TDP43 pathology in chronic traumatic encephalopathy retinas

Abstract

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head trauma. Brain pathology in CTE is characterized by neuronal loss, gliosis, and a distinctive pattern of neuronal accumulation of hyper-phosphorylated tau (p-tau) and phospho-TDP43 (p-TDP43). Visual anomalies have been reported by patients with CTE, but the ocular pathology underlying these symptoms is unknown. We evaluated retinal pathology in post-mortem eyes collected from 8 contact sport athletes with brain autopsy-confirmed stage IV CTE and compared their findings to retinas from 8 control patients without CTE and with no known history of head injury. Pupil-optic nerve cross sections were prepared and stained with hematoxylin and eosin (H&E), p-tau, p-TDP43, and total TDP43 by immunohistochemistry. No significant retinal degeneration was observed in CTE eyes compared to control eyes by H&E. Strong cytoplasmic p-TDP43 and total TDP43 staining was found in 6/8 CTE eyes in a subset of inner nuclear layer interneurons (INL) of the retina, while only 1/8 control eyes showed similar p-TDP43 pathology. The morphology and location of these inner nuclear layer interneurons were most compatible with retinal horizontal cells, although other retinal cell types present in INL could not be ruled out. No p-tau pathology was observed in CTE or control retinas. These findings identify novel retinal TDP43 pathology in CTE retinas and support further investigation into the role of p-TDP43 in producing visual deficits in patients with CTE.

Keywords: Chronic traumatic encephalopathy (CTE); Eye pathology; Inner nuclear layer; Retina; TDP43; Tau.

Fig. 1

H&E. A, B Retinal thickness was comparable between control eyes (A) and CTE eyes (B); scale bar = 40 μm. C Quantification of retinal thickness in number of nuclei by layer, 1 mm (GCL1, INL1, ONL1) or 2 mm (GCL2, INL2, ONL2) from the optic nerve toward both equators per retina, in CTE (n = 6–7) and control eyes (n = 7). Error bars show mean ± standard errors. Student’s t-test comparisons of means between CTE and controls are shown, and p < 0.05 was considered statistically significant. RNFL, retinal nerve fiber layer, GCL, ganglion cell layer, IPL, inner plexiform layer, INL, inner nuclear layer, OPL, outer plexiform layer, ONL, outer nuclear layer

Fig. 2

p-TDP43 immunohistochemistry. A Negative control—section of hippocampal dentate from a normal autopsy brain shows no p-TDP43 staining; scale bar = 80 μm. B Positive control—section of hippocampal dentate from patient with FTLD-TDP shows neuronal staining. C, D Representative control retinas show no p-TDP43 staining; scale bar = 60 μm. E–H Sections of retina from representative CTE cases show staining for p-TDP43 in outermost subset of cells (red arrow) in the inner nuclear layer. H Shows enlarged blow-up of area in square in (G); scale bar = 40 μm. All retina pictures are oriented with ONL at bottom

Fig. 3

Positive p-TDP43 immunohistochemistry in control retina. p-TDP43 immunohistochemistry of the control retina (case #1) with p-TDP43 staining in outermost subset of cells in the INL. ONL is oriented at the bottom

Fig. 4

Total TDP43 immunohistochemistry. A Positive control—amygdala from a patient diagnosed with Alzheimer’s Disease, showing cytoplasmic positive, nuclear negative total TDP43 staining; scale bar = 50 μm. B CTE retina showing cytoplasmic positive, nuclear negative total TDP-43 staining of a cell (arrow) in the outermost aspect of inner nuclear layer; scale bar = 25 μm. Retina images are oriented with ONL at bottom

Fig. 5

p-tau (AT8) immunohistochemistry. A Negative control—Frontal cortex from autopsy of a patient with no history of dementia; scale bar = 150 µm. B Positive control – Frontal cortex of Alzheimer’s disease patient; scale bar = 150 μm. C Control retina shows no p-tau (AT8) staining; scale bar = 60 μm. D Sections of retina from cases of CTE show no immunoreactivity for p-tau; scale bar = 60 μm