Can We Detect Neurological Diseases Through the Eyes?

Gisbi Susan Shaji, M.Optom

Junior Research Fellow, Manipal Academy of Higher Education, Manipal, India

Understanding how the brain works is one of the most fundamental scientific concerns today. Conventional brain imaging techniques make it difficult to study problems like vascular function and protein aggregation in the brain.  It takes a large degree of change in the neurons for a person to begin to exhibit symptoms. The delayed onset of symptoms frequently results in a delayed diagnosis of the condition.

The retina is located in the posterior part of the eye and comprises a layer of photoreceptors that include neurons responsible for converting light into electrical signals and initiating the visual process. The retina’s proximity to the brain and direct connection to the optic nerve makes it one of the central nervous system’s closest extensions, rendering it vulnerable to neuron degeneration or death. ⁽¹⁾ So, any changes in the brain can also be mirrored in the retina. ^{(2; 3)} Anomalies in any part of the brain may be discerned by observing abnormalities in the retina and advanced technologies in capturing retinal images give unprecedented resolution, which offers an unique systems biological view on the cellular and molecular changes underlying these pathologies, which makes it promising for biomarker development.

In the 1980s, optical coherence tomography (OCT) was widely utilised to diagnose optic neuropathies and with the invention of OCT angiography (OCTA), it became even more effective in finding anomalies in retinal arteries and capillaries. With further technological developments, we were able to identify cell deaths, protein aggregation, and perfusions while also developing unique methodologies based on existing confocal laser scanning ophthalmoscopy (cSLO) techniques. ⁽⁴⁾ These techniques along with electrophysiological techniques, provide a cost-effective and time-efficient non-invasive method for studying retinal physiology.

Neurodegenerative proteinopathies are conditions that cause an accumulation of proteins in the brain that can cause degeneration of neurons, such as beta-amyloid (Ab) plaques and tau tangles in Alzheimer’s disease and alpha-synuclein (aSYN) aggregates in Parkinson’s disease. (1) There is only a limited number of studies that have examined the prevalence of aggregated- Ab, tau, and aSYN in the AD/PD retina. (5; 6; 7; 8; 9) Retinal abnormalities in Alzheimer’s and Parkinson’s patients include ganglion cell neurodegeneration, alterations in microvascular perfusion density, vessel calibres, and vascular network structural modifications. Multimodal retinal imaging has the potential to improve biomarker-based classification of a variety of neurodegenerative disorders. Integrating retinal imaging techniques into current biomarker classification schemes, such as the ATN (Amyloid, Tau, Neurodegeneration) system for Alzheimer’s disease, can increase diagnostic accuracy. (1) Table 1 summarises biomarker categories, imaging modalities used in clinical practice, and key findings in Alzheimer’s and Parkinson’s disease patients./p>

Table 1: Key biomarkers and imaging findings in Alzheimer’s and Parkinson’s disease ⁽¹⁾

A few of the retinal imaging modalities shown in Table 2 provide a comprehensive view of disease processes affecting the neurovascular unit in the retina. Notably, in a multimodal approach, these imaging biomarkers can be combined with electrophysiological measures and chemical biomarkers in the tear film, aqueous, or vitreous humour. It is crucial to note that some procedures are still experimental, while others have not yet been employed in Alzheimer’s and Parkinson’s disease studies, although they are a useful diagnostic tool. (1)

Table 2: Retinal imaging techniques used in different constituents of the neurovascular unit in the retina ⁽¹⁾

References:

1. Lieve Moons, Lies De Groef, Multimodal retinal imaging to detect and understand Alzheimer’s and Parkinson’s disease, Current Opinion in Neurobiology, Volume 72, 022, Pages 1-7, ISSN 0959-4388, https://doi.org/10.1016/j.conb.2021.07.007.
2. Past, present, and future role of retinal imaging in neurodegenerative disease, Progress in Retinal and Eye Research,Volume 83,2021,100938,ISSN 1350-9462,https://doi.org/10.1016/j.preteyeres.2020.100938. Amir H. Kashani, Samuel Asanad, Jane W. Chan, Maxwell.
3. Den Haan J, Morrema THJ, Verbraak FD, de Boer JF, Scheltens P, Rozemuller AJ, Bergen AAB, Bouwman FH,Hoozemans JJ: Amyloid-beta and phosphorylated tau in postmortem Alzheimer’s disease retinas. Acta Neuropatholy Commun 2018, 6:147.
4. Ortuño-Lizarán I, Beach TG, Serrano GE, Walker DG, Adler CH, Cuenca N: Phosphorylated a-synuclein in the retina is a biomarker of Parkinson’s disease pathology severity. MovDisord 2018, 33:1315–1324.
5. Jiang J, Wang H, Li W, Cao X, Li C: Amyloid plaques in retina for diagnosis in alzheimer’s patients: a Meta-analysis. Front Aging Neurosci 2016, 8:267.
6. den Haan J, Morrema THJ, Verbraak FD, de Boer JF, Scheltens P, Rozemuller AJ, Bergen AAB, Bouwman FH, Hoozemans JJ: Amyloid-beta and phosphorylated tau in postmortem Alzheimer’s disease retinas. Acta Neuropathol Commun 2018, 6:147.
7. Ortuño-Lizarán I, Beach TG, Serrano GE, Walker DG, Adler CH, Cuenca N: Phosphorylated a-synuclein in the retina is a biomarker of Parkinson’s disease pathology severity. MovDisord 2018, 33:1315–1324.
8. Veys L, Vandenabeele M, Ortuno-Lizaran I, Baekelandt V, Cuenca N, Moons L, De Groef L: Retinal alpha- Synuclein deposits in Parkinson’s disease patients and animal models. Acta Neuropathol 2019, 137:379–395.
9. Schön, C., Hoffmann, N. A., Ochs, S. M., Burgold, S., Filser, S., Steinbach, S., … & Herms, J. (2012). Long-term in vivo imaging of fibrillar tau in the retina of P301S transgenic mice. PloS one, 7(12), e53547.