Retinal Lipofuscinosis as a Potential FTLD Biomarker (P05.059)

Objective: To determine if retinal lipofuscinosis can be used as a biomarker of brain pathology in a mouse model of familial frontotemporal lobar dementia (FTLD). Background A major impediment to the development of new treatments for neurodegenerative diseases is a lack of readily accessible, rapid, and inexpensive methods to follow disease progression in response to therapy. Non-invasive retinal imaging may be an ideal technology to address this problem, given mounting evidence of early retinal pathology in a range of neurodegenerative diseases. Recently, it was discovered that progranulin-deficient mice, which model a form of familial FTLD, accumulate intracerebral aggregates of an autofluorescent substance called lipofuscin. Since brain lipofuscinosis is accompanied by retinal lipofuscinosis in other neurological diseases, we hypothesized that aging progranulin-deficient mice would develop retinal lipofuscinosis, and that retinal lipofuscin could be visualized by commercially-available retinal imaging techniques. Design/Methods: Pathology and lipofuscinosis in the brains and retinas of aging wild-type and progranulin-knockout mice was determined using standard histological techniques. Scanning-laser ophthalmoscopy was used to image GFP-tagged microglia and lipofuscin in living mice. Results: Progranulin-KO mice developed a striking degree of retinal lipofuscinosis as they aged, and retinal lipofuscinosis correlated with brain lipofuscinosis. In aged progranulin-KO mice, severe loss of retinal ganglion cells (RGCs) occurred. Large aggregates of lipofuscin were found in retinal microglia prior to the accumulation of lipofuscin in brain microglia, suggesting early loss of lipofuscin-laden neurons in the retina. Furthermore, we observed microgliosis and lipofuscin deposition via laser-scanning ophthalmoscopy in living progranulin-KO mice. Conclusions: Retinal lipofuscinosis and loss of RGCs is an age-dependent phenotype of progranulin-KO mice, and this lipofuscinosis can be imaged non-invasively in living mice using commercially-available technology. These results pave the way for future clinical trials with human subjects to determine if retinal lipofuscinosis can serve as a FTLD biomarker. Supported by: Chartrand Eye Research Foundation. UCSF Research Allocation Program. Bluefield Foundation Postdoctoral Fellowship. Disclosure: Dr. Ward has nothing to disclose. Dr. Taubes has nothing to disclose. Dr. Gan has nothing to disclose. Dr. Green has received personal compensation for activities with Novartis and Biogen Idec as a consultant and/or participant on an advisory board and adjudication committee.