RESUMO
PURPOSE OF REVIEW: Advances in technology have expanded telemedicine opportunities covering medical practice, research, and education. This is of particular importance in movement disorders (MDs), where the combination of disease progression, mobility limitations, and the sparse distribution of MD specialists increase the difficulty to access. In this review, we discuss the prospects, challenges, and strategies for telemedicine in MDs. RECENT FINDINGS: Telemedicine for MDs has been mainly evaluated in Parkinson's disease (PD) and compared to in-office care is cost-effective with similar clinical care, despite the barriers to engagement. However, particular groups including pediatric patients, rare MDs, and the use of telemedicine in underserved areas need further research. Interdisciplinary telemedicine and tele-education for MDs are feasible, provide similar care, and reduce travel costs and travel time compared to in-person visits. These benefits have been mainly demonstrated for PD but serve as a model for further validation in other movement disorders.
Assuntos
Transtornos dos Movimentos/terapia , Equipe de Assistência ao Paciente/organização & administração , Telemedicina , Humanos , Doença de Parkinson/terapiaRESUMO
Hydrogen/deuterium exchange coupled to mass spectrometry (HDX-MS) has emerged as a technique for studying glycoproteins, which are often refractory to classical methods. Glycan chains are generally assumed to exchange protons very rapidly, making them invisible to this technique. Here, we show that under conditions commonly used for HDX-MS, acetamido groups within glycan chains retain a significant amount of deuterium. Using mono- and polysaccharide standards along with glycopeptides from a panel of glycoproteins, we demonstrate that N-acetyl hexosamines, along with modified Asn side chains, are responsible for this effect. Model compounds for sialic acid also displayed similar exchange kinetics, but terminal sialic acids in the context of an entire glycan chain did not contribute to deuterium retention. Furthermore, the presence of sialic acid appears to enhance the exchange rate of the nearby N-acetyl glucosamines. The ability to detect deuterium exchange at the glycan level opens the possibility of applying HDX-MS to monitor glycan interactions and dynamics.
Assuntos
Medição da Troca de Deutério , Glicoproteínas/química , Polissacarídeos/química , Animais , Configuração de Carboidratos , Bovinos , Humanos , Espectrometria de MassasRESUMO
The influenza virus hemagglutinin (HA) fusion protein has long been viewed as a "spring-loaded" fusion machine whereby activation at low pH initiates a rapid and irreversible cascade of conformational changes that drives the membrane fusion reaction. This mechanism has shaped our understanding of how type 1 viral fusion proteins function as a whole. Experimental limitations have hindered efforts to expand our mechanistic and structural understanding of viral membrane fusion. Here, we used pulse-labeling hydrogen/deuterium exchange mass spectrometry and cryo-electron tomography to monitor and characterize the structural dynamics of HA during fusion activation on intact virions. Our data reveal how concurrent reorganizations at the HA1 receptor binding domain interface and HA2 fusion subunit produce a dynamic fusion intermediate ensemble in full-length HA. The soluble HA ectodomain transitions directly to the postfusion state with no observable intermediate.
