Fundus imaging results promising for early Alzheimer’s diagnosis

Studies in mice suggest that a technology based on topical endoscope fundus imaging could allow early diagnosis of Alzheimer’s disease, researchers have said.

“We saw changes in the retinas of Alzheimer’s mice before the typical age at which neurological signs are observed,” said co-author Swati More of the University of Minnesota in Minneapolis (UMN), in a press release. “The results are close to our best-case scenario for outcomes of this project.”

Dr More and colleagues published the findings in Investigative Ophthalmology & Visual Science. 

“Early detection of Alzheimer’s is critical for two reasons,” said co-author Robert Vince, also of UMN, in the press release.

“First, effective treatments need to be administered well before patients show actual neurological signs. Second, since there are no available early detection techniques, drugs currently cannot be tested to determine if they are effective against early Alzheimer’s disease. An early diagnostic tool like ours could help the development of drugs as well.” 

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Whether or not the eyes are the “windows of the soul” as the French poet Guillaume de Salluste Du Bartas suggested, they do provide the closest thing you can get to a direct view of the brain without surgery.

“The retina of the eye is not just ‘connected’ to the brain-it is part of the central nervous system,” said Dr More.

Already researchers have documented changes to the retinal vasculature and optic disc, retinal cell loss, and thinning of the retinal nerve fibre layer (RNFL) in people with Alzheimer’s, but these were not specific to the disease.

NeuroVision Imaging (Sacramento, CA, USA) has developed retinal fluorescence photography to scan the supranuclear region of the retina for a fluorescent signature typical of plaques characteristic of Alzheimer’s, the researchers note. But this approach requires administration of curcumin prior to imaging, which binds to the plaques.

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In a previous study of flat-mounted retinas from transgenic Alzheimer's mice (APP/PS1), the UMN team showed through hyperspectral dark-field microscopy that certain optical property aberrations of the retina are unique to Alzheimer’s, correlate with Alzheimer’s progression, and occur before retinal plaques can be observed. 

The researchers observed optical signals consistent with Rayleigh light scattering changes in the spectrum from whole mount APP/PS1 mice retinas and their age-matched counterparts. They speculated that these changes could be from the assemblies of amyloid beta molecules.

Research progression

In recent years, evidence has mounted implicating amyloid beta aggregates as playing a key part in the development of Alzheimer’s, the researchers write.

Soluble amyloid beta aggregates such as globulomers and pore-forming hollow rods appear to interact specifically with neuronal cell-membrane components.

On one hand, pore-forming rods compromise membrane integrity, allowing for general disruption of homoeostasis. On the other hand, globulomers strongly agonise N-methyl-D-aspartate receptors, causing psychiatric changes as well as intense oxidative stress in the cytoplasm that will lead to neuronal cell-death over time.

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The researchers argue that their technique is the first to exploit the unique optical properties of suspended particles in the size-range of around 50 to 500 nm (Rayleigh scattering itself and various magnitudes and directionalities of Mie scattering phenomenon). They point out that this size-range coincides with that of those amyloid aggregation orders that have been shown to cause the symptoms as well as the neuronal damage of Alzheimer’s disease, they write. 

As the next step, the UMN team wanted to see if they could observe the same changes in living Alzheimer’s mice. So they used a machine vision camera and tuneable wavelength system to obtain monochromatic optical endoscope fundus images across the visible to near-infrared spectral range.

They imaged Alzheimer's and age-matched, wild-type mice monthly from months 3 through 8 to assess changes in the fundus reflection spectrum. They fit optical changes to Rayleigh light scatter models as measures of amyloid aggregation.

They rated as “good quality” the spectral images they obtained of the central retina. Short-wavelength reflectance from Alzheimer's mice retinas appeared to diminish over time compared with wild-type mice.

They judged the optical changes to be consistent with an increase in Rayleigh light scattering in neural retina due to soluble amyloid beta aggregates. “The changes in light scatter showed a monotonic increase in soluble amyloid aggregates over a 6-month period, with significant build-up occurring at 7 months,” they write.

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No one has ever before detected early Alzheimer's disease in a live Alzheimer's mouse using hyperspectral imagery without the use of an extraneous agent, the researchers say.

One advantage of this technique is that it is non-invasive. The researchers were able to measure signals in live mice using a safe level of light exposure over 10 seconds.

They anticipate that that a similar exposure duration would be used to examine light scattering changes in patients.

“Timely diagnosis of [Alzheimer’s disease] is paramount for proper treatment and evaluation of the latter's efficacy,” the authors conclude. “We expect this technology to prove suitable for translation into a human diagnostic tool. Such developmental efforts are underway.”