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Tobacco smoking is highly prevalent among patients with psychosis and associated with worse clinical outcomes. Neurometabolites, such as glutamate and choline, are both implicated in psychosis and tobacco smoking. However, the specific associations between smoking and neurometabolites have yet to be investigated in patients with psychosis. The current study examines associations of chronic smoking and neurometabolite levels in the anterior cingulate cortex (ACC) in first-episode psychosis (FEP) patients and controls. Proton magnetic resonance spectroscopy (1H MRS) data of 59 FEP patients and 35 controls were analysed. Associations between smoking status (i.e., smoker yes/no) or cigarettes per day and Glx (glutamate + glutamine, as proxy for glutamate) and total choline (tCh) levels were assessed at baseline in both groups separately. For patients, six months follow-up data were acquired for multi-cross-sectional analysis using linear mixed models. No significant differences in ACC Glx levels were found between smoking (n = 28) and non-smoking (n = 31) FEP patients. Smoking patients showed lower tCh levels compared to non-smoking patients at baseline, although not surving multiple comparisons correction, and in multi-cross-sectional analysis (pFDR = 0.08 and pFDR = 0.044, respectively). Negative associations were observed between cigarettes smoked per day, and ACC Glx (pFDR = 0.02) and tCh levels (pFDR = 0.02) in controls. Differences between patients and controls regarding Glx might be explained by pre-existing disease-related glutamate deficits or alterations at nicotine acetylcholine receptor level, resulting in differences in tobacco-related associations with neurometabolites. Additionally, observed alterations in tCh levels, suggesting reduced cellular proliferation processes, might result from exposure to the neurotoxic effects of smoking.
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Background: No established medical treatment options currently exist for patients with non-functioning pituitary macroadenoma (NFPMA). Somatostatin analogues may prevent tumour growth, but randomised controlled trials are lacking. In vivo somatostatin receptor assessment with 68Ga-DOTATATE PET could help in selecting patients for treatment. We aimed to determine the effect of the somatostatin analogue lanreotide on tumour size in patients with a 68Ga-DOTATATE PET-positive NFPMA. Methods: The GALANT study was an investigator-initiated, multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial with recruitment at three academic hospitals in the Netherlands. Adult patients with a suprasellar extending NFPMA, either surgery-naïve or postoperative remnant ≥10 mm, were eligible for inclusion. Important exclusion criteria were previous sellar radiotherapy and use of dopamine receptor agonists. Somatostatin receptor expression in the NFPMA was determined through 68Ga-DOTATATE PET/CT, co-registered with MRI. A predefined sample of 44 patients with PET-positive NFPMA were randomly assigned (1:1) to lanreotide acetate 120 mg or placebo, both administered as deep subcutaneous injections every 28 days for 72 weeks. Primary outcome was the change in cranio-caudal tumour diameter measured on pituitary MRI from baseline to end-of-treatment in the intention-to-treat population. Participants, investigators and outcome assessors were masked to treatment allocation. The trial is registered with the Netherlands Trial Registry, NL5136, and EudraCT, 2015-001234-22. Findings: Between Nov 3, 2015, and Dec 10, 2019, 49 patients were included in the study. Forty-four patients with a 68Ga-DOTATATE PET-positive NFPMA were randomly assigned to lanreotide (22 [50%]) or placebo (22 [50%]). Study treatment was completed in 13 (59%) lanreotide and 19 (86%) placebo participants. The mean (SD) change from baseline in cranio-caudal tumour diameter after treatment was +1·2 (2·5) mm with lanreotide and +1·3 (1·5) mm with placebo; adjusted mean difference versus placebo -0·1 mm (95% CI -1·3 to 1·2, p = 0·93). Adverse events occurred in 22 (100%, 147 events) lanreotide and 21 (95%, 94 events) placebo participants. Gastrointestinal complaints were most common, reported by 18 (82%) lanreotide and 8 (36%) placebo participants. There were no treatment-related serious adverse events. Interpretation: Compared with placebo, lanreotide treatment did not reduce tumour size or growth in patients with 68Ga-DOTATATE PET-positive NFPMA. Funding: Ipsen Farmaceutica BV.
