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

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.

Phosphodiesterase 10A levels are related to striatal function in schizophrenia: a combined positron emission tomography and functional magnetic resonance imaging study

“…If the inhibition of PDE10A is indeed a viable treatment option, an increase in striatal PDE10A levels in schizophrenia would be expected. However, we recently found that striatal PDE10A was reduced in patients with schizophrenia compared to controls [11]. Understanding whether and how this relates to changes in brain function in the striatum and its associated symptoms would help to clarify the role of PDE10A in schizophrenia.…”

“…The aim of this study was to investigate whether an earlier reported reduction in striatal PDE10A levels [11] relates to striatal function in schizophrenia. The relationship between PDE10A availability and ALFF within the striatum and its basal ganglia output regions was assessed.…”

“…The patients were the same as described in a prior publication [11], consisting of ten males between 18 and 45 years old, with a diagnosis of schizophrenia since at least 2 years prior to inclusion. One patient was treated with quetiapine, two with olanzapine, and among the remaining seven patients who was treated with clozapine, one patient had concomitant treatment with perphenazine, three with aripiprazole, one with quetiapine, and one with risperidone.…”

“…The PET data are the same as reported in a previous study, where the PET scanning and preprocessing procedures are described in more detail [11]. Briefly, an intravenous bolus injection of the PET tracer [ 11 C]Lu AE92686, a PDE10A antagonist, was administered and data were collected during a 90 min dynamic scanning session.…”

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

“…In a study investigating the role of PDE10A in schizophrenia, 11 C -IMA107 showed no significant difference between patients and HC in any brain region, with all average differences within the variability of the tracer from previous testretest data [282]. In contrast, 11 C-Lu AE92686 showed significantly lower BP ND in the putamen and caudate nucleus compared with that in HC, but no correlation to symptoms was found [142].…”