RESUMO
BACKGROUND: Pathogenic mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been found to cause typical, later-onset Parkinson disease (PD). Although G2019S is the most common mutation, other mutations have also been reported. It is critical to catalog the types of mutations found in LRRK2 that can cause PD, so as to provide insight regarding disease susceptibility and potential novel treatments. METHODS: We performed a comprehensive study of all 51 exons of the LRRK2 gene in one PD patient from each of 88 multiplex PD families who had the highest family-specific multipoint lod score at the LRRK2 locus from a cohort of 430 PD families without the G2019S mutation. RESULTS: Five families (5.7%) harbored what seem to be novel, pathogenic mutations (L1795F, I1192V, E10K, E334K, Q1111H). Three of these apparent mutations were in known, functional domains of the LRRK2 protein, where other studies have also identified disease producing mutations. However, two of the novel variants were found in the N-terminal region of LRRK2, where no pathogenic substitutions have yet been reported. Similar to previous studies, all subjects with an LRRK2 mutation had classic symptoms of PD and typical, later age at onset. CONCLUSIONS: We have identified five novel variants in LRRK2, with two of these in the N-terminal region of LRRK2, where no pathogenic substitutions have been previously reported. If confirmed to be causative, these mutations would broaden the potential mechanisms whereby mutations in LRRK2 result in Parkinson disease.
Assuntos
Análise Mutacional de DNA , Ligação Genética , Doença de Parkinson/genética , Mutação Puntual , Proteínas Serina-Treonina Quinases/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Éxons , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Escore Lod , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Linhagem , Polimorfismo GenéticoRESUMO
In multiple system atrophy (MSA), increased venous compliance with excessive venous pooling is assumed to be a major contributor to orthostatic hypotension (OH); however, venous compliance has never been assessed in MSA patients. We evaluated the severity and distribution of adrenergic, cardiovagal, and sudomotor failure in 11 patients with probable MSA, 14 age- and sex-matched control subjects, and 8 patients with Parkinson's disease (PD) but not OH. Calf venous compliance, venous filling, and capillary filtration were measured using calf plethysmography. The response to the directly acting alpha-adrenergic stimulation (10 mg midodrine) on calf venous compliance was additionally evaluated. Contrary to our hypothesis, pressure-volume curves in the legs of MSA patients were flatter than in PD patients (P < 0.05) or controls (P < 0.001); this indicated reduced calf venous compliance in MSA. The MSA group had reduced venous filling compared with control (P < 0.001) or PD subjects (P < 0.001) but had a normal capillary filtration rate (P = 0.73). Direct alpha-adrenergic stimulation resulted in a slight but significant reduction of calf venous compliance in controls (P = 0.001) and PD subjects (P < 0.001) but not in the MSA group. The compliance change in MSA significantly regressed with autonomic failure (composite autonomic severity scale, r(2) = 0.56) but not with parkinsonism (Unified MSA Rating Scale, r(2) = 0.12). Our data indicate that MSA patients with chronic OH have reduced, rather than increased, venous compliance in the lower leg. We postulate that chronic venous distension that is associated with OH results in structural remodeling of veins, leading to reduced compliance, a change which may protect patients against orthostatic stress.
Assuntos
Perna (Membro)/irrigação sanguínea , Perna (Membro)/fisiopatologia , Modelos Cardiovasculares , Atrofia de Múltiplos Sistemas/fisiopatologia , Veias/fisiopatologia , Idoso , Simulação por Computador , Elasticidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Grau de Desobstrução VascularRESUMO
The North American Multiple System Atrophy Study Group involves investigators in 12 US medical centers funded by a grant from the National Institutes of Health. The objectives are to examine the environmental and genetic risk factors for MSA; elucidate pathogenic mechanisms underlying the disorder; and refine evaluations used for assessment. During its first year, the group enrolled 87 patients, implemented four cores, and initiated four scientific projects. Most patients among the 87 had parkinsonian features, which frequently began asymmetrically and remained asymmetrical; one-third responded to levodopa and many developed levodopa complications; almost two-thirds of the patients had cerebellar dysfunction, of these 90% had ataxia; urinary incontinence occurred commonly, and sleep disorders affected most. The investigators studied the effects of oxidative and nitrative stress upon the formation of alpha-synuclein inclusions; generated transgenic models of alpha-synuclein accumulation that recapitulate several behavioral and neuropathological features of MSA; and compared the severity of the autonomic features of MSA, Parkinson's disease and dementia with Lewy bodies.
