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1.
Mov Disord ; 37(11): 2301-2307, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36102173

RESUMO

BACKGROUND: Both Parkinson's disease (PD) and multiple system atrophy (MSA) exhibit degeneration of brainstem serotoninergic nuclei, affecting multiple subcortical and cortical serotoninergic projections. In MSA, medullary serotoninergic neuron pathology is well documented, but serotonin system changes throughout the rest of the brain are less well characterized. OBJECTIVES: To use serotonin transporter [11 C]3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile positron emission tomography (PET) to compare serotoninergic innervation in patients with MSA and PD. METHODS: We performed serotonin transporter PET imaging in 18 patients with MSA, 23 patients with PD, and 16 healthy controls to explore differences in brainstem, subcortical, and cortical regions of interest. RESULTS: Patients with MSA showed lower serotonin transporter distribution volume ratios compared with patients with PD in the medulla, raphe pontis, ventral striatum, limbic cortex, and thalamic regions, but no differences in the dorsal striatal, ventral anterior cingulate, or total cortical regions. Controls showed greater cortical serotonin transporter binding compared with PD or MSA groups but lower serotonin transporter binding in the striatum and other relevant basal ganglia regions. There were no regional differences in binding between patients with MSA-parkinsonian subtype (n = 8) and patients with MSA-cerebellar subtype (n = 10). Serotonin transporter distribution volume ratios in multiple different regions of interest showed an inverse correlation with the severity of Movement Disorders Society Unified Parkinson's Disease Rating Scale motor score in patients with MSA but not patients with PD. CONCLUSIONS: Brainstem and some forebrain subcortical region serotoninergic deficits are more severe in MSA compared with PD and show an MSA-specific correlation with the severity of motor impairments. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Atrofia de Múltiplos Sistemas , Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Serotonina/metabolismo
2.
Neuroimage ; 199: 466-479, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158479

RESUMO

Positron Emission Tomography (PET) is an important neuroimaging tool to quantify the distribution of specific molecules in the brain. The quantification is based on a series of individually designed data preprocessing steps (pipeline) and an optimal preprocessing strategy is per definition associated with less noise and improved statistical power, potentially allowing for more valid neurobiological interpretations. In spite of this, it is currently unclear how to design the best preprocessing pipeline and to what extent the choice of each preprocessing step in the pipeline minimizes subject-specific errors. To evaluate the impact of various preprocessing strategies, we systematically examined 384 different pipeline strategies in data from 30 healthy participants scanned twice with the serotonin transporter (5-HTT) radioligand [11C]DASB. Five commonly used preprocessing steps with two to four options were investigated: (1) motion correction (MC) (2) co-registration (3) delineation of volumes of interest (VOI's) (4) partial volume correction (PVC), and (5) kinetic modeling. To quantitatively compare and evaluate the impact of various preprocessing strategies, we used the performance metrics: test-retest bias, within- and between-subject variability, the intraclass-correlation coefficient, and global signal-to-noise ratio. We also performed a power analysis to estimate the required sample size to detect either a 5% or 10% difference in 5-HTT binding as a function of preprocessing pipeline. The results showed a complex downstream dependency between the various preprocessing steps on the performance metrics. The choice of MC had the most profound effect on 5-HTT binding, prior to the effects caused by PVC and kinetic modeling, and the effects differed across VOI's. Notably, we observed a negative bias in 5-HTT binding across test and retest in 98% of pipelines, ranging from 0 to 6% depending on the pipeline. Optimization of the performance metrics revealed a trade-off in within- and between-subject variability at the group-level with opposite effects (i.e. minimization of within-subject variability increased between-subject variability and vice versa). The sample size required to detect a given effect size was also compromised by the preprocessing strategy, resulting in up to 80% increases in sample size needed to detect a 5% difference in 5-HTT binding. This is the first study to systematically investigate and demonstrate the effect of choosing different preprocessing strategies on the outcome of dynamic PET studies. We provide a framework to show how optimal and maximally powered neuroimaging results can be obtained by choosing appropriate preprocessing strategies and we provide recommendations depending on the study design. In addition, the results contribute to a better understanding of methodological uncertainty and variability in preprocessing decisions for future group- and/or longitudinal PET studies.


Assuntos
Encéfalo/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Adolescente , Adulto , Compostos de Anilina , Encéfalo/metabolismo , Feminino , Humanos , Processamento de Imagem Assistida por Computador/normas , Imageamento por Ressonância Magnética , Neuroimagem/normas , Tomografia por Emissão de Pósitrons/normas , Compostos Radiofarmacêuticos , Sulfetos , Adulto Jovem
3.
Synapse ; 72(3)2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29216407

