RESUMO
Mitochondrial dysfunction hypothetically contributes to neuronal degeneration in patients with Parkinson's disease. While several in vitro data exist, the measurement of cerebral mitochondrial dysfunction in living patients with Parkinson's disease is challenging. Anatomical magnetic resonance imaging combined with phosphorus and proton magnetic resonance spectroscopic imaging provides information about the functional integrity of mitochondria in specific brain areas. We measured partial volume corrected concentrations of low-energy metabolites and high-energy phosphates with sufficient resolution to focus on pathology related target areas in Parkinson's disease. Combined phosphorus and proton magnetic resonance spectroscopic imaging in the mesostriatal region was performed in 16 early and 13 advanced patients with Parkinson's disease and compared to 19 age-matched controls at 3 Tesla. In the putamen and midbrain of both Parkinson's disease groups, we found a bilateral reduction of high-energy phosphates such as adenosine triphophosphate and phosphocreatine as final acceptors of energy from mitochondrial oxidative phosphorylation. In contrast, low-energy metabolites such as adenosine diphophosphate and inorganic phosphate were within normal ranges. These results provide strong in vivo evidence that mitochondrial dysfunction of mesostriatal neurons is a central and persistent phenomenon in the pathogenesis cascade of Parkinson's disease which occurs early in the course of the disease.
Assuntos
Encefalopatias Metabólicas/metabolismo , Encéfalo/metabolismo , Metabolismo Energético/fisiologia , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Doença de Parkinson/metabolismo , Trifosfato de Adenosina/análise , Trifosfato de Adenosina/metabolismo , Idoso , Biomarcadores/análise , Biomarcadores/metabolismo , Encéfalo/fisiopatologia , Química Encefálica/fisiologia , Encefalopatias Metabólicas/diagnóstico , Encefalopatias Metabólicas/fisiopatologia , Progressão da Doença , Feminino , Humanos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/fisiopatologia , Fosforilação Oxidativa , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Fosfocreatina/análise , Fosfocreatina/metabolismo , Fósforo/metabolismo , Valor Preditivo dos Testes , Prótons , Putamen/metabolismo , Putamen/fisiopatologia , Substância Negra/metabolismo , Substância Negra/fisiopatologiaRESUMO
Indirect evidence from laboratory studies suggests that mitochondrial energy metabolism is impaired in progressive supranuclear palsy (PSP), but brain energy metabolism has not yet been studied directly in vivo in a comprehensive manner in patients. We have used combined phosphorus and proton magnetic resonance spectroscopy to measure adenosine-triphosphate (ATP), adenosine-diphosphate (ADP), phosphorylated creatine, unphosphorylated creatine, inorganic phosphate and lactate in the basal ganglia and the frontal and occipital lobes of clinically probable patients (N=21; PSP stages II to III) and healthy controls (N=9). In the basal ganglia, which are severely affected creatine in PSP patients, the concentrations of high-energy phosphates (=ATP+phosphorylated creatine) and inorganic phosphate, but not low-energy phosphates (=ADP+unphosphorylated creatine), were decreased. The decrease probably does not reflect neuronal death, as the neuronal marker N-acetylaspartate was not yet significantly reduced in the early-stage patients examined. The frontal lobe, also prone to neurodegeneration in PSP, showed similar alterations, whereas the occipital lobe, typically unaffected, showed less pronounced alterations. The levels of lactate, a product of anaerobic glycolysis, were elevated in 35% of the patients. The observed changes in the levels of cerebral energy metabolites in PSP are consistent with a functionally relevant impairment of oxidative phosphorylation.