Alzheimer’s disease diagnosis

Retinal pathology targeted as accessible indicator of disease in the brain. Cheryl Guttman Krader reports

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The identification of ocular biomarkers of Alzheimer’s disease (AD) pathology in the retina has been an area of active research for more than 10 years as investigators aim to develop non-invasive techniques for diagnosis, monitoring disease progression and evaluating responses to therapeutic interventions. To date there have been promising advances. However, there is much work yet to be done before any finding related to the eye becomes accepted as a biomarker for AD, said Maya Koronyo-Hamaoui PhD. Dr Koronyo-Hamaoui is Associate Professor of Neurosurgery and Biomedical Sciences at Cedars-Sinai Medical Centre, Los Angeles, CA, USA. A decade ago, she, Yosef Koronyo and colleagues showed for the first time that amyloid-β protein (Aβ) plaques, which represent the neuropathological hallmarks of AD, were present in the retina of post-mortem eyes of patients with AD. Dr Koronyo-Hamaoui told EuroTimes that while there has been much progress in the development of structural, functional, and molecular imaging technologies for identifying AD-related pathology in the brain, the molecular tools are more suitable for research purposes and are still limited for wide-scale deployment in the clinical setting. “Current brain imaging technologies used for AD diagnosis, including positron emission tomography among others, are expensive, not widely available, have limited resolution or specificity, and some are invasive, requiring the use of unsafe radioisotopes,” she said. Interest in studying the retina lies in the fact that this neural tissue is an extension of the brain that shares many structural, functional, and biochemical characteristics, and it is the only central nervous system structure that is not shielded by bone. Therefore, it is accessible to live imaging with non-invasive techniques, she explained. FOCUSING ON THE EYE Investigators searching for ocular biomarkers of AD have followed a number of different paths. Their studies include characterisation of functional consequences, including changes in contrast sensitivity, colour perception, pupillary responses, saccadic eye movements and circadian rhythms, which are modulated by photosensitive retinal ganglion cells. In addition, researchers have looked for signs of structural changes in the retina using OCT, changes in vascular structure and blood flow using OCT angiography, and evidence of inflammation. However, Dr Koronyo-Hamaoui believes that identification of Aβ plaques in the retina may be the most appropriate target. She explained: “AD is associated with neurodegeneration, inflammation and vascular pathology. Those changes in the brain lead to cognitive impairment and in the eye they have functional implications as well. However, neurodegeneration, inflammation and vascular changes in the retina can occur with ageing and with other CNS, vascular diseases, or purely ocular diseases.” “Aβ deposition along with pTau protein pathology are recognised as very early biomarkers of AD and thought to induce and amplify the development of the inflammation and vascular changes that result in the synaptic and neuronal losses, which ultimately manifest as clinically evident dementia. While a person with Aβ plaques in the brain will not necessarily develop AD, nor is it known for certain that Aβ deposition is the earliest sign of AD and the driving factor for other AD pathology, Aβ plaques are specific to AD and necessary for AD diagnosis.” DOCUMENTING RETINAL AβDEPOSITION Evidence supporting a focus on retinal Aβ comes from studies of paired brain and retina post-mortem tissue from patients with neuropathologically-confirmed AD that showed a strong correlation between the two sites in the severity of the Aβ burden and in other AD-related pathology, including presence of pTau, neurodegenerative changes and atrophy. Non-invasive in vivo retinal amyloid imaging became possible when the Cedars-Sinai group developed technology that was subsequently developed for commercial use by several manufacturers. The approach involves oral administration of curcumin, a safe and natural fluorochrome that binds specifically to amyloid, and its detection with laser ophthalmoscopy. More recently, researchers at the University of Minnesota, Minneapolis, USA, developed a hyperspectral imaging technique as another non-invasive approach for detecting retinal Aβ. Based on the principle that Aβ has a wavelength-dependent effect on light scatter, it measures a retinal reflectance spectrum without the need for an exogenously administered label. Using their system in clinical studies, Dr Koronyo-Hamaoui and colleagues showed the retinal Aβ burden in patients with AD was higher than in cognitively normal controls. In another study, they showed that it correlated with hippocampal volume in patients with mild cognitive impairment. Forthcoming publications from the Cedars-Sinai group are reporting that retinal Aβ burden predicts a certain AD-related memory domain loss, Dr Koronyo-Hamaoui said. The imaging technique has also been used in animal models and pilot clinical trials that documented reduction in retinal Aβ plaques in response to immunomodulation therapy. It is now being used in larger scale studies to assess outcomes of investigational interventions for AD. “It can take up to 20 years before AD-related pathology in the brain progresses to a state where clinical symptoms appear. Early intervention during the preclinical stage will be key for limiting the devastating consequences of AD. Finding non-invasive tools that will provide early AD diagnosis and allow repeated monitoring to evaluate therapeutic response is critical for identifying effective treatments,” Dr Koronyo-Hamaoui added. Maya Koronyo-Hamaoui: Maya.Koronyo@cshs.org