Assuntos
Estudos Multicêntricos como Assunto/métodos , Estudos Multicêntricos como Assunto/tendências , Atrofia de Múltiplos Sistemas/epidemiologia , Animais , Humanos , Atrofia de Múltiplos Sistemas/fisiopatologia , América do Norte , Estados UnidosRESUMO
Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]beta-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.
Assuntos
Corpo Estriado/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Compostos Radiofarmacêuticos , Substância Negra/diagnóstico por imagem , Biomarcadores , Biotransformação , Barreira Hematoencefálica , Radioisótopos de Carbono/farmacocinética , Ensaios Clínicos como Assunto/métodos , Cocaína/análogos & derivados , Cocaína/farmacocinética , Corpo Estriado/metabolismo , Di-Hidroxifenilalanina/análogos & derivados , Di-Hidroxifenilalanina/farmacocinética , Dopamina/metabolismo , Radioisótopos de Flúor/farmacocinética , Fluordesoxiglucose F18/farmacocinética , Previsões , Humanos , Radioisótopos do Iodo/farmacocinética , Neurônios/química , Neurônios/diagnóstico por imagem , Doença de Parkinson/diagnóstico , Doença de Parkinson/terapia , Tomografia por Emissão de Pósitrons , Prognóstico , Compostos Radiofarmacêuticos/farmacocinética , Receptores Dopaminérgicos/metabolismo , Substância Negra/metabolismo , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacocinética , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
A genome screen to identify genes influencing the age at Parkinson disease (PD) onset was completed using 276 families without parkin mutations. Significant evidence of linkage to chromosome 2p near the PARK3 locus (logarithm of odds [lod] = 4.8) was observed. Evidence of linkage was also detected to chromosomes 1q (lod = 3.0) and 8q (lod = 2.6). These data suggest that the genes influencing age at PD onset likely differ from those that contribute to PD susceptibility.
Assuntos
Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 2/genética , Doença de Parkinson/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idade de Início , Idoso , Mapeamento Cromossômico , Família , Feminino , Genótipo , Alemanha/etnologia , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Mutação , Doença de Parkinson/etnologia , Estados Unidos/etnologia , População Branca/genéticaRESUMO
A major goal of research in Parkinson's disease (PD) has been the development of treatments to slow the progressive degeneration of the nigrostriatal dopaminergic system and to reduce the functional decline of patients. Because of the uncertainty in the ability of the clinical evaluation to reflect the status of the nigrostriatal dopaminergic system once dopaminergic therapy has commenced, investigators in PD have sought to develop alternative measures of disease. One approach, which has been extensively explored, is neuroimaging with radiotracers that interact with processes central to dopaminergic neurotransmission in the nigrostriatal dopaminergic axons-conversion of levodopa to dopamine through aromatic amino acid decarboxylase (AADC), [(18)F]fluorodopa PET, storage of dopamine in synaptic vesicles via the vesicular monoamine transporter 2 (VMAT2), (+)-[(11)C]dihydrotetrabenazine PET, and reuptake of dopamine into axons via the dopamine transporter (DAT), [(123)I]beta-CIT SPECT, and a number of other PET and SPECT ligands. During the 54(th) Annual Meeting of the American Academy of Neurology, a group of investigators active in the fields of biomakers, neuroimaging, and neuroprotection met to review the three techniques mentioned above. Prior to the meeting, the participants developed consensus on a set of 10 criteria for a neuroimaging technique to be considered adequate as a biomarker for progression of PD and levels at which the available data for each technique indicate that the criterion was met. The criteria and each of the three imaging techniques mentioned above were reviewed, and the results of that meeting are presented.
