Abstract
<title>Abstract</title> <p>Angelman syndrome (AS) is a neurodevelopmental disorder for which non-invasive biomarkers suitable for longitudinal monitoring and clinical trials remain limited. Although EEG abnormalities have shown promise as treatment-responsive biomarkers, their applicability may be constrained by tolerability and developmental variability. Here, we identify visually evoked hemodynamic responses as a robust cross-species functional biomarker of AS. Using intrinsic optical signal (IOS) imaging, we show that AS mouse model exhibits enhanced visual cortical responses that persist across development and partially reflect disease severity in adulthood. These alterations are highly sensitive to therapeutic interventions: restoration of UBE3A expression normalizes visual responses and scales with both behavioral recovery and molecular rescue. To assess translational relevance, we performed functional near-infrared spectroscopy (fNIRS) in individuals with AS during visual stimulation, demonstrating the feasibility of fNIRS in behaviorally challenging settings. Individuals with AS display amplified and temporally altered hemodynamic responses that are consistently detected across preprocessing strategies and remaine stable across age. Our findings demonstrate that visually evoked hemodynamic responses capture a disease-specific cortical signature of AS conserved across species. The scalability, non-invasiveness, and feasibility of fNIRS, combined with preclinical sensitivity to therapeutic interventions, position neurovascular imaging as a promising biomarker for future clinical trials in AS.</p>