RESUMO

SEP-227162 [R(-)-O-desmethylvenlafaxine] is an enantiomer of the venlafaxine metabolite O-desmethylvenlafaxine (ODV, Pristiq™, Wyeth). This study compared the serotonin transporter (SERT) occupancy achieved by SEP-227162 and ODV, at daily doses of 25, 50, 100, and 150 mg using [11 C]DASB positron emission tomography (PET). Sixteen healthy male subjects participated in one of four dose groups (N = 4 per group) during which they were administered two doses of the study drug (SEP-227162 or ODV). For each study drug, total daily doses of 25, 50, 100, and150 mg were studied. Subjects underwent three PET scans with [11 C]DASB. A baseline, off-medication, scan was performed prior to dosing and a [11 C]DASB PET scan was performed after 72 hr at each dose level. [11 C]DASB binding potential (BPND ) was calculated using the simplified reference tissue method. SERT occupancy was calculated as the change in BPND (ΔBPND ) from baseline scan to the on-medication scan relative to the baseline BPND value. SEP-227162 and ODV significantly reduced regional distribution volumes and region BPND values in a dose-dependent manner. Across all doses ODV produced significantly greater SERT occupancy than SEP-227162 (ANOVA F = 21.8, df = 1,23, p < .001). The total daily dose required to provide 50% SERT occupancy was 24.8 mg for SEP-227162 and 14.4 mg for ODV. In vitro data suggests a ratio of 3.3:1 for binding at human SERT for SEP-227162 relative to ODV. Our study suggests a ratio of 1.7:1, highlighting the value of in vivo imaging in the drug development process.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Succinato de Desvenlafaxina/análogos & derivados , Succinato de Desvenlafaxina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Adulto , Compostos de Anilina , Encéfalo/diagnóstico por imagem , Succinato de Desvenlafaxina/sangue , Relação Dose-Resposta a Droga , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Inibidores da Recaptação de Serotonina e Norepinefrina/sangue , Sulfetos , Adulto Jovem
4.
Hum Psychopharmacol ; 33(1)2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29210107

RESUMO

OBJECTIVE: Early-onset obsessive-compulsive disorder (EOCD) and late-onset obsessive-compulsive disorder (LOCD) are distinct subtypes of obsessive-compulsive disorder (OCD). OCD patients are treated with serotonin reuptake inhibitors, but the difference in serotonin transporter (SERT) availability between medicated EOCD and LOCD is unexplored yet. METHODS: Six EOCD and 6 LOCD patients were enrolled. They underwent serial [11 C]DASB positron emission tomography scans during maintenance therapy with escitalopram, and their plasma concentration of escitalopram was measured simultaneously with the scan. Then, the drug-free binding potential of SERT was calculated by pharmacokinetic-pharmacodynamic modelling. RESULTS: In comparison with LOCD patients, SERT availability was significantly higher in the putamen of EOCD patients (U = 4, p = .026), but not in the caudate nucleus (U = 14, p = .589), thalamus (U = 16, p = .818), and dorsal raphe nucleus (U = 7, p = .093). Binding potential of putamen showed a negative correlation (r = -.580, p = .048) with age of onset of the disease, but not with the Yale-Brown Obsessive Compulsive Scale scores. CONCLUSIONS: These findings indicate that the earlier the age of onset of OCD, the less serotonergic pathology there is and that this difference remains even after long-term serotonin reuptake inhibitor treatment. Clinically, it might suggest that nonserotonergic treatments would be a better option for EOCD patients.


Assuntos
Encéfalo/efeitos dos fármacos , Citalopram/uso terapêutico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Adulto , Idade de Início , Benzilaminas , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Mapeamento Encefálico , Radioisótopos de Carbono , Estudos de Casos e Controles , Citalopram/farmacocinética , Humanos , Masculino , Modelos Biológicos , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/metabolismo , Tomografia por Emissão de Pósitrons , Escalas de Graduação Psiquiátrica , Compostos Radiofarmacêuticos , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética
5.
Neuroimage ; 149: 23-32, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28119137

