RESUMO
OBJECTIVES: Dopaminergic degeneration affects both nigrostriatal projection neurons and retinal amacrine cells in Parkinson disease (PD). Parkinsonian retinopathy is associated with impaired color discrimination and contrast sensitivity. Some prior studies described associations between color discrimination deficits and cognitive deficits in PD, suggesting that contrast discrimination deficits are due, at least in part, to cognitive deficits in PD. We investigated the relationship between cognitive deficits and impaired contrast sensitivity in PD. METHODS: PD subjects, n = 43; 15F/28M; mean age 66.5 ± 8.2, Hoehn and Yahr stage 2.6 ± 0.6, and duration of disease of 6.2 ± 5.0 years underwent neuropsychological and Rabin contrast sensitivity testing. RESULTS: Mean Rabin contrast sensitivity score was 1.34 ± 0.40. Bivariate analyses showed significant correlation between Rabin contrast sensitivity scores and global cognitive z-scores (R = 0.54, P = 0.0002). Cognitive domain Z-score post hoc analysis demonstrated most robust correlation between Rabin scores and executive functions (R = 0.49, P = 0.0009), followed by verbal learning (R = 0.44, P = 0.0028), visuospatial (R = 0.39, P = 0.001) and attention z-scores (R = 0.32, P = 0.036). CONCLUSIONS: Impaired contrast sensitivity in PD is robustly associated with cognitive deficits, particularly executive function deficits. These results suggest that contrast sensitivity may be a useful biomarker for cognitive changes in PD and may have implications for driving safety evaluations in PD.
Assuntos
Transtornos Cognitivos/etiologia , Sensibilidades de Contraste/fisiologia , Função Executiva/fisiologia , Doença de Parkinson/complicações , Transtornos de Sensação/etiologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estimulação Luminosa , Índice de Gravidade de Doença , Aprendizagem Verbal/fisiologiaRESUMO
Purpose: To evaluate the frequency of 99mTc-MAA uptake in extrahepatic organs during 90Y radioembolization therapy planning. Methods: This retrospective case series of 70 subjects who underwent 99mTc-MAA hepatic artery perfusion studies between January 2014 and July 2016 for 90Y radioembolization therapy planning at our institution involved direct image review for all subjects, with endpoints recorded: lung shunt fraction, extrahepatic radiotracer uptake, time from MAA injection to imaging. Results: Combined planar and SPECT/CT imaging findings in the 70 subjects demonstrated lung shunt fraction measurements of less than 10% in 53 (76%) subjects and greater than 10% in 17 (24%) subjects. All patients demonstrated renal cortical uptake, 23 (33%) demonstrated salivary gland uptake, 23 (33%) demonstrated thyroid uptake, and 32 (46%) demonstrated gastric mucosal uptake, with significant overlap between these groups. The range of elapsed times between MAA injection and initial imaging was 41-138 min, with a mean of 92 min. There was no correlation between time to imaging and the presence of extrahepatic radiotracer uptake at any site. Conclusions: During hepatic artery perfusion scanning for 90Y radioembolization therapy planning, extrahepatic uptake is common, particularly in the kidney, salivary gland, thyroid and gastric mucosa, and is hypothesized to result from breakdown of 99mTc-MAA over time. Given the breakdown to smaller aggregates and ultimately pertechnetate, this should not be a contraindication to actual Y-90 microsphere therapy. Although we found no correlation between time to imaging and extrahepatic uptake, most of our injection to imaging times were relatively short.
