In vivo evidence of lower synaptic vesicle density in schizophrenia

Decreased synaptic spine density has been the most consistently reported postmortem finding in schizophrenia (SCZ). A recently developed in vivo measure of synaptic vesicle density estimated using the novel positron emission tomography (PET) ligand [¹¹C]UCB-J is a proxy measure of synaptic density. In this study we determined whether [¹¹C]UCB-J binding, an in vivo measure of synaptic vesicle density, is altered in SCZ. SCZ patients (n = 13, 3 F) and age-, gender-matched healthy controls (HCs) (n = 15, 3 F) underwent PET imaging using [¹¹C]UCB-J and high-resolution research tomography (HRRT). [¹¹C]UCB-J distribution volume (V_T) and binding potential (BP_ND) were estimated using a 1T model with centrum-semiovale as the reference region. Relative to HCs, SCZ patients, showed significantly lower [¹¹C]UCB-J BP_ND with significant differences in the frontal cortex (-10%, Cohen's d = 1.01), anterior cingulate (-11%, Cohen's d = 1.24), hippocampus (-15%, Cohen's d = 1.29), occipital cortex (-14%, Cohen's d = 1.34), parietal cortex (-10%, p = 0.03, Cohen's d = 0.85) and temporal cortex (-11%, Cohen's d = 1.23). These differences remained significant after partial volume correction. [¹¹C]UCB-J BP_ND did not correlate with cumulative antipsychotic exposure or gray-matter volume. Consistent with the postmortem and in vivo findings, synaptic vesicle density is lower across several brain regions in SCZ. Frontal synaptic vesicle density correlated with psychosis symptom severity and cognitive performance on social cognition and processing speed. These findings indicate that [¹¹C]UCB-J PET is a sensitive tool to detect lower synaptic density in SCZ and holds promise for future studies of early detection and disease progression.