Striatal dopamine synthesis capacity in twins discordant for schizophrenia

BackgroundElevated striatal dopamine synthesis capacity is thought to be fundamental to the pathophysiology of schizophrenia and has also been reported in people at risk of psychosis. It is therefore unclear if striatal hyperdopaminergia is a vulnerability marker for schizophrenia, or a state feature related to the psychosis itself. Relatives of patients with schizophrenia are themselves at increased risk of developing the condition. In this study we examined striatal dopamine synthesis capacity in both members of twin pairs discordant for schizophrenia.MethodIn vivo striatal dopamine synthesis capacity was examined using fluorine-18-l-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) scans in seven twin pairs discordant for schizophrenia and in a control sample of 10 healthy control twin pairs.ResultsStriatal 18F-DOPA uptake was not elevated in the unaffected co-twins of patients with schizophrenia (p=0.65) or indeed in the twins with schizophrenia (p=0.89) compared to the control group. Levels of psychotic symptoms were low in the patients with schizophrenia who were in general stable [mean (s.d.) Positive and Negative Syndrome Scale (PANSS) total=56.8 (25.5)] whereas the unaffected co-twins were largely asymptomatic.ConclusionsStriatal dopamine synthesis capacity is not elevated in symptom-free individuals at genetic risk of schizophrenia, or in well-treated stable patients with chronic schizophrenia. These findings suggest that striatal hyperdopaminergia is not a vulnerability marker for schizophrenia.

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The relationship between childhood trauma, dopamine release and dexamphetamine-induced positive psychotic symptoms: a [11C]-(+)-PHNO PET study

Translational Psychiatry ◽

10.1038/s41398-019-0627-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Tarik Dahoun ◽

Matthew M. Nour ◽

Robert A. McCutcheon ◽

Rick A. Adams ◽

Michael A. P. Bloomfield ◽

...

Keyword(s):

Childhood Trauma ◽

Dopamine Release ◽

Striatal Dopamine ◽

Psychotic Symptoms ◽

Childhood Trauma Questionnaire ◽

Mediation Analyses ◽

Positron Emission ◽

Syndrome Scale ◽

Negative Syndrome ◽

The Relationship

Abstract Childhood trauma is a risk factor for psychosis. Amphetamine increases synaptic striatal dopamine levels and can induce positive psychotic symptoms in healthy individuals and patients with schizophrenia. Socio-developmental hypotheses of psychosis propose that childhood trauma and other environmental risk factors sensitize the dopamine system to increase the risk of psychotic symptoms, but this remains to be tested in humans. We used [11C]-(+)-PHNO positron emission tomography to measure striatal dopamine-2/3 receptor (D2/3R) availability and ventral striatal dexamphetamine-induced dopamine release in healthy participants (n = 24). The relationships between dexamphetamine-induced dopamine release, dexamphetamine-induced positive psychotic symptoms using the Positive and Negative Syndrome Scale (PANSS), and childhood trauma using the Childhood Trauma Questionnaire (CTQ) were assessed using linear regression and mediation analyses, with childhood trauma as the independent variable, dexamphetamine-induced dopamine release as the mediator variable, and dexamphetamine-induced symptoms as the dependent variable. There was a significant interaction between childhood trauma and ventral striatal dopamine release in predicting dexamphetamine-induced positive psychotic symptoms (standardized β = 1.83, p = 0.003), but a mediation analysis was not significant (standardized β = −0.18, p = 0.158). There were no significant effects of dopamine release and childhood trauma on change in negative (p = 0.280) or general PANSS symptoms (p = 0.061), and there was no relationship between ventral striatal baseline D2/3R availability and positive symptoms (p = 0.368). This indicates childhood trauma and dopamine release interact to influence the induction of positive psychotic symptoms. This is not consistent with a simple sensitization hypothesis, but suggests that childhood trauma moderates the cognitive response to dopamine release to make psychotic experiences more likely.