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The dopamine hypothesis of schizophrenia posits that elevated striatal dopamine functioning underlies the development of psychotic symptoms. Chronic exposure to social stressors increases psychosis risk, possibly by upregulating striatal dopamine functioning. Here we systematically review single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies that examined the relationship between chronic social stress exposure and in vivo striatal dopamine functioning in humans. We searched the scientific databases PubMed and PsycINFO from inception to August 2023. The quality of the included studies was evaluated with the ten-item Observational Study Quality Evaluation (PROSPERO: CRD42022308883). Twenty-eight studies were included, which measured different aspects of striatal dopamine functioning including dopamine synthesis capacity (DSC), vesicular monoamine transporter type 2 binding, dopamine release following a pharmacological or behavioral challenge, D2/3 receptor binding, and dopamine transporter binding. We observed preliminary evidence of an association between childhood trauma and increased striatal DSC and dopamine release. However, exposure to low socioeconomic status, stressful life events, or other social stressors was not consistently associated with altered striatal dopamine functioning. The quality of available studies was generally low. In conclusion, there is insufficient evidence that chronic social stressors upregulate striatal dopamine functioning in humans. We propose avenues for future research, in particular to improve the measurement of chronic social stressors and the methodological quality of study designs.
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PURPOSE: [123I]I-FP-CIT SPECT is an imaging tool to support the diagnosis of parkinsonian syndromes characterized by nigrostriatal dopaminergic degeneration. After intravenous injection, [123I]I-FP-CIT is metabolized for a small part by the enzyme CYP3A4, leading to the formation of [123I]I-nor-ß-CIT. [123I]I-nor-ß-CIT passes the blood-brain barrier and has a very high affinity for the serotonin transporter (SERT). The SERT is expressed in the striatum and cortical areas. So, at least theoretical, the use of frequently used CYP3A4 inhibitors (like amiodarone) may influence the specific to non-specific striatal [123I]I-FP-CIT ratio. Here we tested this novel hypothesis. METHODS: Using a retrospective design, we determined the specific to non-specific striatal [123I]I-FP-CIT ratio (using BRASS software) in 6 subjects that were using an CYP3A4 inhibitor and 18 matched controls. Only subjects were included with a normal rated [123I]I-FP-CIT SPECT scan, and all participants were scanned on the same brain-dedicated SPECT system. RESULTS: The specific to non-specific (assessed in the occipital cortex) striatal [123I]I-FP-CIT binding ratio was significantly higher in CYP3A4 users than in the control group (3.52 ± 0.33 vs. 2.90 ± 0.78, p < 0.001). CONCLUSION: Our preliminary data suggest that the use of CYP3A4 inhibitors may influence striatal [123I]I-FP-CIT binding ratios. This information, when reproduced in larger studies, may be relevant for studies in which quantification of [123I]I-FP-CIT SPECT imaging is used for diagnostic or research purposes.
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OBJECTIVE: Markers for treatment resistance in schizophrenia are needed to reduce delays in effective treatment. Nigrostriatal hyperdopaminergic function plays a critical role in the pathology of schizophrenia, yet antipsychotic nonresponders do not show increased dopamine function. Neuromelanin-sensitive MRI (NM-MRI), which indirectly measures dopamine function in the substantia nigra, has potential as a noninvasive marker for nonresponders. Increased NM-MRI signal has been shown in psychosis, but has not yet been assessed in nonresponders. In this study, the authors investigated whether nonresponders show lower NM-MRI signal than responders. METHODS: NM-MRI scans were acquired in 79 patients with first-episode psychosis and 20 matched healthy control subjects. Treatment response was assessed at a 6-month follow-up. An a priori voxel-wise analysis within the substantia nigra tested the relation between NM-MRI signal and treatment response in patients. RESULTS: Fifteen patients were classified as nonresponders and 47 patients as responders. Seventeen patients were excluded, primarily because of medication nonadherence or change in diagnosis. Voxel-wise analysis revealed 297 significant voxels in the ventral tier of the substantia nigra that were negatively associated with treatment response. Nonresponders and healthy control subjects had significantly lower NM-MRI signal than responders. Receiver operating characteristic curve analysis showed that NM-MRI signal separated nonresponders with areas under the curve between 0.62 and 0.85. In addition, NM-MRI signal in patients did not change over 6 months. CONCLUSIONS: These findings provide further evidence for dopaminergic differences between medication responders and nonresponders and support the potential of NM-MRI as a clinically applicable marker for treatment resistance in schizophrenia.
