RESUMO
The causes of cognitive impairment among older HIV+ individuals may overlap with causes among elderly HIV seronegative (HIV-) individuals. The objective of this study was to determine if beta-amyloid (Aß) deposition measured by [18F] AV-45 (florbetapir) positron emission tomography (PET) is increased in older HIV+ individuals compared to HIV- individuals. Forty-eight HIV+ and 25 HIV- individuals underwent [18F] AV-45 PET imaging. [18F] AV-45 binding to Aß was measured by standardized uptake value ratios (SUVR) relative to the cerebellum in 16 cortical and subcortical regions of interest. Global and regional cortical SUVRs were compared by (1) serostatus, (2) HAND stage, and (3) age decade, comparing individuals in their 50s and > 60s. There were no differences in median global cortical SUVR stratified by HIV serostatus or HAND stage. The proportion of HIV+ participants in their 50s with elevated global amyloid uptake (SUVR > 1.40) was significantly higher than the proportion in HIV- participants (67% versus 25%, p = 0.04), and selected regional SUVR values were also higher (p < 0.05) in HIV+ compared to HIV- participants in their 50s. However, these group differences were not seen in participants in their 60s. In conclusion, PET imaging found no differences in overall global Aß deposition stratified by HIV serostatus or HAND stage. Although there was some evidence of increased Aß deposition in HIV+ individuals in their 50s compared to HIV- individuals which might indicate premature aging, the most parsimonious explanation for this is the relatively small sample size in this cross-sectional cohort study.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Mapeamento Encefálico/métodos , Disfunção Cognitiva/diagnóstico por imagem , Infecções por HIV/diagnóstico por imagem , HIV/patogenicidade , Idoso , Compostos de Anilina , Transporte Biológico , Encéfalo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/virologia , Estudos Transversais , Etilenoglicóis , Feminino , Radioisótopos de Flúor , HIV/crescimento & desenvolvimento , Infecções por HIV/metabolismo , Infecções por HIV/fisiopatologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Índice de Gravidade de DoençaRESUMO
Plasma is a complex system involving diverse collisional processes and interactions, such as electron-impact excitation, ionization, recombination, etc. One of the most important methods for studying the properties and dynamics of plasma is to analyze the radiations from plasma. Here, we demonstrate the high-order harmonic (HH) spectroscopy for probing the complex electron-atom collision (EAC) dynamics in a laser-induced gas plasma. These measurements were carried out by using an elliptically polarized pump and a time-delayed linearly polarized probe. The HH spectra from argon and krypton plasmas were recorded by scanning the time delay up to hundreds of picoseconds. We found that the delay-dependent HH yield contains three distinct regions, i.e., the first enhancement, the subsequent suppression, and the final restoration regions. A qualitative analysis shows that these features are clear signatures of the EAC processes and interactions involved in the delay-dependent HH spectroscopy.
RESUMO
The Alpinia oxyphylla fruit (AOF) is a popular condiment and traditional Chinese medicine in Asia, known for its neuroprotective compound nootkatone. However, there has not been a comprehensive study of its flavor or the relationship between sensory and bioactive compounds. To address this issue, we examined AOF's microstructure, flavor, and metabolomic profiles during fruit maturation. The key markers used to distinguish samples included fruit expansion, testa pigmentation, aril liquefaction, oil cell expansion, peel spiciness, aril sweetness, and seed bitterness. A full-spectrum metabolomic analysis, combining a nontargeted metabolomics approach for volatile compounds and a widely targeted metabolomics approach for nonvolatile compounds, identified 1,448 metabolites, including 1,410 differentially accumulated metabolites (DAMs). Notably, 31 DAMs, including nootkatone, were associated with spicy peel, sweet aril, and bitter seeds. Correlational analysis indicated that bitterness intensity is an easy-to-use biomarker for nootkatone content in seeds. KEGG enrichment analysis linked peel spiciness to phenylpropanoid and capsaicin biosynthesis, seed bitterness to terpenoid (especially nootkatone) biosynthesis, and aril sweetness to starch and sucrose metabolism. This investigation advances the understanding of AOF's complex flavor chemistry and underlying bioactive principle, encapsulating the essence of the adage: "no bitterness, no intelligence" within the realm of phytochemistry.
