RESUMEN
BACKGROUND: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson's disease. OBJECTIVE: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson's disease. RESULTS: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson's disease phenotype and a broad range of onset age (34 to 73 years). CONCLUSIONS: G2019S is the most common genetic determinant of Parkinson's disease identified so far. It is especially frequent among cases with familial Parkinson's disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson's disease.
Asunto(s)
Mutación , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Anciano , Alelos , Secuencia de Bases , Femenino , Efecto Fundador , Heterocigoto , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Persona de Mediana Edad , Datos de Secuencia MolecularRESUMEN
We used SPECT and the tracer (123)I-Ioflupane to measure dopamine transporter (DAT) binding in the caudate nucleus and the putamen of 70 patients with Parkinson's disease (PD), 10 with multiple system atrophy (MSA-P type), and 10 with progressive supranuclear palsy (PSP). Data were compared with 12 age-matched control subjects. We found significant reductions in mean striatal values in all three forms of parkinsonism. However, decrements were significantly greater in PSP (0.51+/-0.39, p<0.01) compared with MSA-P (0.70+/-0.33) and PD (0.95+/-0.38). No differences were found between MSA and PD. Putamen/caudate ratios were greater in PSP (0.83+/-0.12, p<0.01) than in PD (0.51+/-0.11), suggesting a more-uniform involvement of dopamine nerve terminals in both caudate nucleus and putamen. Our results confirm that DAT binding can provide an accurate and highly sensitive measure of dopamine degeneration. PSP patients may show a different pattern of neuronal loss compared with MSA and PD.
Asunto(s)
Cuerpo Estriado/diagnóstico por imagen , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana/metabolismo , Atrofia de Múltiples Sistemas/diagnóstico por imagen , Proteínas del Tejido Nervioso , Enfermedad de Parkinson/diagnóstico por imagen , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único , Tropanos/farmacocinética , Anciano , Estudios de Casos y Controles , Cuerpo Estriado/anatomía & histología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Humanos , Radioisótopos de Yodo/farmacocinética , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/patología , Enfermedad de Parkinson/patología , Parálisis Supranuclear Progresiva/patologíaRESUMEN
Depression is a common finding in patients with Parkinson's disease (PD). Traditionally, depression has been treated with tricyclic antidepressants, which are often associated with undesirable side effects that may limit their use in PD. Few studies have been performed with selective serotonin reuptake inhibitors (SSRIs) in these patients. We assessed the tolerability of the SSRI antidepressant paroxetine (10-20 mg once per day) in 65 outpatients with PD and depression for a period of at least 3 months. Treatment was continued for 125.3+/-89.6 days (mean +/- standard deviation) in 52 patients. In these subjects the Hamilton Disease Rating Scale improved from 21.7+/-6.4 to 13.8+/-5.8 (p <0.001). Overall, 13 patients stopped paroxetine after 9.6+/-10.6 days because of adverse reactions. Two patients reported increased "off" time and tremor that reversed after treatment was stopped. No risk factors for intolerance were identified. Paroxetine is a safe and effective drug to treat depression in PD.
