Alzheimer’s Disease Peep Show

Alzheimer’s disease (AD) represents a unique challenge to researchers and clinicians – and society in general. There are a number of factors at play: much like glaucoma, it’s predominantly an age-related disease with symptoms that start to appear only after significant damage has occurred. Like with age-related macular degeneration, the societal problems are stark: caring for these patients is healthcare resource-intensive; the baby boomer generation is now getting to the age where AD is affecting large numbers of them, and this is a trend that’s set to continue for decades yet. But unlike either eye disease, objectively diagnosing and staging AD is a huge challenge. The current standard of care is essentially documenting mental decline, and biomarker assays of the blood, urine and cerebrospinal fluid are still in the research stage. Positron emission tomography scans using radioactive tracers can take a peek at β-amyloid buildup in the brain – but that’s expensive and not always conclusive. A biopsy of the hippocampus would likely be definitive – but that’s really only available at autopsy. A reliable, objective early diagnostic tool is a huge currently unmet need for patients with AD – and would be welcomed by researchers who are attempting to develop drugs to slow or stop progression.

It’s a tired cliché that the “eye is the window to the soul,” but it is a window to vascular and neural tissue: the retina. And retinal tissue undergoes similar changes to the rest of the brain in patients with AD. It was with this in mind that a team from the Center for Drug Design at the University of Minnesota (UMN) started to develop a technique that uses noninvasive hyperspectral endoscopy as a method for detecting amyloidopathy in mice – something that in humans, occurs early in AD, before cognitive decline becomes evident. In essence, a topical endoscope fundus imaging system was modified to use a machine vision camera with a tunable wavelength system for the acquisition of monochromatic images across the visible to near-infrared spectral range. When β-amyloid aggregates in the eye, it causes a reduction in the short-wavelength reflectance and an increase in Rayleigh light scattering from the retina. Using this method, they found it possible to distinguish between transgenic mice that express AD-like amyloid plaques in neural tissue (APP/PS1 mice) from wild type controls, and found that the changes in light scatter became more pronounced as the amount of amyloid aggregate increased (1). “We saw changes in the retinas of Alzheimer’s mice before the typical age at which neurological signs are observed. The results are close to our best-case scenario for outcomes of this project,” says Swati More, the first author of the publication that described the technique. Previous studies have shown that the retina can provide useful insight into amyloid in the brain, but detection required systemic injection of curcumin in order to bind to the plaques (2) – whereas the UMN procedure is noninvasive and does not label the amyloid prior to imaging. The team now plans to progress to human trials to further test the method, and think that in the future, checking for amyloid aggregates could potentially form part of a routine eye exam. They hope a test that can offer early diagnosis before the onset of symptoms could also play an important role in future drug development.