Assuntos
Alpinia , Frutas , Sesquiterpenos Policíclicos , Sementes , Paladar , Alpinia/química , Sementes/química , Sesquiterpenos Policíclicos/metabolismo , Frutas/química , Metabolômica , Metaboloma , Análise Espaço-Temporal , Compostos Orgânicos Voláteis/análise , Compostos Orgânicos Voláteis/metabolismoRESUMO
In quantitative dynamic PET studies, graphical analysis methods including the Gjedde-Patlak plot, the Logan plot, and the relative equilibrium-based graphical plot (RE plot) (Zhou Y., Ye W., Brasic J.R., Crabb A.H., Hilton J., Wong D.F. 2009b. A consistent and efficient graphical analysis method to improve the quantification of reversible tracer binding in radioligand receptor dynamic PET studies. Neuroimage 44(3):661-670) are based on the theory of a compartmental model with assumptions on tissue tracer kinetics. If those assumptions are violated, then the resulting estimates may be biased. In this study, a multi-graphical analysis method was developed to characterize the non-relative equilibrium effects on the estimates of total distribution volume (DV(T)) from the RE plot. A novel bi-graphical analysis method using the RE plot with the Gjedde-Patlak plot (RE-GP plots) was proposed to estimate DV(T) for the quantification of reversible tracer kinetics that may not be at relative equilibrium states during PET study period. The RE-GP plots and the Logan plot were evaluated by 19 [(11)C]WIN35,428 and 10 [(11)C]MDL100,907 normal human dynamic PET studies with brain tissue tracer kinetics measured at both region of interest (ROI) and pixel levels. A 2-tissue compartment model (2TCM) was used to fit ROI time activity curves (TACs). By applying multi-graphical plots to the 2TCM fitted ROI TACs which were considered as the noise-free tracer kinetics, the estimates of DV(T) from the RE-GP plots, the Logan plot, and the 2TCM fitting were equal to each other. For the measured ROI TACs, there was no significant difference between the estimates of the DV(T) from the RE-GP plots and those from 2TCM fitting (p=0.77), but the estimates of the DV(T) from the Logan plot were significantly (p<0.001) lower, 2.3% on average, than those from 2TCM fitting. There was a highly linear correlation between the ROI DV(T) from the parametric images (Y) and those from the ROI kinetics (X) by using the RE-GP plots (Y=1.01X+0.23, R(2)=0.99). For the Logan plot, the ROI estimates from the parametric images were 13% to 83% lower than those from ROI kinetics. The computational time for generating parametric images was reduced by 69% on average by the RE-GP plots in contrast to the Logan plot. In conclusion, the bi-graphical analysis method using the RE-GP plots was a reliable, robust and computationally efficient kinetic modeling approach to improve the quantification of dynamic PET.
Assuntos
Algoritmos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Interpretação de Imagem Assistida por Computador/métodos , Modelos Biológicos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Simulação por Computador , Humanos , Aumento da Imagem/métodos , Taxa de Depuração Metabólica , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição TecidualRESUMO
Several studies have examined the link between the cannabinoid CB1 receptor and several neuropsychiatric illnesses, including schizophrenia. As such, there is a need for in vivo imaging tracers so that the relationship between CB1 and schizophrenia (SZ) can be further studied. In this paper, we present our first human studies in both healthy control patients and patients with schizophrenia using the novel PET tracer, [(11)C]OMAR (JHU75528), we have shown its utility as a tracer for imaging human CB1 receptors and to investigate normal aging and the differences in the cannabinoid system of healthy controls versus patients with schizophrenia. A total of ten healthy controls and nine patients with schizophrenia were included and studied with high specific activity [(11)C]OMAR. The CB1 binding (expressed as the distribution volume; V(T)) was highest in the globus pallidus and the cortex in both controls and patients with schizophrenia. Controls showed a correlation with the known distribution of CB1 and decline of [(11)C]OMAR binding with age, most significantly in the globus pallidus. Overall, we observed elevated mean binding in patients with schizophrenia across all regions studied, and this increase was statistically significant in the pons (p<0.05), by the Students t-test. When we ran a regression of the control subjects V(T) values with age and then compared the patient data to 95% prediction limits of the linear regression, three patients fell completely outside for the globus pallidus, and in all other regions there were at least 1-3 patients outside of the prediction intervals. There was no statistically significant correlations between PET measures and the individual Brief Psychiatry Rating Score (BPRS) subscores (r=0.49), but there was a significant correlation between V(T) and the ratio of the BPRS psychosis to withdrawal score in the frontal lobe (r=0.60), and middle and posterior cingulate regions (r=0.71 and r=0.79 respectively). In conclusion, we found that [(11)C] OMAR can image human CB1 receptors in normal aging and schizophrenia. In addition, our initial data in subjects with schizophrenia seem to suggest an association of elevated binding specific brain regions and symptoms of the disease.
