Synaptic Terminal Density Early in the Course of Schizophrenia: An In Vivo UCB-J Positron Emission Tomographic Imaging Study of SV2A

Abstract

Background: The synaptic hypothesis is an influential theory of the pathoetiology of schizophrenia (SCZ), which is supported by the finding that there is lower uptake of the synaptic terminal density marker [¹¹C]UCB-J in patients with chronic SCZ than in control participants. However, it is unclear whether these differences are present early in the illness. To address this, we investigated [¹¹C]UCB-J volume of distribution (V_T) in antipsychotic-naïve/free patients with SCZ who were recruited from first-episode services compared with healthy volunteers.

Methods: Forty-two volunteers (SCZ n = 21, healthy volunteers n = 21) underwent [¹¹C]UCB-J positron emission tomography to index [¹¹C]UCB-J V_T and distribution volume ratio in the anterior cingulate, frontal, and dorsolateral prefrontal cortices; the temporal, parietal and occipital lobes; and the hippocampus, thalamus, and amygdala. Symptom severity was assessed in the SCZ group using the Positive and Negative Syndrome Scale.

Results: We found no significant effects of group on [¹¹C]UCB-J V_T or distribution volume ratio in most regions of interest (effect sizes from d = 0.0-0.7, p > .05), with two exceptions: we found lower distribution volume ratio in the temporal lobe (d = 0.7, uncorrected p < .05) and lower V_T/f_p in the anterior cingulate cortex in patients (d = 0.7, uncorrected p < .05). The Positive and Negative Syndrome Scale total score was negatively associated with [¹¹C]UCB-J V_T in the hippocampus in the SCZ group (r = -0.48, p = .03).

Conclusions: These findings indicate that large differences in synaptic terminal density are not present early in SCZ, although there may be more subtle effects. When taken together with previous evidence of lower [¹¹C]UCB-J V_T in patients with chronic illness, this may indicate synaptic density changes during the course of SCZ.

Keywords: Antipsychotic-free; Positron emission tomography; SV2A; Schizophrenia; Synaptic density; UCB-J.