RESUMO

INTRODUCTION: In-vivo quantification of serotonin transporters (SERT) in human brain has been a mainstay of molecular imaging in the field of neuropsychiatric disorders and helped to explore the underpinnings of several medical conditions, therapeutic and environmental influences. The emergence of PET/MR hybrid systems and the heterogeneity of SERT binding call for the development of efficient methods making the investigation of larger or vulnerable populations with limited scanner time and simultaneous changes in molecular and functional measures possible. We propose [11C]DASB bolus plus constant infusion for these applications and validate it against standard analyses of dynamic PET data. METHODS: [11C]DASB bolus/infusion optimization was performed on data acquired after [11C]DASB bolus in 8 healthy subjects. Subsequently, 16 subjects underwent one scan using [11C]DASB bolus plus constant infusion with Kbol 160-179min and one scan after [11C]DASB bolus for inter-method reliability analysis. Arterial blood sampling and metabolite analysis were performed for all scans. Distribution volumes (VT) were obtained using Logan plots for bolus scans and ratios between tissue and plasma parent activity for bolus plus infusion scans for different time spans of the scan (VT-70 for 60-70min after start of tracer infusion, VT-90 for 75-90min, VT-120 for 100-120min) in 9 subjects. Omitting blood data, binding potentials (BPND) obtained using multilinear reference tissue modeling (MRTM2) and cerebellar gray matter as reference region were compared in 11 subjects. RESULTS: A Kbol of 160min was observed to be optimal for rapid equilibration in thalamus and striatum. VT-70 showed good intraclass correlation coefficients (ICCs) of 0.61-0.70 for thalamus, striatal regions and olfactory cortex with bias ≤5.1% compared to bolus scans. ICCs increased to 0.72-0.78 for VT-90 and 0.77-0.93 for VT-120 in these regions. BPND-90 had negligible bias ≤2.5%, low variability ≤7.9% and ICCs of 0.74-0.87; BPND-120 had ICCs of 0.73-0.90. Low-binding cortical regions and cerebellar gray matter showed a positive bias of ~8% and ICCs 0.57-0.68 at VT-90. Cortical BPND suffered from high variability and bias, best results were obtained for olfactory cortex and anterior cingulate cortex with ICC=0.74-0.75 for BPND-90. High-density regions amygdala and midbrain had a negative bias of -5.5% and -22.5% at VT-90 with ICC 0.70 and 0.63, respectively. CONCLUSIONS: We have optimized the equilibrium method with [11C]DASB bolus plus constant infusion and demonstrated good inter-method reliability with accepted standard methods and for SERT quantification using both VT and BPND in a range of different brain regions. With as little as 10-15min of scanning valid estimates of SERT VT and BPND in thalamus, amygdala, striatal and high-binding cortical regions could be obtained. Blood sampling seems vital for valid quantification of SERT in low-binding cortical regions. These methods allow the investigation of up to three subjects with a single radiosynthesis.


Assuntos
Benzilaminas/administração & dosagem , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono/administração & dosagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Proteínas da Membrana Plasmática de Transporte de Serotonina/análise , Adulto , Benzilaminas/farmacocinética , Radioisótopos de Carbono/farmacocinética , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Injeções Intravenosas , Masculino , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
6.
Synapse ; 70(1): 24-32, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26426356

RESUMO

OBJECTIVES: Bipolar disorder (BD) is associated with abnormalities in the serotonin transporter (5-HTT), but specific in vivo findings have been discrepant. Using positron emission tomography (PET) and [(11)C]DASB, we compared 5-HTT binding between unmedicated depressed BD subjects and healthy volunteers (HVs). EXPERIMENTAL DESIGN: 5-HTT binding in six brain regions was compared between 17 depressed, unmedicated BD subjects and 31 HVs, using the outcome measure of VT/fP (proportional to the total number of available transporters). Alternative outcome measures were examined as well. 47% of BD were BP I; and 65% reported a prior suicide attempt. PRINCIPAL OBSERVATIONS: 5-HTT binding (VT/fP ) did not differ between BD and HV groups considering six brain regions of interest simultaneously (P = 0.24). In contrast, alternative outcome measures (BPF*, BPP*, and BPND*) indicated lower binding in BD compared with HV across these six regions of interest (BPF*: P = 0.047; BPP*: P = 0.032; BPND*: P = 0.031). 5-HTT binding was unrelated to suicide attempt history, depression severity, bipolar subtype, or history of past substance use disorder. CONCLUSIONS: Choice of outcome measure strongly affects comparisons of serotonin transporter binding using PET with [(11)C]DASB. We do not find evidence of abnormal 5-HTT binding in bipolar depression using our primary outcome measure, VT /fP . However, we did observe lower 5-HTT binding in BD with alternative outcome measures that are frequently used with [(11)C]DASB. Relative merits and assumptions of different outcome measures are discussed. Evaluation in larger samples and during different mood states, including remission, is warranted.


Assuntos
Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Adulto , Benzilaminas , Mapeamento Encefálico , Radioisótopos de Carbono , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tentativa de Suicídio , Adulto Jovem
7.
J Neurochem ; 130(1): 126-35, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24646401

RESUMO

Chronic stress represents a major environmental risk factor for mood disorders in vulnerable individuals. The neurobiological mechanisms underlying these disorders involve serotonergic and endocannabinoid systems. In this study, we have investigated the relationships between these two neurochemical systems in emotional control using genetic and imaging tools. CB1 cannabinoid receptor knockout mice (KO) and wild-type littermates (WT) were exposed to chronic restraint stress. Depressive-like symptoms (anhedonia and helplessness) were produced by chronic stress exposure in WT mice. CB1 KO mice already showed these depressive-like manifestations in non-stress conditions and the same phenotype was observed after chronic restraint stress. Chronic stress similarly impaired long-term memory in both genotypes. In addition, brain levels of serotonin transporter (5-HTT) were assessed using positron emission tomography. Decreased brain 5-HTT levels were revealed in CB1 KO mice under basal conditions, as well as in WT mice after chronic stress. Our results show that chronic restraint stress induced depressive-like behavioral alterations and brain changes in 5-HTT levels similarly to those revealed in CB1 KO mice in non-stressed conditions. These results underline the relevance of chronic environmental stress on serotonergic and endocannabinoid transmission for the development of depressive symptoms. Chronic restraint stress induces depressive-like behavior and reduced 5-HTT levels in WT mice similar to those revealed in non-stressed CB1-KO mice. Reduced 5-HTT in both genotypes increases synaptic 5-HT concentration. The 5-HT release is modulated through CB1 receptors and the absence of inhibitory CB1 receptor causes decreased inhibition of 5-HT release resulting in high synaptic 5-HT concentration that are not further enhanced by stress.