Assuntos
Encéfalo/metabolismo , Piperidinas/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Pirazóis/farmacocinética , Receptor CB1 de Canabinoide/metabolismo , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/metabolismo , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
OBJECTIVE: To analyse the epidemiological distribution of dermatitis patients in hospital and provide basis for studying the basic conditions and the prevention of dermatitis especially TCE-induced dermatitis in Baoan District of Shenzhen City. METHODS: All dermatitis patients in hospital in Baoan District from 1992 to 2006 were descriptively analysed. RESULTS: There were 645 dermatitis patients in hospital in Baoan District. The total number of patients is tended to rise in recent years. The main age group of 16 approximately years old, followed by 26 approximately years old, the majority are workers. The clinical diagnosis are allergic dermatitis, drug-induced dermatitis, TCE-induced dermatitis. Compared with other dermatitis, women are more than men in TCE-induced dermatitis (P < 0.05). The risk of hepatic dysfunction in TCE-induced dermatitis was significantly greater than other dermatitis (P < 0.05). It is mainly distributed in electronic, metal, electroplating industry. CONCLUSION: The TCE-induced dermatitis was one of the main occupational hazards in Baoan district. To strengthen self-protection awareness of workers, pay more attention to early work observed and occupational screening in key industries and trades workers, reduce opportunities for occupational exposure, all above can effectively reduce the occurrence of TCE-induced dermatitis.
Assuntos
Dermatite de Contato/epidemiologia , Adolescente , Adulto , Idoso , China/epidemiologia , Dermatite/epidemiologia , Feminino , Humanos , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Tricloroetileno/toxicidade , Adulto JovemRESUMO
The widely used Logan plot in radioligand receptor dynamic PET studies produces marked noise-induced negative biases in the estimates of total distribution volume (DV(T)) and binding potential (BP). To avoid the inconsistencies in the estimates from the Logan plot, a new graphical analysis method was proposed and characterized in this study. The new plot with plasma input and with reference tissue input was first derived to estimate DV(T) and BP. A condition was provided to ensure that the estimate from the new plot equals DV(T) or BP. It was demonstrated theoretically that 1) the statistical expectations of the estimates from the new plot with given input are independent of the noise of the target tissue concentration measured by PET; and 2) the estimates from the time activity curves of regions of interest are identical to those from the parametric images for the new plot. The theoretical results of the new plot were also confirmed by computer simulations and fifty-five human [(11)C]raclopride dynamic PET studies. By contrast, the marked noise-induced underestimation in the DV(T) and BP images and noise-induced negative bias in the estimates from the Logan plot were demonstrated by the same data sets used for the new plot. The computational time for generating DV(T) or BP images in the human studies was reduced by 80% on average by the new plot in contrast to the Logan plot. In conclusion, the new plot is a consistent and computationally efficient graphical analysis method to improve the quantification of reversible tracer binding in radioligand receptor dynamic PET studies.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Tomografia por Emissão de Pósitrons/métodos , Racloprida/farmacocinética , Adulto , Algoritmos , Sítios de Ligação , Simulação por Computador , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Modelos Neurológicos , Análise Numérica Assistida por Computador , Ligação Proteica , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
AIMS: RPR 102681, a cholecystokinin-B antagonist, increased dopamine (DA) release and reduced cocaine self-administration in animals. This pilot study sought to assess the safety and pharmacokinetics (PK) of co-administration of RPR 102681 and cocaine, and to confirm the DA release mechanism of RPR 102681. METHODS: Sixteen cocaine-dependent participants were randomized to either placebo or RPR102681 at 3 ascending doses; cocaine was co-administered at steady state of RPR 102681. [11 C]raclopride positron emission tomography scans were conducted at baseline and at each RPR102681 dose. RESULTS: RPR 102681 was well tolerated, and safe to co-administer with cocaine. RPR 102681 did not alter the PK of either cocaine or its metabolite benzoylecgonine and showed no intrinsic abuse liability. There was a trend toward reduction of cocaine craving scores. In contrast to animal studies, RPR 102681 significantly increased the binding potential of [11 C]raclopride in the ventral striatum (t test, P < .001) and caudate nucleus (t test, P < .0001) in a small subset of patients, suggesting that it may reduce intrasynaptic striatal DA. CONCLUSION: Overall, this pilot study suggests that RPR 102681 would be unlikely candidate, as an agonist medication for the treatment for cocaine addiction but worth investigating further for possible role in reducing craving.