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M149. THE TOPOGRAPHY OF STRIATAL DOPAMINE AND SYMPTOMS IN PSYCHOSIS: AN INTEGRATIVE PET AND MRI STUDY

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa030.461 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S192-S192

Author(s):

Rob McCutcheon ◽

Sameer Jauhar ◽

Fiona Pepper ◽

Matthew Nour ◽

Maria Rogdaki ◽

...

Keyword(s):

Functional Connectivity ◽

Resting State ◽

Negative Symptoms ◽

Striatal Dopamine ◽

Psychotic Symptoms ◽

Dopamine Synthesis ◽

First Episode ◽

Resting State Functional Connectivity ◽

Positron Emission ◽

Mri Study

Abstract Background Striatal dopamine dysfunction is proposed to underlie symptoms in psychosis, yet it is not known how changes in a single neurotransmitter could underlie the heterogenous presentations that are seen clinically. One hypothesis is that the symptomatic consequences of aberrant dopamine signalling may depend on where within the striatum dysfunction occurs. Positron emission tomography (PET) allows for the measurement of dopamine function across the striatum. However, when using typical atlas-based parcellation methods, the collinearity between measures of dopamine function within each striatal subdivision precludes investigation of this hypothesis. Methods We use a novel and data-driven parcellation method to address the above, and investigate relationships between spatial variability in dopamine synthesis capacity and psychotic symptoms. We employ a multimodal imaging approach combining 18F-DOPA PET and resting state MRI in 29 unmedicated and minimally-treated patients with first episode psychosis and 21 healthy controls. In each participant, we use resting state functional connectivity maps to quantify the functional connectivity of each striatal voxel to cortical networks. Network-specific striatal dopamine synthesis capacity (Kicer) was calculated for the resulting connectivity defined parcellations. Results Connectivity defined parcellations generated Kicer values with equivalent reliability, and significantly greater orthogonality to standard anatomical parcellation methods. Dopamine function within striatal areas connected to the default mode network is strongly associated with negative symptoms (p<0.001). Discussion These findings suggest that individual differences in the topography of striatal dopamine dysfunction contribute to shaping psychotic symptomatology.

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Interactions between hippocampal activity and striatal dopamine in people at clinical high risk for psychosis: relationship to adverse outcomes

Neuropsychopharmacology ◽

10.1038/s41386-021-01019-0 ◽

2021 ◽

Author(s):

Gemma Modinos ◽

Anja Richter ◽

Alice Egerton ◽

Ilaria Bonoldi ◽

Matilda Azis ◽

...

Keyword(s):

High Risk ◽

Functional Outcomes ◽

Mental States ◽

Adverse Outcomes ◽

Striatal Dopamine ◽

Psychotic Symptoms ◽

Dopamine Synthesis ◽

Clinical High Risk ◽

Hippocampal Activity ◽

The Relationship

AbstractPreclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CHR) for psychosis and investigated its association with subsequent clinical and functional outcomes. Ninety-five participants (67 CHR and 28 healthy controls) underwent arterial spin labeling MRI and 18F-DOPA PET imaging at baseline. CHR participants were followed up for a median of 15 months to determine functional outcomes with the global assessment of function (GAF) scale and clinical outcomes using the comprehensive assessment of at-risk mental states (CAARMS). CHR participants with poor functional outcomes (follow-up GAF < 65, n = 25) showed higher rCBF in the right hippocampus compared to CHRs with good functional outcomes (GAF ≥ 65, n = 25) (pfwe = 0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (pfwe = 0.035); the association was negative in CHR with poor outcomes (pfwe = 0.012), but non-significant in CHR with good outcomes. Furthermore, the correlation between right hippocampal rCBF and striatal dopamine function predicted a longitudinal increase in the severity of positive psychotic symptoms within the total CHR group (p = 0.041). There were no differences in rCBF, dopamine, or their associations in the total CHR group relative to controls. These findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of adverse outcomes in the CHR state.

