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bioRxiv · 10.1101/2025.11.14.688435

Fixel-Based Analysis reveals microstructural visual pathway changes associated with retinal remodeling in retinitis pigmentosa

Righetti, G.·Cuevas Villanueva, V.·Reith, M.·Wolfram, L.·Merle, D. A.·Kühlewein, L.·Braun, C.·Stingl, K.
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Abstract

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, traditionally considered a photoreceptor degenerative disorder. However, the relationship between retinal degeneration and structural alterations along central visual pathways remains poorly understood. We investigated possible structural links across the retinocortical pathway in 15 genetically characterized RP patients (RHO, PDE6A, PDE6B mutations) compared with 22 healthy controls, using spectral-domain optical coherence tomography (SD-OCT) combined with diffusion-weighted MRI and fixel-based analysis (FBA). Retinal segmentation revealed marked outer layer thinning (outer nuclear layer: -55% foveal, -77% parafoveal) with significant inner layer thickening at the fovea (inner plexiform layer +29%, inner nuclear layer +40%). Parafoveal regions showed near-complete photoreceptor loss but inner retinal thickness approaching normal values. FBA demonstrated significant fiber density reductions in optic tracts and optic radiations, without corresponding macrostructural changes in tract cross-section, suggesting early microstructural disruption preceding atrophy. Correlation analyses revealed significant associations between parafoveal inner plexiform layer thickness and fiber density in both optic tracts (r=0.856) and radiations (r=0.768), with no correlations observed at the foveal level. These findings demonstrate complex, region-specific retinal remodeling in RP, likely reflecting Muller cell gliosis rather than mechanical compensation. The fiber density reduction without tract atrophy suggests trans-synaptic degeneration along visual pathways. This multimodal framework provides insights into structural propagation in inherited retinal dystrophies and may serve as a biomarker for evaluating therapeutic interventions aimed at photoreceptor restoration.

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Righetti, G., Cuevas Villanueva, V., Reith, M., Wolfram, L., Merle, D. A., Kühlewein, L., Braun, C., Stingl, K.. 2025-11-15. Fixel-Based Analysis reveals microstructural visual pathway changes associated with retinal remodeling in retinitis pigmentosa. https://doi.org/10.1101/2025.11.14.688435

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