Assuntos
Influenza Humana , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Hemaglutininas , Humanos , Concentração de Íons de Hidrogênio , Conformação Proteica , Vírion/metabolismoRESUMO
OBJECTIVE: Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A(2A) receptor antagonist, istradefylline, shows promise for the treatment of PD. METHODS: Istradefylline (40mg/day) was studied in levodopa-treated PD subjects experiencing prominent wearing-off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double-blind, 12-week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake "off" time, recorded by subjects using a patient PD diary. Secondary end points evaluated "on" time (including "on time with dyskinesia"), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression-Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring. RESULTS: After randomization, approximately 88% of subjects completed the double-blind period. Compared with baseline, the decrease of daily awake "off" time for istradefylline was a mean (+/- standard deviation) of -10.8 +/- 16.6% (95% confidence interval, -13.46 to -7.52) and for placebo, -4.0 +/- 15.7% (95% confidence interval, -7.73-0.31; p = 0.007 using two-way analysis of variance). This effect corresponded to changes from baseline in total daily awake "off" time of -1.8 +/- 2.8 hours for istradefylline and -0.6 +/- 2.7 hours for placebo (p = 0.005). Treatment-emergent adverse effects with istradefylline were generally mild. INTERPRETATION: Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in "off" time without increased troublesome dyskinesia.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Doença de Parkinson/tratamento farmacológico , Purinas/uso terapêutico , Idoso , Antiparkinsonianos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Receptor A2A de Adenosina/fisiologiaRESUMO
OBJECTIVE: The objective of the Predict-HD study is to use genetic, neurobiological and refined clinical markers to understand the early progression of Huntington's disease (HD), prior to the point of traditional diagnosis, in persons with a known gene mutation. Here we estimate the approximate onset and initial course of various measurable aspects of HD relative to the time of eventual diagnosis. METHODS: We studied 438 participants who were positive for the HD gene mutation, but did not yet meet the diagnostic criteria for HD and had no functional decline. Predictability of baseline cognitive, motor, psychiatric and imaging measures was modelled non-linearly using estimated time until diagnosis (based on CAG repeat length and current age) as the predictor. RESULTS: Estimated time to diagnosis was related to most clinical and neuroimaging markers. The patterns of association suggested the commencement of detectable changes one to two decades prior to the predicted time of clinical diagnosis. The patterns were highly robust and consistent, despite the varied types of markers and diverse measurement methodologies. CONCLUSIONS: These findings from the Predict-HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials.
Assuntos
Testes Genéticos , Doença de Huntington/diagnóstico , Imageamento por Ressonância Magnética , Proteínas do Tecido Nervoso/genética , Exame Neurológico , Testes Neuropsicológicos , Proteínas Nucleares/genética , Adulto , Idoso , Atenção , Núcleo Caudado/patologia , Cromossomos Humanos Par 4/genética , Diagnóstico Precoce , Feminino , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Estudos Longitudinais , Masculino , Rememoração Mental , Pessoa de Meia-Idade , Transtornos do Olfato/diagnóstico , Transtornos do Olfato/genética , Valor Preditivo dos Testes , Probabilidade , Putamen/patologia , Tempo de Reação , Repetições de Trinucleotídeos , Aprendizagem VerbalRESUMO
The neural basis for the transition from preclinical to symptomatic Huntington's disease (HD) is unknown. We used serial positron emission tomography (PET) imaging in preclinical HD gene carriers (p-HD) to assess the metabolic changes that occur during this period. Twelve p-HD subjects were followed longitudinally with [11C]-raclopride and [18F]-fluorodeoxyglucose PET imaging, with scans at baseline, 18 and 44 months. Progressive declines in striatal D2-receptor binding were correlated with concurrent changes in regional metabolism and in the activity of an HD-related metabolic network. We found that striatal D2 binding declined over time (P < 0.005). The activity of a reproducible HD-related metabolic covariance pattern increased between baseline and 18 months (P < 0.003) but declined at 44 months (P < 0.04). These network changes coincided with progressive declines in striatal and thalamic metabolic activity (P < 0.01). Striatal metabolism was abnormally low at all time points (P < 0.005). By contrast, thalamic metabolism was elevated at baseline (P < 0.01), but fell to subnormal levels in the p-HD subjects who developed symptoms. These findings were confirmed with an MRI-based atrophy correction for each individual PET scan. Increases in network expression and thalamic glucose metabolism may be compensatory for early neuronal losses in p-HD. Declines in these measures may herald the onset of symptoms in gene carriers.
Assuntos
Doença de Huntington/diagnóstico por imagem , Doença de Huntington/metabolismo , Tálamo/metabolismo , Adulto , Análise de Variância , Estudos de Casos e Controles , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Progressão da Doença , Fluordesoxiglucose F18/metabolismo , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/metabolismo , Heterozigoto , Humanos , Doença de Huntington/genética , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Córtex Motor/diagnóstico por imagem , Córtex Motor/metabolismo , Testes Neuropsicológicos , Lobo Occipital/diagnóstico por imagem , Lobo Occipital/metabolismo , Tomografia por Emissão de Pósitrons , Ligação Proteica , Racloprida/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Receptores de Dopamina D2/metabolismo , Tálamo/diagnóstico por imagemRESUMO
Early post-mortem data suggest that damage to brain serotonin neurones might play a role in some features (e.g., depression) of Parkinson's disease (PD). However, it is not known whether such damage is a typical characteristic of living patients with PD or whether the changes are regionally widespread. To address this question we measured, by positron emission tomography imaging, levels of the brain serotonin transporter (SERT), a marker for serotonin neurones, as inferred from binding of [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB), a second generation SERT radioligand, in subcortical and cerebral cortical brain areas of clinically advanced non-depressed (confirmed by structured psychiatric interview) patients with PD. SERT binding levels in PD were lower than those in controls in all examined brain areas, with the changes statistically significant in orbitofrontal cortex (-22%), caudate (-30%), putamen (-26%), and midbrain (-29%). However, only a slight non-significant reduction (-7%) was observed in dorsolateral pre-frontal cortex, an area implicated in major depression. Our imaging data suggests that a modest, regionally widespread loss of brain serotonergic innervation might be a common feature of advanced PD. Further investigation will be required to establish whether SERT binding is more or less decreased in those patients with PD who also have major depressive disorder.