RESUMO
RATIONALE AND OBJECTIVES: Parkinson disease (PD) is a progressive neurodegenerative disorder affecting motor and cognitive functions. Prior studies showed that patients with PD and diabetes (DM) demonstrate worse clinical outcomes compared to nondiabetic subjects with PD. Our study aimed at defining the relationship between DM, gray matter volume, and cognition in patients with PD. MATERIALS AND METHODS: This study included 36 subjects with PD (12 with DM, 24 without DM, mean age = 66). Subjects underwent high-resolution T1-weighted brain magnetic resonance imaging, [(11)C]dihydrotetrabenazine positron emission tomography imaging to quantify nigrostriatal dopaminergic denervation, clinical, and cognitive assessments. Magnetic resonance images were postprocessed to determine total and lobar cortical gray matter volumes. Cognitive testing scores were converted to z-scores for specific cognitive domains and a composite global cognitive z-score based on normative data computed. Analysis of covariance, accounting for effects of age, gender, intracranial volume, and striatal [(11)C]dihydrotetrabenazine binding, was used to test the relationship between DM and gray matter volumes. RESULTS: Impact of DM on total gray matter volume was significant (P = 0.02). Post hoc analyses of lobar cortical gray matter volumes revealed that DM was more selectively associated with lower gray matter volumes in the frontal regions (P = 0.01). Cognitive post hoc analyses showed that interaction of total gray matter volume and DM status was significantly associated with composite (P = 0.007), executive (P = 0.02), and visuospatial domain cognitive z-scores (P = 0.005). These associations were also significant for the frontal cortical gray matter. CONCLUSION: DM may exacerbate brain atrophy and cognitive functions in PD with greater vulnerability in the frontal lobes. Given the high prevalence of DM in the elderly, delineating its effects on patient outcomes in the PD population is of importance.
Assuntos
Encefalopatias/complicações , Cognição/fisiologia , Complicações do Diabetes , Substância Cinzenta/patologia , Doença de Parkinson/complicações , Idoso , Atrofia , Atenção/fisiologia , Gânglios da Base/diagnóstico por imagem , Radioisótopos de Carbono , Estudos de Casos e Controles , Estudos Transversais , Neurônios Dopaminérgicos/patologia , Função Executiva/fisiologia , Feminino , Lobo Frontal/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico por imagem , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Tetrabenazina/análogos & derivadosRESUMO
Focal incidental renal lesions are commonly encountered on positron emission tomography (PET)/computed tomography (CT) imaging. The vast majority of these lesions are benign. However, the interpretation of renal lesions can be problematic if the imaging criteria of simple cysts are not met. Limited literature exists on the characterisation of renal masses with metabolic imaging. The purpose of this article is to focus on the imaging features of benign and malignant renal masses with PET/CT. The lesions discussed include renal cyst, angiomyolipoma, oncocytoma, renal cell carcinoma, renal metastases and other infiltrating neoplastic processes affecting the kidney. Both the anatomical and metabolic features which characterise these benign and malignant entities are described. We emphasise the importance of viewing the CT component to identify the typical morphological features and discuss how to best use hybrid imaging for management of renal lesions. Metabolic imaging has a promising role in the imaging of renal lesions and can help prevent unnecessary biopsies and ensure optimal management of suspicious lesions.
Assuntos
Carcinoma de Células Renais/diagnóstico , Fluordesoxiglucose F18 , Neoplasias Renais/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X/métodos , Adenoma Oxífilo/diagnóstico , Angiomiolipoma/diagnóstico , Cistos/diagnóstico , Humanos , Achados Incidentais , Rim/diagnóstico por imagem , Nefropatias/diagnóstico , Leucemia/diagnóstico , Linfoma/diagnósticoRESUMO
OBJECTIVE: To investigate the relationships between history of falls and cholinergic vs dopaminergic denervation in patients with Parkinson disease (PD). BACKGROUND: There is a need to explore nondopaminergic mechanisms of gait control as the majority of motor impairments associated with falls in PD are resistant to dopaminergic treatment. Alterations in cholinergic neurotransmission in PD may be implicated because of evidence that gait control depends on cholinergic system-mediated higher-level cortical and subcortical processing, including pedunculopontine nucleus (PPN) function. METHODS: In this cross-sectional study, 44 patients with PD (Hoehn & Yahr stages I-III) without dementia and 15 control subjects underwent a clinical assessment and [(11)C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) and [(11)C]dihydrotetrabenazine (DTBZ) vesicular monoamine transporter type 2 (VMAT2) brain PET imaging. RESULTS: Seventeen patients (38.6%) reported a history of falls and 27 patients had no falls. Analysis of covariance of the cortical AChE hydrolysis rates demonstrated reduced cortical AChE in the PD fallers group (-12.3%) followed by the PD nonfallers (-6.6%) compared to control subjects (F = 7.22, p = 0.0004). Thalamic AChE activity was lower only in the PD fallers group (-11.8%; F = 4.36, p = 0.008). There was no significant difference in nigrostriatal dopaminergic activity between PD fallers and nonfallers. CONCLUSIONS: Unlike nigrostriatal dopaminergic denervation, cholinergic hypofunction is associated with fall status in Parkinson disease (PD). Thalamic AChE activity in part represents cholinergic output of the pedunculopontine nucleus (PPN), a key node for gait control. Our results are consistent with other data indicating that PPN degeneration is a major factor leading to impaired postural control and gait dysfunction in PD.
