A novel fluorescent ocular tracer enables detection of TDP-43 pathology in ALS and related TDP-43 proteinopathies using retinal imaging

Molecular biomarkers of neurodegenerative disease are positioned to facilitate earlier diagnosis and treatment, therapeutic development, and define disease heterogeneities that inform precision interventions. The retina, an optically accessible extension of the central nervous system, manifests biomarkers for many neurodegenerative diseases, providing an opportunity for simple, non-invasive detection. This study evaluates a new method to fluorescently label retinal deposits associated with TDP-43 pathology, a key biomarker of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE), using a prototype of a clinical-stage small molecule, AMDX-8050. In cadaveric ALS retinas, AMDX-8050 labeled cytoplasmic retinal deposits that co-localized with TDP-43 pathology and revealed a dense and spatially varied distribution of deposits resembling those observed in matched spinal cord and motor cortex cadaver tissues. Additionally, AMDX-8050 labeled deposits that co-localized with TDP-43 pathology in retinas from FTD-TDP-43 and LATE cadaver tissues. These results support the potential of a new class of retinal tracers with broad utility for the TDP-43 proteinopathies.