[Show abstract][Hide abstract] ABSTRACT: In specialized movement disorder centers, Parkinson's disease (PD) is wrongly diagnosed in 6 to 25% of cases. To improve the accuracy of the clinical diagnosis, it is necessary to have a reliable and practical reference standard. Dopamine transporter single-photon emission computed tomography (DAT SPECT) imaging might have the potential (high diagnostic accuracy and practical to use) to act as reference standard in detecting nigrostriatal cell loss in patients with (early stage) parkinsonism. We performed a systematic review to evaluate if DAT SPECT imaging can be used as such. Relevant studies were searched in the MEDLINE and EMBASE databases. Studies were selected when they met the following criteria: (1) all patients were adults with a clinical diagnosis of PD or clinically uncertain parkinsonism and (2) the study reported original data. In addition, studies needed to fulfill one of the two following criteria: (1) patients underwent at least one DAT SPECT and had a neuropathological confirmed diagnosis and (2) patients underwent at least two DAT SPECT scans, performed at least 2 years apart. The search identified 1,649 articles. Eight studies fulfilled our selection criteria and were included in this review. There was only one study including patients with diagnostic uncertainty. Sensitivity and specificity of DAT SPECT imaging to detect nigrostriatal cell loss were 98%. The other studies included patients with a diagnosis of PD in whom there was no uncertainty. In these studies, sensitivity was 100%. Our systematic review indicates that DAT SPECT imaging seems to be accurate to detect nigrostriatal cell loss in patients with parkinsonism.
EJNMMI Research 12/2015; 5(1):12. DOI:10.1186/s13550-015-0087-1
[Show abstract][Hide abstract] ABSTRACT: Agonist positron emission tomography (PET) tracers for dopamine D2/3 receptors (D2/3Rs) offer greater sensitivity to changes in endogenous dopamine levels than D2/3R antagonist tracers. D2/3R agonist tracers currently available for clinical research are labeled with the short-lived isotope carbon-11, which limits their use. We aimed to develop high-affinity D2R agonists amenable for labeling with the longer-living fluorine-18. Here, we report the evaluation as potential PET tracers of two homologous series of [(18)F]fluorinated tracers based on the 2-aminomethylchroman-7-ol (AMC) scaffold: (R)-2-((4-(2-fluoroalkoxy)benzylamino)methyl)chroman-7-ols (AMC13 homologues) and (R)-2-((2-(4-(4-(fluoroalkoxy)phenyl)piperazin-1-yl)ethylamino)methyl)chroman-7-ols (AMC15 homologues). We varied the length of the (18)F-fluoroalkyl chain in these structures to balance brain penetration and non-specific binding of the radioligands by adjusting their lipophilicity.
The tracers were evaluated in brain slices of Sprague-Dawley rats by in vitro autoradiography and in living rats by microPET imaging and ex vivo autoradiography. PET data were analyzed with one- and two-tissue compartmental models (1TCM/2TCM), simplified reference tissue model (SRTM), and Logan graphical analysis. Specificity of binding was tested by blocking D2/3R with raclopride.
Homologues with a shorter fluoroalkyl chain consistently showed greater D2/3R-specific-to-total binding ratios in the striatum than those with longer chains. The fluoroethoxy homologue of AMC13 ([(18)F]FEt-AMC13) demonstrated the highest degree of D2/3R-specific binding among the evaluated tracers: mean striatum-to-cerebellum uptake ratio reached 4.4 in vitro and 2.1/2.8 in vivo/ex vivo (PET/autoradiography). Striatal binding potential (BPND) relative to cerebellum was 0.51-0.63 depending on the estimation method. Radiometabolites of [(18)F]FEt-AMC13 did not enter the brain. In vitro, application of 10 μmol/L raclopride reduced D2/3R-specific binding of [(18)F]FEt-AMC13 in the striatum by 81 %. In vivo, pre-treatment with 1 mg/kg (2.9 μmol/kg) raclopride led to 17-39 % decrease in D2/3R-specific binding in the striatum.