Assuntos
Química Encefálica/fisiologia , Encéfalo/metabolismo , Doença de Parkinson/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Serotonina/metabolismo , Idoso , Benzilaminas , Ligação Competitiva/fisiologia , Biomarcadores/análise , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Radioisótopos de Carbono , Transtorno Depressivo/metabolismo , Transtorno Depressivo/fisiopatologia , Regulação para Baixo/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/fisiopatologia , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Transmissão Sináptica/fisiologiaRESUMO
In a study designed to reveal the rates of blood-brain transfer and decarboxylation of fluoro-L-3,4-dihydroxyphenylalanine (FDOPA), we discovered a major discrepancy between the DOPA decarboxylase activity reported in the literature and the rate of FDOPA decarboxylation measured in the study. "Donor" rats received intravenous injections of 6 mCi fluorine-18-labeled FDOPA. The donor rats synthesized methyl-FDOPA. Arterial plasma, containing both FDOPA and methyl-FDOPA, was sampled from the donor rats at different times and reinjected into "recipient" rats in which it circulated for 20 s. The blood-brain clearance of the mixture of labeled tracers in the plasma was determined by an integral method. The individual permeabilities were determined by linear regression analysis, according to which the average methyl-FDOPA permeability in the blood-brain barrier was twice that of FDOPA, which averaged 0.037 ml g-1 min-1. The permeability ratio was used to determine the fractional clearance from the brain of FDOPA (and hence of methyl-FDOPA), which averaged 0.081 min-1. In the striatum, the measured average FDOPA decarboxylation rate constant (kD3) was 0.010 min-1, or no more than 1% of the rate of striatal decarboxylation of DOPA measured in vitro and in vivo. We interpreted this finding as further evidence in favor of the hypothesis that striatum has two dopamine (DA) pools, of which only DA in the large pool is protected from metabolism. Hence, no more than 1% of the quantity of fluoro-DA theoretically synthesized was actually retained in striatum.
Assuntos
Barreira Hematoencefálica , Di-Hidroxifenilalanina/análogos & derivados , Animais , Encéfalo/metabolismo , Descarboxilação , Di-Hidroxifenilalanina/metabolismo , Di-Hidroxifenilalanina/farmacocinética , Dopa Descarboxilase/metabolismo , Radioisótopos de Flúor , Modelos Lineares , Modelos Neurológicos , Ratos , Ratos EndogâmicosRESUMO
In 11 normal volunteers and six patients with Parkinson's disease, we compared six different analyses of dopaminergic function with L-3,4-dihydroxy-6-[18F]fluorophenylalanine (FDOPA) and positron emission tomography (PET). The caudate nucleus, putamen, and several reference regions were identified in PET images, using magnetic resonance imaging (MRI). The six analyses included two direct determinations of DOPA decarboxylase activity (k3D, k3*), the slope-intercept plot based on plasma concentration (K), two slope-intercept plots based on tissue content (k3r, k3s), and the striato-occipital ratio [R(T)]. For all analyses, the difference between two groups of subjects (normal volunteers and patients with Parkinson's disease) was larger in the putamen than in the caudate. For the caudate nucleus, the DOPA decarboxylase activity (k3D, k3*), tissue slope-intercept plots (kr3, ks3); and striato-occipital ratio [R(T)] analyses significantly discriminated between the normal volunteers and the patients with Parkinson's disease (p < 0.005) [with least significance for k3* (p < 0.05)], while the plasma slope-intercept plot (K) failed to do so. For the putamen, the values for k3D, k3*, K, k3r, k3s, and R(T) of normal volunteers were significantly higher than those of patients (p < 0.005) [with least significance for K (p < 0.025)]. Linear correlations were significant between k3D and k3s; k3D and k3r; k3D and R(T); and k3D and k3*, in this order of significance. We found no correlation between k3D and K values in the caudate nucleus.
