Periodic Reporting for period 4 - OPTIMALZ (Optical imaging of ocular pathology in Alzheimer’s disease)
Reporting period: 2020-03-01 to 2020-08-31
The research funded by ERC Starting Grant OPTIMALZ (contract number 640396) focused on the development and application of novel optical techniques for imaging pathology related to Alzheimer’s disease in the eye and brain. Alzheimer’s disease is the most common form of dementia which affects increasing numbers of patients in our continuously aging society. Therefore, the search for powerful therapeutics as well as for reliable and early diagnostics poses an important research topic for the scientific community. Regarding the eye as an easily accessible outpost of the brain, OPTIMALZ explored new imaging techniques which shine a laser beam onto the neural tissue in the back of the eye and reconstruct 3D images of the optical properties of these tissues. These 3D images were then investigated in order to spot lesions in the eye related to Alzheimer’s disease. In parallel to investigating the retina in the back of the eye, we developed two optical imagers for studying the lens of the eye and brain tissue. Our multidisciplinary team consisting of physicists, engineers, biologists, and neuropathologists then applied the three prototypes for longitudinal studies of pathological lesions related to Alzheimer’s disease. We demonstrated that our technology is capable of visualizing and quantifying Alzheimeric lesions in the brain. We also found disruptions of the retinal morphology and focal deposits in the retina of a mouse model developing typical features of Alzheimer’s disease in the brain. However, at least to a certain extent, ocular lesions also occur in normal subjects, in particular at old age. We further observed opacifications and cataract in the crystalline lens of both wildtype and transgenic subjects of the specific model system we investigated. In summary, we developed novel optical imaging technology for the non-invasive visualization and quantitative assessment of lesions related to Alzheimer’s disease, which however may appear concurrently with other age-related abnormalities.
Three imaging devices were developed during the five years of OPTIMALZ. Tailored for imaging retina, lens and brain tissue, the three prototypes were used in longitudinal preclinical studies. Prototype 1 was designed for retinal imaging. Surpassing the resolution of state-of-the-art devices by more than five times, the prototype enabled 3D imaging of the retina with sub-micrometer resolution. In addition, it provided enhanced tissue contrast by means of a polarization-sensitive layout such that different retinal structures were distinguished based on their light polarizing properties. This was deemed particularly interesting for Alzheimer’s disease since we had demonstrated earlier that plaques found in the brains of patients can be visualized based on their polarization characteristics. Prototype 2 included a novel detection unit which can assess the way light is scattered by tissue structures. We experimentally confirmed that this approach can effectively identify lesions in the brain related to Alzheimer’s disease. Prototype 3 was a microscopy setup for three dimensional imaging of tissue samples, thereby providing both ultrahigh resolution and spectroscopic contrast. After having finished the design, assembly, programming, specification measurements and imaging test runs, the diagnostic potential of the three prototypes was explored for longitudinal in vivo and ex vivo imaging of Alzheimer’s disease related pathology. The outcome of OPTIMALZ was – thus far – published in 25 articles in peer-reviewed journals and presented by the team members at more than 30 international conferences.
The diagnosis of Alzheimer’s disease is challenging. The advantages of the approach explored in OPTIMALZ are twofold. Firstly, using an optical technique enables rapid, three-dimensional, micrometer-scale resolution imaging at rather low cost. Second, targeting the eye as an easily accessible outpost of the brain, neuropathology may be diagnosed in an unconventional yet simple way. While we have demonstrated that some of the ocular pathology attributed to Alzheimer’s disease were similarly observed in non-Alzheimer eyes such that disease patterns have to be interpreted with care, the methods developed and explored in OPTIMALZ may ultimately open the door to low-cost screening tools of neurological disease. Moreover, the technological advances resulting from this project have the potential to impact the development of novel imaging technology in other medical and non-medical fields.