RESUMEN
BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) has demonstrated its efficacy on motor complications in advanced Parkinson's disease (PD) but does not modify disease progression. Genetic forms of PD have been associated with different cognitive progression profiles. OBJECTIVE: To assess the effect of PD-related genetic mutations on cognitive outcome after STN-DBS. METHODS: Patients with STN-DBS were screened for LRRK2, GBA, and PRKN mutations at the Pitié-Salpêtrière Hospital between 1997 and 2009. Patients with known monogenetic forms of PD from six other centers were also included. The Mattis Dementia Rating Scale (MDRS) was used to evaluate cognition at baseline and one-year post-surgery. The standardized Unified PD Rating Scale (UPDRS) evaluation On and Off medication/DBS was also administered. A generalized linear model adjusted for sex, ethnicity, age at onset, and disease duration was used to evaluate the effect of genetic factors on MDRS changes. RESULTS: We analyzed 208 patients (131 males, 77 females, 54.3 ± 8.8 years) including 25 GBA, 18 LRRK2, 22 PRKN, and 143 PD patients without mutations. PRKN patients were younger and had a longer disease duration at baseline. A GBA mutation was the only significant genetic factor associated with MDRS change (ß = -2.51, p = 0.009). GBA mutation carriers had a more pronounced post-operative MDRS decline (3.2 ± 5.1) than patients with LRRK2 (0.9 ± 4.8), PRKN (0.5 ± 2.7) or controls (1.4 ± 4.4). The motor response to DBS was similar between groups. CONCLUSION: GBA mutations are associated with early cognitive decline following STN-DBS. Neuropsychological assessment and discussions on the benefit/risk ratio of DBS are particularly important for this population.
Asunto(s)
Disfunción Cognitiva , Estimulación Encefálica Profunda , Progresión de la Enfermedad , Glucosilceramidasa/genética , Enfermedad de Parkinson , Núcleo Subtalámico , Anciano , Disfunción Cognitiva/etiología , Disfunción Cognitiva/genética , Disfunción Cognitiva/fisiopatología , Estimulación Encefálica Profunda/efectos adversos , Femenino , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/terapia , Estudios Retrospectivos , Núcleo Subtalámico/cirugía , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
We have previously observed that in vivo lipoic acid (LA) treatment induced a protective effect onto primary cortical neurons after brain injury. In an effort to better understand LA action mechanism in the brain, in the present study, we stressed brain cells in vitro and ex vivo and then analyzed by inmmunocytochemistry and biochemical assays, the changes induced by LA on cell survival and on the concentration of oxidative stress markers, such as glutathione (GSH), oxidized glutathione (GSSG), and malondialdehyde (MDA). The stressors used were lipopolysaccharide (LPS), dopamine, and l-buthionine-S,R-sulfoximine (BSO). Our results showed that LA decreased cell death and increased GSH/GSSG ratio in cells stressed by LPS + dopamine, suggesting that the mechanism underlying LA action is regeneration of GSSG to GSH. When cells were stressed by BSO, LA diminished cell death and decreased GSH/GSSG ratio. In this case, it could be concluded that, due to the low GSH basal levels, GSSG reduction is not possible and therefore it might be thought that cell death prevention might be mediated through other mechanisms. Finally, we induced chemical oxidative damage in brain homogenate. After LA treatment, GSH and GSH/GSSG ratio increased and MDA concentration decreased, demonstrating again that LA was not able to increase de novo GSH synthesis but is able to increase GSSG conversion to GSH.
