Project Summary Cerebral small vessel disease (CSVD) is thought to be among the most prevalent central nervous system disorders and contributes significantly to vascular cognitive impairment and dementia. However, our understanding of the fundamental mechanisms is limited due to technical constraints hindering direct examination of cerebral small vessel integrity. Currently, we rely on MRI scans to detect white matter hyperintensities as a marker of CSVD, but this method lacks sensitivity and specificity. Although it is difficult and expensive to use imaging tests on the brain, it may be possible to detect CSVD by imaging the eye, specifically the retina. The retina and brain share similar anatomic and physiologic features, and retinal changes can be easily detected. Our research aims to a novel imaging technique which will detect precise changes in capillary function by tracking high-order hemodynamics in retinal capillaries. To achieve this, we will develop a new high-speed wide-field adaptive optics near-confocal ophthalmoscope (AONCO) with a green light capable of precisely assessing higher-order flow dynamics in retinal capillaries to detect and monitor CSVD. Our research has three aims. In Aim 1, we will develop a new high-speed wide-field AONCO, which is capable of precisely assessing higher-order flow dynamics in retinal vessels of various sizes, from the largest arterioles to the smallest capillaries. In Aim 2, we will demonstrate AONCO-measured retinal capillary pulsatile hemodynamics as a sensitive biomarker of CSVD. In Aim 3, we will develop a novel machine learning (ML) approach for fully automatic analysis of flow dynamics in retinal vessels using AONCO and compare the ML measurements to conventional measurements. Our research has the potential to offer groundbreaking insights into microcirculation at the capillary level, providing crucial information about the vascular health of the central nervous system. This is particularly important given the prevalence of small vessel abnormalities and their impact on microvascular health, with significant implications for our understanding of CSVD.