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Antipsicóticos , Biomarcadores , Imageamento por Ressonância Magnética , Melaninas , Substância Negra , Humanos , Masculino , Melaninas/metabolismo , Imageamento por Ressonância Magnética/métodos , Feminino , Adulto , Substância Negra/diagnóstico por imagem , Substância Negra/metabolismo , Antipsicóticos/uso terapêutico , Biomarcadores/metabolismo , Esquizofrenia Resistente ao Tratamento/tratamento farmacológico , Esquizofrenia Resistente ao Tratamento/diagnóstico por imagem , Esquizofrenia/tratamento farmacológico , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/metabolismo , Adulto Jovem , Estudos de Casos e Controles , Dopamina/metabolismoRESUMO
BACKGROUND: Interactions between the endocannabinoid system (ECS) and neurotransmitter systems might mediate the risk of developing a schizophrenia spectrum disorder (SSD). Consequently, we investigated in patients with SSD and healthy controls (HC) the relations between (1) plasma concentrations of two prototypical endocannabinoids (N-arachidonoylethanolamine [anandamide] and 2-arachidonoylglycerol [2-AG]) and (2) striatal dopamine synthesis capacity (DSC), and glutamate and y-aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC). As anandamide and 2-AG might reduce the activity of these neurotransmitters, we hypothesized negative correlations between their plasma levels and the abovementioned neurotransmitters in both groups. METHODS: Blood samples were obtained from 18 patients and 16 HC to measure anandamide and 2-AG plasma concentrations. For all subjects, we acquired proton magnetic resonance spectroscopy scans to assess Glx (i.e. glutamate plus glutamine) and GABA + (i.e. GABA plus macromolecules) concentrations in the ACC. Ten patients and 14 HC also underwent [18F]F-DOPA positron emission tomography for assessment of striatal DSC. Multiple linear regression analyses were used to investigate the relations between the outcome measures. RESULTS: A negative association between 2-AG plasma concentration and ACC Glx concentration was found in patients (p = 0.008). We found no evidence of other significant relationships between 2-AG or anandamide plasma concentrations and dopaminergic, glutamatergic, or GABAergic measures in either group. CONCLUSIONS: Our preliminary results suggest an association between peripheral 2-AG and ACC Glx levels in patients.
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BACKGROUND: Around 30 % of schizophrenia patients do not respond sufficiently to conventional antipsychotic treatment. Glutamate and γ-aminobutyric acid (GABA) may be implicated in treatment resistant (TR) patients. Some data indicate that TR patients show increased glutamate levels compared to responders, but findings are inconclusive and limited in the early disease stage. Furthermore, the two neurotransmitters have rarely been assessed in conjunction. We therefore aimed to investigate the role of GABA+ and glutamate in first episode TR patients and explore whether these neurometabolites could be potential predictive markers for TR schizophrenia. STUDY DESIGN: We used proton magnetic resonance spectroscopy (MRS) to assess glutamate + glutamine (Glx) and GABA including macromolecules (GABA+) in the anterior cingulate cortex (ACC) of 58 first episode psychosis patients. At six months follow-up treatment response was determined and in a subgroup of 33 patients a follow-up MRS scan was acquired. STUDY RESULTS: Glx and GABA+ levels were not significantly different between TR patients and responders at baseline and the levels did not change at six months follow-up. The groups differed in voxel fractions, which could have influenced our results even though we corrected for these differences. CONCLUSIONS: Our findings do not provide evidence that ACC Glx or GABA+ levels are potential biomarkers for TR in first episode psychosis. Future research needs to take in to account voxel fractions and report potential differences. Comparison with previous literature suggests that illness duration, clozapine responsiveness and medication effects may partly explain the heterogeneous results on Glx and GABA+ levels in TR.