Assuntos
Acetamidas/farmacologia , Fármacos do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Compostos de Fenilureia/farmacologia , Receptor de Colecistocinina B/antagonistas & inibidores , Acetamidas/efeitos adversos , Acetamidas/farmacocinética , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fármacos do Sistema Nervoso Central/efeitos adversos , Fármacos do Sistema Nervoso Central/farmacocinética , Cocaína/farmacocinética , Transtornos Relacionados ao Uso de Cocaína/diagnóstico por imagem , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Fissura/efeitos dos fármacos , Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Projetos Piloto , Tomografia por Emissão de Pósitrons , Racloprida , Compostos RadiofarmacêuticosRESUMO
Dopamine D2 receptor occupancy (D2RO) is a key feature of all currently approved antipsychotic medications. However, antipsychotic efficacy associated with high D2RO is often limited by side effects such as motor disturbances and hyperprolactinemia. Lumateperone (ITI-007) is a first-in-class selective and simultaneous modulator of serotonin, dopamine and glutamate in development for the treatment of schizophrenia and other disorders. The primary objective of the present study was to determine D2RO at plasma steady state of 60 mg ITI-007, a dose that previously demonstrated antipsychotic efficacy in a controlled trial, administered orally open-label once daily in the morning for two weeks in patients with schizophrenia (N = 10) and after at least a two-week washout period from standard of care antipsychotics. D2RO was determined using positron emission tomography with 11C-raclopride as the radiotracer. Mean peak dorsal striatal D2RO was 39% at 60 mg ITI-007 occurring 1 h post-dose. Lumateperone was well-tolerated with a favorable safety profile in this study. There were no clinically significant changes in vital signs, ECGs, or clinical chemistry laboratory values, including prolactin levels. There were no adverse event reports of akathisia or other extrapyramidal motor side effects; mean scores on motor function scales indicated no motor disturbances with lumateperone treatment. This level of occupancy is lower than most other antipsychotic drugs at their efficacious doses and likely contributes to the favorable safety and tolerability profile of lumateperone with reduced risk for movement disorders and hyperprolactinemia. If approved, lumateperone may provide a new and safe treatment option for individuals living with schizophrenia.
Assuntos
Antipsicóticos/farmacocinética , Butirofenonas/farmacocinética , Neostriado/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Adulto , Radioisótopos de Carbono , Antagonistas dos Receptores de Dopamina D2/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neostriado/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Racloprida/farmacocinética , Esquizofrenia/diagnóstico por imagemRESUMO
Tourette syndrome (TS) is a neuropsychiatric disorder with childhood onset characterized by motor and phonic tics. Obsessive-compulsive disorder (OCD) is often concomitant with TS. Dysfunctional tonic and phasic dopamine (DA) and serotonin (5-HT) metabolism may play a role in the pathophysiology of TS. We simultaneously measured the density, affinity, and brain distribution of dopamine D2 receptors (D2-R's), dopamine transporter binding potential (BP), and amphetamine-induced dopamine release (DA(rel)) in 14 adults with TS and 10 normal adult controls. We also measured the brain distribution and BP of serotonin 5-HT2A receptors (5-HT2AR), and serotonin transporter (SERT) BP, in 11 subjects with TS and 10 normal control subjects. As compared with controls, DA rel was significantly increased in the ventral striatum among subjects with TS. Adults with TS+OCD exhibited a significant D(2)-R increase in left ventral striatum. SERT BP in midbrain and caudate/putamen was significantly increased in adults with TS (TS+OCD and TS-OCD). In three subjects with TS+OCD, in whom D2-R, 5-HT2AR, and SERT were measured within a 12-month period, there was a weakly significant elevation of DA rel and 5-HT2A BP, when compared with TS-OCD subjects and normal controls. The current study confirms, with a larger sample size and higher resolution PET scanning, our earlier report that elevated DA rel is a primary defect in TS. The finding of decreased SERT BP, and the possible elevation in 5-HT2AR in individuals with TS who had increased DA rel, suggest a condition of increased phasic DA rel modulated by low 5-HT in concomitant OCD.