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11C- and 18F-Radiotracers for In Vivo Imaging of the Dopamine System: Past, Present and Future

Biomedicines ◽

10.3390/biomedicines9020108 ◽

2021 ◽

Vol 9 (2) ◽

pp. 108

Author(s):

Michael R. Kilbourn

Keyword(s):

Pet Imaging ◽

In Vivo Imaging ◽

Dopamine Synthesis ◽

Dopamine System ◽

Synaptic Release ◽

Positron Emission ◽

The Central Nervous System ◽

Pet Radiotracers ◽

Selection Of

The applications of positron emission tomography (PET) imaging to study brain biochemistry, and in particular the aspects of dopamine neurotransmission, have grown significantly over the 40 years since the first successful in vivo imaging studies in humans. In vivo PET imaging of dopaminergic functions of the central nervous system (CNS) including dopamine synthesis, vesicular storage, synaptic release and receptor binding, and reuptake processes, are now routinely used for studies in neurology, psychiatry, drug abuse and addiction, and drug development. Underlying these advances in PET imaging has been the development of the unique radiotracers labeled with positron-emitting radionuclides such as carbon-11 and fluorine-18. This review focuses on a selection of the more accepted and utilized PET radiotracers currently available, with a look at their past, present and future.

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Tolerability and treatment response in patients with recently diagnosed vs. chronic schizophrenia treated with paliperidone ER

European Psychiatry ◽

10.1016/s0924-9338(11)73206-0 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 1502-1502

Author(s):

A. Schreiner ◽

D. Hoeben ◽

C. Tessier ◽

M. Lahaye ◽

J. Turczynski ◽

...

Keyword(s):

Treatment Response ◽

Chronic Schizophrenia ◽

Psychotic Symptoms ◽

Chronic Patients ◽

Open Label ◽

Patient Functioning ◽

Syndrome Scale ◽

Negative Syndrome ◽

Mean Time ◽

Time Since Diagnosis

ObjectiveTo explore tolerability and treatment response in adult patients with recently diagnosed (<5 years) and chronic (>5 years) schizophrenia treated with flexible doses of paliperidone ER.MethodsInternational prospective open-label 6-month study. Endpoints were the Positive and Negative Syndrome Scale (PANSS), patient functioning and treatment-emergent adverse events (TEAEs).ResultsOf 713 recently diagnosed patients, most were male (60.9%), mean age was 33.6 ± 11.2 years and mean time since diagnosis was 2.3 ± 1.7 years. Chronic patients (n = 1003) were predominantly male (59.2%) with a mean age of 43.8 ± 11.4 and mean time since diagnosis of 15.6 ± 9.2 years. 70.4% and 71.7% of patients completed the study, respectively. Mean mode doses of paliperidone ER were similar between recently diagnosed and chronic patients (7.0 ± 2.9 mg/day and 7.2 ± 2.9 mg/day). 63.1% of recently diagnosed and 60.8% of chronic patients switching due to lack of efficacy with their previous antipsychotic had a >20% improvement in PANSS total score at endpoint, and improvement with other switching reasons was consistently numerically higher in recently diagnosed patients. The rate of patients with mild or no functional impairment increased from 17.7% to 39.8% in recently diagnosed and from 14.4% to 32.9% in chronic patients. TEAEs reported in >5% were insomnia (10.7% and 8.1%), anxiety (8.6% and 6.0%) and somnolence (5.8% and 3.4%), respectively.ConclusionThese data suggest that both recently diagnosed and chronic patients previously unsuccessfully treated with other oral antipsychotics may benefit from paliperidone ER, with a tendency for recently diagnosed patients showing some higher treatment response in psychotic symptoms and patient functioning.

