TRACKING BRAIN FUNCTION IN ANGELMAN SYNDROME: A FUNCTIONAL NEUROIMAGING BIOMARKER

Angelman Syndrome (AS) is a rare neurodevelopmental disorder caused by the loss-of-expression of the UBE3A gene in neurons. This disorder clinically manifests with a severe impairment of cognitive and motor functions, lack of speech, behavioral abnormalities, and seizures. To date, effective therapies for AS are lacking, posing significant challenges for patients and their caregivers. Despite significant advances in therapeutic development, the lack of objective, quantitative, and reliable biomarkers remains a major obstacle for assessing disease progression and treatment efficacy. Here, we evaluated the use of visually evoked responses measured with intrinsic optical signal (IOS) imaging—a non-invasive neuroimaging technique with high translational value—as a functional biomarker for AS. Monitoring of visual IOS (V-IOS) responses in Ube3a-deficient (HET) and wild-type (WT) animals at postnatal day (P) 45 and 90 revealed a significant increase in the amplitude of V-IOS responses elicited by contralateral eye stimulation in HET mice compared to controls, demonstrating that our biomarker reliably discriminates between genotypes across development. Importantly, V-IOS amplitude partially correlated with motor impairments, with higher responses associated with poorer performance in the rotarod test, indicating that V-IOS reflects disease severity. Finally, we assessed the sensitivity of this biomarker to therapeutic intervention. Neonatal reinstatement of UBE3A via gene therapy normalized V-IOS amplitudes in HET mice, and the extent of V-IOS recovery correlated with both improvements in motor performance and cortical UBE3A levels. Together, these results identify V-IOS imaging as a robust, non-invasive functional biomarker for monitoring brain function in AS.