RESUMO
AKT1 controls important processes in medial temporal lobe (MTL) development and plasticity, but the impact of human genetic variation in AKT1 on these processes is not known in healthy or disease states. Here, we report that an AKT1 variant (rs1130233) previously associated with AKT1 protein expression, prefrontal function and schizophrenia, affects human MTL structure and memory function. Further, supporting AKT1's role in transducing hippocampal neuroplasticity and dopaminergic processes, we found epistasis with functional polymorphisms in BDNF and COMT--genes also implicated in MTL biology related to AKT1. Consistent with prior predictions that these biologic processes relate to schizophrenia, we found epistasis between the same AKT1, BDNF and COMT functional variants on schizophrenia risk, and pharmacogenetic interactions of AKT1 with the effects on cognition and brain volume measures by AKT1 activators in common clinical use--lithium and sodium valproate. Our findings suggest that AKT1 affects risk for schizophrenia and accompanying cognitive deficits, at least in part through specific genetic interactions related to brain neuroplasticity and development, and that these AKT1 effects may be pharmacologically modulated in patients.
Assuntos
Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas c-akt/genética , Esquizofrenia/genética , Esquizofrenia/patologia , Lobo Temporal/patologia , Antipsicóticos/uso terapêutico , Mapeamento Encefálico , Fator Neurotrófico Derivado do Encéfalo/genética , Catecol O-Metiltransferase/genética , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Farmacoeconomia , Epistasia Genética/efeitos dos fármacos , Epistasia Genética/genética , Feminino , Estudos de Associação Genética , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Transtornos da Memória/genética , Testes Neuropsicológicos , Oxigênio/sangue , Estimulação Luminosa , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/genética , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Lobo Temporal/irrigação sanguínea , Lobo Temporal/efeitos dos fármacosRESUMO
OBJECTIVE: Our goal was to develop and test a 3D bolus-tracking MR technique for perfusion imaging of normal and pathological (infarcted) human brain. MATERIALS AND METHODS: All experiments were performed on standard 1.5 T GE/Signa clinical scanners. Five normal volunteers and one patient with a subacute brain infarct were studied. Modified [frequency-shifted (FS)] BURST MRI was performed during injection of a bolus of Gd-DTPA (0.13 mmol/kg) in the antecubital vein. The 3D datasets were acquired with a time resolution of 2.2 s and an effective spatial resolution of 4.3 x 4.3 x 6.4 mm. Three-dimensional maps of blood volume and bolus arrival time were determined by fitting a synthetic curve to the intensity time course on a voxel-by-voxel basis. RESULTS: Both relative cerebral blood volume and arrival time maps demonstrated sensitivity to regional differences in blood supply in both normal brain and in the subacute brain infarction. The transit time maps showed arrival time delays of 5-7 s within and around the infarct and confirmed the diagnosis of left middle cerebral artery occlusion. CONCLUSION: The results of the measurements on both normal and diseased human brain demonstrated the ability to acquire valuable 3D information about brain perfusion using FS BURST MRI.