Varying the length of the [(18)F]fluoroalkyl chain helped improve the characteristics of the original candidate tracers. Further modifications of the current lead [(18)F]FEt-AMC13 can provide an agonist radiopharmaceutical suitable for D2/3R imaging by PET.
EJNMMI Research 12/2015; 5(1):119. DOI:10.1186/s13550-015-0119-x
[Show abstract][Hide abstract] ABSTRACT: Dexamphetamine (dAMPH) is not only used for the treatment of attention deficit hyperactivity disorder (ADHD), but also as a recreational drug. Acutely, dAMPH induces release of predominantly dopamine (DA) in the striatum, and in the cortex both DA and noradrenaline. Recent animal studies have shown that chronic dAMPH administration can induce changes in the DA system following long-term exposure, as evidenced by reductions in DA transporters, D2/3 receptors and endogenous DA levels. However, only a limited number of studies have investigated the effects of dAMPH in the human brain. We used a combination of resting-state functional magnetic resonance imaging (rs-fMRI) and [(123)I]IBZM single-photon emission computed tomography (SPECT) (to assess baseline D2/3 receptor binding and DA release) in 15 recreational AMPH users and 20 matched healthy controls to investigate the short-, and long-term effects of AMPH before and after an acute intravenous challenge with dAMPH. We found that acute dAMPH administration reduced functional connectivity in the cortico-striatal-thalamic network. dAMPH-induced DA release, but not DA D2/3 receptor binding, was positively associated with connectivity changes in this network. In addition, acute dAMPH reduced connectivity in default mode networks and salience-executive-networks networks in both groups. In contrast to our hypothesis, no significant group differences were found in any of the rs-fMRI networks investigated, possibly due to lack of sensitivity or compensatory mechanisms. Our findings thus support the use of ICA-based resting-state functional connectivity as a tool to investigate acute, but not chronic, alterations induced by dAMPH on dopaminergic processing in the striatum.
Brain Imaging and Behavior 07/2015; DOI:10.1007/s11682-015-9419-z · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Stress is an important risk factor in the etiology of psychotic disorder. Preclinical work has shown that stress primarily increases dopamine (DA) transmission in the frontal cortex. Given that DA-mediated hypofrontality is hypothesized to be a cardinal feature of psychotic disorder, stress-related extrastriatal DA release may be altered in psychotic disorder. Here we quantified for the first time stress-induced extrastriatal DA release and the spatial extent of extrastriatal DA release in individuals with non-affective psychotic disorder (NAPD). Twelve healthy volunteers (HV) and 12 matched drug-free NAPD patients underwent a single infusion [18F]fallypride positron emission tomography scan during which they completed the control and stress condition of the Montreal Imaging Stress Task. HV and NAPD did not differ in stress-induced [18F]fallypride displacement and the spatial extent of stress-induced [18F]fallypride displacement in medial prefrontal cortex (mPFC) and temporal cortex (TC). In the whole sample, the spatial extent of stress-induced radioligand displacement in right ventro-mPFC, but not dorso-mPFC or TC, was positively associated with task-induced subjective stress. Psychotic symptoms during the scan or negative, positive and general subscales of the Positive and Negative Syndrome Scale were not associated with stress-induced [18F]fallypride displacement nor the spatial extent of stress-induced [18F]fallypride displacement in NAPD. Our results do not offer evidence for altered stress-induced extrastriatal DA signaling in NAPD, nor altered functional relevance. The implications of these findings for the role of the DA system in NAPD and stress processing are discussed.
[Show abstract][Hide abstract] ABSTRACT: Extended-release naltrexone (XRNT), an opioid receptor antagonist, is successfully used in the treatment of opioid dependence. However, naltrexone treatment of opioid-dependent patients may reduce striatal dopamine transporter (DAT) availability and cause depression and anhedonia.
The aim of this study is to investigate changes in striatal DAT availability and symptoms of depression (Beck Depression Inventory (BDI)) and anhedonia (Snaith Hamilton Pleasure Scale (SHAPS)) before and during XRNT treatment.