Assuntos
Compostos de Anilina/metabolismo , Depressão/diagnóstico por imagem , Depressão/metabolismo , Tomografia por Emissão de Pósitrons , Receptor CB1 de Canabinoide/fisiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Serotonina/metabolismo , Sulfetos/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Carbono , Depressão/psicologia , Masculino , Camundongos , Camundongos Knockout , Tomografia por Emissão de Pósitrons/métodos , Receptor CB1 de Canabinoide/deficiência , Receptor CB1 de Canabinoide/metabolismo , Estresse Psicológico/diagnóstico por imagem , Estresse Psicológico/metabolismo
8.
Front Sleep ; 22024.
Artigo em Inglês | MEDLINE | ID: mdl-38765701

RESUMO

Background/objective: The serotoninergic nervous system is known to play a role in the maintenance of rapid eye movement (REM) sleep. Serotoninergic projections are known to be vulnerable in synucleinopathies. To date, positron emission tomography (PET) studies using serotonin-specific tracers have not been reported in isolated REM sleep behavior disorder (iRBD). Methods: We conducted a cross-sectional imaging study using serotonin transporter (SERT) 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile (DASB) PET to identify differences in serotonin system integrity between 11 participants with iRBD and 16 older healthy controls. Results: Participants with iRBD showed lower DASB distribution volume ratios (DVRs) in the total neocortical mantle [1.13 (SD: 0.07) vs. 1.19 (SD: 0.06); t = 2.33, p = 0.028)], putamen [2.07 (SD: 0.19) vs. 2.25 (SD: 0.18); t = 2.55, p = 0.017], and insula [1.26 (SD: 0.11) vs. 1.39 (SD: 0.09); t = 3.58, p = 0.001]. Paradoxical increases relative to controls were seen in cerebellar hemispheres [0.98 (SD: 0.04) vs. 0.95 (SD: 0.02); t = 2.93, p = 0.007)]. No intergroup differences were seen in caudate, substantia nigra, or other brainstem regions with the exception of the dorsal mesencephalic raphe [3.08 (SD: 0.53) vs. 3.47 (SD: 0.48); t = 2.00, p = 0.056] that showed a non-significant trend toward lower values in iRBD. Conclusions: Insular, neocortical, and striatal serotoninergic terminal loss may be common in prodromal synucleinopathies before the onset of parkinsonism or dementia. Given our small sample size, these results should be interpreted as hypothesis-generating/exploratory in nature.

9.
Pharmaceuticals (Basel) ; 16(5)2023 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-37242542

RESUMO

To elucidate the potential roles of serotonergic activity in human character traits (i.e., self-directedness, cooperativeness, and self-transcendence), we investigated the relationship between these character traits and serotonin transporter (5-HTT) in healthy subjects. Twenty-four participants underwent High-Resolution Research Tomograph-positron emission tomography scans with [11C]DASB. To quantify 5-HTT availability, binding potential (BPND) of [11C]DASB was obtained using the simplified reference tissue model. The Temperament and Character Inventory was used to assess subjects' levels of three character traits. There were no significant correlations between the three character traits. Self-directedness was significantly positively correlated with [11C]DASB BPND in the left hippocampus, left middle occipital gyrus, bilateral superior parietal gyrus, left inferior parietal gyrus, left middle temporal gyrus (MTG), and left inferior temporal gyrus (ITG). Cooperativeness was significantly negatively correlated with [11C]DASB BPND in the median raphe nucleus. Self-transcendence was significantly negatively correlated with [11C]DASB BPND in the right MTG and right ITG. Our results show significant correlations between the three character traits and 5-HTT availability in specific brain regions. In particular, self-directedness was significantly positively correlated with 5-HTT availability, suggesting that a goal-oriented, self-confident, and resourceful character may be related to higher serotonergic neurotransmission.

