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The 22q11.2 deletion syndrome (22q11DS) is caused by a deletion on chromosome 22 locus q11.2. This copy number variant results in haplo-insufficiency of the catechol-O-methyltransferase (COMT) gene, and is associated with a significant increase in the risk for developing cognitive impairments and psychosis. The COMT gene encodes an enzyme that primarily modulates clearance of dopamine (DA) from the synaptic cleft, especially in the prefrontal cortical areas. Consequently, extracellular DA levels may be increased in prefrontal brain areas in 22q11DS, which may underlie the well-documented susceptibility for cognitive impairments and psychosis in affected individuals. This study aims to examine DA D2/3 receptor binding in frontal brain regions in adults with 22q11DS, as a proxy of frontal DA levels.
The study was performed in 14 non-psychotic, relatively high functioning adults with 22q11DS and 16 age- and gender-matched healthy controls (HCs), who underwent DA D2/3 receptor [18F]fallypride PET imaging. Frontal binding potential (BPND) was used as the main outcome measure.
BPND was significantly lower in adults with 22q11DS compared with HCs in the prefrontal cortex and the anterior cingulate gyrus. After Bonferroni correction significance remained for the anterior cingulate gyrus. There were no between-group differences in BPND in the orbitofrontal cortex and anterior cingulate cortex.
This study is the first to demonstrate lower frontal D2/3 receptor binding in adults with 22q11DS. It suggests that a 22q11.2 deletion affects frontal dopaminergic neurotransmission.
22q11.2 deletion syndrome (22q11DS), one of the most common recurrent copy number variant disorders, is associated with dopaminergic abnormalities and increased risk for psychotic disorders.
Given the elevated prevalence of substance use and dopaminergic abnormalities in non-deleted patients with psychosis, we investigated the prevalence of substance use in 22q11DS, compared with that in non-deleted patients with psychosis and matched healthy controls.
This cross-sectional study involved 434 patients with 22q11DS, 265 non-deleted patients with psychosis and 134 healthy controls. Psychiatric diagnosis, full-scale IQ and COMT Val158Met genotype were determined in the 22q11DS group. Substance use data were collected according to the Composite International Diagnostic Interview.
The prevalence of total substance use (36.9%) and substance use disorders (1.2%), and weekly amounts of alcohol and nicotine use, in patients with 22q11DS was significantly lower than in non-deleted patients with psychosis or controls. Compared with patients with 22q11DS, healthy controls were 20 times more likely to use substances in general (P < 0.001); results were also significant for alcohol and nicotine use separately. Within the 22q11DS group, there was no relationship between the prevalence of substance use and psychosis or COMT genotype. Male patients with 22q11DS were more likely to use substances than female patients with 22q11DS.
The results suggest that patients with 22q11DS are at decreased risk for substance use and substance use disorders despite the increased risk of psychotic disorders. Further research into neurobiological and environmental factors involved in substance use in 22q11DS is necessary to elucidate the mechanisms involved.
Abnormalities in reward learning in psychotic disorders have been proposed to be linked to dysregulated subcortical dopaminergic (DA) neurotransmission, which in turn is a suspected mechanism for predisposition to psychosis. We therefore explored the striatal dopaminergic modulation of reward processing and its behavioral correlates in individuals at familial risk for psychosis.
We performed a DA D2/3 receptor [18F]fallypride positron emission tomography scan during a probabilistic reinforcement learning task in 16 healthy first-degree relatives of patients with psychosis and 16 healthy volunteers, followed by a 6-day ecological momentary assessment study capturing reward-oriented behavior in the everyday life.
We detected significant reward-induced DA release in bilateral caudate, putamen and ventral striatum of both groups, with no group differences in its magnitude nor spatial extent. In both groups alike, greater extent of reward-induced DA release in all regions of interest was associated with better performance in the task, as well as in greater tendency to be engaged in reward-oriented behavior in the daily life.
These findings suggest intact striatal dopaminergic modulation of reinforcement learning and reward-oriented behavior in individuals with familial predisposition to psychosis. Furthermore, this study points towards a key link between striatal reward-related DA release and pursuit of ecologically relevant rewards.
