TDP-43 proteinopathy in the retina of patients with frontotemporal lobar degeneration

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a clinically and pathologically heterogeneous disease. The distinct underlying pathologies include aggregation of TDP-43, tau and FUS. Currently, no ante-mortem biomarkers are available to distinguish between the different pathological subtypes, providing challenges for diagnosis and therapeutic interventions. As an extension of the brain, the retina displays similarities in terms of anatomy and functionality. The accessibility of the retina provides a 'window' into the brain and a great potential for noninvasive imaging of neurodegenerative changes in patients. The aim of this study is to assess the presence of TDP-43 in the retina. METHOD: Post-mortem retina tissue was obtained from donors with FTLD-TDP (n=6), of which 3 donors carried a C9orf72 repeat expansion, one progranulin (PRGN) mutation and two sporadic donors. We also included donors with FTLD-tau (n=5), FTLD-FUS (n=1) , AD with limbic TDP-43 depositions (n=2), and donors with ALS-TDP (n=2). Immunohistochemical stainings were performed for panTDP-43, phosphorylated TDP-43 (pTDP-43), p62, and dipeptides (polyGA and polyGP). RESULT: In C9orf72 and PRGN mutation carriers, as well as one sporadic FTLD-TDP donor, TDP-43 inclusions were observed in the outer plexiform layer of the retina. One sporadic donor showed granular TDP-43 deposits in amacrine cells. No TDP-43 inclusions were observed in FTLD-tau, ALS and AD donors. Interestingly, all C9orf72 mutation carriers showed abundant presence of p62 and dipeptide inclusions in the inner nuclear layer of the retina. CONCLUSION: Manifestations of TDP-43 and dipeptide pathology are present in the retina of patients with FTLD-TDP. No TDP-43 inclusions are present in the retina of ALS or AD patients with limbic TDP-43 pathology, suggesting that retinal TDP-43 pathology is specific for FTLD-TDP. With the advances in ocular imaging techniques these findings provide opportunities for non-invasive retinal imaging for diagnosis and monitoring progression of FTLD-TDP.