Imaging the Vesicular Acetylcholine Transporter in Schizophrenia: A Positron Emission Tomography Study Using [¹⁸F]-VAT

Background: Despite longstanding interest in the central cholinergic system in schizophrenia (SCZ), cholinergic imaging studies with patients have been limited to receptors. Here, we conducted a proof-of-concept positron emission tomography study using [¹⁸F]-VAT, a new radiotracer that targets the vesicular acetylcholine transporter as a proxy measure of acetylcholine transmission capacity, in patients with SCZ and explored relationships of vesicular acetylcholine transporter with clinical symptoms and cognition. Methods: A total of 18 adult patients with SCZ or schizoaffective disorder (the SCZ group) and 14 healthy control participants underwent a positron emission tomography scan with [¹⁸F]-VAT. Distribution volume (V_T) for [¹⁸F]-VAT was derived for each region of interest, and group differences in V_T were assessed with 2-sample t tests. Functional significance was explored through correlations between V_T and scores on the Positive and Negative Syndrome Scale and a computerized neurocognitive battery (PennCNB). Results: No group differences in [¹⁸F]-VAT V_T were observed. However, within the SCZ group, psychosis symptom severity was positively associated with V_T in multiple regions of interest, with the strongest effects in the hippocampus, thalamus, midbrain, cerebellum, and cortex. In addition, in the SCZ group, working memory performance was negatively associated with V_T in the substantia innominata and several cortical regions of interest including the dorsolateral prefrontal cortex. Conclusions: In this initial study, the severity of 2 important features of SCZ—psychosis and working memory deficit—was strongly associated with [¹⁸F]-VAT V_T in several cortical and subcortical regions. These correlations provide preliminary evidence of cholinergic activity involvement in SCZ and, if replicated in larger samples, could lead to a more complete mechanistic understanding of psychosis and cognitive deficits in SCZ and the development of therapeutic targets.