Assuntos
Dopamina/metabolismo , Tomografia por Emissão de Pósitrons , Serotonina/metabolismo , Transmissão Sináptica/fisiologia , Síndrome de Tourette/diagnóstico por imagem , Adulto , Anfetamina/administração & dosagem , Mapeamento Encefálico , Dopaminérgicos/administração & dosagem , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Modelos Teóricos , Testes Neuropsicológicos , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Escalas de Graduação Psiquiátrica , Racloprida/metabolismo , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Transmissão Sináptica/efeitos dos fármacosRESUMO
BACKGROUND: Sex differences in addictive disorders have been described. Preclinical studies have implicated the striatal dopamine system in these differences, but human studies have yet to substantiate these findings. METHODS: Using positron emission tomography (PET) scans with high-specific-activity [11C] raclopride and a reference tissue approach, we compared baseline striatal dopamine binding potential (BP) and dopamine release in men and women following amphetamine and placebo challenges. Subjective drug effects and plasma cortisol and growth hormone responses were also examined. RESULTS: Although there was no sex difference in baseline BP, men had markedly greater dopamine release than women in the ventral striatum. Secondary analyses indicated that men also had greater dopamine release in three of four additional striatal regions. Paralleling the PET findings, men's ratings of the positive effects of amphetamine were greater than women's. We found no sex difference in neuroendocrine hormone responses. CONCLUSIONS: We report for the first time a sex difference in dopamine release in humans. The robust dopamine release in men could account for increased vulnerability to stimulant use disorders and methamphetamine toxicity. Our findings indicate that future studies should control for sex and may have implications for the interpretation of sex differences in other illnesses involving the striatum.
Assuntos
Corpo Estriado/diagnóstico por imagem , Dopamina/metabolismo , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Caracteres Sexuais , Adulto , Anfetamina/farmacologia , Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico por imagem , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/efeitos dos fármacos , Mapeamento Encefálico , Radioisótopos de Carbono , Núcleo Caudado/diagnóstico por imagem , Núcleo Caudado/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Dominância Cerebral/fisiologia , Feminino , Humanos , Injeções Intravenosas , Masculino , Metanfetamina/toxicidade , Putamen/diagnóstico por imagem , Putamen/efeitos dos fármacos , Racloprida , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D3/efeitos dos fármacosRESUMO
RATIONALE: Although it is well established that acute benzodiazepine administration impairs episodic memory encoding, little is known about the neuroanatomical substrates of this effect. OBJECTIVE: The objective was to examine the acute dose effects of the benzodiazepine hypnotic triazolam on brain activity during episodic memory encoding. METHODS: After oral capsule administration (placebo, 0.1, 0.2, and 0.4 mg/70 kg triazolam), regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) with 15O-H2O during performance of semantic categorization and orthographic categorization tasks in a double-blind, within-subject design in 12 healthy volunteers. The rCBF associated with episodic memory encoding was measured by subtracting the rCBF during orthographic categorization from that during semantic categorization and by examining correlations between brain activity during encoding and subsequent recognition memory performance. RESULTS: Results in the placebo condition replicated those of nonpharmacological encoding studies, including activation in left ventrolateral prefrontal cortex. Correlations between brain activity and subsequent memory performance additionally showed medial temporal activation. Triazolam produced dose-related impairment in memory performance and dose-related deactivation in encoding-associated areas including right prefrontal cortex, left parahippocampal gyrus, and left anterior cingulate cortex. CONCLUSIONS: Results are consistent with behavioral evidence that benzodiazepines impair prefrontal control processes as well as contextual memory and episodic binding processes thought to be controlled by the medial temporal lobe. In addition to elucidating the brain mechanisms underlying these benzodiazepine-induced behavioral deficits, results of this study also help validate hypotheses generated in nonpharmacological neuroimaging studies regarding the processes controlled by these brain regions.
Assuntos
Moduladores GABAérgicos/farmacologia , Memória/efeitos dos fármacos , Triazolam/farmacologia , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Cognição/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Tomografia por Emissão de PósitronsRESUMO
RATIONALE: Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. OBJECTIVES: The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. METHODS: Carbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT2A receptors, D2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. RESULTS: Oral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT2A receptors and low occupancy of striatal D2 receptors (~12 %). D2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r (2) = 0.68, p = 0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D2 receptors and 33 % of striatal serotonin transporters. CONCLUSIONS: The results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials.
