Bart Van Berckel

Microglia Activation in Recent-Onset Schizophrenia: A Quantitative (R)-[11C]PK11195 Positron Emission Tomography Study

BACKGROUNDnSchizophrenia is a brain disease involving progressive loss of gray matter of unknown cause. Most likely, this loss reflects neuronal damage, which should, in turn, be accompanied by microglia activation. Microglia activation can be quantified in vivo using (R)-[(11)C]PK11195 and positron emission tomography (PET). The purpose of this study was to investigate whether microglia activation occurs in patients with recent-onset schizophrenia.nnnMETHODSnTen patients with recent-onset schizophrenia and 10 age-matched healthy control subjects were included. A fully quantitative (R)-[(11)C]PK11195 PET scan was performed on all subjects, including arterial sampling to generate a metabolite-corrected input curve.nnnRESULTSnCompared with control subjects, binding potential of (R)-[(11)C]PK11195 in total gray matter was increased in patients with schizophrenia. There were no differences in other PET parameters.nnnCONCLUSIONSnActivated microglia are present in schizophrenia patients within the first 5 years of disease onset. This suggests that, in this period, neuronal injury is present and that neuronal damage may be involved in the loss of gray matter associated with this disease. Microglia may form a novel target for neuroprotective therapies in schizophrenia.

Dopaminergic activity in Tourette syndrome and obsessive-compulsive disorder

Tourette syndrome (TS) and obsessive-compulsive disorder (OCD) both are neuropsychiatric disorders associated with abnormalities in dopamine neurotransmission. Aims of this study were to quantify striatal D2/3 receptor availability in TS and OCD, and to examine dopamine release and symptom severity changes in both disorders following amphetamine challenge. Changes in [(11)C]raclopride binding potential (BP(ND)) were assessed using positron emission tomography before and after administration of d-amphetamine (0.3 mg kg(-1)) in 12 TS patients without comorbid OCD, 12 OCD patients without comorbid tics, and 12 healthy controls. Main outcome measures were baseline striatal D2/3 receptor BP(ND) and change in BP(ND) following amphetamine as a measure of dopamine release. Voxel-based analysis revealed significantly decreased baseline [(11)C]raclopride BP(ND) in bilateral putamen of both patient groups vs. healthy controls, differences being more pronounced in the TS than in the OCD group. Changes in BP(ND) following amphetamine were not significantly different between groups. Following amphetamine administration, tic severity increased in the TS group, which correlated with BP(ND) changes in right ventral striatum. Symptom severity in the OCD group did not change significantly following amphetamine challenge and was not associated with changes in BP(ND). This study provides evidence for decreased striatal D2/3 receptor availability in TS and OCD, presumably reflecting higher endogenous dopamine levels in both disorders. In addition, it provides the first direct evidence that ventral striatal dopamine release is related to the pathophysiology of tics.

P50 suppression and prepulse inhibition of the startle reflex in humans: a correlational study.

BACKGROUNDnSensory gating is an important feature of the normally functioning brain. When not operating correctly, it can contribute to different kinds of psychiatric illnesses by flooding the higher brain functions with useless information. Over the years, two paradigms have evolved to quantify the amount of sensory gating: the prepulse inhibition (PPI) of the startle reflex and the suppression of the P50 evoked potential. To enable comparison across studies it is important to find out to what extent these paradigms reflect the same processes. In the present study, this relationship was explored.nnnMETHODSnThirty-one healthy male volunteers with no personal or family history of mental illness were tested on their ability to suppress the P50 wave and to inhibit the startle reflex.nnnRESULTSnA significant positive correlation was found between PPI and P50 suppression mainly early in testing, when habituation of the startle reflex is taking place. Furthermore, a significant negative correlation was found between P50 suppression in the second half of testing and the habituation of the startle reflex.nnnCONCLUSIONSnPPI and P50 suppression are correlated at an early stage of testing, when the process of habituation of the startle reflex is active. The role of the habituation in the correlation between these two measures needs to be further explored.

Further human evidence for striatal dopamine release induced by administration of ∆9-tetrahydrocannabinol (THC): selectivity to limbic striatum

RationaleElevated dopamine function is thought to play a key role in both the rewarding effects of addictive drugs and the pathophysiology of schizophrenia. Accumulating epidemiological evidence indicates that cannabis use is a risk factor for the development of schizophrenia. However, human neurochemical imaging studies that examined the impact of ∆9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, on striatal dopamine release have provided inconsistent results.ObjectivesThe objective of this study is to assess the effect of a THC challenge on human striatal dopamine release in a large sample of healthy participants.MethodsWe combined human neurochemical imaging data from two previous studies that used [11C]raclopride positron emission tomography (PET) (nu2009=u20097 and nu2009=u200913, respectively) to examine the effect of THC on striatal dopamine neurotransmission in humans. PET images were re-analysed to overcome differences in PET data analysis.ResultsTHC administration induced a significant reduction in [11C]raclopride binding in the limbic striatum (−3.65xa0%, from 2.39u2009±u20090.26 to 2.30u2009±u20090.23, pu2009=u20090.023). This is consistent with increased dopamine levels in this region. No significant differences between THC and placebo were found in other striatal subdivisions.ConclusionsIn the largest data set of healthy participants so far, we provide evidence for a modest increase in human striatal dopamine transmission after administration of THC compared to other drugs of abuse. This finding suggests limited involvement of the endocannabinoid system in regulating human striatal dopamine release and thereby challenges the hypothesis that an increase in striatal dopamine levels after cannabis use is the primary biological mechanism underlying the associated higher risk of schizophrenia.