Assuntos
Acidentes por Quedas , Acetilcolinesterase/metabolismo , Encéfalo/fisiopatologia , Doença de Parkinson/fisiopatologia , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/fisiopatologia , Estudos Transversais , Dopamina/metabolismo , Feminino , Humanos , Hidrólise , Cinética , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Substância Negra/diagnóstico por imagem , Substância Negra/fisiopatologia , Tálamo/diagnóstico por imagem , Tálamo/fisiopatologiaRESUMO
Hybrid imaging modalities such as radioiodine single photon emission CT with integrated CT ((131)I SPECT-CT) and 2-(fluorine-18)-fluoro-2-deoxy-D-glucose positron emission tomography with integrated CT (FDG PET-CT) allow the rapid and efficient fusion of functional and anatomic images, and provide diagnostic information that may influence management decisions in patients with differentiated thyroid carcinoma (DTC). Diagnostic localisation and therapy of these tumours are dependent upon their capacity to concentrate radioiodine ((131)I) via uptake through the sodium-iodide symporter and retention within the tumour. The prognosis for most patients with DTC is favourable, although controversy exists regarding the role of post-operative (131)I therapy in patients at low-risk for disease. Accurate identification of functional thyroid tissue (benign or malignant) using diagnostic (131)I planar scintigraphy complemented by SPECT-CT imaging enables the completion of post-operative staging and patient risk stratification prior to (131)I therapy administration. In patients with non-iodine-avid tumours (negative (131)I scan but elevated thyroglobulin indicative of persistent or recurrent disease), FDG PET-CT is used to identify tumours with enhanced glucose metabolism and to localise the source of thyroglobulin production. The CT component of this hybrid technology provides anatomic localisation of activity and allows CT-based attenuation correction of PET images. Images from 15 patients illustrate the applications of (131)I SPECT-CT and FDG PET-CT.
Assuntos
Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Fluordesoxiglucose F18 , Humanos , Radioisótopos do Iodo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico por imagem , Radiografia , Compostos Radiofarmacêuticos , Simportadores , Adulto JovemRESUMO
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
Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.