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Ácido Glutâmico , Transtornos Psicóticos , Humanos , Glutamina , Giro do Cíngulo/diagnóstico por imagem , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/tratamento farmacológico , Ácido gama-AminobutíricoRESUMO
BACKGROUND: Prediction of treatment resistance in schizophrenia (TRS) would be helpful to reduce the duration of ineffective treatment and avoid delays in clozapine initiation. We applied machine learning to identify clinical, sociodemographic, familial, and environmental variables that are associated with TRS and could potentially predict TRS in the future. STUDY DESIGN: Baseline and follow-up data on trait(-like) variables from the Genetic Risk and Outcome of Psychosis (GROUP) study were used. For the main analysis, we selected patients with non-affective psychotic disorders who met TRS (n = 200) or antipsychotic-responsive criteria (n = 423) throughout the study. For a sensitivity analysis, we only selected patients who met TRS (n = 76) or antipsychotic-responsive criteria (n = 123) at follow-up but not at baseline. Random forest models were trained to predict TRS in both datasets. SHapley Additive exPlanation values were used to examine the variables' contributions to the prediction. STUDY RESULTS: Premorbid functioning, age at onset, and educational degree were most consistently associated with TRS across both analyses. Marital status, current household, intelligence quotient, number of moves, and family loading score for substance abuse also consistently contributed to the prediction of TRS in the main or sensitivity analysis. The diagnostic performance of our models was modest (area under the curve: 0.66-0.69). CONCLUSIONS: We demonstrate that various clinical, sociodemographic, familial, and environmental variables are associated with TRS. Our models only showed modest performance in predicting TRS. Prospective large multi-centre studies are needed to validate our findings and investigate whether the model's performance can be improved by adding data from different modalities.
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Antipsicóticos , Clozapina , Transtornos Psicóticos , Esquizofrenia , Humanos , Antipsicóticos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Esquizofrenia/diagnóstico , Estudos Prospectivos , Clozapina/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/genéticaRESUMO
BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) potentiate serotonergic neurotransmission by blocking the serotonin transporter (5-HTT), but the functional brain response to SSRIs involves neural circuits beyond regions with high 5-HTT expression. Currently, it is unclear whether and how changes in 5-HTT availability after SSRI administration modulate brain function of key serotoninergic circuits, including those characterized by high availability of the serotonin 1A receptor (5-HT1AR). AIM: We investigated the association between 5-HTT availability and 5-HTT- and 5-HT1AR-enriched functional connectivity (FC) after an acute citalopram challenge. METHODS: We analyzed multimodal data from a dose-response, placebo-controlled, double-blind study, in which 45 healthy women were randomized into three groups receiving placebo, a low (4 mg), or high (16 mg) oral dose of citalopram. Receptor-Enhanced Analysis of functional Connectivity by Targets was used to estimate 5-HTT- and 5-HT1AR-enriched FC from resting-state and task-based fMRI. 5-HTT availability was determined using [123I]FP-CIT single-photon emission computerized tomography. RESULTS: 5-HTT availability was negatively correlated with resting-state 5-HTT-enriched FC, and with task-dependent 5-HT1AR-enriched FC. Our exploratory analyses revealed lower 5-HT1AR-enriched FC in the low-dose group compared to the high-dose group at rest and the placebo group during the emotional face-matching task. CONCLUSIONS: Taken together, our findings provide evidence for differential links between 5-HTT availability and brain function within 5-HTT and 5-HT1AR pathways and in context- and dose-dependent manner. As such, they support a potential pivotal role of the 5-HT1AR in the effects of citalopram on the brain and add to its potential as a therapeutic avenue for mood and anxiety disturbances.
