Retina tissue validation of optical coherence tomography determined outer nuclear layer loss in FTLD-tau

Benjamin J Kim,Edward B Lee,Adrienne Saludades,John Q Trojanowski,Murray Grossman,David J Irwin,Vivian Lee,Joshua L Dunaief

doi:10.1186/s40478-021-01290-8

Benjamin J Kim, Edward B Lee + Show 6 more

Open Access

https://doi.org/10.1186/s40478-021-01290-8

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Abstract

Alzheimer’s disease (AD) is associated with inner retina (nerve fiber and ganglion cell layers) thinning. In contrast, we have seen outer retina thinning driven by photoreceptor outer nuclear layer (ONL) thinning with antemortem optical coherence tomography (OCT) among patients considered to have a frontotemporal degeneration tauopathy (FTLD-Tau). Our objective was to determine if postmortem retinal tissue from FTLD-Tau patients demonstrates ONL loss observed antemortem on OCT. Two probable FTLD-Tau patients that were deeply phenotyped by clinical and genetic testing were imaged with OCT and followed to autopsy. Postmortem brain and retinal tissue were evaluated by a neuropathologist and ocular pathologist, respectively, masked to diagnosis. OCT findings were correlated with retinal histology. The two patients had autopsy-confirmed FTLD-Tau neuropathology and had antemortem OCT measurements showing ONL thinning (66.9 μm, patient #1; 74.9 μm, patient #2) below the 95% confidence interval of normal limits (75.1–120.7 μm) in our healthy control cohort. Postmortem, retinal tissue from both patients demonstrated loss of nuclei in the ONL, matching ONL loss visualized on antemortem OCT. Nuclei counts from each area of ONL loss (2 – 3 nuclei per column) seen in patient eyes were below the 95% confidence interval (4 – 8 nuclei per column for ONL) of 3 normal control retinas analyzed at the same location. Our evaluation of retinal tissue from FTLD-Tau patients confirms ONL loss seen antemortem by OCT. Continued investigation of ONL thinning as a biomarker that may distinguish FTLD-Tau from other dementias is warranted.

Highlights

Tauopathies are a class of frontotemporal lobar degeneration proteinopathies (FTLD-Tau) commonly associated with frontotemporal dementia (FTD) syndromes
This outer retina thinning correlates with global cognitive impairment, and longitudinal Optical coherence tomography (OCT) analysis found persistent and progressive outer nuclear layer (ONL) thinning among the probable FTLD-Tau patients [12, 13]
Patient #2 was a 58-year-old Caucasian woman diagnosed with the behavioral variant of FTD after 5 years of progressive cognitive and behavioral symptoms, as well as features of single-word and object knowledge later in her disease course from severe anterior temporal lobe disease

Summary

Introduction

Tauopathies are a class of frontotemporal lobar degeneration proteinopathies (FTLD-Tau) commonly associated with frontotemporal dementia (FTD) syndromes. Our OCT studies revealed outer retina thinning with normal inner retina thicknesses in living FTD patients with clinical features or genetic mutations predictive of FTLD-Tau pathology [12, 13, 18]. The outer retina thinning is driven by loss of the outer nuclear layer (ONL), which consists of photoreceptor nuclei and composes most of the outer retina’s thickness. This outer retina thinning correlates with global cognitive impairment, and longitudinal OCT analysis found persistent and progressive ONL thinning among the probable FTLD-Tau patients [12, 13]

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