10.
Psychopharmacology (Berl) ; 240(2): 361-371, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36640190

RESUMO

RATIONALE: Characterizing the neuroanatomical basis of serotonergic abnormalities in severe, chronic, impulsive aggression will allow for rational treatment selection, development of novel therapeutics, and biomarkers to identify at-risk individuals. OBJECTIVES: The aim of this study is to identify associations between regional serotonin transporter (5-HTT) availability and trait and state aggression, as well as response to the anti-aggressive effects of fluoxetine. METHODS: We examined 5-HTT availability using positron emission tomography (PET) imaging with [11C]DASB in personality disordered patients with current physical intermittent explosive disorder (IED; n = 18), and healthy comparison participants (HC; n = 11), in the anterior cingulate cortex (ACC), amygdala (AMY), ventral striatum (VST), and midbrain (MID). After PET imaging, IED patients were treated with fluoxetine 20 mg daily (n = 9) or placebo (n = 6) for 12 weeks. Trait and state aggression, trait callousness, and childhood trauma were assessed. RESULTS: In IED patients, trait aggression was positively associated with [11C]DASB binding in the ACC and VST; covarying for trait callousness and childhood trauma enhanced these correlations. Baseline state aggression was positively correlated with ACC [11C]DASB in IED patients. Greater baseline VST [11C]DASB binding predicted greater decreases in state aggression with fluoxetine treatment. CONCLUSIONS: Consistent with prior reports, ACC 5-HTT is related to trait aggression, and adjusting for factors related to proactive (callousness) and reactive (childhood trauma) aggression subtypes further resolves this relationship. Novel findings of the study include a better understanding of the association between regional 5-HTT availability and state aggression, and the involvement of VST 5-HTT with trait aggression, and with the anti-aggressive effects of fluoxetine.


Assuntos
Fluoxetina , Proteínas da Membrana Plasmática de Transporte de Serotonina , Humanos , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Transtornos da Personalidade , Agressão , Tomografia por Emissão de Pósitrons , Personalidade
11.
J Clin Med ; 11(6)2022 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-35329857

RESUMO

Repetitive transcranial magnetic stimulation (rTMS) is thought to partly exert its antidepressant action through the serotonergic system. Accelerated rTMS may have the potential to result in similar but faster onset of clinical improvement compared to the classical daily rTMS protocols, but given that delayed clinical responses have been reported, the neurobiological effects of accelerated paradigms remain to be elucidated including on this neurotransmitter system. This sham-controlled study aimed to evaluate the effects of accelerated high frequency rTMS (aHF-rTMS) over the left frontal cortex on the serotonin transporter (SERT) in healthy beagle dogs. A total of twenty-two dogs were randomly divided into three unequal groups: five active stimulation sessions (five sessions in one day, n = 10), 20 active stimulation sessions (five sessions/day for four days, n = 8), and 20 sham stimulation sessions (five sessions/day for four days, n = 4). The SERT binding index (BI) was obtained at baseline, 24 h post stimulation protocol, one month, and three months post stimulation by a [11C]DASB PET scan. It was found that one day of active aHF-rTMS (five sessions) did not result in significant SERT BI changes at any time point. For the 20 sessions of active aHF-rTMS, one month after stimulation the SERT BI attenuated in the sgACC. No significant SERT BI changes were found after 20 sessions of sham aHF-rTMS. A total of four days of active aHF-rTMS modified sgACC SERT BI one month post-stimulation, explaining to some extent the delayed clinical effects of accelerated rTMS paradigms found in human psychopathologies.

12.
Neuropsychiatr Dis Treat ; 17: 3195-3203, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34707358

RESUMO

BACKGROUND: Previous studies suggested a link between serotonergic neurotransmission and impaired insight in schizophrenia. In this study, we examined the relationship between serotonin transporter (SERT) availability in regions of the prefrontal cortex (dorsolateral, ventrolateral, ventromedial, and orbitofrontal cortices) and insight deficits in antipsychotic-free patients with schizophrenia using high-resolution positron emission tomography (PET) with [11C]DASB. METHODS: Nineteen patients underwent [11C]DASB PET and 7-Tesla magnetic resonance imaging scans. To assess SERT availability, the binding potential with respect to non-displaceable compartment (BPND) was derived using the simplified reference tissue model. Patients' level of insight was assessed using the Insight and Treatment Attitude Questionnaire (ITAQ). The relationship between ITAQ scores and [11C]DASB BPND values was examined using the region-of-interest (ROI)- and voxel-based analyses with relevant variables as covariates. The prefrontal cortex and its four subregions were selected as a priori ROIs since the prefrontal cortex has been implicated as the critical neuroanatomical substrate of impaired insight in schizophrenia. RESULTS: The ROI-based analysis revealed that the ITAQ illness insight dimension had significant negative correlations with the [11C]DASB BPND in the left dorsolateral, left orbitofrontal, and bilateral ventrolateral prefrontal cortices. The ITAQ treatment insight dimension had significant negative correlations with the [11C]DASB BPND in the bilateral dorsolateral, left orbitofrontal, and bilateral ventrolateral prefrontal cortices. The ITAQ total score showed significant negative correlations with the [11C]DASB BPND in the bilateral prefrontal cortex and three subregions (dorsolateral, ventrolateral, and orbitofrontal cortices). A supplementary voxel-based analysis corroborated a significant negative association between the ITAQ score and the [11C]DASB BPND in the prefrontal cortices. CONCLUSION: Our study provides in vivo evidence of significant negative correlations between insight deficits and prefrontal SERT availability in patients with schizophrenia, suggesting significant involvement of prefrontal serotonergic signaling in impaired insight, one of the core symptoms of schizophrenia.