At baseline, ten detoxified heroin-dependent patients and 11 matched healthy controls underwent [(123)I]FP-CIT single photon emission computed tomography (SPECT) imaging to assess striatal DAT binding. Patients underwent a second SPECT scan 2 weeks after an intramuscular injection with XRNT.
At baseline, the mean binding potential (BPND) in the putamen was at a trend level lower and the mean BDI score was significantly higher in heroin patients (n = 10) than in controls (n = 11) (3.45 ± 0.88 vs. 3.80 ± 0.61, p = 0.067, d = -0.48 and 12.75 ± 7.40 vs. 5.20 ± 4.83, p = 0.019, d = 1.24, respectively). Post hoc analyses in subgroups with negative urine analyses for opioids and cocaine showed significantly lower baseline putamen BPND in heroin patients (n = 8) than controls (n = 10) (3.19 ± 0.43 vs. 3.80 ± 0.64, p = 0.049, d = -1.03). XRNT treatment in heroin patients was not significantly associated with changes in striatal DAT availability (p = 0.348, d = 0.48), but the mean BDI score after XRNT treatment was significantly lower than before treatment (7.75 ± 7.21 vs. 12.75 ± 7.40, p = 0.004, d = -0.68).
The results of this study suggest that XRNT treatment does not reduce striatal DAT availability and has no significant effect on anhedonia, but is associated with a significant reduction of depressive symptoms.
[Show abstract][Hide abstract] ABSTRACT: For imaging of dopamine D2/3 receptors, agonist tracers are favoured over antagonists because they are more sensitive to detection of dopamine release and because they may selectively label the high-affinity receptor state. We have developed novel D2/3 receptor selective agonists that can be radiolabelled with [(123)I], which label is advantageous over most other labels, such as carbon-11, as it has a longer half-life. Particularly, we considered (R) N-[7-hydroxychroman-2-yl]-methyl 4-iodobenzyl amine (compound 1) as an attractive candidate for development as it shows high binding affinity to D2/3 receptors in vitro, and here we report on the characterization of this first [(123)I]-labelled D2/3 receptor agonist radiopharmaceutical intended for SPECT imaging. The appropriate tin precursor for [(123)I]-1 was developed and was successfully radiolabelled with iodine-123 giving a moderate yield (30-35%) and a good purity (>95%) for [(123)I]-1. In biodistribution experiments in Wistar rats intravenous injection of [(123)I]-1 resulted in a fast brain uptake, where the observed binding in the D2/3 receptor-rich striatum was slightly higher than that in the cerebellum 30 min to 4 h p.i. Storage phosphor imaging experiments, however, did not show specific D2/3 receptor binding. In conclusion, despite promising in vitro data for 1, neither specific ex vivo binding nor high signal-to-noise ratios were found in rodents for [(123)I]-1.
[Show abstract][Hide abstract] ABSTRACT: Background:
Minor stresses measured in daily life have repeatedly been associated with increased momentary psychotic experiences, both in individuals with psychotic disorders and in persons who are genetically at an increased risk for these disorders. Severe hearing impairment (SHI) is an environmental risk factor for psychotic disorder, possibly due to the experience of social exclusion. The aim of the current study is to investigate whether people with SHI exhibit higher levels of psychotic reactivity to social stressors in daily life than normal-hearing controls and whether this reactivity is associated with decreased baseline dopamine (DA) D2/3 receptor availability and/or elevated DA release following a dexamphetamine challenge.
We conducted an experience sampling study in 15 young adults with SHI and 19 matched normal-hearing controls who had previously participated in a single photon emission computed tomography study measuring DA D2/3 receptor availability and DA release in response to dexamphetamine.
The association between social stress and momentary psychotic experiences in daily life was stronger among SHI participants than among normal-hearing controls. Interactions between social stress and baseline striatal DA D2/3 receptor availability or DA release were not significant in multilevel models of momentary psychotic experiences including age, sex and tobacco use.
