Corneal Confocal Microscopy: a Surrogate Endpoint for Neurodegeneration in Clinical Trials


Corneal Confocal Microscopy in Friedreich’s Ataxia and Beyond

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Friedreich’s ataxia (FRDA), an autosomal recessive neurodegenerative disease caused by mutations in the gene encoding for the mitochondrial protein frataxin, is characterized by ataxia and gait instability, immobility, and eventual death. We evaluated corneal confocal microscopy (CCM) quantification of corneal nerve morphology as a novel, noninvasive, in vivo quantitative imaging biomarker for the severity of neurological manifestations in FRDA. Corneal nerve fiber density, branch density, and fiber length were quantified in individuals with FRDA (n?=?23) and healthy age-matched controls (n?=?14). All individuals underwent genetic testing and a detailed neurological assessment with the Scale for the Assessment and Rating of Ataxia (SARA) and Friedreich's Ataxia Rating Scale (FARS). A subset of individuals with FRDA who were ambulatory underwent quantitative gait assessment. CCM demonstrated a significant reduction in nerve fiber density and length in FRDA compared to healthy controls. Importantly, CCM parameters correlated with genotype, SARA and FARS neurological scales, and linear regression modeling of CCM nerve parameter-generated equations that predict the neurologic severity of FRDA. Together, the data suggest that CCM quantification of corneal nerve morphology is a rapid, sensitive imaging biomarker for quantifying the severity of neurologic disease in individuals with FRDA.