Retinal Horizontal Cell TDP-43 Pathology in Chronic Traumatic Encephalopathy Patients’ Retinas

Abstract

Purpose : Brain pathology in chronic traumatic encephalopathy (CTE) includes the accumulation of hyperphosphorylated tau (p-tau), as well as TAR DNA binding protein 43 kDa (TDP-43) in late stages. Visual abnormalities including photophobia, visuospatial perception defects, and hallucinations have been described in CTE; however, retinal pathology and its contribution to visual defects in CTE are unknown. In this retrospective study, we examined the retinal histopathology from patients with autopsy-confirmed stage IV CTE.

Methods : Enucleation specimens from 8 control patients (6 males and 2 females; ages 61-81; mean: 69.6; SD: 6.9) and 8 patients with stage IV CTE (8 males; ages 62-93, mean: 77.5, SD: 9.9) were collected. Control patients had no known history of traumatic brain injury and no evidence of CTE at autopsy. CTE patients were former contact sport athletes (football, rugby, or boxing). Pupil-optic nerve cross sections were prepared and stained with hematoxylin and eosin (H&E). Immunohistochemistry was performed using anti-p-tau (AT8, Thermo Fisher; 1:1000), anti-pTDP-43 (Cosmo Bio; 1:1000), and anti-TDP-43 antibodies (Proteintech; 1:6000).

Results : Retinal anatomy including retinal lamina thickness was comparable between CTE and control by H&E. No p-tau pathology was observed in either CTE or normal retinas. pTDP-43 staining was commonly found in CTE retinas (7/8) but rarely seen in controls (1/8). Staining was limited to a small subset of inner nuclear layer (INL) interneurons at the junction between INL and outer plexiform layer. TDP-43 staining also revealed a small subset of INL interneurons with cytoplasmic TDP-43+ inclusions and loss of nuclear TDP-43 expression. The location of these cells in INL is most consistent with retinal horizontal cells. TDP-43 pathology was not identified elsewhere in the retina.

Conclusions : This study identified that stage IV CTE is associated with novel retinal TDP-43 and pTDP-43 neuropathology in a discrete subset of retinal INL interneurons consistent with horizontal cells. Additional studies in larger cohorts are needed to define the role of TDP-43 in normal and diseased horizontal cells. Our findings suggest that abnormalities in horizontal cell functions (e.g., light/dark adaptation, contrast sensitivity) secondary to pTDP-43 accumulation may be possible clinical symptoms in CTE patients.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.