Assuntos
Transtornos Parkinsonianos/complicações , Tauopatias/complicações , Animais , Biomarcadores , Demência/complicações , Demência/genética , Demência/fisiopatologia , Desenho de Fármacos , Geografia , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Modelos Biológicos , Mutação , Doença de Niemann-Pick Tipo C/complicações , Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/fisiopatologia , Doença de Parkinson Pós-Encefalítica/complicações , Doença de Parkinson Pós-Encefalítica/fisiopatologia , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/terapia , Doença de Pick/complicações , Doença de Pick/patologia , Proteínas Serina-Treonina Quinases/genética , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/diagnóstico , Paralisia Supranuclear Progressiva/fisiopatologia , Tauopatias/patologia , Tauopatias/fisiopatologia , Tauopatias/terapia , Proteínas tau/genéticaRESUMO
Previous reports have documented an improvement in night vision among Jamaican fishermen after ingestion of a crude tincture of herbal cannabis, while two members of this group noted that Moroccan fishermen and mountain dwellers observe an analogous improvement after smoking kif, sifted Cannabis sativa mixed with tobacco (Nicotiana rustica). Field-testing of night vision has become possible with a portable device, the LKC Technologies Scotopic Sensitivity Tester-1 (SST-1). This study examines the results of double-blinded graduated THC administration 0-20 mg (as Marinol) versus placebo in one subject on measures of dark adaptometry and scotopic sensitivity. Analogous field studies were performed in Morocco with the SST-1 in three subjects before and after smoking kif. In both test situations, improvements in night vision measures were noted after THC or cannabis. It is believed that this effect is dose-dependent and cannabinoid-mediated at the retinal level. Further testing may assess possible clinical application of these results in retinitis pigmentosa or other conditions.
Assuntos
Cannabis , Adaptação à Escuridão/efeitos dos fármacos , Dronabinol/farmacologia , Visão Ocular/efeitos dos fármacos , Adulto , Adaptação à Escuridão/fisiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Marrocos , Visão Ocular/fisiologiaRESUMO
A major goal of research in Parkinson's disease (PD) has been the development of treatments to slow the progressive degeneration of the nigrostriatal dopaminergic system and to reduce the functional decline of patients. Because of the uncertainty in the ability of the clinical evaluation to reflect the status of the nigrostriatal dopaminergic system once dopaminergic therapy has commenced, investigators in PD have sought to develop alternative measures of disease. One approach, which has been extensively explored, is neuroimaging with radiotracers that interact with processes central to dopaminergic neurotransmission in the nigrostriatal dopaminergic axons-conversion of levodopa to dopamine through aromatic amino acid decarboxylase (AADC), [(18)F]fluorodopa PET, storage of dopamine in synaptic vesicles via the vesicular monoamine transporter 2 (VMAT2), (+)-[(11)C]dihydrotetrabenazine PET, and reuptake of dopamine into axons via the dopamine transporter (DAT), [(123)I]beta-CIT SPECT, and a number of other PET and SPECT ligands. During the 54(th) Annual Meeting of the American Academy of Neurology, a group of investigators active in the fields of biomakers, neuroimaging, and neuroprotection met to review the three techniques mentioned above. Prior to the meeting, the participants developed consensus on a set of 10 criteria for a neuroimaging technique to be considered adequate as a biomarker for progression of PD and levels at which the available data for each technique indicate that the criterion was met. The criteria and each of the three imaging techniques mentioned above were reviewed, and the results of that meeting are presented.
Assuntos
Diagnóstico por Imagem/normas , Di-Hidroxifenilalanina/análogos & derivados , Proteínas do Tecido Nervoso , Neuropeptídeos , Doença de Parkinson/diagnóstico , Avaliação da Tecnologia Biomédica/métodos , Tetrabenazina/análogos & derivados , Animais , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Biomarcadores/análise , Cocaína/análogos & derivados , Progressão da Doença , Proteínas da Membrana Plasmática de Transporte de Dopamina , Humanos , Levodopa , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Compostos Radiofarmacêuticos , Tetrabenazina/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Proteínas Vesiculares de Transporte de Aminas Biogênicas , Proteínas Vesiculares de Transporte de MonoaminaRESUMO
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
RATIONALE: There exists a wide range of animal models and measures designed to assess anxiety or fearfulness. However, the relationship between these models and clinical anxiety symptoms and syndromes is unclear. The National Institute of Mental Health convened a workshop to discuss the relationship between existing behavioral models of anxiety and the clinical profile of anxiety disorders. A second goal of this workshop was to outline various approaches towards modeling components of anxiety disorders. OBJECTIVES: To briefly describe epidemiological and behavioral manifestations of clinical anxiety syndromes and how they relate to commonly employed animal models of anxiety. To describe approaches and considerations for developing, improving, and adapting anxiety models to better understand the neurobiology of anxiety. METHODS: Clinicians, psychiatrists and clinical and basic neuroscientists presented data exemplifying different approaches towards understanding anxiety and the role of animal models. Panel members outlined what they considered to be critical issues in developing and employing animal models of anxiety. RESULTS: This review summarizes the discussions and conclusions of the workshop including recommendations for improving upon existing models and strategies for developing novel models. CONCLUSIONS: The probability of developing comprehensive animal models that accurately reflect the relative influences of factors contributing to anxiety disorder syndromes is quite low. However, ample opportunity remains to better define and extend existing models and behavioral measures related to specific processes that may be disrupted in anxiety disorders and to develop new models that consider the impact of combined factors in determining anxious behaviors.