Assuntos
Diagnóstico por Imagem/normas , Di-Hidroxifenilalanina/análogos & derivados , Proteínas do Tecido Nervoso , Neuropeptídeos , Doença de Parkinson/diagnóstico , Avaliação da Tecnologia Biomédica/métodos , Tetrabenazina/análogos & derivados , Animais , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Biomarcadores/análise , Cocaína/análogos & derivados , Progressão da Doença , Proteínas da Membrana Plasmática de Transporte de Dopamina , Humanos , Levodopa , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Compostos Radiofarmacêuticos , Tetrabenazina/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Proteínas Vesiculares de Transporte de Aminas Biogênicas , Proteínas Vesiculares de Transporte de MonoaminaRESUMO
We investigated the survival, distribution and differentiation capabilities of adult rat hippocampus-derived progenitor cells (AHPs) by grafting them into either the intact or dopamine (DA)-denervated adult rat striatum (ST). Furthermore, we tested the effects of the in vivo administration of retinoic acid (RA) on the differentiation of the grafted cells. AHPs, prelabeled in vitro with bromodeoxyuridine (BrdU) and primed with RA, were transplanted bilaterally into the ST of hemiparkinsonian rats. Twenty animals were divided in four groups: three groups received i.p. injections of RA (1.5 mg/kg/day) for 1, 2 or 4 weeks and one group received vehicle injections for 4 weeks. Approximately 60% of the implanted BrdU-immunoreactive (BrdU+) cells were present in either intact or lesioned ST after 5 weeks of transplantation, with a striking widespread radial distribution from the implantation site. The cells became morphologically integrated with the surrounding host tissue, with no evidence of tumor formation. Approximately 18% of the BrdU+ cells were immunoreactive for the glial precursor marker NG2 and occasionally BrdU+ cells co-expressed the neuronal marker TuJ1. This differentiation pattern was similar in the intact and DA-denervated ST. Although further research is needed to find more adequate methods to drive the differentiation of these cells toward the desired phenotypes, the survival, differentiation potential and widespread distribution throughout the ST observed in this study suggest that AHPs may be useful in treatment of degenerative disorders affecting the nervous system.
Assuntos
Corpo Estriado/patologia , Neurônios/citologia , Transtornos Parkinsonianos/terapia , Transplante de Células-Tronco/métodos , Células-Tronco/citologia , Animais , Antígenos/biossíntese , Diferenciação Celular , Movimento Celular , Sobrevivência Celular , Corpo Estriado/citologia , Modelos Animais de Doenças , Feminino , Genes Reporter , Sobrevivência de Enxerto , Proteínas de Fluorescência Verde , Hipocampo/citologia , Proteínas Luminescentes/biossíntese , Proteínas Luminescentes/genética , Neurônios/efeitos dos fármacos , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , Proteoglicanas/biossíntese , Ratos , Ratos Endogâmicos F344 , Células-Tronco/metabolismoRESUMO
We tested the hypothesis that fibroblasts, which had been genetically engineered to produce fibroblast growth factor-2 (FGF-2), can protect nigrostriatal dopaminergic neurons. Three groups of rats received either a burr hole only (n=5) or implantation of fibroblasts, which had been genetically engineered to produce beta-galactosidase (beta-gal) (n=8) or FGF-2 (n=8), at two sites in the right striatum. Two weeks later, the animals received an injection of 25 microg of 6-hydroxydopamine hydrobromide (6-OHDA) midway between the two implant sites. The group that received FGF-2-fibroblasts had significantly fewer apomorphine-induced rotations than the groups that received a burr hole only or beta-gal-fibroblasts at weeks 2 and 3 following lesioning with 6-OHDA. Testing for amphetamine-induced rotation revealed a mild reduction in rotation in the beta-gal-fibroblast group compared to the burr hole only group, but a striking attenuation of amphetamine-induced rotation in the FGF-2-fibroblast group. There was also preservation of TH-IR neurons on the lesioned side