Transcranial optical and optoacoustic super-resolution cortical microangiography in aged and Alzheimer mice

Abstract Cerebrovascular alterations and dysfunction are increasingly recognized as key contributors to aging and Alzheimer’s disease (AD), yet longitudinal in vivo imaging of cortical microvascular networks remains challenged by limited penetration of ballistic photons and transcranial ultrasound aberrations. While super-resolution ultrasound (SRUS) has enabled unprecedented capabilities for microangiography via microbubble localization and tracking, aberrations arising from bidirectional ultrasound propagation through the thickened skull of aged mice remain a significant challenge, often necessitating cranial windows. Here, we propose a complementary localization-based framework combining diffuse optical localization imaging (DOLI) and localization optoacoustic tomography (LOT) for super-resolution vascular imaging in aged and AD mice. DOLI capitalizes on the reduced light scattering in the second near-infrared window (NIR-II) to achieve transcranial visualization of the cortical microvasculature, while LOT leverages the unidirectional ultrasound propagation in optoacoustics to resolve pial microvessels and penetrating branches in a fully non-invasive manner. Both modalities reveal structural microvascular alterations in aging and AD, including increased vessel convolution and tortuosity at different scales, highlighting their potential for longitudinal studies of cerebrovascular pathology.