Asunto(s)
Depresión/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Paroxetina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Anciano , Antiparkinsonianos/uso terapéutico , Protocolos Clínicos , Depresión/etiología , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/psicología , Paroxetina/administración & dosificación , Paroxetina/efectos adversos , Estudios Prospectivos , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Single cases of parkinsonism have been associated with hydrocarbon solvents. OBJECTIVE: To determine whether exposure to hydrocarbon solvents is related to PD. METHODS: Cohort study of 990 patients with PD according to Core Assessment Program for Intracerebral Transplantations (CAPIT) criteria, selected from 1455 consecutive subjects presenting at a referral center; case-control study assessing Unified PD Rating Scale scores (motor score as primary endpoint) in all subjects with positive history of hydrocarbon solvent exposure (n = 188), matched for duration of disease and gender to 188 subjects selected from the remaining 802 with a negative history. Two subgroups in the case-control study included the following: 1) response to apomorphine (n = 26); 2) brain MRI (n = 15). PET imaging (n = 9) was compared with that of historic controls. RESULTS: Exposed patients were younger (61.0 +/- 9.4 versus 64.7 +/- 9.4 years, p = 0.002), predominantly male (76.4% versus 45.2%, p = 0.0001), less educated (8.4 +/- 4.2 versus 10.1 +/- 4.4 years, p = 0.0001), and younger at onset of disease (55.2 +/- 9.8 versus 58.6 +/- 10 years, p = 0.014). Exposure to hydrocarbon solvents directly correlated to disease severity (r = 0. 311) and inversely correlated to latency period (r = -0.252). Nine blue-collar occupations accounted for 91.1% of exposures. CONCLUSIONS: Occupations involving the use of hydrocarbon solvents are a risk factor for earlier onset of symptoms of PD and more severe disease throughout its course. Hydrocarbon solvents may be involved in the etiopathogenesis of PD, which does not have a major genetic component.
Asunto(s)
Hidrocarburos/efectos adversos , Exposición Profesional/efectos adversos , Enfermedad de Parkinson Secundaria/inducido químicamente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Solventes/efectos adversosRESUMEN
Patients with Parkinson's disease (n = 68) switched from pergolide or bromocriptine to ropinirole overnight (dose equivalence ratios 1:6 and 10:6, respectively). The activities of daily living score for the Unified Parkinson's Disease Rating Scale (UPDRS) was significantly improved 4 weeks after the bromocriptine-ropinirole switch. All other UPDRS scores, including that for the side-effect component, were not significantly different after either switch. Overnight switching may be a safe therapeutic approach that may reduce hospitalisation and related socio-economic costs.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Bromocriptina/uso terapéutico , Indoles/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Pergolida/uso terapéutico , Actividades Cotidianas , Anciano , Antiparkinsonianos/farmacocinética , Bromocriptina/farmacocinética , Femenino , Humanos , Indoles/farmacocinética , Masculino , Persona de Mediana Edad , Pergolida/farmacocinética , Equivalencia TerapéuticaRESUMEN
A neuropathological examination was performed on a patient with parkinsonism induced by prolonged exposure to a mixture of aliphatic hydrocarbons, mainly n-hexane and halogenated compounds. The patient developed a rapid-course disease that progressed even after withdrawal from the toxic exposure. Pathological examination and immunohistochemical analysis of the brain revealed severe and widespread dopaminergic neuronal loss, associated with severe gliosis, in the substantia nigra, and almost complete loss of tyrosine hydroxylase immunostaining in the striatum. No Lewy bodies were detected. Neuronal loss was also observed in the periaqueductal gray matter, locus ceruleus, and pedunculopontine nucleus. These changes, combined with the moderate anemia due to marrow suppression, and the mild axonal neuropathy observed in vivo, are suggestive of a hydrocarbon toxic insult.
Asunto(s)
Hidrocarburos/efectos adversos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/patología , Femenino , Gliosis/patología , Humanos , Persona de Mediana Edad , Exposición Profesional , Puente/patología , Sustancia Negra/patologíaRESUMEN
The first gamma knife (GK) treatment of a pituitary adenoma in 1967 was meant as an alternative to the primitive surgical approaches that prevailed at the time, with consequent unsatisfactory results. Surprisingly, pituitary adenomas still account for only 7.8% of the 27,000 cases treated in GK centers worldwide. Transnasosphenoidal surgery has greatly improved and surgeons are reluctant to give up a relatively safe and effective operative technique. Radiosurgery is not currently vying to be the primary method of "surgery", but has a definite role following failed pituitary surgery and for tumors that extend into the cavernous sinus. Of 300 patients treated in our GK service, 30 had pituitary adenomas and most had undergone surgery. To date, we have not noted any side effects in the pituitary group. Published information is also reviewed and divided, where possible, into the pre-computed tomography (CT) era and the era of CT-magnetic resonance imaging (MRI). Growth hormone (GH)-secreting adenomas and prolactinomas tend to be larger and cannot be treated with the high doses successful against corticotropin (ACTH)-secreting tumors in Cushing's disease. Radiation fall-off is steep in GK radiosurgery, with the 20% isodose curve being only millimeters away from the point of maximal radiation. The effective dose has mostly been decided on the basis of maintaining safe levels at the sensitive perisellar neural structures. The safety of GK treatment (with no mortality and no permanent morbidity) is compared with other radiosurgical techniques. Good patient response owes much to the cumulative experience of GK pioneers and also to recent advances in images and computers that have enabled increasingly precise stereotaxic targeting and dose planning.
