Impairment of the glymphatic system may contribute to atypical brain development and increased vulnerability to psychiatric conditions such as psychosis. In particular, disrupted glymphatic efficiency may affect neurochemical homeostasis during critical maturational windows, leading to structural and circuit-level alterations. However, its role in early neurodevelopmental trajectories remains largely unexplored. We combined longitudinal diffusion tensor imaging (DTI) in 85 individuals with 22q11.2 deletion syndrome (22q11DS), a neurodevelopmental condition associated with elevated psychosis risk (143 scans), with cross-sectional magnetic resonance spectroscopy (MRS) in a subset of 39 individuals with 22q11DS. Glymphatic function was estimated indirectly using the DTI-ALPS index, a diffusion-based proxy derived from manual and automated ROI placement. Excitation/inhibition ratio was assessed in the right hippocampus via CSF-corrected Glx and GABA levels. ALPS index was significantly reduced in 22q11DS compared to controls ( p = 0.017), especially in the right hemisphere. Individuals with positive psychotic symptoms (PPS+) showed a divergent developmental trajectory, failing to exhibit the age-related ALPS increase seen in PPS− (group x age interaction: p = 0.009). In a subset with spectroscopy data (n = 39), lower ALPS predicted higher Glx/GABA ratio in the right hippocampus ( p = 0.002). These findings provide in vivo evidence that glymphatic-related dysfunction, as indexed by the DTI-ALPS proxy, emerges early and follows atypical developmental trajectories in those at risk for psychosis. Impaired ALPS index is also associated with excitatory/inhibitory imbalance. This dysfunction may represent a novel pathway contributing to psychosis vulnerability and a potential target for early intervention.
Pascucci et al. (Sun,) studied this question.