Assuntos
Núcleo Caudado/metabolismo , Di-Hidroxifenilalanina/análogos & derivados , Levodopa/farmacocinética , Doença de Parkinson/metabolismo , Putamen/metabolismo , Adulto , Núcleo Caudado/diagnóstico por imagem , Di-Hidroxifenilalanina/metabolismo , Di-Hidroxifenilalanina/farmacocinética , Radioisótopos de Flúor/farmacocinética , Humanos , Pessoa de Meia-Idade , Modelos Biológicos , Putamen/diagnóstico por imagem , Tomografia Computadorizada de EmissãoRESUMO
We performed positron emission tomography using 18F-6-fluorodopa on four Guamanians with an amyotrophic lateral sclerosis syndrome, eight Guamanians with parkinsonism, and seven clinically normal Guamanians; the results were compared with those of nine Vancouver control subjects. The Guamanian subjects had all been exposed to similar Chamorro lifestyles. The scans were analyzed using a graphic method that calculates a constant for whole striatal 18F-6-fluorodopa uptake. The parkinsonian subjects all had significantly reduced striatal 18F-6-fluorodopa uptake. The group with amyotrophic lateral sclerosis had significantly reduced uptake that was intermediate between that of the control group and the parkinsonian group. Two Guamanian normal subjects had reduced striatal 18F-6-fluorodopa uptake. The nigrostriatal dopaminergic lesion in Guamanian parkinsonism is similar to that found in idiopathic parkinsonism. The nigrostriatal lesions in the subjects with amyotrophic lateral sclerosis and the Guamanian normal subjects are examples of subclinical neuronal damage demonstrable in living subjects with positron emission tomography.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico por imagem , Demência/diagnóstico por imagem , Dopamina/metabolismo , Doença de Parkinson/diagnóstico por imagem , Sinapses/diagnóstico por imagem , Adulto , Idoso , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/metabolismo , Demência/complicações , Demência/diagnóstico , Demência/metabolismo , Eletromiografia , Feminino , Guam/epidemiologia , Humanos , Incidência , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Doença de Parkinson/metabolismo , Sinapses/metabolismo , Tomografia Computadorizada de EmissãoRESUMO
Although cognitive impairment is commonly associated with Parkinson's disease, the relative importance of cortical and subcortical pathologic changes to the development of dementia is controversial. Characteristic abnormalities in cortical glucose metabolism have been reported previously in Alzheimer's disease, a disease in which cortical changes predominate. We measured cerebral glucose metabolism with positron emission tomography in 20 control subjects and in 14 patients with PD with mental status ranging from normal to severely demented to determine whether changes in cortical glucose metabolism occur in early PD and whether the degree and pattern of metabolic change relate to the severity of dementia. The patients were divided into demented and nondemented groups according to the results of neuropsychological assessment. Age-adjusted covariance analyses were performed, since the age distribution varied between groups. The nondemented patients with PD showed widespread cortical glucose hypometabolism without any selective temporoparietal defects. The pattern of glucose hypometabolism seen in the demented patients with PD resembled that described in patients with Alzheimer's disease; ie, there was a global decrease in glucose metabolism, with more severe abnormalities observed in the temporoparietal regions.