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The effect of perinatal brain injury on dopaminergic function and hippocampal volume in adult life

10.1101/128710 ◽

2017 ◽

Author(s):

Sean Froudist-Walsh ◽

Michael A.P. Bloomfield ◽

Mattia Veronese ◽

Jasmin Kroll ◽

Vyacheslav Karolis ◽

...

Keyword(s):

Preterm Birth ◽

Brain Injury ◽

Hippocampal Volume ◽

Dopamine Synthesis ◽

Control Group ◽

Perinatal Brain Injury ◽

Very Preterm ◽

Very Preterm Birth ◽

Injury Group ◽

Increased Risk

AbstractBackgroundVery preterm birth (<32 weeks of gestation) is associated with long-lasting brain alterations and an increased risk of psychiatric disorders associated with dopaminergic abnormalities. Preclinical studies have shown perinatal brain injuries, including hippocampal lesions, cause lasting changes in dopamine function, but it is not known if this occurs in humans. The purpose of this study was to determine whether very preterm birth and perinatal brain injury were associated with altered dopamine synthesis and reduced hippocampal volume in humans in adulthood.MethodsWe compared adults who were born very preterm with associated perinatal brain injury to adults born very preterm without perinatal brain injury, and age-matched controls born at full term using [18F]-DOPA PET and structural MRI imaging.ResultsDopamine synthesis capacity was significantly reduced in the perinatal brain injury group relative to both the group born very preterm without brain injury (Cohen’s d=1.36, p=0.02) and the control group (Cohen’s d=1.07, p=0.01). Hippocampal volume was reduced in the perinatal brain injury group relative to controls (Cohen’s d = 1.17, p = 0.01). There was a significant correlation between hippocampal volume and striatal dopamine synthesis capacity (r = 0.344, p= 0.03).ConclusionsPerinatal brain injury, but not very preterm birth without macroscopic brain injury, is associated with persistent alterations in dopaminergic function and reductions in hippocampal volume. This is the first evidence in humans linking neonatal hippocampal injury to adult dopamine dysfunction, and has implications for understanding the mechanism underlying cognitive impairments and neuropsychiatric disorders following very preterm birth.

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Frontostriatal functional connectivity and striatal dopamine synthesis capacity in schizophrenia in terms of antipsychotic responsiveness: an [18F]DOPA PET and fMRI study

Psychological Medicine ◽

10.1017/s0033291718003471 ◽

2018 ◽

Vol 49 (15) ◽

pp. 2533-2542 ◽

Cited By ~ 3

Author(s):

Seoyoung Kim ◽

Wi Hoon Jung ◽

Oliver D. Howes ◽

Mattia Veronese ◽

Federico E. Turkheimer ◽

...

Keyword(s):

Functional Connectivity ◽

Antipsychotic Drugs ◽

Striatal Dopamine ◽

University Hospital ◽

Dopamine Synthesis ◽

Control Group ◽

First Line ◽

Influx Rate ◽

Significant Difference ◽

The Relationship

AbstractBackgroundGiven that only a subgroup of patients with schizophrenia responds to first-line antipsychotic drugs, a key clinical question is what underlies treatment response. Observations that prefrontal activity correlates with striatal dopaminergic function, have led to the hypothesis that disrupted frontostriatal functional connectivity (FC) could be associated with altered dopaminergic function. Thus, the aim of this study was to investigate the relationship between frontostriatal FC and striatal dopamine synthesis capacity in patients with schizophrenia who had responded to first-line antipsychotic drug compared with those who had failed but responded to clozapine.MethodsTwenty-four symptomatically stable patients with schizophrenia were recruited from Seoul National University Hospital, 12 of which responded to first-line antipsychotic drugs (first-line AP group) and 12 under clozapine (clozapine group), along with 12 matched healthy controls. All participants underwent resting-state functional magnetic resonance imaging and [18F]DOPA PET scans.ResultsNo significant difference was found in the total PANSS score between the patient groups. Voxel-based analysis showed a significant correlation between frontal FC to the associative striatum and the influx rate constant of [18F]DOPA in the corresponding region in the first-line AP group. Region-of-interest analysis confirmed the result (control group: R2 = 0.019, p = 0.665; first-line AP group: R2 = 0.675, p < 0.001; clozapine group: R2 = 0.324, p = 0.054) and the correlation coefficients were significantly different between the groups.ConclusionsThe relationship between striatal dopamine synthesis capacity and frontostriatal FC is different between responders to first-line treatment and clozapine treatment in schizophrenia, indicating that a different pathophysiology could underlie schizophrenia in patients who respond to first-line treatments relative to those who do not.