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Citalopram , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Feminino , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/metabolismo , Neuroimagem/métodos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismoRESUMO
BACKGROUND: Preliminary studies suggested seasonality of dopaminergic functioning, but it is unknown whether dopamine transporter (DAT) expression in humans is also dependent on the seasons. We, therefore, investigated seasonal and sunlight-dependent effects on DAT availability in early Parkinson's disease (PD) patients and healthy controls. METHODS: DAT single-photon emission computed tomography scans (n = 730) were gathered from the Parkinson's Progression Marker Initiative (PPMI) database. We used global horizontal irradiance (GHI) as proxy for sun exposure/month and assessed associations between striatal DAT availability and season (autumn/winter versus spring/summer), GHI and latitude of the PPMI site. RESULTS: In PD patients, DAT availability in the left caudate nucleus was higher in spring/summer (B [standard error (SE)] = 0.05 [0.02], P = 0.03) and positively associated with higher sun exposure (B [SE] = 0.59 [0.22] × 10-3 , P = 0.007). Latitude (in degrees north) of the PPMI site was negatively associated with DAT availability in both PD and healthy controls. CONCLUSION: Striatal DAT availability may be influenced by daylight exposure. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Proteínas da Membrana Plasmática de Transporte de Dopamina , Doença de Parkinson , Luz Solar , Humanos , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Doença de Parkinson/complicações , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
PURPOSE: A high SUV max tumor-to-liver ratio (TLR) of 68 Ga-DOTATATE can be used to select patients with neuroendocrine tumors (NETs) for peptide receptor radionuclide therapy (PRRT). In addition, an SUV max TLR ≥ 8.1 is associated with increased progression-free survival in NET patients treated with somatostatin analogs (SSAs). To avoid a theoretical interaction, several guidelines recommend performing PET/CT just before the monthly administration of long-acting SSAs. We aimed to investigate the effect of SSA on the SUV max of 68 Ga-DOTATATE in patients with NET and to identify independent predictors for high SUV max TLR. PATIENTS AND METHODS: For this retrospective study, 192 68 Ga-DOTATATE PET/CT scans of 165 patients without (n = 115) and with (n = 77) SSA (octreotide or lanreotide) in the 3 months before PET/CT were collected and reviewed. The effect of SSA on SUV max values was analyzed by a maximum likelihood mixed model. RESULTS: Patients with SSA had a significantly higher median SUV max TLR than patients without SSA (4.7 [IQR], 3.1-7.7) versus 3.2 [IQR, 2.0-5.4]; P < 0.001). Multivariable logistic regression analysis showed that SSA use was an independent predictor for SUV max TLR ≥ 8.1 (odds ratio, 2.91; 95% confidence interval, 1.26-6.72; P = 0.012). CONCLUSIONS: Our data suggest that higher SSA concentrations do not have a negative effect on 68 Ga-DOTATATE uptake in tumor lesions. In addition, we found that only SSA use was associated with SUV max TLR ≥ 8.1. Our results are consistent with previously conducted studies and in line with the recently published guideline that suggests that the relatively recent use of SSA does not necessitate any delay in 68 Ga-DOTATATE PET/CT imaging.