Asunto(s)
Adenoma/cirugía , Neoplasias Hipofisarias/cirugía , Radiocirugia , Técnicas Estereotáxicas , Humanos , Radiocirugia/efectos adversos , Resultado del TratamientoRESUMEN
n-Hexane, similar hydrocarbons, and derivatives are common environmental pollutants and by-products of lipid peroxidation, and they may have a nigrotoxic effect like that of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. This report describes our second case of parkinsonism in a subject exposed to n-hexane. Positron emission tomography studies demonstrated regional striatal abnormalities of the nigrostriatal dopaminergic system and of glucose metabolism that were different from those found in idiopathic Parkinson's disease.
Asunto(s)
Contaminantes Ocupacionales del Aire/efectos adversos , Encéfalo/efectos de los fármacos , Hexanos/efectos adversos , Enfermedades Profesionales/inducido químicamente , Enfermedad de Parkinson Secundaria/inducido químicamente , Tomografía Computarizada de Emisión , Glucemia/metabolismo , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/efectos de los fármacos , Humanos , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/fisiología , Masculino , Persona de Mediana Edad , Examen Neurológico/efectos de los fármacos , Enfermedades Profesionales/diagnóstico por imagen , Enfermedad de Parkinson Secundaria/diagnóstico por imagen , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Dopaminérgicos/fisiología , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/efectos de los fármacos , CurtiembreRESUMEN
Recent studies have suggested that patients with Parkinson's disease (PD) share many of the behavioral deficits found following lesions to the pre-frontal cortex. We assessed the performance of a group of 22 mildly impaired, not-demented parkisonians (I or II Hoehn & Yahr stage) in a test of classification and recall of pictures of familiar objects, which has been demonstrated to be sensitive to frontal damage in patients with unilateral cerebral excision. Parkinsonians utilized fewer categories than normal controls for object classification, while no significant difference was found in the immediate and delayed recall scores. These results support the contention that a subclinical dysfunction of frontal type may be present even in the early stages of PD. A subanalysis of the data suggests that this dysfunction could possibly be aggravated by anticholinergic drugs.
Asunto(s)
Trastornos del Conocimiento/fisiopatología , Enfermedad de Parkinson/fisiopatología , Corteza Prefrontal/fisiopatología , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
We assessed the effect of a 35-day delayed intracerebroventricular (ICV) infusion of epidermal growth factor (EGF) on the survival and function of the substantia nigra (SN) dopaminergic neurons after a unilateral mechanical transection of rat nigrostriatal pathway. EGF infusion for 28 days resulted in a twofold increase in the number of surviving tyrosine-hydroxylase (TH)-positive SN neurons and a significant increase in ipsilateral striatal TH-positive fiber staining compared to controls at 200 days following the injury. In addition, there was a persistent enhancement of behavioral recovery, as indicated by a reduction in amphetamine-induced rotations. We conclude that EGF exerts a neurotrophic effect on the dopaminergic neurons in this experimental model of parkinsonism.