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The Precuneus – A Witness for Excessive Aβ Gathering in Alzheimer’s Disease Pathology

Neurodegenerative Diseases ◽

10.1159/000492945 ◽

2018 ◽

Vol 18 (5-6) ◽

pp. 302-309 ◽

Cited By ~ 1

Author(s):

Gayane Aghakhanyan ◽

Andrea Vergallo ◽

Marta Gennaro ◽

Sara Mazzarri ◽

Federica Guidoccio ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Duration ◽

Standardized Uptake Value ◽

Positive Association ◽

Analysis Of Covariance ◽

Qualitative Assessment ◽

Control Group ◽

Positron Emission

Evidence of cortical beta-amyloid (Aβ) load, assessed by Aβ positron emission tomography (Aβ-PET), is an established in vivo biomarker of Alzheimer’s disease (AD)-related pathophysiology. Qualitative assessment of Aβ-PET provides binary information; meanwhile semiquantitative approaches require a parcellation of PET image either manually or by placement of atlas-based volumes of interest. We supposed that a whole-brain approach with voxel-by-voxel standardized uptake value ratio (SUVr) parametric images may better elucidate the spatial trajectories of Aβ burden along the continuum of AD. Methods: We recruited 32 subjects with a diagnosis of probable AD dementia (ADD, n = 20) and mild cognitive impairment due to AD (MCI-AD, n = 12) according to the NIA-AA 2011 criteria. We also enrolled a control group of 6 cognitively healthy individuals (HCs) with preserved cognitive functions and negative Aβ-PET scan. The PET images were spatially normalized using the AV45 PET template in the MNI brain space. Subsequently, parametric SUVr images were calculated using the whole cerebellum as a reference region. A voxel-wise analysis of covariance was used to compare (between groups) the Αβ distribution pattern considering age as a nuisance covariate. Results: Both ADD and MCI-AD subjects showed a widespread increase in radiotracer uptake when compared with HC participants (p < 0.001, uncorrected). After applying a multiple comparison correction (p < 0.05, corrected), a relative large cluster of increased [18F]-florbetapir uptake was observed in the precuneus in the ADD and MCI-AD groups compared to HCs. Voxel-wise regression analysis showed a significant positive linear association between the voxel-wise SUVr values and the disease duration. Conclusions: The voxel-wise semiquantitative analysis shows that the precuneus is a region with higher vulnerability to Aβ depositions when compared to other cortical regions in both MCI-AD and ADD subjects. We think that the precuneus is a promising PET-based outcome measure for clinical trials of drugs targeting brain Aβ. We found a positive association between the overall Aβ-PET SUVr and the disease duration suggesting that the region-specific slow saturation of Aβ deposition continuously takes place as the disease progresses.

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Aberrant striatal dopamine links topographically with cortico-thalamic dysconnectivity in schizophrenia

Brain ◽

10.1093/brain/awaa296 ◽

2020 ◽

Vol 143 (11) ◽

pp. 3495-3505 ◽

Cited By ~ 1

Author(s):

Mihai Avram ◽

Felix Brandl ◽

Franziska Knolle ◽

Jorge Cabello ◽

Claudia Leucht ◽

...