Impulsivity is a multidimensional construct, including impulsive decision-making and impulsive action, representing relatively independent neurocircuitries. ADHD is treated with methylphenidate, a drug that binds to dopamine transporters. This study in 24 adult male patients with ADHD shows that dopamine transporter occupancy by methylphenidate in the putamen correlates with improvements in cognitive but not in motor impulsivity.
Martijn Figee, Department of Psychiatry University of Amsterdam Amsterdam, The Netherlands,
Jan Booij, Department of Nuclear Medicine University of Amsterdam Amsterdam, The Netherlands,
Damiaan Denys, Department of Psychiatry University of Amsterdam Amsterdam, The Netherlands
Functional imaging studies indicate involvement of the cortico-striatal-thalamic-cortical circuit in Obsessive-compulsive disorder (OCD) pathophysiology. This chapter reviews positron emission tomography (PET) and single photon emission computed tomography (SPECT) binding studies on serotonin and dopamine, and all available 1H magnetic resonance spectroscopy (1H MRS) research into glutamate levels in OCD. It combines these findings into a pathophysiological model for dysfunctional neurotransmission in OCD. Eight studies have investigated serotonergic neurotransmission in OCD, by comparing the availability of serotonin transporter (SERT) or 5-HT2a receptors between patients and healthy controls. Five studies used 1H MRS to estimate brain levels of glutamate in OCD patients and healthy controls, including one study that performed measures before and after serotonin reuptake inhibitors (SRI) treatment. Results from SPECT and PET binding studies suggest that OCD is related to decreased presynaptic SERT availability in thalamic and midbrain-pons regions, along with increased post-synaptic 5-HT2a receptor availability in cortical areas.
123I-FP-CIT SPECT (single photon emission computed tomography) can help in the differential diagnosis of probable dementia with Lewy bodies (Lewy body dementia) and Alzheimer's disease.
Our aim was to determine the accuracy of 123I-FP-CIT SPECT in diagnosing people with possible dementia with Lewy bodies.
We undertook a 12-month follow-up of 325 individuals with probable or possible Lewy body or non-Lewy body dementia who had previously undergone 123I-FP-CIT SPECT. A consensus panel masked to SPECT findings, established diagnosis at 12 months in 264 people.
Of 44 people with possible dementia with Lewy bodies at baseline, at follow-up the diagnosis for 19 people was probable dementia with Lewy bodies (43%), in 7 people non-Lewy body dementia (16%) and for 18 individuals it remained possible dementia with Lewy bodies (41%). Of the 19 who at follow-up were diagnosed with probable dementia with Lewy bodies, 12 had abnormal scans at baseline (sensitivity 63%); all 7 individuals with a possible diagnosis who were diagnosed as having Alzheimer's disease at follow-up had normal scans (specificity 100%).
Our findings confirm the diagnostic accuracy of 123I-FP-CIT SPECT in distinguishing Lewy body from non-Lewy body dementia and also suggest a clinically useful role in diagnostically uncertain cases, as an abnormal scan in a person with possible dementia with Lewy bodies is strongly suggestive of dementia with Lewy bodies.
Neurotoxic effects of ecstasy have been reported, although it remains
unclear whether effects can be attributed to ecstasy, other recreational
drugs or a combination of these.
To assess specific/independent neurotoxic effects of heavy ecstasy use
and contributions of amphetamine, cocaine and cannabis as part of The
Netherlands XTC Toxicity (NeXT) study.
Effects of ecstasy and other substances were assessed with
1H-magnetic resonance spectroscopy, diffusion tensor imaging,
perfusion weighted imaging and
([123I]β-CIT) single photon emission computed tomography
(serotonin transporters) in a sample (n=71) with broad
variation in drug use, using multiple regression analyses.
Ecstasy showed specific effects in the thalamus with decreased
[123I]β-CIT binding, suggesting serotonergic axonal damage;
decreased fractional anisotropy, suggesting axonal loss; and increased
cerebral blood volume probably caused by serotonin depletion. Ecstasy had
no effect on brain metabolites and apparent diffusion coefficients.
Converging evidence was found for a specific toxic effect of ecstasy on
serotonergic axons in the thalamus.
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