While both elevated striatal DA release and elevated psychotic stress reactivity have been found in the same population defined by an environmental risk factor, SHI, their inter-relationship cannot be established. Further research is warranted to clarify the association between biological and psychological endophenotypes and psychosis risk.
Psychological Medicine 12/2014; 45(08):1-10. DOI:10.1017/S0033291714002797 · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dopamine D2/3 receptor (D2/3R) agonist PET tracers are better suited for the imaging of synaptic dopaminergic neurotransmission than D2/3R antagonists and may also offer the opportunity to study in vivo the high-affinity state of D2/3R (D2/3RHigh). With the aim to develop 18F-labeled D2/3R agonists suitable for widespread clinical application, we report here on the synthesis and in vitro and in vivo evaluation of a D2/3R agonist ligand from the aminomethyl chromane (AMC) class-(R)-2-[(4-18F-fluorobenzylamino)methyl]chroman-7-ol (18F-AMC20).
Journal of Nuclear Medicine 12/2014; 56(1). DOI:10.2967/jnumed.114.145466 · 6.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Most studies investigating the role of personality as a risk factor for the development of opioid dependence compare dependent opioid users with healthy controls who never used heroin. In order to understand the potential protective role of personality, it is crucial to compare illicit opioid users who never became dependent with dependent opioid users.
This study aims to examine the role of personality as a risk factor for opioid use and as a protective factor for the development of opioid dependence.
Comparing personality factors between three groups: (1) 161 never-dependent illicit opioid users who have been using illicit opioids but never became opioid dependent; (2) 402 dependent opioid users in methadone maintenance treatment or heroin-assisted treatment; and (3) 135 healthy controls who never used heroin. Personality was assessed with a short version of Cloninger's Temperament and Character Inventory.
Never-dependent opioid users reported more Novelty Seeking and Harm Avoidance and less Self-Directedness and Cooperativeness than healthy controls and more Reward Dependence and Self-Directedness, and less Harm Avoidance than dependent opioid users. Furthermore, never-dependent opioid users reported more Self-Transcendence than both dependent opioid users and healthy controls.
Never-dependent opioid users may have started to use opioids partly due to their tendency to seek novel and/or spiritual experiences (high Novelty Seeking, high Self-Transcendence) and their tendency to avoid aversive stimuli (high Harm Avoidance), whereas they may have been protected against the development of dependence by their need for social approval (high Reward Dependence) and their self-efficacy (high Self-Directedness).
Drug and Alcohol Dependence 12/2014; 145. DOI:10.1016/j.drugalcdep.2014.09.783 · 3.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dopamine D2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists are more sensitive to detect dopamine release than antagonist radiopharmaceuticals, but this theory has been challenged. Interestingly, not all agonists similarly activate the classic cyclic adenosine mono phosphate (cAMP) and the ?-arrestin-2 pathway, some stimulate preferentially one of these pathways; a phenomenon called biased agonism. Because these pathways can be affected separately by pathologies or drugs (including dopamine releasers), it is important to know how agonist radiotracers act on these pathways. Therefore, we characterized the intracellular signalling of the well-known D2/3R agonist radiopharmaceuticals NPA and PHNO and of several novel D2/3R agonists.
cAMP accumulation and ?-arrestin-2 recruitment were measured on cells expressing human D2R.
All tested agonists showed (almost) full agonism in both pathways.
The tested D2/3R agonist radiopharmaceuticals did not exhibit biased agonism in vitro. Consequently, it is likely that drugs (including psychostimulants like amphetamines) and/or pathologies that influence the cAMP and/or the ?-arrestin-2 pathway may influence the binding of these radiopharmaceuticals.