13.
Mol Imaging Biol ; 22(3): 634-642, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31392531

RESUMO

PURPOSE: The development of L-DOPA-induced dyskinesia (LID) is one of the most severe side effects of chronic L-DOPA treatment in Parkinson's disease patients. [11C]DASB positron emission tomography (PET) provides a prominent tool to visualize and quantify serotonin transporter (SERT) pathology in vivo in patients and in animal models. To evaluate the effect of chronic L-DOPA treatment on SERT availability in an animal model of LID, we performed a longitudinal PET study. PROCEDURES: Rats received a unilateral 6-hydroxydopamine (6-OHDA) lesion, and striatal and extrastriatal SERT expression levels were studied with [11C]DASB, a marker of SERT availability, before and after daily treatment with L-DOPA. Dyskinesias were evaluated at different time points over a period of 21 days. RESULTS: [11C]DASB binding was found to be decreased after 6-OHDA lesions in the striatum, cortex, and hippocampus 5 weeks after 6-OHDA injection in the lesioned hemisphere of the rat brain. Chronic L-DOPA priming resulted in a relative preservation of SERT availability in the lesioned and healthy hemisphere compared to baseline measurements. CONCLUSIONS: Our longitudinal PET data support a preservation of SERT availability after the induction of L-DOPA-induced dyskinesia, which is in line with previous reports in dyskinetic PD patients.


Assuntos
Encéfalo/patologia , Radioisótopos de Carbono/farmacocinética , Discinesia Induzida por Medicamentos/diagnóstico por imagem , Atividade Motora/fisiologia , Tomografia por Emissão de Pósitrons/métodos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Carbono/química , Modelos Animais de Doenças , Dopaminérgicos/toxicidade , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/patologia , Levodopa/toxicidade , Masculino , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Sprague-Dawley
14.
J Cereb Blood Flow Metab ; 39(2): 210-222, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29651896

RESUMO

Positron Emission Tomography (PET) imaging has become a prominent tool to capture the spatiotemporal distribution of neurotransmitters and receptors in the brain. The outcome of a PET study can, however, potentially be obscured by suboptimal and/or inconsistent choices made in complex processing pipelines required to reach a quantitative estimate of radioligand binding. Variations in subject selection, experimental design, data acquisition, preprocessing, and statistical analysis may lead to different outcomes and neurobiological interpretations. We here review the approaches used in 105 original research articles published by 21 different PET centres, using the tracer [11C]DASB for quantification of cerebral serotonin transporter binding, as an exemplary case. We highlight and quantify the impact of the remarkable variety of ways in which researchers are currently conducting their studies, while implicitly expecting generalizable results across research groups. Our review provides evidence that the foundation for a given choice of a preprocessing pipeline seems to be an overlooked aspect in modern PET neuroscience. Furthermore, we believe that a thorough testing of pipeline performance is necessary to produce reproducible research outcomes, avoiding biased results and allowing for better understanding of human brain function.


Assuntos
Benzilaminas/uso terapêutico , Encéfalo , Radioisótopos de Carbono/uso terapêutico , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Feminino , Humanos , Masculino
15.
Eur Neuropsychopharmacol ; 29(2): 171-178, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30587400

RESUMO

Although preclinical studies clearly indicate an effect of 5-HTTLPR genotype on 5-HT transporter (5-HTT) expression, studies in humans provided inconclusive results, hypothetically due to environmental factors and differences in individual behavior. For example, nicotine and other constituents of tobacco smoke elevate serotonin (5-HT) levels in the brain and may thereby cause homeostatic adaptations in 5-HTT availability that moderate effects of 5-HTTLPR genotype. To test whether 5-HTT availability in the midbrain is affected by smoking status and 5-HTTLPR genotype, we pooled data from prior studies on in vivo 5-HTT availability (BPND) measured with positron emission tomography (PET) and [11C]DASB. In total, we reanalyzed 5-HTT availability in 116 subjects using ANCOVA statistics. ROI analysis revealed that current smokers and non-smokers do not differ in midbrain BPND. Interestingly, smoking status significantly interacted with 5-HTTLPR genotype: active smoking was associated with reduced 5-HTT availability only in LL subjects but not in carriers of the S-allele. From the perspective of genotype effects, non-smokers showed the expected association with 5-HTTLPR, i.e. higher 5-HTT availability in LL subjects compared to carriers of the S-allele, whereas this pattern was actually reversed for active smokers. Our study indicates that smoking status moderates the association of 5-HTTLPR genotype and 5-HTT expression, which may help to explain inconsistent findings in previous studies. Regarding the mechanism, we suggest that smoking may induce epigenetic processes such as methylation of SLC6A4, which can differ depending on its genetic constitution.