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Neoplasias Hepáticas , Tumores Neuroendócrinos , Compostos Organometálicos , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Estudos Retrospectivos , Receptores de Somatostatina , Somatostatina/uso terapêutico , Compostos Organometálicos/uso terapêuticoRESUMO
Post-ingestive nutrient signals to the brain regulate eating behaviour in rodents, and impaired responses to these signals have been associated with pathological feeding behaviour and obesity. To study this in humans, we performed a single-blinded, randomized, controlled, crossover study in 30 humans with a healthy body weight (females N = 12, males N = 18) and 30 humans with obesity (females N = 18, males N = 12). We assessed the effect of intragastric glucose, lipid and water (noncaloric isovolumetric control) infusions on the primary endpoints cerebral neuronal activity and striatal dopamine release, as well as on the secondary endpoints plasma hormones and glucose, hunger scores and caloric intake. To study whether impaired responses in participants with obesity would be partially reversible with diet-induced weight loss, imaging was repeated after 10% diet-induced weight loss. We show that intragastric glucose and lipid infusions induce orosensory-independent and preference-independent, nutrient-specific cerebral neuronal activity and striatal dopamine release in lean participants. In contrast, participants with obesity have severely impaired brain responses to post-ingestive nutrients. Importantly, the impaired neuronal responses are not restored after diet-induced weight loss. Impaired neuronal responses to nutritional signals may contribute to overeating and obesity, and ongoing resistance to post-ingestive nutrient signals after significant weight loss may in part explain the high rate of weight regain after successful weight loss.
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Dopamina , Obesidade , Masculino , Feminino , Humanos , Estudos Cross-Over , Redução de Peso , Encéfalo , Nutrientes , Glucose , LipídeosRESUMO
Catecholamine-enhancing psychostimulants, such as methylphenidate have long been argued to undermine creative thinking. However, prior evidence for this is weak or contradictory, stemming from studies with small sample sizes that do not consider the well-established large variability in psychostimulant effects across different individuals and task demands. We aimed to definitively establish the link between psychostimulants and creative thinking by measuring effects of methylphenidate in 90 healthy participants on distinct creative tasks that measure convergent and divergent thinking, as a function of individuals' baseline dopamine synthesis capacity, indexed with 18F-FDOPA PET imaging. In a double-blind, within-subject design, participants were administered methylphenidate, placebo or selective D2 receptor antagonist sulpiride. The results showed that striatal dopamine synthesis capacity and/or methylphenidate administration did not affect divergent and convergent thinking. However, exploratory analysis demonstrated a baseline dopamine-dependent effect of methylphenidate on a measure of response divergence, a creativity measure that measures response variability. Response divergence was reduced by methylphenidate in participants with low dopamine synthesis capacity but enhanced in those with high dopamine synthesis capacity. No evidence of any effect of sulpiride was found. These results show that methylphenidate can undermine certain forms of divergent creativity but only in individuals with low baseline dopamine levels.
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Estimulantes do Sistema Nervoso Central , Metilfenidato , Humanos , Estimulantes do Sistema Nervoso Central/farmacologia , Criatividade , Dopamina , Metilfenidato/farmacologia , Sulpirida/farmacologia , Método Duplo-CegoRESUMO
Physical exercise training has been positioned as a behavioral strategy to prevent or alleviate obesity via promotion of energy expenditure as well as modulation of energy intake resulting from changes in dietary preference. Brain adaptations underlying the latter process are incompletely understood. Voluntary wheel running (VWR) is a self-reinforcing rodent paradigm that mimics aspects of human physical exercise training. Behavioral and mechanistic insight from such fundamental studies can help optimize therapies that improve body weight and metabolic health based on physical exercise training in humans. To assess the effects of VWR on dietary self-selection, male Wistar rats were given access to a two-component "no-choice" control diet (CD; consisting of prefabricated nutritionally complete pellets and a bottle with tap water) or a four-component free-choice high-fat high-sucrose diet (fc-HFHSD; consisting of a container with prefabricated nutritionally complete pellets, a dish with beef tallow, a bottle with tap water, and a bottle with 30% sucrose solution). Metabolic parameters and baseline dietary self-selection behavior during sedentary (SED) housing were measured for 21 days, after which half of the animals were allowed to run on a vertical running wheel (VWR) for another 30 days. This resulted in four experimental groups (SEDCD, SEDfc-HFHSD, VWRCD, and VWRfc-HFHSD). Gene expression of opioid and dopamine neurotransmission components, which are associated with dietary self-selection, was assessed in the lateral hypothalamus (LH) and nucleus accumbens (NAc), two brain regions involved in reward-related behavior, following 51 and 30 days of diet consumption and VWR, respectively. Compared to CD controls, consumption of fc-HFHSD before and during VWR did not alter total running distances. VWR and fc-HFHSD had opposite effects on body weight gain and terminal fat mass. VWR transiently lowered caloric intake and increased and decreased terminal adrenal and thymus mass, respectively, independent of diet. VWR during fc-HFHSD consumption consistently increased CD self-selection, had an acute negative effect on fat self-selection, and a delayed negative effect on sucrose solution self-selection compared to SED controls. Gene expression of opioid and dopamine neurotransmission components in LH and NAc were unaltered by fc-HFHSD or VWR. We conclude that VWR modulates fc-HFHSD component self-selection in a time-dependent manner in male Wistar rats.