Assuntos
Transtornos de Ansiedade/psicologia , Animais , Transtornos de Ansiedade/genética , Modelos Animais de Doenças , Humanos , National Institute of Mental Health (U.S.) , Estados UnidosRESUMO
Seeking antemortem markers to distinguish Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), we examined brain glucose metabolism of DLB and AD. Eleven DLB patients (7 Lewy body variant of AD [LBVAD] and 4 pure diffuse Lewy body disease [DLBD]) who had antemortem position emission tomography imaging and autopsy confirmation were compared to 10 autopsy-confirmed pure AD patients. In addition, 53 patients with clinically-diagnosed probable AD, 13 of whom later fulfilled clinical diagnoses of DLB, were examined. Autopsy-confirmed AD and DLB patients showed significant metabolic reductions involving parietotemporal association, posterior cingulate, and frontal association cortices. Only DLB patients showed significant metabolic reductions in the occipital cortex, particularly in the primary visual cortex (LBVAD -23% and DLBD -29% vs AD -8%), which distinguished DLB versus AD with 90% sensitivity and 80% specificity. Multivariate analysis revealed that occipital metabolic changes in DLB were independent from those in the adjacent parietotemporal cortices. Analysis of clinically diagnosed probable AD patients showed a significantly higher frequency of primary visual metabolic reduction among patients who fulfilled later dinical criteria for DLB. In these patients, occipital hypometabolism preceded some clinical features of DLB. Occipital hypometabolism is a potential antemortem marker to distinguish DLB versus AD.
Assuntos
Doença de Alzheimer/diagnóstico , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Doença por Corpos de Lewy/diagnóstico , Idoso , Doença de Alzheimer/patologia , Análise de Variância , Diagnóstico Diferencial , Metabolismo Energético , Feminino , Humanos , Doença por Corpos de Lewy/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Tomografia Computadorizada de EmissãoRESUMO
Quantitative measures of striatal VMAT2 binding sites appear to represent an excellent surrogate of nigrostriatal projection integrity in experimental animal models. Importantly, there does not appear to be a significant effect of dopaminergic drugs or of lesion compensatory effect on the expressed level of VMAT2 binding sites in the striatum. Highly precise and specific measures of human VMAT2 are possible with PET employing the novel tracer (+)11C-DTBZ. This methodology appears particularly suited to the objective measure of PD severity and of its progression. Such measures will be indispensable in the search for disease-modifying effects of PD therapy.