Assuntos
Encéfalo/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Adolescente , Adulto , Antipsicóticos/farmacologia , Encéfalo/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Esquizofrenia/tratamento farmacológico , Serotonina/metabolismo , Adulto JovemRESUMO
A 70-year-old woman was examined because of increasing problems with cognition. She had a history of a cerebral shunt placed surgically 10 years previously. Introduction of Tc-99m DTPA directly into the ventricular cavity revealed good ventricular distribution, followed by progression downward, as though into a previous ventriculoperitoneal shunt. However, a chest radiograph revealed what appeared to be a shunt tube in the right atrium. Delayed lateral images showed activity in proximity to the vertebral column, indicating migration of tracer and cerebrospinal fluid into the dorsal and lumbar subarachnoid space.
Assuntos
Ventrículos Cerebrais/diagnóstico por imagem , Líquido Cefalorraquidiano/diagnóstico por imagem , Espaço Subaracnóideo/diagnóstico por imagem , Derrame Subdural/diagnóstico por imagem , Pentetato de Tecnécio Tc 99m , Idoso , Ventrículos Cerebrais/cirurgia , Derivações do Líquido Cefalorraquidiano , Transtornos Cognitivos/etiologia , Feminino , Humanos , Cintilografia , Compostos Radiofarmacêuticos/líquido cefalorraquidianoRESUMO
Amyloid-ß plaques (Aß) are a hallmark of Alzheimer's disease (AD), begin deposition decades before the incipient disease, and are thought to be associated with neuronal loss, brain atrophy and cognitive impairment. We examine associations between (11)C-PiB-PET measurement of Aß burden and brain volume changes in the preceding years in 57 non-demented individuals (age 64-86; M=78.7). Participants were prospectively followed through the Baltimore Longitudinal Study of Aging, with up to 10 consecutive MRI scans (M=8.1) and an (11)C-PiB scan approximately 10 years after the initial MRI. Linear mixed effects models were used to determine whether mean cortical (11)C-PiB distribution volume ratios, estimated by fitting a reference tissue model to the measured time activity curves, were associated with longitudinal regional brain volume changes of the whole brain, ventricular CSF, frontal, temporal, parietal, and occipital white and gray matter, the hippocampus, orbito-frontal cortex, and the precuneus. Despite significant longitudinal declines in the volumes of all investigated regions (p<0.05), no associations were detected between current Aß burden and regional brain volume decline trajectories in the preceding years, nor did the regional volume trajectories differ between those with highest and lowest Aß burden. Consistent with a threshold model of disease, our findings suggest that Aß load does not seem to affect brain volume changes in individuals without dementia.
Assuntos
Benzotiazóis , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Radioisótopos de Carbono , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/patologia , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina , Atrofia , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Estudos Prospectivos , TiazóisRESUMO
UNLABELLED: An (18)F-labeled PET amyloid-beta (Abeta) imaging agent could facilitate the clinical evaluation of late-life cognitive impairment by providing an objective measure for Alzheimer disease (AD) pathology. Here we present the results of a clinical trial with (E)-4-(2-(6-(2-(2-(2-(18)F-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine ((18)F-AV-45 or florbetapir [corrected] F 18). METHODS: An open-label, multicenter brain imaging, metabolism, and safety study of (18)F-AV-45 was performed on 16 patients with AD (Mini-Mental State Examination score, 19.3 +/- 3.1; mean age +/- SD, 75.8 +/- 9.2 y) and 16 cognitively healthy controls (HCs) (Mini-Mental State Examination score, 29.8 +/- 0.45; mean age +/- SD, 72.5 +/- 11.6 y). Dynamic PET was performed over a period of approximately 90 min after injection of the tracer (370 MBq [10 mCi]). Standardized uptake values and cortical-to-cerebellum standardized uptake value ratios (SUVRs) were calculated. A simplified reference tissue method was used to generate distribution volume ratio (DVR) parametric maps for a subset of subjects. RESULTS: Valid PET data were available for 11 AD patients and 15 HCs. (18)F-AV-45 accumulated in cortical regions expected to be high in Abeta deposition (e.g., precuneus and frontal and temporal cortices) in AD patients; minimal accumulation of the tracer was seen in cortical regions of HCs. The cortical-to-cerebellar SUVRs in AD patients showed continual substantial increases through 30 min after administration, reaching a plateau within 50 min. The 10-min period from 50 to 60 min after administration was taken as a representative sample for further analysis. The cortical average SUVR for this period was 1.67 +/- 0.175 for patients with AD versus 1.25 +/- 0.177 for HCs. Spatially normalized DVRs generated from PET dynamic scans were highly correlated with SUVR (r = 0.58-0.88, P < 0.005) and were significantly greater for AD patients than for HCs in cortical regions but not in subcortical white matter or cerebellar regions. No clinically significant changes in vital signs, electrocardiogram, or laboratory values were observed. CONCLUSION: (18)F-AV-45 was well tolerated, and PET showed significant discrimination between AD patients and HCs, using either a parametric reference region method (DVR) or a simplified SUVR calculated from 10 min of scanning 50-60 min after (18)F-AV-45 administration.