RESUMO
OBJECTIVE: Tourette syndrome (TS) is a common neurodevelopmental disorder marked by tics and behavioral comorbidities. Clinical pharmacology suggests that dopaminergic signaling abnormalities are part of the pathophysiology of TS. Prior molecular imaging studies of nigrostriatal dopaminergic terminal markers report conflicting results. Our goal was to characterize the distribution of nigrostriatal dopaminergic terminals in subjects with TS. METHODS: Thirty-three adult subjects with TS were studied with PET using [11C]dihydrotetrabenazine (DTBZ), a ligand for the type 2 vesicular monoamine transporter, and with [11C] methylphenidate (MP), a ligand for the plasmalemmal dopamine transporter. Subjects were characterized with standard rating instruments for tic severity, obsessive-compulsive behaviors, and attentional deficits. RESULTS: We found no differences between subjects with TS and control subjects in DTBZ and MP binding in any striatal region. There was no correlation between binding measures and clinical variables. Ventral striatal DTBZ and MP binding distributions in subjects with TS were normal. CONCLUSIONS: We found no evidence of increased striatal dopaminergic innervation in Tourette syndrome (TS). Discrepancy between our present results and those of other studies may be explained by heterogeneity of TS.
Assuntos
Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Dopamina/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Síndrome de Tourette/diagnóstico por imagem , Síndrome de Tourette/metabolismo , Adolescente , Adulto , Ligação Competitiva/fisiologia , Radioisótopos de Carbono , Corpo Estriado/fisiopatologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina , Feminino , Humanos , Masculino , Metilfenidato , Pessoa de Meia-Idade , Terminações Pré-Sinápticas/metabolismo , Substância Negra/metabolismo , Substância Negra/fisiopatologia , Tetrabenazina/análogos & derivados , Síndrome de Tourette/fisiopatologia , Proteínas Vesiculares de Transporte de Monoamina/análise , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Adulto JovemRESUMO
BACKGROUND: Excessive striatal dopaminergic innervation is suggested to underlie Tourette syndrome (TS). Prior imaging and postmortem studies yield conflicting data. METHODS: The authors used PET with the type 2 vesicular monoamine transporter ligand [(11)C]dihydrotetrabenazine (DTBZ) to quantify striatal monoaminergic innervation in patients with TS (n = 19) and control subjects (n = 27). Compartmental modeling was used to determine blood to brain ligand transport (K(1)) and tissue to plasma distribution volume (a measure of ligand binding) during continuous infusion of DTBZ. TS data were compared with control data using predefined regions of interest and on a voxel by voxel basis. RESULTS: There were no significant differences in ligand binding or ligand transport between patients with TS and control subjects in the dorsal striatum. With voxel by voxel analysis, there was increased DTBZ binding in the right ventral striatum. CONCLUSIONS: Previously reported differences between patients with TS and control subjects in dorsal striatal dopamine terminal markers may reflect medication-induced regulation of terminal marker expression or be the result of intrinsic differences in striatal dopaminergic synaptic function. Increased right ventral striatal DTBZ binding suggests that abnormal ventral striatal dopaminergic innervation may underlie tics.
Assuntos
Monoaminas Biogênicas/metabolismo , Corpo Estriado/diagnóstico por imagem , Proteínas de Membrana Transportadoras , Neuropeptídeos , Tetrabenazina/análogos & derivados , Síndrome de Tourette/diagnóstico por imagem , Síndrome de Tourette/metabolismo , Adolescente , Adulto , Ligação Competitiva , Compartimentos de Líquidos Corporais , Radioisótopos de Carbono , Corpo Estriado/metabolismo , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Ligantes , Imageamento por Ressonância Magnética , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Modelos Biológicos , Neurônios/diagnóstico por imagem , Neurônios/metabolismo , Terminações Pré-Sinápticas/diagnóstico por imagem , Terminações Pré-Sinápticas/metabolismo , Valores de Referência , Tetrabenazina/farmacocinética , Tomografia Computadorizada de Emissão , Síndrome de Tourette/etiologia , Proteínas Vesiculares de Transporte de Aminas Biogênicas , Proteínas Vesiculares de Transporte de MonoaminaRESUMO
REM sleep behavior disorder (RBD) is a possible herald of neurodegenerative disorders with parkinsonism. The authors determined the density of striatal dopaminergic terminals with [11C]dihydrotetrabenazine PET in six elderly subjects with chronic idiopathic RBD and 19 age-appropriate controls. In subjects with RBD, there were significant reductions in striatal [11C]dihydrotetrabenazine binding, particularly in the posterior putamen.