relative to both control groups. The size of the grafts and the gliosis surrounding the injection sites did not differ between the FGF-2-fibroblast and beta-gal-fibroblast groups. To further characterize the production of FGF-2 by the FGF-2-fibroblasts, we implanted FGF-2-fibroblasts and beta-gal-fibroblast into the striatum of rats but did not lesion the animals with 6-OHDA. The animals were then sacrificed at 1, 2 and 5 weeks following implantation. Prior to implantation the FGF-2 fibroblasts contained 148 ng/mg of FGF-2-immunoreactive (FGF-2-IR) material per mg of protein of cell lysate. After implantation FGF-2-IR material was noted in the grafts of FGF-2-fibroblasts, most conspicuously at 1 and 2 weeks following implantation. We also noted FGF-2-IR material in the nuclei of reactive astrocytes adjacent to the implants, and OX-42-immunoreactive (OX-42-IR) cells adjacent and occasionally within the implants. Our work indicates that fibroblasts genetically engineered to produce FGF-2 and implanted in the striatum can protect the nigrostriatal dopaminergic system and may be useful in the treatment of Parkinson's disease.
Assuntos
Corpo Estriado/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fibroblastos/metabolismo , Degeneração Estriatonigral/metabolismo , Substância Negra/metabolismo , Adrenérgicos , Animais , Corpo Estriado/transplante , Feminino , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/uso terapêutico , Fibroblastos/transplante , Oxidopamina , Doença de Parkinson/tratamento farmacológico , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Degeneração Estriatonigral/induzido quimicamente , Degeneração Estriatonigral/tratamento farmacológico , Substância Negra/transplante , beta-Galactosidase/genética , beta-Galactosidase/metabolismoRESUMO
In two previous experiments, we studied how stimulus motion affects both the self-report of emotion experience and the physiological sequelae of emotion. In both studies, image motion intensified emotional responding, and the effect of motion was relatively specific to the arousal dimension of the emotion; there was little evidence that image motion altered the valence of the image. Moving images also appeared to sustain the attention of the participants for a longer period of time than did the still images. In these two experiments, however, image motion was manipulated within participants. In the present experiment, we used a between-subjects manipulation of image motion and found a nearly identical pattern of results. These data indicate that motion inherently increments the arousal value of an image and that this increment is not dependent on the context in which motion is introduced.
Assuntos
Percepção de Movimento/fisiologia , Adulto , Feminino , Humanos , Individualidade , Masculino , Estimulação LuminosaRESUMO
Relative preservation of dopaminergic axons in patches and a subcallosal layer was observed in the dorsal, lateral and caudal striatum 4 weeks after intrastriatal injection of 6-hydroxydopamine (6-OHDA), a neurotoxin selective for catecholaminergic neurons. Since calcium binding proteins are reported to provide neuroprotective influence in neurons, differences in the distribution of the calcium binding proteins might be related to the different vulnerabilities of dopaminergic neurons and axons to neurotoxins. To address this possibility, we characterized patches of relatively dense tyrosine hydroxylase-immunoreactive (TH-IR) axons in intrastriatal 6-OHDA lesioned rats, focusing on two calcium binding proteins, calbindin (CB) and calretinin (CR). The patches and subcallosal layer of preserved dopaminergic axons in the striatum of rats lesioned with 6-OHDA contained CR, a 31-kDa calcium-binding protein, but interestingly not CB. Dopaminergic neurons containing CR in the substantia nigra pars compacta (SNpc) were relatively spared compared to those that did not contain CR. Taken together, our data indicate that dopaminergic axons and neurons containing CR in the nigrostriatal pathway are more resistant to 6-OHDA lesion than those that do not contain CR.