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Compostos de Anilina , Etilenoglicóis , Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons , Idoso , Compostos de Anilina/efeitos adversos , Compostos de Anilina/farmacocinética , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Estudos de Casos e Controles , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Etilenoglicóis/efeitos adversos , Etilenoglicóis/farmacocinética , Feminino , Humanos , Masculino , Radiometria , Irradiação Corporal TotalRESUMO
BACKGROUND: Studies in abstinent methamphetamine (METH) users have demonstrated reductions in brain dopamine transporter (DAT) binding potential (BP), as well as cognitive and motor deficits, but it is not yet clear whether cognitive deficits and brain DAT reductions fully reverse with sustained abstinence, or whether behavioral deficits in METH users are related to dopamine (DA) deficits. This study was conducted to further investigate potential persistent psychomotor deficits secondary to METH abuse, and their relationship to brain DAT availability, as measured using quantitative PET methods with [(11)C]WIN 35428. METHODS: Twenty-two abstinent METH users and 17 healthy non-METH using controls underwent psychometric testing to test the hypothesis that METH users would demonstrate selective deficits in neuropsychiatric domains known to involve DA neurons (e.g., working memory, executive function, motor function). A subset of subjects also underwent PET scanning with [(11)C]WIN 35428. RESULTS: METH users were found to have modest deficits in short-term memory, executive function, and manual dexterity. Exploratory correlational analyses revealed that deficits in memory, but not those in executive or motor function, were associated with decreases in striatal DAT BP. CONCLUSIONS: These results suggest a possible relationship between DAT BP and memory deficits in abstinent METH users, and lend support to the notion that METH produces lasting effects on central DA neurons in humans. As METH can also produce toxic effects on serotonin (5-HT) neurons, further study is needed to address the potential role of brain 5-HT depletion in cognitive deficits in abstinent METH users.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Cognição/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Dopamina/metabolismo , Metanfetamina/administração & dosagem , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico por imagem , Análise de Variância , Cocaína/análogos & derivados , Cocaína/metabolismo , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/diagnóstico por imagem , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/fisiopatologia , Tomografia por Emissão de Pósitrons/métodosRESUMO
INTRODUCTION: Reference tissue model (RTM) is a compartmental modeling approach that uses reference tissue time activity curve (TAC) as input for quantification of ligand-receptor dynamic PET without blood sampling. There are limitations in applying the RTM for kinetic analysis of PET studies using [11C]Pittsburgh compound B ([11C]PIB). For region of interest (ROI) based kinetic modeling, the low specific binding of [11C]PIB in a target ROI can result in a high linear relationship between the output and input. This condition may result in amplification of errors in estimates using RTM. For pixel-wise quantification, due to the high noise level of pixel kinetics, the parametric images generated by RTM with conventional linear or nonlinear regression may be too noisy for use in clinical studies. METHODS: We applied RTM with parameter coupling and a simultaneous fitting method as a spatial constraint for ROI kinetic analysis. Three RTMs with parameter coupling were derived from a classical compartment model with plasma input: an RTM of 4 parameters (R(1), k'(2R), k(4), BP) (RTM4P); an RTM of 5 parameters (R(1), k(2R), NS, k(6), BP) (RTM5P); and a simplified RTM (SRTM) of 3 parameters (R(1), k'(2R), BP) (RTM3P). The parameter sets [k'(2R), k(4)], [k(2R), NS, k(6)], and k'(2R) are coupled among ROIs for RTM4P, RTM5P, and RTM3P, respectively. A linear regression with spatial constraint (LRSC) algorithm was applied to the SRTM for parametric imaging. Logan plots were used to estimate the distribution volume ratio (DVR) (=1+BP (binding potential)) in ROI and pixel levels. Ninety-minute [11C]PIB dynamic PET was performed in 28 controls and 6 individuals with mild cognitive impairment (MCI) on a GE Advance scanner. ROIs of cerebellum (reference tissue) and 15 other regions were defined on coregistered MRIs. RESULTS: The coefficients of variation of DVR estimates from RTM3P obtained by the simultaneous fitting method were lower