EJNMMI Research 12/2014; 4(1):53. DOI:10.1186/s13550-014-0053-3
[Show abstract][Hide abstract] ABSTRACT: Several studies demonstrated improvement of depressive symptoms in treatment resistant depression (TRD) after administering dopamine agonists which suggest abnormal dopaminergic neurotransmission in TRD. However, the role of dopaminergic signaling through measurement of striatal dopamine D2/3 receptor (D2/3R) binding has not been investigated in TRD subjects. We used [123I]IBZM single photon emission computed tomography (SPECT) to investigate striatal D2/3R binding in TRD. We included 6 severe TRD patients, 11 severe TRD patients on antipsychotics (TRD AP group) and 15 matched healthy controls. Results showed no significant difference (p = 0.75) in striatal D2/3R availability was found between TRD patients and healthy controls. In the TRD AP group D2/3R availability was significantly decreased (reflecting occupancy of D2/3Rs by antipsychotics) relative to TRD patients and healthy controls (p<0.001) but there were no differences in clinical symptoms between TRD AP and TRD patients. This preliminary study therefore does not provide evidence for large differences in D2/3 availability in severe TRD patients and suggests this TRD subgroup is not characterized by altered dopaminergic transmission. Atypical antipsychotics appear to have no clinical benefit in severe TRD patients who remain depressed, despite their strong occupancy of D2/3Rs.
PLoS ONE 11/2014; 9(11):e113612. DOI:10.1371/journal.pone.0113612 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dexamphetamine (dAMPH) is a stimulant drug that is widely used recreationally as well as for treatment of attention deficit hyperactivity disorder (ADHD). Although animal studies have shown neurotoxic effects of dAMPH on the dopaminergic system, little is known about such effects on the human brain. Here, we studied the dopaminergic system at multiple physiological levels in recreational dAMPH users and age, gender and IQ-matched dAMPH-naïve healthy controls. We assessed baseline D2/3 receptor availability, in addition to changes in DA release using single-photon emission computed tomography (SPECT) and DA functionality using pharmacological magnetic resonance imaging (phMRI) following a dAMPH challenge. Also, the subjective responses to the challenge were determined. dAMPH users displayed significantly lower striatal DA D2/3 receptor binding compared to healthy controls. In dAMPH users we further observed a blunted DA release and DA functionality to an acute dAMPH challenge, as well as a blunted subjective response. Finally, the lower D2/3 availability, the more pleasant the dAMPH administration was experienced by control subjects, but not by dAMPH users. Thus, in agreement with preclinical studies, we show that recreational use of dAMPH in human subjects is associated with dopaminergic system dysfunction. These findings warrant further (longitudinal) investigations, and call for caution when using this drug recreationally and for ADHD.Neuropsychopharmacology accepted article preview online, 14 November 2014. doi:10.1038/npp.2014.301.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2014; 40(5). DOI:10.1038/npp.2014.301 · 7.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
Overeating and obesity are associated with impulsivity. In studies among patients with a substance use disorder, impulsivity was found to be associated with substance-related attentional bias. This study examined whether obesity, impulsivity and food craving are associated with an attentional bias for high-calorie food.
Obese (n = 185, mean BMI = 38.18 ± 6.17) and matched healthy-weight (n = 134, mean BMI = 22.35 ± 1.63) men (27.9%) and women (72.1%), aged 18-45 years, took part in the study. Participants were tested on several self-report and behavioral measures of impulsivity (i.e., response inhibition and reward sensitivity) and self-reported trait craving. In addition, they performed a visual search task to measure attentional bias for high- and low-caloric foods.
Self-reported impulsivity influenced the relationship between weight status and detection speed of high- and low-caloric food items: High-impulsive participants with obesity were significantly faster than high-impulsive healthy-weight participants in detecting a high-caloric food item among neutral items, whereas no such difference was observed among low-impulsive participants. No significant effects were found on low-caloric food items, for trait craving or any of the behavioral measures of impulsivity.
Self-reported impulsivity, but not trait craving or behavioral measures of impulsivity, is associated with an attentional bias for high-caloric foods, but only in people with obesity. It is in particular the speedy detection of high-caloric foods in the environment that characterizes the impulsive person with obesity, which in turn may cause risky eating patterns in a society were high-caloric food is overly present.
Health Psychology 11/2014; 34(6). DOI:10.1037/hea0000167 · 3.59 Impact Factor