Assuntos
Encéfalo/diagnóstico por imagem , Transtorno Depressivo Maior/genética , Polimorfismo Genético/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Fumar/genética , Adulto , Benzilaminas/metabolismo , Radioisótopos de Carbono/metabolismo , Transtorno Depressivo Maior/diagnóstico por imagem , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/genética , Tomografia por Emissão de Pósitrons , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
16.
Eur Neuropsychopharmacol ; 29(4): 493-500, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30826156

RESUMO

Depression is a debilitating mental illness and two thirds of patients respond insufficiently to conventional antidepressants. Electroconvulsive therapy (ECT) remains the most effective treatment to alleviate drug-refractory depression, however the neurobiological mechanisms are mostly unknown. The serotonergic system plays an important role in depression and alterations in the serotonin transporter (SERT) are seen both in depression and response to antidepressant pharmacotherapies. The first aim of this study was to investigate SERT density in a genetic rat model of depression, Flinders Sensitive Line (FSL), compared to control Flinders Resistant Line (FRL) and Sprague-Dawley (SD) rats. The second aim was to investigate SERT density in response to electroconvulsive stimuli (ECS), an animal model of ECT. Female rats of each strain were treated with ECS or sham (ear-clip placement with no current) for 10 days before brains were removed, frozen and cut into 20 µm thick sections. SERT density was measured in striatal and cortical regions by quantitative in vitro autoradiography using the SERT-radioligand, [3H]-DASB. Higher SERT density was observed in FSL rats compared to SD rats by 36-48% in motor cortex and striatum under sham conditions. In response to ECS, SD rats displayed a significant effect of treatment, whereas no changes were observed in FRL and FSL rats. Increased SERT binding in FSL rats compared to SD supports a dysfunction of the serotonergic system in depression. The increased SERT density after ECS, seen in SD rats but not FSL rats, suggests a different mechanism of action between depressive-like rats and controls.


Assuntos
Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Depressão/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Animais , Benzilaminas/metabolismo , Estudos de Casos e Controles , Depressão/genética , Eletrochoque , Feminino , Masculino , Ensaio Radioligante , Ratos , Ratos Endogâmicos , Especificidade da Espécie , Trítio/metabolismo
17.
Front Physiol ; 10: 1422, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824335

RESUMO

BACKGROUND: Several MR-based attenuation correction (AC) approaches were developed to conquer the challenging AC in hybrid PET/MR imaging. These AC methods are commonly evaluated on standardized uptake values or tissue concentration. However, in neurotransmitter system studies absolute quantification is more favorable due to its accuracy. Therefore, our aim was to investigate the accuracy of segmentation- and atlas-based MR AC approaches on serotonin transporter (SERT) distribution volumes and occupancy after a drug challenge. METHODS: 18 healthy subjects (7 male) underwent two [11C]DASB PET/MRI measurements in a double-blinded, placebo controlled, cross-over design. After 70 min the selective serotonin reuptake inhibitor (SSRI) citalopram or a placebo was infused. The parameters total and specific volume of distribution (VT, VS = BPP) and occupancy were quantified. All subjects underwent a low-dose CT scan as reference AC method. Besides the standard AC approaches DIXON and UTE, a T1-weighted structural image was recorded to estimate a pseudo-CT based on an MR/CT database (pseudoCT). Another evaluated AC approach superimposed a bone model on AC DIXON. Lastly, an approach optimizing the segmentation of UTE images was analyzed (RESOLUTE). PET emission data were reconstructed with all 6 AC methods. The accuracy of the AC approaches was evaluated on a region of interest-basis for the parameters VT, BPP, and occupancy with respect to the results of AC CT. RESULTS: Variations for VT and BPP were found with all AC methods with bias ranging from -15 to 17%. The smallest relative errors for all regions were found with AC pseudoCT (<|5%|). Although the bias between BPP SSRI and BPP placebo varied markedly with AC DIXON (<|12%|) and AC UTE (<|9%|), a high correlation to AC CT was obtained (r 2∼1). The relative difference of the occupancy for all tested AC methods was small for SERT high binding regions (<|4%|). CONCLUSION: The high correlation might offer a rescaling from the biased parameters VT and BPP to the true values. Overall, the pseudoCT approach yielded smallest errors and the best agreement with AC CT. For SERT occupancy, all AC methods showed little bias in high binding regions, indicating that errors may cancel out in longitudinal assessments.

