Elucidating Cholinergic Relationships with Psychosis And Cognitive Deficits in Schizophrenia

PROJECT SUMMARY / ABSTRACT Schizophrenia (SCZ) is among the most severe and disabling medical conditions worldwide, yet the brain alterations that lead to the symptoms of SCZ remain unknown and the treatments are currently limited to dopaminergic (D2 receptor modulating) medications for their antipsychotic properties. Antipsychotic medications have incomplete efficacy and carry a substantial side effect burden. There is thus an imperative to characterize non-dopaminergic markers to guide diagnosis and treatment of SCZ. One such promising marker to explore is the vesicular acetylcholinergic transporter (VAChT), levels of which provide a critical indicator of cholinergic terminal activity in the brain. Although the pathophysiology by which the cholinergic system may mediate SCZ symptoms is unclear, an increasing body of evidence suggests that presynaptic cholinergic transmission may be involved in multiple disabling features of SCZ and new drugs directed at presynaptic cholinergic activity show promise in the treatment of SCZ, including an M1/M4 muscarinic agonist therapeutic in Phase 3 trials which was recently reported to be effective in significantly reducing positive and negative symptoms of psychosis, and improving cognitive impairment, in patients with SCZ. We have exciting preliminary data using a new radiotracer that targets VAChT ([18F]-VAT) with positron emission tomography (PET) imaging suggesting that cortical, hippocampal, and thalamic VAChT strongly relates to positive psychotic symptoms and working memory deficits in patients with SCZ. The proposed 5-year R01 study aims to replicate and extend these observations relating in vivo cholinergic transmission to two of the most disabling features of SCZ. We will measure VAChT using PET with [18F]-VAT VT in a new, larger sample of 40 patients with SCZ – 20 patients on antipsychotic medication and 20 unmedicated patients – and 20 healthy controls; and examine VAChT’s relationships among and within groups with clinical pathology. If replicated and substantiated in a larger cohort, VAChT could be a reliable biological indicator of multiple key features of SCZ that may serve as a marker of illness severity and a potentially valuable tool for the development of biomarkers for diagnosis and treatment of SCZ.