Assuntos
Encéfalo/metabolismo , Demência/metabolismo , Glucose/metabolismo , Doença de Parkinson/metabolismo , Idoso , Doença de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagem , Demência/complicações , Demência/diagnóstico por imagem , Humanos , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Tomografia Computadorizada de EmissãoRESUMO
BACKGROUND: Although the abnormal gene products responsible for several hereditary neurodegenerative disorders caused by repeat CAG trinucleotides have been identified, the mechanism by which the proteins containing the expanded polyglutamine domains cause cell death is unknown. The observation that several of the mutant proteins interact in vitro with the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) suggests that interaction between the different gene products and GAPDH might damage brain neurons. OBJECTIVE: To measure the activity of GAPDH in postmortem brain of patients with CAG repeat disorders. PATIENTS AND METHODS: Activity of GAPDH was measured in morphologically affected and unaffected brain areas of patients with 4 different CAG repeat disorders (Huntington disease, spinocerebellar ataxia 1 [SCA1], SCA2, and SCA3-Machado-Joseph disease), in brains of patients with Friedreich ataxia (a GAA repeat disorder) and Alzheimer disease, and in brains of matched control subjects. RESULTS: Brain GAPDH activity was normal in all groups with the exception of a slight but statistically significant region-specific reduction in the patients with Huntington disease (caudate nucleus, -12%) and Alzheimer disease (temporal cortex, -19%). CONCLUSION: The presence of the polyglutamine-containing proteins in CAG repeat disorders does not result in substantial irreversible inactivation or in increased activity of GAPDH in human brain.
Assuntos
Encéfalo/enzimologia , Encéfalo/metabolismo , Gliceraldeído 3-Fosfato/genética , Gliceraldeído 3-Fosfato/metabolismo , Doenças Neurodegenerativas/genética , Oxirredutases/genética , Oxirredutases/metabolismo , Repetições de Trinucleotídeos/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/enzimologia , Mutação Puntual/genética , Reação em Cadeia da Polimerase/métodosRESUMO
Pramipexole is a new, selective, nonergoline dopamine agonist that acts on D2 and preferentially on D3 dopamine receptors. Phase II and III clinical trials have shown this drug to be useful in treating both early and advanced Parkinson's disease (PD) patients. A double-blind, randomized, multicenter study was performed to compare the safety, tolerance, and efficacy of pramipexole versus placebo in patients with advanced PD with motor fluctuations. A bromocriptine treatment group was included to enable comparisons between bromocriptine and placebo groups, but the study was not powered to show statistical differences between the active treatment groups. The study included 247 patients with "wearing off." Patients were Hoehn and Yahr stages II to IV during "on" times. The trial included three phases: dose escalation, 6 months' maintenance, and dose reduction. The primary end points were the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III. Up to 4.5 mg per day of pramipexole and 30 mg per day of bromocriptine were used. The results of the study showed that the UPDRS part II improved by 26.7% for pramipexole (p = 0.0002) and 14% for bromocriptine (p = 0.02) versus 4.8% for placebo. The UPDRS part III showed improvements of 34% for pramipexole (p = 0.0006) and 23.8% for bromocriptine (p = 0.01) versus 5.7% for placebo. There were no major differences in safety data. In the active treatment groups there were more reports of dyskinesia and nausea compared with placebo. In regard to comparison of the Global Clinical Assessment of Efficacy between active treatment groups, there was a trend to significance (p = 0.056) in favor of pramipexole. We conclude that pramipexole-treated patients with advanced PD improved significantly more than placebo for both primary end points.
Assuntos
Antiparkinsonianos/uso terapêutico , Bromocriptina/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Tiazóis/uso terapêutico , Adulto , Idoso , Antiparkinsonianos/efeitos adversos , Benzotiazóis , Bromocriptina/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Placebos/uso terapêutico , Pramipexol , Qualidade de Vida , Índice de Gravidade de Doença , Tiazóis/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: PD was associated with increased mortality before levodopa therapy became available. There have been conflicting reports of PD mortality in the modern era. OBJECTIVE: To assess current mortality rates in a large unselected population receiving treatment for parkinsonism (PKM) followed for up to 6 years. METHODS: Cases were identified using linked administrative databases, including physician service and prescription drug claims, generated in Ontario's universal health insurance system. Control subjects were identified from the provincial registry of citizens and age and sex matched to cases. Comparative mortality was evaluated over the 6-year period of the study (1993/94 to 1998/99). The sensitivity of the findings was tested with differing case definitions. RESULTS: In 1993, 15,304 patients with PKM were identified and were age and sex matched to 30,608 control subjects (1:2 ratio). Over the study period, 50.8% (7,779) of the cases with PKM died compared with 29.1% (8,899) of the control subjects. The cases with PKM had an overall mortality odds ratio of 2.5 (95% CI: 2.4, 2.6) compared with the control group. Results were consistent whether cases were defined by physician diagnosis, use of anti-PD drugs, or both criteria. CONCLUSION: Despite modern drug therapy, PKM continues to confer a sharply increased mortality on unselected patients followed for several years.