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Analgésicos Opioides , Atividade Motora , Ratos , Animais , Bovinos , Masculino , Humanos , Ratos Wistar , Analgésicos Opioides/farmacologia , Dopamina/farmacologia , Dieta Hiperlipídica , Peso Corporal , Sacarose/farmacologiaRESUMO
Individual differences in striatal dopamine synthesis capacity have been associated with working memory capacity, trait impulsivity, and spontaneous eye-blink rate (sEBR), as measured with readily available and easily administered, 'off-the-shelf' tests. Such findings have raised the suggestion that individual variation in dopamine synthesis capacity, estimated with expensive and invasive brain positron emission tomography (PET) scans, can be approximated with simple, more pragmatic tests. However, direct evidence for the relationship between these simple trait measures and striatal dopamine synthesis capacity has been limited and inconclusive. We measured striatal dopamine synthesis capacity using [18F]-FDOPA PET in a large sample of healthy volunteers (N = 94) and assessed the correlation with simple, short tests of working memory capacity, trait impulsivity, and sEBR. We additionally explored the relationship with an index of subjective reward sensitivity. None of these trait measures correlated significantly with striatal dopamine synthesis capacity, nor did they have out-of-sample predictive power. Bayes factor analyses indicated the evidence was in favour of absence of correlations for all but subjective reward sensitivity. These results warrant caution for using these off-the-shelf trait measures as proxies of striatal dopamine synthesis capacity.
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Dopamina , Memória de Curto Prazo , Humanos , Teorema de Bayes , Corpo Estriado/diagnóstico por imagem , Comportamento ImpulsivoRESUMO
PURPOSE: In routine practice, dopamine transporter (DAT) imaging is frequently used as a diagnostic tool to support the diagnosis of Parkinson's disease or dementia with Lewy bodies. In 2008, we published a review on which medications and drugs of abuse may influence striatal [123I]I-FP-CIT binding and consequently may influence the visual read of an [123I]I-FP-CIT SPECT scan. We made recommendations on which drugs should be withdrawn before performing DAT imaging in routine practice. Here, we provide an update of the original work based on published research since 2008. METHODS: We performed a systematic review of literature without language restriction from January 2008 until November 2022 to evaluate the possible effects of medications and drugs of abuse, including the use of tobacco and alcohol, on striatal DAT binding in humans. RESULTS: The systematic literature search identified 838 unique publications, of which 44 clinical studies were selected. Using this approach, we found additional evidence to support our original recommendations as well as some new findings on potential effect of other medications on striatal DAT binding. Consequently, we updated the list of medications and drugs of abuse that may influence the visual read of [123I]I-FP-CIT SPECT scans in routine clinical practice. CONCLUSION: We expect that a timely withdrawal of these medications and drugs of abuse before DAT imaging may reduce the incidence of false-positive reporting. Nevertheless, the decision to withdraw any medication must be made by the specialist in charge of the patient's care and considering the pros and cons of doing so.
