Reductions in synaptic marker SV2A in early-course Schizophrenia.

Excess synaptic pruning during neurodevelopment has emerged as one of the leading hypotheses on the causal mechanism for schizophrenia. It proposes that excess synaptic elimination occurs during development before the formal onset of illness. Accordingly, synaptic deficits may be observable at all stages of illnesses, including in the early phases. The availability of [ ¹¹ C]UCB-J, the first-in-human in vivo synaptic marker, represents an opportunity for testing this hypothesis with a relatively high level of precision. The first two published [ ¹¹ C]UCB-J schizophrenia studies have documented significant, widespread reductions in binding in chronic patients. The present study tested the hypothesis that reductions are present in early-course patients. 18 subjects completed [ ¹¹ C]UCB-J PET scans, (nine with schizophrenia, average duration of illness of 3.36 years, and nine demographically-matched healthy individuals). We compared binding levels, quantified as non-displaceable specific binding (BP _ND ), in a set of a priori-specified brain regions of interest (ROIs). Eight ROIs (left and right hippocampus, right superior temporal and Heschl's gyrus, left and right putamen, and right caudal and rostral middle frontal gyrus) showed large reductions meeting Bonferroni corrected significant levels, p < 0.0036. Exploratory, atlas-wide analyses confirmed widespread reductions in schizophrenia. We also observed significant positive correlations between binding levels and cognitive performance and a negative correlation with the severity of delusions. These results largely replicate findings from chronic patients, indicating that extensive [ ¹¹ C]UCB-J binding deficits are reliable and reproducible. Moreover, these results add to the growing evidence that excess synaptic pruning is a major disease mechanism for schizophrenia.
Competing Interests: Declaration of competing interest Drs. Yoon, Minzenberg, Naganawa, Levinson, Hardy, Khalighi, Park, Davidzon, and Chin reports no financial relationships with commercial interests. Dr. Mormino: Consultant for Eli Lilly, Hoffman La-Roche, and Neurotrack. Dr. Ballon: Scientific advisory board for Alkermes; consultant for Teva, Corcept, Indivior, and Alto Pharmacy; research study support from Corcept, Roche, Alkermes, Janssen. Dr. Kalinowski: Consultant for Pasithea. Dr. Hardy: Consultant for Click Digital Therapeutics. Dr. Carson: Research study support from Bristol Myers Squibb, Cerevel, Invicro, and Pfizer.
(Published by Elsevier Ltd.)