Assuntos
Doença de Parkinson/mortalidade , Distribuição por Idade , Estudos de Coortes , Feminino , Humanos , Masculino , Ontário , Distribuição por Sexo , Análise de SobrevidaRESUMO
BACKGROUND: Animal data indicate that chronic exposure to dopaminergic drugs can alter levels of the dopamine transporter (DAT), which is critically involved in regulation of synaptic dopamine levels. DAT changes could influence the response to therapy in PD. METHODS: A randomized, assessor-blinded, placebo-controlled clinical trial was performed in subjects with early PD to determine whether L-dopa or pramipexole might regulate striatal DAT binding as measured by PET with [(11)C]RTI-32. Thirty clinically asymmetrical patients were randomly assigned to receive 6 weeks of L-dopa (300/75 mg/d), pramipexole (1.5 mg/d), or placebo; PET studies were performed before and after treatment. RESULTS: Mean interval change in DAT binding was significantly reduced by 16% to 22% in all striatal regions (caudate, anterior and posterior putamen) of the L-dopa-treated patients, whereas significant changes in the pramipexole-treated patients were limited to the contralateral caudate (-15%), ipsilateral anterior putamen (-14%), and posterior putamen (-20%). In the placebo group there were significant changes in contralateral caudate (-11%) and ipsilateral anterior putamen (-12%). L-dopa and pramipexole produced similar clinical benefit. CONCLUSIONS: Short-term therapy with L-dopa and, to a lesser extent, pramipexole can modestly down-regulate striatal DAT in patients with early PD. Decreased striatal DAT could increase dopaminergic neurotransmission with potential benefit, but might also play a role in the development of dopamine-related response fluctuations in patients with advanced disease. Our data also suggest caution in interpretation of longitudinal imaging studies employing DAT to assess disease progression and the efficacy of neuroprotective agents.
Assuntos
Antiparkinsonianos/administração & dosagem , Proteínas de Transporte/metabolismo , Levodopa/administração & dosagem , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Doença de Parkinson/tratamento farmacológico , Tiazóis/administração & dosagem , Idoso , Benzotiazóis , Química Encefálica/efeitos dos fármacos , Radioisótopos de Carbono , Cocaína/análogos & derivados , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Pramipexol , Receptores Dopaminérgicos/metabolismo , Tomografia Computadorizada de EmissãoRESUMO
We previously reported markedly reduced (-76%) dopamine (DA) levels in the putamen of seven patients with spinocerebellar ataxia type 1 (SCA1) who had no evidence of nigral cell loss or parkinsonism. To determine whether the DA reduction was accompanied by loss of DA nerve terminals, we measured levels of the DA transporter ([3H]WIN, 35,428 binding; DA transporter protein) and the vesicular monoamine transporter ([3H]DTBZ binding) in the putamen of these patients. As compared with the controls (n = 14), mean putamen concentrations of [3H]WIN 35,428 binding (-45%), dopamine transporter protein (-61%), and [3H]DTBZ binding (-48%) were significantly reduced in this SCA1 subgroup. We conclude that the degeneration in nigrostriatal DA neurons begins at the nerve ending in SCA1.
Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Terminações Nervosas/metabolismo , Proteínas do Tecido Nervoso , Degenerações Espinocerebelares/metabolismo , Degenerações Espinocerebelares/patologia , Substância Negra/patologia , Adulto , Biomarcadores , Cadáver , Proteínas de Transporte/metabolismo , Cocaína/análogos & derivados , Cocaína/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Inibidores da Captação de Dopamina/metabolismo , Humanos , Pessoa de Meia-Idade , Putamen/metabolismo , Tetrabenazina/análogos & derivados , Tetrabenazina/metabolismoRESUMO
To estimate the threshold of nigrostriatal dysfunction required for symptomatic Parkinson's disease (PD), we employed [11C]RTI-32 and PET to study the dopamine transporter in striatal subdivisions of 11 L-dopa-naive patients with very early parkinsonism. As compared with the controls (N = 10), the PD group had on the side contralateral to the maximal clinical symptoms, significantly reduced binding in the posterior putamen (-56%) and anterior putamen (-28%), with the reduction in caudate (-12%) not significantly different. To the extent that dopamine transporter binding accurately reflects the number of nigrostriatal dopamine nerve terminals, these findings suggest that the clinical threshold for PD in the middle-age human is approximately 50% loss of dopaminergic innervation to the posterior putamen. Our data also suggest that damage to the putamen component of the striatum is sufficient for the clinical expression of PD.