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Proteínas da Membrana Plasmática de Transporte de Dopamina , Imageamento Dopaminérgico , Humanos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , TropanosRESUMO
Dysregulation of striatal dopamine is considered to be an important driver of pathophysiological processes in schizophrenia. Despite being one of the main origins of dopaminergic input to the striatum, the (dys)functioning of the substantia nigra (SN) has been relatively understudied in schizophrenia. Hence, this paper aims to review different molecular aspects of nigral functioning in patients with schizophrenia compared to healthy controls by integrating post-mortem and molecular imaging studies. We found evidence for hyperdopaminergic functioning in the SN of patients with schizophrenia (i.e. increased AADC activity in antipsychotic-free/-naïve patients and elevated neuromelanin accumulation). Reduced GABAergic inhibition (i.e. decreased density of GABAergic synapses, lower VGAT mRNA levels and lower mRNA levels for GABAA receptor subunits), excessive glutamatergic excitation (i.e. increased NR1 and Glur5 mRNA levels and a reduced number of astrocytes), and several other disturbances implicating the SN (i.e. immune functioning and copper concentrations) could potentially underlie this nigral hyperactivity and associated striatal hyperdopaminergic functioning in schizophrenia. These results highlight the importance of the SN in schizophrenia pathology and suggest that some aspects of molecular functioning in the SN could potentially be used as treatment targets or biomarkers.
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Esquizofrenia , Humanos , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/patologia , Dopamina/fisiologia , Corpo Estriado , Substância Negra/diagnóstico por imagem , Substância Negra/fisiologia , Receptores de GABA-A , RNA MensageiroRESUMO
PURPOSE: Neuromelanin MRI (NM-MRI) is applied as a proxy measurement of dopaminergic functioning of the substantia nigra pars compacta (SN). To increase its clinical applicability, a fast and easily applicable NM-MRI sequence is needed. This study therefore compared accelerated NM-MRI sequences using standard available MRI options with a validated 2D gradient recalled echo NM-MRI sequence with off-resonance magnetization transfer (MT) pulse (2D-MToffRes). METHODS: We used different combinations of compressed sense (CS) acceleration, repetition times (TR), and MT pulse to accelerate the validated 2D-MToffRes. In addition, we compared a recently introduced 3D sequence with the 2D-MToffRes. RESULTS: Our results show that the 2D sequences perform best with good to excellent reliability. Only excellent intraclass correlation coefficients were found for the CS factor 2 sequences. CONCLUSION: We conclude that there are several reliable approaches to accelerate NM-MRI, in particular by using CS.
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Doença de Parkinson , Humanos , Reprodutibilidade dos Testes , Substância Negra/diagnóstico por imagem , Melaninas , Imageamento por Ressonância Magnética/métodos , AceleraçãoRESUMO
PURPOSE: Two commonly used imaging techniques to aid in the diagnosis of neurodegenerative parkinsonian syndromes are dopamine transporter (DAT) imaging with [123I]-FP-CIT single-photon emission computed tomography (DAT-SPECT) and positron emission tomography with [18F]-FDOPA (FDOPA-PET). This paper provides a unique series of parkinsonian patients who received both FDOPA-PET and DAT-SPECT in routine clinical practice and compares the reported results to assess potential differences between these two imaging techniques. METHODS: We present 11 patients with a clinically uncertain parkinsonian syndrome (CUPS), who received both FDOPA-PET and DAT-SPECT. All patients received an FDOPA-PET scan and DAT-SPECT as part of routine clinical care. RESULTS: The median time between the F-DOPA-PET scan and DAT-SPECT scan was 6 months (range 0-15 months). There was a discrepancy in the reported results of the FDOPA-PET and DAT-SPECT scans in nine patients, including 7 patients whose FDOPA-PET scan was reportedly normal, whereas their DAT-SPECT scan was abnormal. CONCLUSIONS: In this case series of CUPS patients, DAT-SPECT was more often rated as abnormal than FDOPA-PET. The striatal loss of FDOPA uptake can be less pronounced than that of DAT binding in CUPS patients in early disease stages. Consequently, the interpretation of FDOPA-PET scans in CUPS can sometimes be challenging in routine practice.