RETINAL IMAGING OF AB DEPOSITS IN AD PATIENTS: FROM HISTOLOGICAL EXAMINATION TO CLINICAL TRIALS

There is an urgent unmet need for noninvasive diagnosis of Alzheimer's disease (AD) especially at early stages to facilitate prevention or therapeutic intervention. The retina as an extension of the brain can be imaged directly and noninvasively with high resolution and sensitivity. We previously identified hallmark amyloid β-protein (Aβ) deposits in postmortem retinas of AD patients and early stage cases. Subsequent studies, found the characteristic brain pathology pTau, Aβ-like deposits, and accumulation of Aβ 1-42 peptides, in postmortem AD patients' retina. To characterize geographical distribution, layer location, and ultrastructural morphology of Aβ deposits, we utilized retinal whole mounts and cross sections from MCI, AD patients, and age-matched controls so as to guide the subsequent live imaging protocol. We further translated our noninvasive rodent retinal Aβ-plaque imaging approach using curcumin labeling into human trials. Screening of whole mount retinas from MCI and AD patients revealed clusters of abluminal Aβ deposits, especially in proximity to blood vessels in the superior and inferior-nasal quadrants. Age-matched controls showed only scarce Aβ deposition. In retinal cross sections, Aβ deposits were abundant in the innermost layers, and occasionally appeared perivascular and intracellular. Moreover, electron microscopy analysis confirmed the ultrastractural morphology of retinal Aβ deposits and fibrils. In pilot clinical trials, we report for the first time the detection of Aβ plaques, via curcumin fluorescence, in the retina of live AD patients. A proprietary oral curcumin formulation with high bioavailability and modified scanning confocal ophthalmoscope were utilized. We further developed and optimized a fully automated calculation of a Retinal Amyloid Index (RAI), a quantitative measure of curcumin-labeling amyloid in the retina. Analysis of RAI scores, including Aβ plaque number, area and distribution, showed a significant increase in RAI geometric means of AD patients (P = 0.0088), approximately 2.7 times higher than the matched controls. This study demonstrates early accumulation of Aβ deposits in AD retina, abundant in the innermost layers and in clusters within distinctive geographical distribution. The feasibility to detect Aβ deposits by noninvasive retinal imaging and differentiate between AD patients and controls may present an excellent modality for early diagnosis and monitoring AD therapies.