Retina-Brain Axis in Postoperative Delirium: Mechanistic Links, Single-Cell/Omics Evidence, and Translational Opportunities

<p> Postoperative Delirium (POD) is a common, mechanistically heterogeneous neuropsychiatric syndrome characterized by acute neuroinflammation and neurovascular dysfunction. Despite its clinical significance, the lack of accessible biomarkers to monitor Central Nervous System (CNS) vulnerability remains a major barrier to effective risk stratification. The retina, as an embryological extension of the CNS, shares highly conserved neurovascular and immune architectures with the brain, including blood-barrier parallels and glial-mediated neurovascular coupling. This biological continuity suggests that retinal structure and microvasculature can serve as a noninvasive "proxy" for cerebral health. Recent single-cell and multiomic atlases have identified overlapping cellular programs in the retina and brain involving complement activation, endothelial activation (e.g., ICAM1, MMP9), and innate immune reprogramming. Furthermore, retinal circadian pathways via intrinsically photosensitive retinal ganglion cells (ipRGCs) provide a direct link to the sleep-wake instability observed in POD. Emerging clinical data demonstrate that preexisting Retinal Nerve Fibre Layer (RNFL) thinning is associated with increased delirium risk, reflecting a lower "neural reserve" to withstand perioperative stress. Handheld Optical Coherence Tomography (OCT) studies further confirm the feasibility of bedside retinal imaging in frail surgical populations, such as hip fracture patients. This review synthesizes these strands into an integrated "Retina–Brain Axis" model. We argue that combining retinal phenotyping with EEG and omics data is not only scientifically justified but also clinically necessary to transition from generic care to precision-based, mechanistically guided POD prevention and monitoring. </p>