Introduction
Schizophrenia is a complex and chronic disease that affects different aspects of cognition and behaviour, including attention, perception, thought processes, emotion and volition. Schizophrenia is a brain disease that particularly involves decrements in grey matter, a finding that is supported by many imaging studies. The pathophysiology of these grey matter changes has not been clarified. Microglia activation is the consequence of virtually all conditions associated with neuronal injury. When activated following neuronal damage, microglia show a marked increase in the expression of peripheral type benzodiazepine binding sites, which are particularly abundant on cells of the mononuclear macrophage cell line. (R)-PK11195 ([1-(2-chlorophenyl)-N-methyl-N-1(1-methylpropyl]-3soquinolinecarboxamide) is a highly selective ligand for the peripheral benzodiazepine binding site. The purpose of the present study was to assess peripheral type benzodiazepine receptors expression, and thus microglia activation, in patients with schizophrenia using [11C](R)-PK11195 and PET.
Methods
In this ongoing protocol, 4 male patients with recent onset paranoid schizophrenia (DSM-IV criteria) and 5 age matched healthy male controls have been included to date. All patients were treated with atypical antipsychotics. PET scans were performed using an ECAT-EXACT HR+ scanner. A dynamic 3D scan, consisting of 22 frames over 60 minutes, was acquired following a bolus injection of ∼370 MBq [11C](R)-PK11195. Arterial whole blood concentration was monitored continuously using an online detection system. In addition, discrete samples were taken in order to derive a metabolite corrected plasma input curve. Finally, for each subject a T1 weighted structural MRI scan was acquired using a Philips 1.5 Tesla scanner. For initial analysis, regions of interest (ROI) were defined on the co-registered MRI scan. ROI were defined for cerebellum, thalamus and whole brain. These ROI were projected onto the dynamic [11C](R)-PK11195 scans, thereby generating time activity curves for each region. A two-tissue reversible compartment model (K1/k2 fixed to values obtained from whole brain) was fitted to the data using the metabolite corrected plasma input curve as input function. Binding potential (BP) was used as primary outcome measure. Results and Discussion Statistical Analysis was performed using Student's t-test. The data suggest a slight, but non-significant global increase in [11C](R)-PK11195 binding in patients with schizophrenia. More subjects are needed, however, to increase statistical power. Insert table 1: A small but statistically significant increase in [11C](R)-PK11195 binding was noted in cerebellum, but not in thalamus in this small sample of patients with schizophrenia. Again, more patients need to be included for the detection of more subtle differences in [11C](R)-PK11195 binding. The results of this pilot study indicate that cerebellum might not be a suitable reference tissue for this patient group and even may be involved in the pathophysiology of schizophrenia.
[11C](R)-PK11195 BP values (two tissue a reversible model, K1/k2 ratio fixed)