue including the ganglion cell-inner plexiform layer (GCIPL) and inner nuclear layer (INL) thicknesses, which had been measured in the two cohorts with OCT.

As expected, individuals in the first cohort with prevalent PD had thinner GCIPL and INL when compared to healthy controls. But what was more intriguing was how, in the prospective cohort in which patients had undergone OCT imaging approximately 2,653 days before the onset of PD, there was also significant GCIPL and INR thinning in those who went on to develop PD.

For example, the hazard ratio for a thinner GCIPL was 0.62 per standard deviation increase. In other words, for each standard deviation increase in GCIPL thickness, the risk of developing PD was reduced by 38%. In fact, the relationship remained significant even after excluding patients who developed PD within the first 24 months after their retinal imaging.

Taken together, the findings from the current study suggest that retinal thinning can be detected almost seven years before the onset of PD.

With the recognition that visual dysfunction in patients with PD is a harbinger of cognitive decline and greater white matter damage over time, it seems that the retina could become a potential imaging target.

There is still much more work that needs to be done, in particular, establishing the sensitivity and specificity of these changes, before the results can be used to predict whether an individual will develop PD. But if retinal thinning does turn out to be an effective biomarker, it could be used to support the early diagnosis of PD, thereby allowing for more effective treatment planning in those deemed to be at risk of developing the condition.

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