Assuntos
Axônios/efeitos dos fármacos , Axônios/metabolismo , Neostriado/efeitos dos fármacos , Fármacos Neuroprotetores/metabolismo , Neurotoxinas/toxicidade , Oxidopamina , Proteína G de Ligação ao Cálcio S100/metabolismo , Animais , Axônios/patologia , Calbindina 2 , Calbindinas , Dopamina/metabolismo , Resistência a Medicamentos/fisiologia , Feminino , Neostriado/metabolismo , Neostriado/patologia , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Ratos , Ratos Sprague-Dawley , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Parkinson's disease (PD) is a degenerative neurological disorder. Recent studies have demonstrated reduced activity of complex I of the electron transport chain in brain and platelets from patients with PD. Platelet mitochondria from parkinsonian patients were found to have lower levels of coenzyme Q10 (CoQ10) than mitochondria from age/sex-matched controls. There was a strong correlation between the levels of CoQ10 and the activities of complexes I and II/III. Oral CoQ10 was found to protect the nigrostriatal dopaminergic system in one-year-old mice treated with MPTP, a toxin injurious to the nigrostriatal dopaminergic system. We further found that oral CoQ10 was well absorbed in parkinsonian patients and caused a trend toward increased complex I activity. These data suggest that CoQ10 may play a role in cellular dysfunction found in PD and may be a potential protective agent for parkinsonian patients.
Assuntos
Antioxidantes/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Ubiquinona/análogos & derivados , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Administração Oral , Animais , Plaquetas/metabolismo , Coenzimas , Humanos , Camundongos , Mitocôndrias/metabolismo , Doença de Parkinson/etiologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/fisiopatologia , Ubiquinona/administração & dosagem , Ubiquinona/fisiologia , Ubiquinona/uso terapêuticoRESUMO
We investigated whether oral administration of coenzyme Q10 (CoQ10) could attenuate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in one-year-old mice. Four groups of one-year-old, male C57BL/6 mice received a either standard diet or a diet supplemented with CoQ10 (200 mg/kg/day) for five weeks. After four weeks, one group that had received the standard diet and one group that had received the CoQ10 supplemented diet were treated with MPTP. The four groups continued on their assigned diets for an additional week prior to sacrifice. Striatal dopamine concentrations were reduced in both groups treated with MPTP, but they were significantly higher (37%) in the group treated with CoQ10 and MPTP than in the group treated with MPTP alone. The density of tyrosine hydroxylase immunoreactive (TH-IR) fibers in the caudal striatum was reduced in both MPTP-treated groups, but the density of TH-IR fibers was significantly (62%) greater in the group treated with CoQ10 and MPTP than in the group treated with MPTP alone. Our results indicate that CoQ10 can attenuate the MPTP-induced loss of striatal dopamine and dopaminergic axons in aged mice and suggest that CoQ10 may be useful in the treatment of Parkinson's disease.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Envelhecimento/metabolismo , Axônios/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Dopamina/análise , Ubiquinona/análogos & derivados , Administração Oral , Envelhecimento/patologia , Animais , Axônios/química , Coenzimas , Corpo Estriado/química , Corpo Estriado/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Substância Negra/química , Substância Negra/efeitos dos fármacos , Substância Negra/ultraestrutura , Ubiquinona/farmacologiaRESUMO
We report a pilot study of three oral doses of coenzyme Q10 (CoQ10) (200 mg administered two, three, or four times per day for 1 month) in 15 subjects with Parkinson's disease. Oral CoQ10 caused a substantial increase in the plasma CoQ10 level. It was well tolerated, but at the highest dose (200 mg four times per day) mild, transient changes in the urine were noted. CoQ10 did not change the mean score on the motor portion of the Unified Parkinson's Disease Rating Scale. There was a trend toward an increase in complex I activity in the subjects.
