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J. A. Moncaster, R. D. Moir, A. G. Mocofanescu, R. Webb, M. A. Burton, N. Casey, J. G. Ghosh, J. I. Clark, R. E. Tanzi, L. E. Goldstein; Second Generation Laser Ophthalmic Technology for Quantitative Non-Invasive Detection of Alzheimer’s Disease Molecular Pathology in the Lens. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5182.
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© ARVO (1962-2015); The Authors (2016-present)
Alzheimer’s disease (AD) is the most common age-related dementia and the sixth leading cause of death in the US. New technology is urgently needed to facilitate early disease detection and early intervention when emerging therapeutics are expected to be most effective and enduring. We previously reported AD-linked Aβ deposition, amyloid pathology, and distinctive co-localizing supranuclear cataracts in human AD lenses (Goldstein et al., Lancet, 2003) and AD transgenic mice (ARVO, 2009). First-generation laser technology non-invasively detected pre-cataractous lenticular Aβ accumulation in AD transgenic mice before brain amyloid pathology. Here we report initial characterization of second-generation ophthalmic AD molecular diagnostic technology with direct biochemical specificity conferred by amyloid-binding fluorescent ligands.
Protoype platform technology combines confocal anterior segment laser scanning ophthalmoscopy, dry optics, single photon detection, and fluorescence correlation spectroscopy with a topically administered highly lipophilic amyloid binding fluophore.
Optical characterization utilizing single photon detection indicates axial resolution of <2µm and confocal volume dimensions suitable for fluorescence correlation spectroscopy in vitro and in vivo. Fluorescence lifetime decay, fluorescence correlational spectroscopy, and quasi-elastic light scattering are demonstrated and compared using model systems that approximate the optical properties and composition of the human AD lens. Systemic and topical (o.u.) administration of a lipophilic amyloid binding fluorescent ligand results in lens bioavailability and clearance.
Our data lend further support for use of AD-linked Aβ pathology in the lens as an optically accessible AD biomarker and highlight the potential of combining specific bioavailable ligands with advanced laser ophthalmic spectroscopic techniques for disease screening, diagnosis, and monitoring.
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