Keyword(s):

Basal Ganglia ◽

Large Scale ◽

Theoretical Models ◽

Striatal Dopamine ◽

Psychotic Symptoms ◽

Dopamine Synthesis ◽

Salience Network ◽

Thalamic Nuclei ◽

Cortical Networks ◽

Sensorimotor Network

Abstract Aberrant dopamine function in the dorsal striatum and aberrant intrinsic functional connectivity (iFC) between distinct cortical networks and thalamic nuclei are among the most consistent large-scale brain imaging findings in schizophrenia. A pathophysiological link between these two alterations is suggested by theoretical models based on striatal dopamine’s topographic modulation of cortico-thalamic connectivity within cortico-basal-ganglia-thalamic circuits. We hypothesized that aberrant striatal dopamine links topographically with aberrant cortico-thalamic iFC, i.e. aberrant associative striatum dopamine is associated with aberrant iFC between the salience network and thalamus, and aberrant sensorimotor striatum dopamine with aberrant iFC between the auditory-sensorimotor network and thalamus. Nineteen patients with schizophrenia during remission of psychotic symptoms and 19 age- and sex-comparable control subjects underwent simultaneous fluorodihydroxyphenyl-l-alanine PET (18F-DOPA-PET) and resting state functional MRI (rs-fMRI). The influx constant kicer based on 18F-DOPA-PET was used to measure striatal dopamine synthesis capacity; correlation coefficients between rs-fMRI time series of cortical networks and thalamic regions of interest were used to measure iFC. In the salience network-centred system, patients had reduced associative striatum dopamine synthesis capacity, which correlated positively with decreased salience network-mediodorsal-thalamus iFC. This correlation was present in both patients and healthy controls. In the auditory-sensorimotor network-centred system, patients had reduced sensorimotor striatum dopamine synthesis capacity, which correlated positively with increased auditory-sensorimotor network-ventrolateral-thalamus iFC. This correlation was present in patients only. Results demonstrate that reduced striatal dopamine synthesis capacity links topographically with cortico-thalamic intrinsic dysconnectivity in schizophrenia. Data suggest that aberrant striatal dopamine and cortico-thalamic dysconnectivity are pathophysiologically related within dopamine-modulated cortico-basal ganglia-thalamic circuits in schizophrenia.

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Positron emission tomography studies of healthy volunteers-no effects on the dopamine terminals and synthesis after short term exposure to toluene

Human & Experimental Toxicology ◽

10.1177/096032719701600307 ◽

1997 ◽

Vol 16 (3) ◽

pp. 171-176 ◽

Cited By ~ 3

Author(s):

C. Edling ◽

B. Hellman ◽

B. Arvidson ◽

G. Johansson ◽

J. Andersson ◽

...

Keyword(s):

Positron Emission Tomography ◽

Healthy Volunteers ◽

Emission Tomography ◽

Dopamine Synthesis ◽

Decarboxylase Activity ◽

Short Term ◽

Positron Emission ◽

Short Term Exposure ◽

Before And After

Despite extensive research, the mechanisms for the effects of organic solvents on the central nervous system are still unknown. One mechanism proposed is that solvents interfere with the synthesis of neurotransmitters. In the present study 11 male healthy volunteers were exposed during 15 min to 100 p.p.m. toluene at light physical exercise, and the dopamine decarboxylase activity and number of terminals in putamen were measured before and after exposure by positron emission tomography. Two different tracers were used, [β-11C]L-DOPA for decarbox ylase activity during the in vivo synthesis of dopamine, and [11C] nomifensine to estimate the number of terminals. Although there was a slight increase in the rate of dopamine synthesis in the putamen after the exposure, this difference was not statistically significant (P=0.4). No effect was observed with regard to the uptake of nomifensine. There was no significant relationship between the dose of toluene and rate of dopamine synthesis, and no significant correlation between the time from end of exposure to start of the PET-camera and DOPA. Our findings indicate that short term exposure to 100 p.p.m. of toluene does not affect the rate of dopamine synthesis or the number of presynaptic terminals.

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