Multimodal Analysis of the Visual Pathways in Friedreich's Ataxia Reveals Novel Biomarkers

Abstract

Friedreich's ataxia; MRI; Biomarkers

Ataxia de Friedreich; Resonancia magnética; Biomarcadores

Atàxia de Friedreich; Ressonància magnètica; Biomarcadors

Background Optic neuropathy is a near ubiquitous feature of Friedreich's ataxia (FRDA). Previous studies have examined varying aspects of the anterior and posterior visual pathways but none so far have comprehensively evaluated the heterogeneity of degeneration across different areas of the retina, changes to the macula layers and combined these with volumetric MRI studies of the visual cortex and frataxin level. Methods We investigated 62 genetically confirmed FRDA patients using an integrated approach as part of an observational cohort study. We included measurement of frataxin protein levels, clinical evaluation of visual and neurological function, optical coherence tomography to determine retinal nerve fibre layer thickness and macular layer volume and volumetric brain MRI. Results We demonstrate that frataxin level correlates with peripapillary retinal nerve fibre layer thickness and that retinal sectors differ in their degree of degeneration. We also shown that retinal nerve fibre layer is thinner in FRDA patients than controls and that this thinning is influenced by the AAO and GAA1. Furthermore we show that the ganglion cell and inner plexiform layers are affected in FRDA. Our MRI data indicate that there are borderline correlations between retinal layers and areas of the cortex involved in visual processing. Conclusion Our study demonstrates the uneven distribution of the axonopathy in the retinal nerve fibre layer and highlight the relative sparing of the papillomacular bundle and temporal sectors. We show that thinning of the retinal nerve fibre layer is associated with frataxin levels, supporting the use the two biomarkers in future clinical trials design. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

This project has received funding under the European Union's Horizon 2020 research and innovation programme under grant agreement No. 634541, from the Engineering and Physical Sciences Research Council (EPSRC EP/R006032/1, M020533/1, G007748, I027084, N018702) and from Rosetrees Trust (UK), which supported FG. FG is currently supported by the investigator-initiated PREdICT study at the Vall d'Hebron Institute of Oncology (Barcelona), funded by AstraZeneca and CRIS Cancer Foundation. Funding support from Spinal Research (UK), Wings for Life (Austria), Craig H. Neilsen Foundation (USA) for jointly funding the INSPIRED study, Wings for Life (#169111), UK Multiple Sclerosis Society (grants 892/08 and 77/2017), Department of Health's National Institute for Health Research (NIHR) Biomedical Research Centres and UCLH NIHR Biomedical Research Centre is also acknowledged. FP is funded by NIHR University College London Hospitals Biomedical Research Council. Claudia A. M. Gandini Wheeler-Kingshott (CGWK) received funding from the MS Society (#77), Wings for Life (#169111), Horizon2020 (Human Brain Project), BRC (#BRC704/CAP/CGW), MRC (#MR/S026088/1), Ataxia UK. CGWK is a shareholder in Queen Square Analytics Ltd. No other authors have any financial disclosures to declare. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The sponsor and funding organisation had no role in the design or conduct of this research.