Asunto(s)
Factor de Crecimiento Epidérmico/administración & dosificación , Receptores ErbB/efectos de los fármacos , Receptores ErbB/fisiología , Hemiplejía/fisiopatología , Hemiplejía/terapia , Regeneración Nerviosa/efectos de los fármacos , Regeneración Nerviosa/fisiología , Enfermedad de Parkinson Secundaria/fisiopatología , Enfermedad de Parkinson Secundaria/terapia , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Dopaminérgicos/fisiología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiopatología , Masculino , Haz Prosencefálico Medial/efectos de los fármacos , Haz Prosencefálico Medial/fisiopatología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Ratas , Ratas Endogámicas , Conducta Estereotipada/efectos de los fármacos , Conducta Estereotipada/fisiología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/fisiopatología , Tirosina 3-Monooxigenasa/fisiologíaRESUMEN
Sixteen parkinsonian patients, mean age 57 (range 41-71), with a mean 9 year duration of Parkinson's disease, with "on-off" motor fluctuations were treated with pergolide mesylate 1.6 mg/die (range 1-5) for three months. The treatment resulted in an improvement of akinesia, tremor and rigidity, of the severity of phase "off" and of the duration of time "on". No significant improvements were obtained in the severity of dyskinesia. Three patients considered the treatment excellent and capable of restoring their working abilities. The drug was generally well tolerated. Pergolide was discontinued because of orthostatic hypotension in two patients and because of hallucinations in one patient. We consider these results a favorable progress in the treatment of Parkinson's disease.
Asunto(s)
Enfermedad de Parkinson/tratamiento farmacológico , Pergolida/uso terapéutico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pergolida/administración & dosificación , Pergolida/efectos adversos , Factores de TiempoAsunto(s)
Médula Suprarrenal/trasplante , Núcleo Caudado , Enfermedad de Parkinson/cirugía , Trasplante Heterotópico/métodos , Núcleo Caudado/cirugía , Terapia Combinada , Estudios de Evaluación como Asunto , Femenino , Alucinaciones/etiología , Humanos , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Técnicas Estereotáxicas , Trasplante Autólogo/efectos adversos , Trasplante Autólogo/métodos , Trasplante Heterotópico/efectos adversosAsunto(s)
Benserazida/administración & dosificación , Hidrazinas/administración & dosificación , Levodopa/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Evaluación de Medicamentos , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatologíaRESUMEN
In an open-label study, we substituted conventional levodopa plus benserazide: 100/25 (Madopar) with a controlled-release form (HBS) in 18 fluctuating parkinsonian patients for 24 months. Significantly positive results were obtained in both peak-dose and diphasic dyskinesias up to 12 months of treatment; morning akinesias were also improved up to 6 months. A general trend of deterioration, compared to the first 3-6 months of HBS treatment, was observed in "off" fluctuations after 1 year: akinesias due to a delayed response worsened after 1 year of treatment also when compared with the conventional treatment. Positive results were obtained with new HBS on standard Madopar-related psychiatric disorders.
Asunto(s)
Benserazida/uso terapéutico , Hidrazinas/uso terapéutico , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Adulto , Anciano , Benserazida/administración & dosificación , Carboxiliasas/antagonistas & inhibidores , Ensayos Clínicos como Asunto , Preparaciones de Acción Retardada , Esquema de Medicación , Combinación de Medicamentos/administración & dosificación , Combinación de Medicamentos/uso terapéutico , Femenino , Humanos , Levodopa/administración & dosificación , Levodopa/sangre , Masculino , Persona de Mediana EdadAsunto(s)
Sistema Cromafín/citología , Enfermedad de Parkinson/terapia , Glándulas Suprarrenales/citología , Glándulas Suprarrenales/embriología , Separación Celular , Células Cultivadas , Sistema Cromafín/metabolismo , Sistema Cromafín/trasplante , Feto , Humanos , Enfermedad de Parkinson/patologíaRESUMEN
It is possible to grow functional primary dissociated cultures and explants from stereotactic biopsies of human parkinsonian caudate nuclei. Two major classes of cells were identified on morphological grounds. The culture cells appear to be stimulated by an unidentified soluble factor(s) obtained from human fetal neuronal cells in vitro. Culture of primary neuronal and glial cells from human adult cerebral nuclei seems to be a useful tool for several research purposes and in particular for studying both trophic factor action and target effects on afferent neurons for prospective human brain grafting.