Assuntos
Proteínas de Transporte/análise , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Doença de Parkinson/metabolismo , Substância Negra/química , Adulto , Radioisótopos de Carbono , Progressão da Doença , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/análise , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/fisiopatologia , Substância Negra/fisiopatologia , Fatores de Tempo , Tomografia Computadorizada de EmissãoRESUMO
The novel finding of decreased activity of aconitase, a key Krebs cycle enzyme highly sensitive to oxidative damage, in cybrid cell lines using mitochondrial DNA from patients with progressive supranuclear palsy (PSP) implies an enzyme abnormality in brain. However, the authors found that postmortem brain aconitase activity is normal in PSP. This suggests that patients with PSP do not have systemic aconitase deficiency and that data derived from cybrid cell models of neurodegenerative disorders might not always predict similar changes in human brain.
Assuntos
Aconitato Hidratase/metabolismo , Encéfalo/enzimologia , Paralisia Supranuclear Progressiva/enzimologia , Idoso , Encéfalo/patologia , Humanos , Atrofia de Múltiplos Sistemas/enzimologia , Atrofia de Múltiplos Sistemas/patologia , Paralisia Supranuclear Progressiva/patologiaRESUMO
OBJECTIVE: There is increasing evidence that neuron loss precedes the phenotypic expression of Huntington's disease (HD). As genes for late-onset neurodegenerative diseases are identified, the need for accurate assessment of phenoconversion (i.e., the transition from health to the disease phenotype) will be important. METHODS: Prospective longitudinal evaluation using the Unified Huntington's Disease Rating Scale (UHDRS) was conducted by Huntington Study Group members from 36 sites. There were 260 persons considered "at risk" for HD who initially did not have manifest disease and had at least one subsequent evaluation. Repeat UHDRS data, obtained an average of 2 years later, showed that 70 persons were given a diagnosis of definite HD based on the quantified neurologic examination. RESULTS: Baseline cognitive performances were consistently worse for the at-risk group who demonstrated conversion to a definitive diagnosis compared with those who did not. Longitudinal change scores showed that the at-risk group who did not demonstrate manifest disease during the follow-up study period demonstrated improvements in all cognitive tests, whereas performances in the at-risk group demonstrating conversion to disease during the study declined across cognitive domains. CONCLUSIONS: Neuropsychological measures show impairment 2 years before the development of more manifest motor disease. Findings suggest that these brief cognitive measures administered over time may capture early striatal neural loss in HD.
Assuntos
Transtornos Cognitivos/psicologia , Doença de Huntington/psicologia , Testes Neuropsicológicos , Adulto , Transtornos Cognitivos/diagnóstico , Feminino , Humanos , Doença de Huntington/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
To determine the extent that different dopamine (DA) neuronal markers provide similar estimates of striatal (caudate and putamen) DA nerve terminal loss in idiopathic Parkinson's disease (PD), we compared, in postmortem striatum of 12 patients with PD and 10 matched controls, levels of five different DA neuronal markers. These markers included DA itself, three different estimates of the density of the DA transporter (DAT) ([3H])GBR 12,935 and [3H]WIN 35,428 binding; DAT protein immunoreactivity), and one estimate of the vesicular monoamine transporter (VMAT2; [3H]DTBZ binding). Striatal levels of all examined DA markers in PD were significantly intercorrelated. However, the magnitude of loss relative to controls was unequal (DAT protein = DA > [3H]WIN 35,428 > [3H]DTBZ > [3H]GBR 12, 935), with the differences more marked in the severely affected putamen. The less severe reduction of binding of the DAT/VMAT2 radioligands relative to DA and DAT protein could be explained by differential regulation/degeneration of different DA nerve terminal components or lack of specificity of the radioligands for the DA neuron. These postmortem data may help in interpretation of in vivo neuroimaging studies in PD in which only one radioligand is routinely employed.