Assuntos
Mitocôndrias/enzimologia , Doença de Parkinson Secundária/tratamento farmacológico , Ubiquinona/análogos & derivados , Absorção , Administração Oral , Idoso , Citrato (si)-Sintase/sangue , Coenzimas , Relação Dose-Resposta a Droga , Portadores de Fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/sangue , Doença de Parkinson Secundária/fisiopatologia , Projetos Piloto , Índice de Gravidade de Doença , Ubiquinona/efeitos adversos , Ubiquinona/farmacocinética , Ubiquinona/uso terapêutico , Vitamina ERESUMO
The activities of complex I and complex II/III in platelet mitochondria are reduced in patients with early, untreated Parkinson's disease. Coenzyme Q10 is the electron acceptor for complex I and complex II. We found that the level of coenzyme Q10 was significantly lower in mitochondria from parkinsonian patients than in mitochondria from age- and sex-matched control subjects and that the levels of coenzyme Q10 and the activities of complex I and complex II/III were significantly correlated.
Assuntos
Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Mitocôndrias/enzimologia , Complexos Multienzimáticos/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Oxirredutases/metabolismo , Doença de Parkinson/enzimologia , Succinato Desidrogenase/metabolismo , Ubiquinona/análogos & derivados , Plaquetas/enzimologia , Coenzimas , Complexo II de Transporte de Elétrons , Feminino , Humanos , Masculino , Doença de Parkinson/sangue , Valores de Referência , Ubiquinona/metabolismoRESUMO
Endogenous and exogenous shifts of attention were examined in nondemented patients with Parkinson's disease (PD). In the endogenous condition, an arrow was used to cue participants' attention to the possible location of an impending target, whereas in the exogenous condition, a brightened box was used to cue attention. Cues were either valid (i.e., the target appeared in the cued location) or invalid (i.e., the target appeared in a noncued location). The time between cue onset and target onset (stimulus onset asynchrony or SOA) was varied in each condition. The results indicated that PD patients were not differentially impaired in shifting attention at the shorter SOAs relative to normal controls. However, at longer SOAs, the PD patients demonstrated less of an effect from cueing than did the normal control participants. PD patients' differential effect from cueing was evident in both exogenous and endogenous conditions. These results suggest that PD patients may experience a rapid decay of attentional inhibition and do not support the notion that a decrement in processing resources underlies their attentional deficits. Moreover, these findings further support the notion that the basal ganglia may play an important role in attentional functions.
Assuntos
Atenção/fisiologia , Orientação/fisiologia , Doença de Parkinson/psicologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tempo de Reação/fisiologia , Percepção Espacial/fisiologia , Análise e Desempenho de TarefasRESUMO
Our study was designed to determine whether intrastriatal administration of glial cell line-derived neurotrophic factor (GDNF) can attenuate the behavioral effects and injury to the mesostriatal dopaminergic system caused by 6-hydroxydopamine (6-OHDA). Four groups of rats received a series of four intrastriatal injections of vehicle or one of three doses of GDNF (0.1, 1 or 10 micrograms per injection) on days 1,3,5 and 8. On day 4 the animals received a single, intrastriatal injection of 25 micrograms 6-OHDA. Treatment with GDNF significantly reduced the development of amphetamine-induced rotation, and the dose of 1 microgram per injection appeared to be the most effective. The group treated with this dose had significantly greater preservation of tyrosine hydroxylase-immunoreactive (TH-IR) fibers adjacent to the injection site in the striatum and significantly greater preservation of Nissl-stained and TH-IR neurons in the substantia nigra pars compacta (SNpc).
