RESUMEN
OBJECTIVE: One proposed mechanism of disease progression in Parkinson's disease includes the interplay of endogenous dopamine toxicity and mitochondrial dysfunction. However, the in-vivo effects of exogenous dopamine administration on cerebral bioenergetics are unknown. METHODS: We performed a double-blinded, cross-over, placebo-controlled trial. Participants received either 200/50 mg levodopa/benserazide or a placebo and vice versa on the second study visit. Clinical assessments and multimodal neuroimaging were performed, including 31phosphorus magnetic resonance spectroscopy of the basal ganglia and the midbrain. RESULTS: In total, 20 (6 female) patients with Parkinson's disease and 22 sex- and age-matched healthy controls (10 female) were enrolled. Treatment with levodopa/benserazide but not with placebo resulted in a substantial reduction of high-energy phosphorus-containing metabolites in the basal ganglia (patients with Parkinson's disease: -40%; healthy controls: -39%) but not in the midbrain. There were no differences in high-energy phosphorus-containing metabolites for patients with Parkinson's disease compared to healthy controls in the OFF state and treatment response. INTERPRETATION: Exogenously administered levodopa/benserazide strongly interferes with basal ganglia high-energy phosphorus-containing metabolite levels in both groups. The lack of effects on midbrain levels suggests that the observed changes are limited to the site of dopamine action. ANN NEUROL 2024;95:849-857.
Asunto(s)
Ganglios Basales , Benserazida , Estudios Cruzados , Metabolismo Energético , Levodopa , Enfermedad de Parkinson , Humanos , Femenino , Masculino , Persona de Mediana Edad , Ganglios Basales/metabolismo , Ganglios Basales/efectos de los fármacos , Ganglios Basales/diagnóstico por imagen , Anciano , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/diagnóstico por imagen , Benserazida/farmacología , Método Doble Ciego , Metabolismo Energético/efectos de los fármacos , Antiparkinsonianos , Combinación de Medicamentos , Espectroscopía de Resonancia Magnética/métodosRESUMEN
BACKGROUND: X-linked dystonia-parkinsonism (XDP) is a rare movement disorder characterized by profound neurodegeneration in the basal ganglia. The molecular consequences and the bioenergetic state of affected individuals remain largely unexplored. OBJECTIVES: To investigate the bioenergetic state in male patients with XDP and female carriers using 31phosphorus magnetic resonance spectroscopy imaging and to correlate these findings with clinical manifestations. METHODS: We examined the levels of high-energy phosphorus-containing metabolites (HEP) in the basal ganglia and cerebellum of five male patients with XDP, 10 asymptomatic female heterozygous carriers, and 10 SVA-insertion-free controls. RESULTS: HEP levels were reduced in the basal ganglia of patients with XDP (PwXDP) compared to controls, but increased in the cerebellum of both male patients and female carriers. CONCLUSIONS: Our findings suggest a potential compensatory mechanism in the cerebellum of female carriers regardless of sex. Our study highlights alterations in HEP levels in PwXDP patients and female carriers.
Asunto(s)
Ganglios Basales , Cerebelo , Trastornos Distónicos , Enfermedades Genéticas Ligadas al Cromosoma X , Heterocigoto , Humanos , Femenino , Masculino , Trastornos Distónicos/genética , Trastornos Distónicos/metabolismo , Trastornos Distónicos/diagnóstico por imagen , Trastornos Distónicos/fisiopatología , Trastornos Distónicos/patología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Adulto , Persona de Mediana Edad , Ganglios Basales/metabolismo , Ganglios Basales/diagnóstico por imagen , Cerebelo/metabolismo , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Espectroscopía de Resonancia Magnética , Adulto Joven , Metabolismo EnergéticoRESUMEN
Although characterized as a movement disorder, Parkinson's disease (PD) affects more than just the motor system. Within the heterogenous non-motor symptoms, language impairment is frequent but poorly understood beyond semantic processing. This study investigates the impact of PD on syntactic subordination in spontaneous language production. Fifteen PD patients in ON levodopa status narrated a short story guided by a set of pictures. Thirteen PD patients were also assessed in OFF levodopa status. Narrations were digitally recorded, subsequently transcribed and annotated, making the produced speech accessible to systematical quantitative analysis. Compared to a healthy matched control group, PD patients showed a significant reduction of subordinating structures while the number of non-embedding sentences remained unaffected. No significant effect comparing ON versus OFF levodopa status emerged. Our results suggest a contribution of the basal ganglia to language processing, such as syntactic composition, which, however, does not seem to be dopamine dependent.