Assuntos
Corpo Estriado/diagnóstico por imagem , Dopamina/análise , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada de EmissãoRESUMO
OBJECTIVE: To evaluate the integrity of the dorsal striatal dopaminergic innervation in rigid and choreic Huntington disease (HD). BACKGROUND: Some patients with HD have an akinetic-rigid phenotype. It has been suggested that nigrostriatal in addition to striatal pathology is present in this subgroup. The authors sought to determine whether in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding could distinguish patients with akinetic-rigid (HDr) from typical choreiform (HDc) HD. METHODS: Nineteen patients with HD (mean age 48 +/- 16 years) and 64 normal controls (mean age 50 +/- 14 years) underwent (+)-alpha-[11C]dihydrotetrabenazine (DTBZ) PET imaging. DTBZ blood to brain ligand transport (K1) and tissue to plasma distribution volume (DV) in the caudate nucleus, anterior putamen, and posterior putamen were normalized to the occipital cortex. RESULTS: The normalized striatal specific DV was reduced in HDr (n = 6) when compared with controls: caudate nucleus -33% (p < 0.001), anterior putamen -56% (p < 0.0001), and posterior putamen -75% (p < 0.0001). Patients with HDc (n = 13) also had reduced striatal DV: caudate nucleus -6% (NS), anterior putamen -19% (p < 0.01), and posterior putamen -35% (p < 0.0001). Patients with HDr had significantly lower striatal (+)-alpha-[11C]DTBZ binding than HDc patients. After correction for tissue atrophy effects, normalized DV differences were less significant, with values somewhat increased in the caudate, slightly reduced in the anterior putamen, and moderately decreased in the posterior putamen. There were no significant regional differences in K1 reductions among caudate, anterior, and posterior putamen in HD. CONCLUSIONS: Reduced striatal VMAT2 binding suggests nigrostriatal pathology in HD, most severely in the HDr phenotype. Striatal DV reductions were most prominent in the posterior putamen, similar to PD.
Assuntos
Corpo Estriado/fisiopatologia , Doença de Huntington/diagnóstico , Glicoproteínas de Membrana/fisiologia , Proteínas de Membrana Transportadoras , Neuropeptídeos , Neurotransmissores/fisiologia , Adulto , Idoso , Mapeamento Encefálico , Feminino , Humanos , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Neurotransmissores/genética , Valor Preditivo dos Testes , Substância Negra/fisiopatologia , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacocinética , Tomografia Computadorizada de Emissão , Proteínas Vesiculares de Transporte de Aminas Biogênicas , Proteínas Vesiculares de Transporte de MonoaminaRESUMO
BACKGROUND: Abnormal function of striatal dopaminergic synapses is suggested to underlie Tourette's syndrome (TS). OBJECTIVE: To determine dorsal striatal dopaminergic innervation in TS. Prior in vitro and in vivo studies of dopamine reuptake transporter binding sites suggest increased striatal dopaminergic innervation in TS. METHODS: We used in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding to quantify striatal dopaminergic innervation in TS. Eight TS patients (mean age 30+/-9 years) and 22 age-comparable normal controls (age 34+/-8 years) underwent PET imaging with the VMAT2 ligand (+)-alpha-[11C]dihydrotetrabenazine (DTBZ). Compartmental modeling was used to quantify blood-to-brain ligand transport and VMAT2 binding site density from the tissue-to-plasma distribution volume (DV) during continuous (+)-alpha-[11C]DTBZ infusion. DTBZ DV in dorsal striatal regions was expressed relative to the occipital cortex to estimate relative specific VMAT2 binding (binding potential). RESULTS: We found no significant differences in VMAT2 binding potential between patients and controls in the caudate nucleus, anterior putamen, or posterior putamen. There were no significant differences in striatal VMAT2 binding between patients with (n = 5) or without (n = 3) features of obsessive-compulsive disorder. CONCLUSIONS: There is no evidence for increased binding to the VMAT2 in TS striatum and that dorsal striatal dopaminergic innervation density is normal in TS. The previously reported changes in dopamine transporter binding sites may reflect medication effect and/or altered synaptic activity or regulation of dopamine transporter expression in nigrostriatal neurons.
Assuntos
Corpo Estriado/diagnóstico por imagem , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Neuropeptídeos , Neurotransmissores/metabolismo , Síndrome de Tourette/diagnóstico por imagem , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada de Emissão/métodos , Proteínas Vesiculares de Transporte de Aminas Biogênicas , Proteínas Vesiculares de Transporte de MonoaminaRESUMO
The cardiopulmonary effects of 3 dosages of doxapram hydrochloride (0.275 mg/kg, 0.55 mg/kg, and 1.1 mg/kg, IV) were studied in 6 adult horses. Doxapram given IV significantly (P less than 0.05) decreased PaCO2 and increased respiratory rate, cardiac output arterial blood pressures (systolic, mean, and diastolic) arterial pH, and PaO2 at 1 minute after each dose was administered. Heart rate and mean and diastolic pulmonary arterial blood pressure were significantly (P less than 0.05) increased 1 minute after the 2 larger dosages of doxapram were given (0.55 mg/kg and 1.1 mg/kg, IV), but not after the smallest dosage was given. All measurements, except heart rate and cardiac output, had returned to base line by 5 minutes after each dosing. Heart rate remained significantly (P less than 0.05) increased 10 minutes after the 0.55 mg/kg dosage was given and 30 minutes after the 1.1 mg/kg dosage. Cardiac output remained significantly (P less than 0.05) increased at 10 minutes, 5 minutes, and 30 minutes after the 0.275, 0.55, and 1.1 mg/kg dosages, respectively, were given.