RESUMEN
Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor with restorative effects in a wide variety of rodent and primate models of Parkinson disease, but penetration into brain tissue from either the blood or the cerebro-spinal fluid is limited. Here we delivered GDNF directly into the putamen of five Parkinson patients in a phase 1 safety trial. One catheter needed to be repositioned and there were changes in the magnetic resonance images that disappeared after lowering the concentration of GDNF. After one year, there were no serious clinical side effects, a 39% improvement in the off-medication motor sub-score of the Unified Parkinson's Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub-score. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [(18)F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function. This study warrants careful examination of GDNF as a treatment for Parkinson disease.
Asunto(s)
Factores de Crecimiento Nervioso/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Putamen/efectos de los fármacos , Dihidroxifenilalanina/metabolismo , Radioisótopos de Flúor , Factor Neurotrófico Derivado de la Línea Celular Glial , Humanos , Persona de Mediana Edad , Proyectos Piloto , Proyectos de Investigación , Tomografía Computarizada de EmisiónRESUMEN
To investigate the effects of bilateral subthalamic nucleus (STN) stimulation on patterns of brain activation during random number generation (RNG), a task that requires suppression of habitual counting and response selection under competition. We used H(2)(15)O positron emission tomography to investigate the changes of regional cerebral blood flow (rCBF) induced by bilateral STN stimulation during a RNG task, in six patients with Parkinson's disease. Paced RNG at 1 Hz was compared with a control counting task. Both tasks were performed off medication with deep brain stimulation on and off. Subthalamic nucleus stimulation had a negative effect on performance of fast-paced RNG, leading to reduced randomness and increased habitual counting. Subthalamic nucleus stimulation also induced a reduction of rCBF in the left dorsal frontal gyrus, inferior frontal gyrus, dorsolateral prefrontal cortex, posterior and right anterior cingulate, and an increase of rCBF in the right internal globus pallidum (GPi) during RNG. Stimulation of the STN significantly altered pallidal coupling with frontal and temporal areas compared with when the stimulators were off. In conclusion, during RNG: (i) STN stimulation activates its output neurons to the GPi; (ii) STN stimulation induces increased inhibition of a prefrontal-cingulate network. This is the first direct evidence that STN stimulation significantly alters pallidal coupling with prefrontal, cingulate, and temporal cortices during performance of a task that requires response selection under competition.
Asunto(s)
Estimulación Encefálica Profunda , Lóbulo Frontal/fisiología , Globo Pálido/fisiología , Núcleo Subtalámico/fisiología , Circulación Cerebrovascular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radioisótopos de Oxígeno , Enfermedad de Parkinson/fisiopatología , Tomografía de Emisión de Positrones , Análisis y Desempeño de TareasRESUMEN
BACKGROUND: Carotid body (CB) glomus cells are highly dopaminergic and express the glial cell line derived neurotrophic factor. The intrastriatal grafting of CB cell aggregates exerts neurotrophic actions on nigrostriatal neurons in animal models of Parkinson disease (PD). OBJECTIVE: We conducted a phase I-II clinical study to assess the feasibility, long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with PD. METHODS: Thirteen patients with advanced PD underwent bilateral stereotactic implantation of CB cell aggregates into the striatum. They were assessed before surgery and up to 1-3 years after surgery according to CAPIT (Core Assessment Programme for Intracerebral Transplantation) and CAPSIT-PD (Core Assessment Programme for Surgical Interventional Therapies in Parkinson's Disease) protocols. The primary outcome measure was the change in video blinded Unified Parkinson's Disease Rating Scale III score in the off-medication state. Seven patients had 18F-dopa positron emission tomography scans before and 1 year after transplantation. RESULTS: Clinical amelioration in the primary outcome measure was observed in 10 of 12 blindly analysed patients, which was maximal at 6-12 months after transplantation (5-74%). Overall, mean improvement at 6 months was 23%. In the long term (3 years), 3 of 6 patients still maintained improvement (15-48%). None of the patients developed off-period dyskinesias. The main predictive factors for motor improvement were the histological integrity of the CB and a milder disease severity. We observed a non-significant 5% increase in mean putaminal 18F-dopa uptake but there was an inverse relationship between clinical amelioration and annual decline in putaminal 18F-dopa uptake (r = -0.829; p = 0.042). CONCLUSIONS: CB autotransplantation may induce clinical effects in patients with advanced PD which seem partly related to the biological properties of the implanted glomus cells.
Asunto(s)
Cuerpo Carotídeo/citología , Trasplante de Células , Enfermedad de Parkinson/terapia , Adulto , Cuerpo Estriado , Dopamina/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía de Emisión de Positrones , Trasplante Autólogo , Resultado del TratamientoAsunto(s)
Encéfalo/patología , Fibras Nerviosas/efectos de los fármacos , Factores de Crecimiento Nervioso/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dihidroxifenilalanina/farmacocinética , Dopamina/metabolismo , Proteína GAP-43/efectos de los fármacos , Proteína GAP-43/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial , Humanos , Infusiones Intralesiones , Masculino , Persona de Mediana Edad , Fibras Nerviosas/metabolismo , Factores de Crecimiento Nervioso/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Sinaptofisina/efectos de los fármacos , Sinaptofisina/metabolismo , Tirosina 3-Monooxigenasa/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
We previously reported clinical improvement, increase in putamen [(18)F]-dopa uptake on PET imaging, and neuropathologic evidence of sprouting of dopaminergic fibers following chronic intraputaminal delivery of glial cell line-derived neurotrophic factor (GDNF) in idiopathic Parkinson disease (PD).(1-3) We now provide clinical and PET evidence of persistent efficacy lasting for at least 3 years following cessation of GDNF infusion in a patient with PD. This is a single-case observational study, providing Class IV evidence.
Asunto(s)
Antiparkinsonianos/administración & dosificación , Factor Neurotrófico Derivado de la Línea Celular Glial/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Putamen/efectos de los fármacos , Putamen/fisiología , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Índice de Severidad de la Enfermedad , Factores de Tiempo , Tomografía Computarizada de EmisiónRESUMEN
Magnetic resonance imaging (MRI) after implantation of electrodes in the subthalamic nuclei is currently performed at a number of sites, but a recent adverse incident and changes in MRI technology may heighten safety concerns. In this report, it is demonstrated that given whole-head image data, registration of postimplantation computed tomography to preimplantation MRI can enable verification of the position of electrodes to an accuracy of 2 mm. This registration technique can remove the need for potentially risky postoperative MRI.