RESUMO
PURPOSE: Complementing clinical findings with those generated by biomarkers--such as ß-amyloid-targeted positron emission tomography (PET) imaging--has been proposed as a means of increasing overall accuracy in the diagnosis of Alzheimer's disease (AD). Florbetaben ([(18)F]BAY 94-9172) is a novel ß-amyloid PET tracer currently in global clinical development. We present the results of a proof of mechanism study in which the diagnostic efficacy, pharmacokinetics, safety and tolerability of florbetaben were assessed. The value of various quantitative parameters derived from the PET scans as potential surrogate markers of cognitive decline was also investigated. METHODS: Ten patients with mild-moderate probable AD (DSM-IV and NINCDS-ADRDA criteria) and ten age-matched (≥ 55 years) healthy controls (HCs) were administered a single dose of 300 MBq florbetaben, which contained a tracer mass dose of < 5 µg. The 70-90 min post-injection brain PET data were visually analysed by three blinded experts. Quantitative assessment was also performed via MRI-based, anatomical sampling of predefined volumes of interest (VOI) and subsequent calculation of standardized uptake value (SUV) ratios (SUVRs, cerebellar cortex as reference region). Furthermore, single-case, voxelwise analysis was used to calculate individual "whole brain ß-amyloid load". RESULTS: Visual analysis of the PET data revealed nine of the ten AD, but only one of the ten HC brains to be ß-amyloid positive (p = 0.001), with high inter-reader agreement (weighted kappa ≥ 0.88). When compared to HCs, the neocortical SUVRs were significantly higher in the ADs (with descending order of effect size) in frontal cortex, lateral temporal cortex, occipital cortex, anterior and posterior cingulate cortices, and parietal cortex (p = 0.003-0.010). Voxel-based group comparison confirmed these differences. Amongst the PET-derived parameters, the Statistical Parametric Mapping-based whole brain ß-amyloid load yielded the closest correlation with the Mini-Mental State Examination scores (r = -0.736, p < 0.001), following a nonlinear regression curve. No serious adverse events or other safety concerns were seen. CONCLUSION: These results indicate florbetaben to be a safe and efficacious ß-amyloid-targeted tracer with favourable brain kinetics. Subjects with AD could be easily differentiated from HCs by both visual and quantitative assessment of the PET data. The operator-independent, voxel-based analysis yielded whole brain ß-amyloid load which appeared valuable as a surrogate marker of disease severity.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Estilbenos , Compostos de Anilina/efeitos adversos , Compostos de Anilina/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Diagnóstico Diferencial , Estudos de Viabilidade , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Cinética , Masculino , Pessoa de Meia-Idade , Medicina de Precisão , Segurança , Estilbenos/efeitos adversos , Estilbenos/metabolismoRESUMO
Handwriting defects are an early sign of motor impairment in patients with Wilson's disease. The basal ganglia being the primary site of copper accumulation in the brain suggests a correlation with lesions in the nigrostiatal dopaminergic system. We have analysed and correlated striatal dopaminergic innervation using [(123)I]beta-CIT-SPECT and automated handwriting movements in 37 patients with Wilson's disease. There was a significant correlation of putaminal dopaminergic innervation with fine motor ability (p < 0,05 for NIV [number of inversion in velocity], NIA [number of inversion in acceleration], frequency). These data suggest that loss of dorsolateral striatal dopaminergic innervation has a pathophysiological function for decreased automated motor control in Wilson's disease. Furthermore analysis of automated handwriting movements could be useful for therapy monitoring and evaluation of striatal dopaminergic innervation.
Assuntos
Corpo Estriado/metabolismo , Escrita Manual , Degeneração Hepatolenticular/fisiopatologia , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras/metabolismo , Proteínas do Tecido Nervoso , Tomografia Computadorizada de Emissão de Fóton Único , Adulto , Fatores Etários , Idoso , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Destreza Motora/fisiologia , Fatores SexuaisAssuntos
Degeneração Hepatolenticular/fisiopatologia , Degeneração Hepatolenticular/cirurgia , Transplante de Fígado , Adulto , Encéfalo/patologia , Degeneração Hepatolenticular/diagnóstico , Humanos , Masculino , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/fisiopatologia , Doenças do Sistema Nervoso/cirurgiaRESUMO
Wilson's disease, an autosomal recessive disorder of copper metabolism, is caused by about 200 different mutations of the ATP7B gene. Using a genotype-phenotype correlation, 36 patients were examined to see whether the disorder of the automatic handwriting movement depends on the genotype. The findings of this study indicated that no such link exists. Neither the profile of the impairment of the fine motor parameters nor the severity and frequency of pathological findings were different among the three genotype groups (homozygous for H1069Q, compound homozygous for H1069Q and other mutations). By contrast, fine motor disorders were found to correlate with the clinical symptoms recorded when therapy began. The pathophysiology of the basal ganglia and the cerebellar loop therefore cannot be directly attributed to the genotype of the mutation in the ATP7B gene.