Quantification of the novel N-methyl-d-aspartate receptor ligand [11C]GMOM in man

[11C]GMOM (carbon-11 labeled N-(2-chloro-5-thiomethylphenyl)-N′-(3-[11C]methoxy-phenyl)-N′-methylguanidine) is a PET ligand that binds to the N-methyl-d-aspartate receptor with high specificity and affinity. The purpose of this first in human study was to evaluate kinetics of [11C]GMOM in the healthy human brain and to identify the optimal pharmacokinetic model for quantifying these kinetics, both before and after a pharmacological dose of S-ketamine. Dynamic 90u2009min [11C]GMOM PET scans were obtained from 10 subjects. In six of the 10 subjects, a second PET scan was performed following an S-ketamine challenge. Metabolite corrected plasma input functions were obtained for all scans. Regional time activity curves were fitted to various single- and two-tissue compartment models. Best fits were obtained using a two-tissue irreversible model with blood volume parameter. The highest net influx rate (Ki) of [11C]GMOM was observed in regions with high N-methyl-d-aspartate receptor density, such as hippocampus and thalamus. A significant reduction in the Ki was observed for the entire brain after administration of ketamine, suggesting specific binding to the N-methyl-d-aspartate receptors. This initial study suggests that the [11C]GMOM could be used for quantification of N-methyl-d-aspartate receptors.

Effects of sedatives on GABA-mediated chloride flux into cerebral cortical microsacs prepared from emotional and non-emotional mice

Some strains of rats and mice express increased momentary fear or emotionality when exposed to a novel environment. Previous studies have found significantly fewer diazepam binding sites in the brains of Balb/cJ mice compared to C57BL and AKR/J mice and this has been suggested to contribute to the increased emotionally of the nervous Balb strain. The influx of 36Cl into cerebral cortical microsacs was used to functionally assess the effects of GABA, diazepam and pentobarbital in the Balb mice compared to nonemotional animals (C57 and ICR mice). Slight differences in the ability of GABA to increase chloride influx were found among the three strains. Pentobarbital potentiation of GABA-mediated chloride flux was slightly higher in the ICR mice compared to Balb and C57. Diazepam potentiation of the effects of GABA, however, was significantly decreased in the Balb mice, strengthening the hypothesis that the benzodiazepine receptor is involved in mediating animal emotionality.

Assessing brain immune activation in psychiatric disorders: clinical and preclinical PET imaging studies of the 18-kDa translocator protein

Accumulating evidence from different lines of research suggests an involvement of the immune system in the pathophysiology of several psychiatric disorders. During recent years, a series of positron emission tomography (PET) studies have been published using radioligands for the translocator protein (TSPO) to study microglia activation in schizophrenia, bipolar I disorder, major depression, autism spectrum disorder, and drug abuse. The results have been somewhat conflicting, which could be due to differences both in patient sample characteristics and in PET methods. In particular, further work is needed to address both methodological and biological sources of variability in TSPO levels, a process in which the use of animal models and small animal PET systems can be a valuable tool. Given this development, PET studies of immune activation have the potential to further increase our understanding of disease mechanisms in psychiatric disorders, which is a requisite in the search for new treatment approaches. Furthermore, molecular imaging could become an important clinical tool for identifying specific subgroups of patients or disease stages that would benefit from treatment targeting the immune system.

Quantification of the neurokinin 1 receptor ligand [¹¹C]R116301

PurposeNeurokinin 1 (NK1) receptors have been implicated in depression, anxiety, and pain perception. Recently, it was shown that, in the human brain, a specific NK1 receptor-related signal was obtained with the novel radioligand, [11C]R116301, using positron emission tomography. The purpose of this study was to evaluate various methods for quantifying specific [11C]R116301 binding. MethodsTwo dynamic 90-min [11C]R116301 scans, separated by 5 h, were performed in 11 healthy volunteers. In three patients, the second scan was performed after an oral blocking dose of 125 mg of aprepitant, whereas in the other eight, no intervention was performed (test–retest). Whole striatum was used as the tissue of interest, as it has the highest density of NK1 receptors. Cerebellum was used as the reference tissue. ResultsReference tissue models were stable with the simplified reference tissue model (SRTM) performing best. Average (±standard deviation) SRTM-derived mean nondisplaceable binding potential (BPND) of all (first) baseline scans was 0.64±0.31 (n=11), which reduced to −0.01±0.03 (n=3) after aprepitant administration. Test–retest results showed low variability (14.0±10.7%) and excellent reliability, as indicated by the intraclass correlation coefficient (0.93). The ratio of standardized uptake values of striatum and cerebellum minus 1, an approximation of BPND, showed very low variability (6.2±3.1%) with excellent reliability (intraclass correlation coefficient=0.98), and correlated well with SRTM-derived BPND (R2=0.96). ConclusionSRTM is the model of choice for quantifying [11C]R116301 binding. Semiquantitative tissue ratios hold promise for routine clinical applications.

Microglia activation in schizophrenia

Introduction: The pathophysiology of schizophrenia still is not fully understood. Schizophrenia is a brain disease involving progressive loss of gray matter of unknown cause. Most likely, this loss reflects neuronal damage, which should in turn be accompanied by microglia activation. Activated microglia can be assessed using (R)-[C]PK11195 and positron emission tomography (PET). Recently, widespread increase in (R)-[C] PK11195 binding in recent onset schizophrenia patients has been described (van Berckel, B. N. et al. 2008). In the present study, the regional distribution of (R)-[C]PK11195 binding in recent onset schizophrenia was assessed.