Assuntos
Neostriado/fisiologia , Fatores de Crescimento Neural , Proteínas do Tecido Nervoso/farmacologia , Oxidopamina/antagonistas & inibidores , Simpatolíticos/antagonistas & inibidores , Anfetamina/farmacologia , Animais , Apomorfina/farmacologia , Dopaminérgicos/farmacologia , Agonistas de Dopamina/farmacologia , Feminino , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Imuno-Histoquímica , Injeções , Neostriado/anatomia & histologia , Neostriado/efeitos dos fármacos , Proteínas do Tecido Nervoso/administração & dosagem , Oxidopamina/farmacologia , Ratos , Ratos Sprague-Dawley , Comportamento Estereotipado/efeitos dos fármacos , Simpatolíticos/farmacologiaRESUMO
Shifts in attention were examined in patients with Huntington's disease (HD) using a divided attention paradigm that involved the presentation of global-local stimuli. The HD patients' pattern of performance was compared to the previously reported results of groups of patients with Alzheimer's disease (AD; Filoteo et al., 1992) or Parkinson's disease (PD; Filoteo et al., 1994). Across consecutive trials of the divided attention task, a visual target could appear at either the same global-local level or at a different level. When the target changed levels across consecutive trials, the AD patients demonstrated an impairment in disengaging attention from the level at which the last target appeared, whereas the PD patients were impaired in maintaining their attention at the previously attended level. In contrast to these patterns of performances, the HD patients did not demonstrate a significant impairment in shifting attention between hierarchical levels. Both the AD and the PD patients' abnormal shifting ability was significantly related to the number of errors they made in identifying target stimuli; however, the pattern of the relationship was qualitatively distinct. These results suggest that different attentional mechanisms may underlie AD and PD patients' visual-perceptual deficits. The HD patients' shifting ability was not related to the number of errors they made in identifying target stimuli, suggesting that a different mechanism may account for the visual-perceptual impairments exhibited by these patients.
Assuntos
Doença de Alzheimer/fisiopatologia , Atenção/fisiologia , Doença de Huntington/fisiopatologia , Doença de Parkinson/fisiopatologia , Percepção Visual/fisiologia , Idoso , Feminino , Humanos , Doença de Huntington/psicologia , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Tempo de Reação/fisiologiaRESUMO
Following the discovery of inhibition of electron transport complex 1 by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces a parkinsonian syndrome in humans, monkeys, and mice, several laboratories have reported abnormalities of complex I and other electron transport complexes (ETCs) in various tissues from patients with Parkinson's disease (PD). Criticism of the significance of these findings in the etiology of PD has centered on whether drug treatments or the debilitation of the disease process itself produced the low ETC activities. We present results from a blinded study of platelet mitochondrial ETC activities in 18 early untreated PD patients and 18 age- and sex-matched controls and in 13 spousal controls. Lower complex I activity in platelet mitochondria of PD patients was seen in early untreated disease and thus cannot be due to debilitation or drug therapy. Home environmental factors seem an unlikely explanation for the reduced complex I activity in PD patients but have not been excluded. Complex II/III activity was also reduced by 20% in PD compared with age-/sex-matched controls. The low complex I and II/III activities in platelet mitochondria appear to be related to the etiology of PD.
Assuntos
Plaquetas/enzimologia , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Mitocôndrias/enzimologia , Complexos Multienzimáticos/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Oxirredutases/metabolismo , Doença de Parkinson/enzimologia , Succinato Desidrogenase/metabolismo , Adulto , Idoso , Citrato (si)-Sintase/metabolismo , Complexo II de Transporte de Elétrons , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , FumarRESUMO
Groups of eight rats received unilateral, intrastriatal injections of 22.5 micrograms brain-derived neurotrophic factor (BDNF) or cytochrome c on 3 consecutive days. Following the injection of BDNF or cytochrome c on the second day, each animal received an intrastriatal injection of 25 micrograms of 6-hydroxydopamine (6-OHDA). During the second week following treatment and thereafter, the animals that received BDNF had significantly fewer apomorphine-induced, contraversive rotations than did the animals that received cytochrome c. The animals that received BDNF but not those that received cytochrome c had a halo of dopaminergic axons around the injection site. Our data indicate that BDNF can attenuate the loss of dopaminergic axons and rotational asymmetry that result from an intrastriatal injection of 6-OHDA.