18.
Front Mol Neurosci ; 12: 172, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354428

RESUMO

Introduction: In-vivo quantification of the serotonin transporter (SERT) guided our understanding of many neuropsychiatric disorders. A recently introduced bolus plus constant infusion protocol has been shown to allow the reliable determination of SERT binding with reduced scan time. In this work, the outcomes of two methods, a bolus injection paradigm on a GE PET camera, and a bolus plus infusion paradigm on a combined Siemens PET/MR camera were compared. Methods: A total of seven healthy subjects underwent paired PET and paired PET/MR scans each with intravenous double-blind application of 7.5 mg citalopram or saline in a randomized cross-over study design. While PET scans were performed according to standard protocols and non-displaceable binding potentials (BPND) were calculated using the multi-linear reference tissue model, during PET/MR measurements [11C]DASB was applied as bolus plus constant infusion, and BPND was calculated using the steady state method and data acquired at tracer equilibrium. Occupancies were calculated as the relative decrease in BPND between saline and citalopram scans. Results: During placebo scans, a mean difference in BPND of -0.08 (-11.71%) across all ROIs was found between methods. PET/MR scans resulted in higher BPND estimates than PET scans in all ROIs except the midbrain. A mean difference of -0.19 (-109.40%) across all ROIs between methods was observed for citalopram scans. PET/MR scans resulted in higher BPND estimates than PET scans in all ROIs. For occupancy, a mean difference of 23.12% (21.91%) was observed across all ROIs. PET/MR scans resulted in lower occupancy compared to PET scans in all ROIs except the temporal cortex. While for placebo, BPND of high-binding regions (thalamus and striatum) exhibited moderate reliability (ICC = 0.66), during citalopram scans ICC decreased (0.36-0.46). However, reliability for occupancy remained high (0.57-0.82). Conclusion: Here, we demonstrated the feasibility of reliable and non-invasive SERT quantification using a [11C]DASB bolus plus constant infusion protocol at a hybrid PET/MR scanner, which might facilitate future pharmacological imaging studies. Highest agreement with established methods for quantification of occupancy and SERT BPND at baseline was observed in subcortical high-binding regions.

19.
J Affect Disord ; 257: 495-503, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31319341

RESUMO

BACKGROUND: Serotonin transporter (5-HTT) binding and polyunsaturated fatty acids (PUFAs) are implicated in major depressive disorder (MDD). Links between the two systems in animal models have not been investigated in humans. METHODS: Using positron emission tomography (PET) and [11C]DASB, we studied relationships between 5-HTT binding potential and plasma levels of PUFAs docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) in medication-free MDD patients (n = 21). PUFAs were quantified using transesterification and gas chromatography. Binding potential BPP, and alternative outcome measures BPF and BPND, were determined for [11C]DASB in six a priori brain regions of interest (ROIs) using likelihood estimation in graphical analysis (LEGA) to calculate radioligand total distribution volume (VT), and a validated hybrid deconvolution approach (HYDECA) that estimates radioligand non-displaceable distribution volume (VND) without a reference region. Linear mixed models used PUFA levels as predictors and binding potential measures as outcomes across the specified ROIs; age and sex as fixed effects; and subject as random effect to account for across-region binding correlations. As nonlinear relationships were observed, a quadratic term was added to final models. RESULTS: AA predicted both 5-HTT BPP and depression severity nonlinearly, described by an inverted U-shaped curve. 5-HTT binding potential mediated the relationship between AA and depression severity. LIMITATIONS: Given the small sample and multiple comparisons, results require replication. CONCLUSIONS: Our findings suggest that AA status may impact depression pathophysiology through effects on serotonin transport. Future studies should examine whether these relationships explain therapeutic effects of PUFAs in the treatment of MDD.


Assuntos
Ácido Araquidônico/sangue , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Adulto , Animais , Encéfalo/metabolismo , Depressão , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico/análogos & derivados , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons
20.
Alzheimers Res Ther ; 11(1): 38, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043179

RESUMO

BACKGROUND: Discrepant and often contradictory results have accumulated regarding the antidepressant and pro-cognitive effects of serotonin transporter (SERT) antagonists in Alzheimer's disease. METHODS: To address the discrepancy, we measured the activity and density of SERT in the neocortex of 3-24-month-old APPswe/PS1dE9 and wild-type littermate mice, by using [3H]DASB autoradiography and the [3H]5-HT uptake assay. Levels of soluble amyloid-ß (Aß), and pro-inflammatory cytokines that can regulate SERT function, such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor (TNF), were measured in parallel. Neuroinflammation in aging APPswe/PS1dE9 mice was further evaluated by [3H]PK11195 autoradiography. RESULTS: Decreased SERT density was observed in the parietal and frontal cortex of 18-24-month-old APPswe/PS1dE9 mice, compared to age-matched, wild-type animals. The maximal velocity uptake rate (Vmax) of [3H]5-HT was reduced in neocortical preparations from 20-month-old transgenic vs. wild-type mice. The reduction was observed when the proportion of soluble Aß40 in the Aß40/42 ratio increased in the aged transgenic brain. At concentrations compatible with those measured in 20-month-old APPswe/PS1dE9 mice, synthetic human Aß40, but not Aß42, reduced the baseline Vmax of [3H]5-HT by ~ 20%. Neuroinflammation in APPswe/PS1dE9 vs. wild-type mice was evidenced by elevated [3H]PK11195 binding levels and increased concentration of IL-1ß protein, which preceded the reductions in neocortical SERT density and activity. Age-induced increases in the levels of IL-1ß, IL-6, and TNF were observed in both transgenic and wild-type animals. CONCLUSIONS: The progression of cerebral amyloidosis is associated with neuroinflammation and decreased presynaptic markers of serotonergic integrity and activity. The Aß40-induced reduction in the uptake kinetics of [3H]5-HT suggests that the activity of SERT, and potentially the effects of SERT antagonism, depend on the levels of interstitial Aß40.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encefalite/metabolismo , Neocórtex/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Animais , Modelos Animais de Doenças , Encefalite/complicações , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
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