Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study

R Bodén,A Wall,J Persson,G Antoni,E-M Larsson,L Ekselius,M Lubberink

doi:10.1038/tp.2017.11

Abstract

The enzyme phosphodiesterase 10A (PDE10A) is abundant in striatal medium spiny neurons and has been implicated in the pathophysiology of schizophrenia in animal models and is investigated as a possible new pharmacological treatment target. A reduction of prefrontal cortical thickness is common in schizophrenia, but how this relates to PDE10A expression is unknown. Our study aim was to compare, we believe for the first time, the striatal non-displaceable binding potential (BPND) of the new validated PDE10A ligand [11C]Lu AE92686 between patients with schizophrenia and healthy controls. Furthermore, we aimed to assess the correlation of PDE10A BPND to cortical thickness. Sixteen healthy male controls and 10 male patients with schizophrenia treated with clozapine, olanzapine or quetiapine were investigated with positron emission tomography (PET) and magnetic resonance imaging (MRI). Striatal binding potential (BPND) of [11C]Lu AE92686 was acquired through dynamic PET scans and cortical thickness by structural MRI. Clinical assessments of symptoms and cognitive function were performed and the antipsychotic dosage was recorded. Patients with schizophrenia had a significantly lower BPND of [11C]Lu AE92686 in striatum (P=0.003) than healthy controls. The striatal BPND significantly correlated to cortical thickness in the medial prefrontal cortex and superior frontal gyrus across patients with schizophrenia and healthy controls. No significant correlation was observed between the BPND for [11C]Lu AE92686 in striatum and age, schizophrenia symptoms, antipsychotic dosage, coffee consumption, smoking, duration of illness or cognitive function in the patients. In conclusion, PDE10A may be important for functioning in the striato-cortical interaction and in the pathophysiology of schizophrenia.

Highlights

Schizophrenia is a severe mental illness with persisting or recurring symptoms and considerable disability.[1]
The enzyme phosphodiesterase 10A (PDE10A) is found in high concentrations within the medium spiny neurons, and it is crucial for the degradation of cyclic AMP and cyclic GMP.[6]
Lower BPND of [11C]Lu AE92686 was observed in the striatum, including caudate nucleus and putamen in patients compared to controls

Summary

Introduction

Schizophrenia is a severe mental illness with persisting or recurring symptoms and considerable disability.[1]. The striatum is a central hub in the brain networks implicated in the wide range of schizophrenia symptoms.[2,3,4,5] In striatum, the enzyme phosphodiesterase 10A (PDE10A) is found in high concentrations within the medium spiny neurons, and it is crucial for the degradation of cyclic AMP and cyclic GMP.[6] Medium spiny neurons are the principal striatal neurons, either expressing D1 receptors in the direct signaling pathway or D2 receptors in the indirect pathway.[7] PDE10A has opposing effects on the output from these striatal pathways by regulating second messenger cascades, and inhibition of PDE10A does seem to reduce positive and in some studies negative symptoms in animal models of schizophrenia.[8,9,10,11,12] patients with other striatal disorders, such as Parkinson’s and Huntington’s disease, have lower availability of striatal PDE10A early in the disease course.[13,14]

Objectives

Methods

Results

Conclusion