A team with world-class expertise in ophthalmic disease, imaging, retinal pathology, and biomedical engineering will utilize hyperspectral imaging to provide, for the first time, in vivo molecular probing, validated with histopathologic correlation, of age-related macular degeneration (AMD). Their system, a specially modified fundus camera harnessed to cutting-edge biomedical image analysis techniques, will revolutionize the field by identifying the distribution and spectral signature of the various chromophores and fluorophores associated with AMD lesions. Drusen, the hallmark lesions of AMD, are biochemically heterogeneous and are key to understanding this disease. However, their composition cannot be determined in vivo with even the current highest resolution techniques. Hyperspectral imaging data, now uniquely clinically attainable with a new snapshot hyperspectral device, offers a vision of spectral biopsy of the retina. This data is encoded in a four-dimensional hypercube, with two spatial (x and y coordinates) and two spectral (amplitude and wavelength) dimensions. This complex data cube can be explored with advanced unsupervised mathematical tools that search out the dominant spectral signatures in the data matrix. By dissecting the spectral reflectance and autofluorescence (AF) signatures from drusen and other AMD lesions, this research will achieve in vivo spectral classifications of these lesions. To accomplish this, the research team plans to acquire hyperspectral, photographic, AF and infrared scanning laser ophthalmoscope (SLO), and spectral domain optical coherence tomography (SD-OCT) images of all phenotypes of AMD, with analysis of the hyperspectral images by an optimized matrix factorization protocol to recover dominant spectra and their spatial distributions. Hyperspectral AF images will also be acquired simultaneously with the same device by adding appropriate excitation and barrier filters. Further, hyperspectral imaging of genotyped donor eyes will provide histopathologic confirmation of the components of drusen and other AMD lesions that correlate with the drusen spectral signatures, as well as robust genotype/phenotype correlations. Long-term goals: We envision an integrated imaging system for AMD and ophthalmologic care that incorporates this paradigm shift in technology. Having such a system of in vivo molecular probes will be instrumental in research. The insights so obtained will be of high value in clinical diagnosis and treatment. In addition, such a system will accelerate translational research with sensitive and early outcome testing of prospective therapeutic agents, saving sight and thereby providing enormous benefit to society.