Aberrant cerebrovascular reactivity presents as an early biomarker of psychosis susceptibility in patients with 22q11.2DS

Abstract The brain’s ability to regulate blood flow is fundamental to both its function and development. In the context of neurodevelopmental disorders such as schizophrenia, understanding the complex interactions between cerebrovascular health and brain function is crucial for unraveling the pathophysiology of psychosis. This study investigates the developmental trajectory of cerebrovascular reactivity (CVR) in 22q11 deletion syndrome (22q11.2DS) compared to healthy controls, and its association with psychosis susceptibility. Using one of the largest longitudinal data-set of resting-state fMRI, we mapped for the first time voxel-level CVR across development. We found an early reduction in CVR in 22q11.2DS, and in particular in those who later developed positive psychotic symptoms (PPS + ). These reductions were evident within the anterior cingulate cortex, frontal lobes, and globi pallidi (GP). We propose that the pattern of CVR alterations presenting early during childhood is possibly linked to altered blood-brain barrier integrity or permeability, potentially involving endothelial or tight-junction dysfunction; however, BBB integrity was not directly measured in this study. A decrease in CVR during childhood and within the frontal regions and GP was predictive of subsequent development of positive psychotic symptoms), which often occurs during adolescence in 22q11.2DS patients. These findings suggest that cerebrovascular health is critical for normal brain development, particularly in regions like the striatum, which are vulnerable to vascular damage due to their anatomical features. These results underline the potential of CVR as an early biomarker for psychosis vulnerability, emphasizing the need for targeted interventions to mitigate neurodevelopmental disruptions of cerebrovascular health in 22q11.2DS.