by 77-89% (in striatum, frontal, occipital, parietal, and cingulate cortex) as compared to that by conventional single ROI TAC fitting method. There were no significant differences in both TAC fitting and DVR estimates between the RTM3P and the RTM4P or RTM5P. The DVR in striatum, lateral temporal, frontal and cingulate cortex for MCI group was 25% to 38% higher compared to the control group (p < or = 0.05), even in this group of individuals with generally low PIB retention. The DVR images generated by the SRTM with LRSC algorithm had high linear correlations with those from the Logan plot (R2 = 0.99). CONCLUSION: In conclusion, the RTM3P with simultaneous fitting method is shown to be a robust compartmental modeling approach that may be useful in [11C]PIB PET studies to detect early markers of Alzheimer's disease where specific ROIs have been hypothesized. In addition, the SRTM with LRSC algorithm may be useful in generating R(1) and DVR images for pixel-wise quantification of [11C]PIB dynamic PET.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Compostos de Anilina/farmacocinética , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Modelos Neurológicos , Tiazóis/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
A challenging question that continues to plague the field of addiction is why some individuals are more vulnerable for substance use disorders than others. Several important risk factors for substance abuse have been identified in clinical studies, including trait impulsivity and environmental stress. However, the neurobiological mechanisms that underlie the relationships remain poorly understood. The purpose of this study was to examine associations among impulsivity, stress, and striatal dopamine (DA) responses to amphetamine (AMPH) in humans. Forty healthy M, F adults, ages 18-29 years, completed self-report measures of trait impulsivity, life events stress, and perceived stress. Subjects subsequently underwent two consecutive 90-min positron emission tomography (PET) studies with high specific activity [11C]raclopride. The first scan was preceded by an intravenous injection of saline; the second was preceded by 0.3 mg/kg AMPH. Findings showed that high impulsivity was associated with blunted right ventral striatal DA release. However, effects were modified by a significant interaction with life events stress. Dopamine release was greater in low vs. high impulsivity subjects under conditions of low or moderate stress. Under conditions of high stress, both groups had low DA release. Subjects with high impulsivity reported more pleasant effects with AMPH than subjects with low impulsivity. In contrast, stress was negatively associated with pleasant drug effects. No associations were observed between impulsivity or stress and cortisol responses to AMPH. The findings are consistent with notions that blunted DA responses represent an endophenotype for substance use disorders.
Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Processamento de Imagem Assistida por Computador , Comportamento Impulsivo/diagnóstico por imagem , Acontecimentos que Mudam a Vida , Tomografia por Emissão de Pósitrons , Adulto , Radioisótopos de Carbono , Doença Crônica , Corpo Estriado/diagnóstico por imagem , Dominância Cerebral/fisiologia , Feminino , Humanos , Hidrocortisona/sangue , Individualidade , Masculino , RaclopridaRESUMO
BACKGROUND: The offspring of alcohol-dependent individuals are at increased risk for alcoholism. The present study was designed to determine whether mesolimbic dopamine binding potential (BP), dopamine release, stress hormones, and subjective responses to intravenous amphetamine are different in nonalcoholic offspring from families with a history of alcohol dependence [family history positive (FHP)] than in nonalcoholic offspring without a family history of alcohol dependence [family history negative (FHN)]. METHODS: Participants were 41 healthy men and women (11 FHP, 30 FHN; age range 18-29). After completing baseline psychiatric symptom and personality measures, striatal D2/D3 dopamine BP and dopamine release in response to an amphetamine challenge were measured with positron emission tomography (PET) using the D2/D3 dopamine (DA) receptor radioligand [11C]raclopride. Binding potential was defined as Bmax/KD, percent change in BP from baseline defined dopamine release. During the scans, subjects rated the degree to which they were experiencing each of 10 possible drug effects. Plasma cortisol and growth hormone (GH) were also measured at scheduled intervals during the scans. RESULTS: Neither baseline BP nor dopamine release differed by family history. Similarly, subjective responses to amphetamine did not differ by a family history of alcoholism. Although both cortisol and GH increased following administration of amphetamine, these increases did not differ between family history groups. CONCLUSIONS: Using amphetamine to provoke mesolimbic dopamine, we did not show significant differences in dopamine release, subjective responses, or stress hormone measures as a function of family history of alcoholism.