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SAN FRANCISCO, CA 8/29/14. A new study, published this week in the Journal of Experimental Medicine, revealed that retinal thinning is an early marker for progranulin-deficient frontotemporal dementia (FTD). Led by Bluefield Project postdoctoral fellow Michael Ward, MD, PhD, in the lab of senior author and Consortium for FTD Research (CFR) Investigator Dr. Li Gan at the Gladstone Institutes in San Francisco, CA, the new study compared retinas from mice and humans carrying progranulin mutations to those without mutations. Drs. Gan and Ward, together with collaborators from six other CFR-funded labs, observed increased death of retinal cells in mutation carriers, in some cases even before cognitive deficits were apparent.

“Because these patients have mutations in progranulin, we know they are at a greatly increased risk to develop FTD,” said Dr. Gan. “Thus, we could establish retinal thinning as a very early symptom of inherited FTD.”

The retina is an external extension of the brain, thus changes in the retina may predict changes in the parts of the brain known to atrophy in FTD. However, Dr. Ward cautioned that many factors contribute to differences in retinal thickness, including age, gender and ophthalmologic diseases. Thus, retinal thinning is unlikely to be used as a diagnostic tool in individual patients. “This is a population measurement, and there is variability in the population,” said Dr. Ward. While the current study effectively measured a snapshot of a single moment in time, Dr. Ward will next investigate retinal changes over time. “We will ask if the amount of change in an individual’s retinal thickness over months and years correlates with, or potentially even predicts, disease progression.” If so, measuring retinal thickness would provide an inexpensive, non-invasive method to monitor disease-relevant changes in the brain.

In addition, the researchers also investigated molecular changes that correlate with retinal cell death. They found that a protein called TDP-43 behaves abnormally in retinal cells of mice with progranulin mutations even before cell death occurs. TDP-43’s aberrant behavior likely results from changes in another protein called Ran. Proper Ran function is necessary for cells to survive. Exactly how progranulin mutations cause Ran to misbehave is unclear, but by increasing levels of Ran in progranulin-deficient cells, Dr. Ward and colleagues were able to reduce cell death. Thus, therapeutics that increase Ran levels may be beneficial in treating progranulin-deficient FTD.

This study, entitled “Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD” was partially funded by the CFR and the Bluefield Project to Cure FTD and published online in the Journal of Experimental Medicine on August 25, 2014.