Assuntos
Química Encefálica , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Neuropeptídeos , Doença de Parkinson/metabolismo , Animais , Humanos , Doença de Parkinson/diagnóstico por imagem , Cintilografia , Proteínas Vesiculares de Transporte de Aminas Biogênicas , Proteínas Vesiculares de Transporte de MonoaminaRESUMO
Markers of identified neuronal populations have previously suggested selective degeneration of projection neurons in Huntington's disease (HD) striatum. Interpretations are, however, limited by effects of compensatory regulation and atrophy. Studies of the vesicular monoamine transporter type-2 (VMAT2) and of the vesicular acetylcholine transporter (VAChT) in experimental animals indicate that they are robust markers of presynaptic integrity and are not subject to regulation. We measured dopamine and acetylcholine vesicular transporters to characterize the selectivity of degeneration in HD striatum. Brains were obtained at autopsy from four HD patients and five controls. Autoradiography was used to quantify radioligand binding to VMAT2, VAChT, the dopamine plasmalemmal transporter (DAT), benzodiazepine (BZ) binding sites, and D2-type dopamine receptors. The activity of choline acetyltransferase (ChAT) was determined as an additional marker of cholinergic neurons. Autoradiograms were analyzed by video-assisted densitometry and assessment of atrophy was made from regional structural areas in the coronal projection. Striatal VMAT2, DAT, and VAChT concentrations were unchanged or increased, while D2 and BZ binding and ChAT activity were decreased in HD. After atrophy correction, all striatal binding sites were decreased. However, the decrease in ChAT activity was 3-fold greater than that of VAChT binding. In addition to degeneration of striatal projection neurons, there are losses of extrinsic nigrostriatal projections and of striatal cholinergic interneurons in HD on the basis of vesicular transporter measures. There is also markedly reduced expression of ChAT by surviving cholinergic striatal interneurons.
Assuntos
Proteínas de Transporte/análise , Doença de Huntington/metabolismo , Glicoproteínas de Membrana/análise , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Neuropeptídeos , Sinapses/química , Tetrabenazina/análogos & derivados , Proteínas de Transporte Vesicular , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Autorradiografia , Proteínas de Transporte/metabolismo , Colina O-Acetiltransferase/análise , Colina O-Acetiltransferase/metabolismo , Fibras Colinérgicas/química , Fibras Colinérgicas/enzimologia , Corpo Estriado/química , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Flumazenil/metabolismo , Flumazenil/farmacologia , Moduladores GABAérgicos/metabolismo , Moduladores GABAérgicos/farmacologia , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Mudanças Depois da Morte , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/análise , Receptores de Dopamina D2/metabolismo , Receptores de GABA-A/análise , Receptores de GABA-A/metabolismo , Substância Negra/química , Substância Negra/metabolismo , Sinapses/metabolismo , Trítio , Proteínas Vesiculares de Transporte de Acetilcolina , Proteínas Vesiculares de Transporte de Aminas Biogênicas , Proteínas Vesiculares de Transporte de MonoaminaRESUMO
Cerebral cholinergic deficits have been described in Alzheimer disease (AD) and as a result of normal aging. At the present time, there are very limited options for the quantification of cholinergic receptors with in vivo imaging techniques such as PET. In the present study, we examined the feasibility of utilizing [11C]N-methyl-4-piperidyl benzilate (NMPB), a nonselective muscarinic receptor ligand, in the study of aging and neurodegenerative processes associated with cholinergic dysfunction. Based on prior data describing the accuracy of various kinetic methods, we examined the concentration of muscarinic receptors with [11C]NMPB and PET using two- and three-compartment kinetic models. Eighteen healthy subjects and six patients diagnosed with probable AD were studied. Pixel-by-pixel two-compartment model fits showed acceptable precision in the study of normal aging, with comparable results to those obtained with a more complex and less precise three-compartment model. Normal aging was associated with a reduction in muscarinic receptor binding in neocortical regions and thalamus. In AD patients, the three-compartment model appeared capable of dissociating changes in tracer transport from changes in receptor binding, but suffered from statistical uncertainty, requiring normalization to a reference region, and therefore limiting its potential use in the study of neurodegenerative processes. After normalization, no regional changes in muscarinic receptor concentrations were observed in AD.
Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Benzilatos/metabolismo , Piperidinas/metabolismo , Receptores Muscarínicos/análise , Adulto , Fatores Etários , Idoso , Doença de Alzheimer/diagnóstico por imagem , Transporte Biológico , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Química Encefálica , Radioisótopos de Carbono , Simulação por Computador , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada de EmissãoRESUMO
BACKGROUND: Previous analyses of vesicular monoamine transporter (VMAT2) binding in euthymic bipolar disorder type I (BDI) patients have shown increases of this presynaptic marker in the thalamus and ventral midbrain. To assess the diagnostic specificity of those findings, we compared VMAT2 concentrations between euthymic BDI patients, patients diagnosed with schizophrenia (SCH), and age-matched healthy volunteers. METHODS: Binding sites for VMAT2 were quantified with (+)-alpha-[11C]DTBZ (dihydrotetrabenazine) and positron emission tomography. Fifteen euthymic BDI and 12 SCH patients and 15 group-matched healthy controls were studied. [11C]DTBZ tracer transport and binding potentials were examined in the thalamus and ventral midbrain with factorial analyses of variance and post hoc Tukey's honestly significantly different tests. RESULTS: Analysis of variance detected diagnosis effects in binding potentials in both brain regions. Binding of VMAT2 in the thalamus was higher in BDI patients than in control subjects and SCH patients. Conversely, ventral brainstem binding was nearly identical between BDI and SCH patients and were higher than in the control group. CONCLUSIONS: The patterns of regional VMAT2 expression, and by extension, the concentration of monoaminergic synaptic terminals, differ between BDI, SCH, and a control group. These findings may relate to both similarities and differences in the presentation or clinical course of these syndromes and require further examination.
Assuntos
Transtorno Bipolar/metabolismo , Química Encefálica/fisiologia , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Neuropeptídeos , Esquizofrenia/metabolismo , Adulto , Transtorno Bipolar/psicologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Escalas de Graduação Psiquiátrica , Psicologia do Esquizofrênico , Tomografia Computadorizada de Emissão , Proteínas Vesiculares de Transporte de Aminas Biogênicas , Proteínas Vesiculares de Transporte de MonoaminaRESUMO
This overview first discusses issues relating to the selection of radioligand for receptor binding assays, including the isotopic label and considerations pertaining to the pharmacological and chemical profile of the ligand. This is followed by a section on characterization of ligand-binding assays, starting with tissue preparation methods, followed by detection of specific binding, determination of incubation and washing conditions and a discussion of saturation and competition assay formats. Quantification of the assay results can be accomplished by autoradiography or film densitometry. Finally, methods and considerations for analysis of the resulting data are presented.
Assuntos
Ensaio Radioligante/métodos , Ensaio Radioligante/tendências , Receptores de Superfície Celular/química , Receptores de Superfície Celular/metabolismo , Animais , Autorradiografia/métodos , Autorradiografia/tendências , Ligação Competitiva , Humanos , Indicadores e Reagentes/metabolismo , Ligantes , Ligação Proteica , Radioisótopos/metabolismo , Receptores de Superfície Celular/análiseRESUMO
A series of 31 compounds based on the piperidyl or pyrrolidyl benzilate scaffold were prepared from methyl benzilate and 4-piperidinol, (R)-(+)-3-piperidinol, or (R)-(+)-3-pyrrolidinol. Amine substituents included alkyl and aralkyl groups. In vitro K(i) values ranged from 0.05 nM to >100 nM. (R)-N-(2-Fluoroethyl)-3-piperidyl benzilate (3-FEPB, 22, K(i) = 12.1 nM) and N-(2-fluoroethyl)-4-piperidyl benzilate (4-FEPB, 8, K(i) = 1. 83 nM) were selected for radiolabeling with fluorine-18. Using alkylation with 2-[(18)F]fluoroethyl triflate, 3-[(18)F]FEPB (42) and 4-[(18)F]FEPB (43) were produced in 7-9% radiochemical yield and >97% radiochemical purity. For in vivo studies, retention was moderate in mouse brain for 42; however, blocking with scopolamine showed that uptake was not muscarinic cholinergic receptor-mediated. Conversely, 43 exhibited high, receptor-mediated retention in mouse brain, with significant clearance after 1 h. These results suggest that 43 could have applications as an in vivo probe for measuring endogenous acetylcholine levels.