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1.
Nat Genet ; 41(2): 163-5, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19136952

RESUMO

Perry syndrome consists of early-onset parkinsonism, depression, severe weight loss and hypoventilation, with brain pathology characterized by TDP-43 immunostaining. We carried out genome-wide linkage analysis and identified five disease-segregating mutations affecting the CAP-Gly domain of dynactin (encoded by DCTN1) in eight families with Perry syndrome; these mutations diminish microtubule binding and lead to intracytoplasmic inclusions. Our findings show that DCTN1 mutations, previously associated with motor neuron disease, can underlie the selective vulnerability of other neuronal populations in distinct neurodegenerative disorders.


Assuntos
Proteínas Associadas aos Microtúbulos/genética , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas de Ligação a DNA/metabolismo , Depressão/genética , Depressão/metabolismo , Depressão/patologia , Complexo Dinactina , Família , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Hipoventilação/genética , Hipoventilação/metabolismo , Hipoventilação/patologia , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação/fisiologia , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Linhagem , Síndrome , Redução de Peso/genética
2.
Parkinsonism Relat Disord ; 15(4): 281-6, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-18723384

RESUMO

OBJECTIVE: Autosomal dominant parkinsonism, hypoventilation, depression and severe weight loss (Perry syndrome) is an early-onset rapidly progressive disease. At autopsy, previous studies have found severe neuronal loss in the substantia nigra without Lewy bodies. Transactive response DNA-binding protein of 43 kDa (TDP-43) has recently been identified as a major ubiquitinated constituent of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. This study reports clinical, genetic and neuropathologic investigations of Perry syndrome. METHODS: Clinical data and autopsy brain tissue samples were collected from eight patients from four genealogically unrelated kindreds with Perry syndrome. Brain tissue was studied with immunohistochemistry and biochemistry for TDP-43. Patients were screened for mutations in the progranulin (GRN) and TDP-43 (TARDBP) genes. RESULTS: The mean age at onset was 47 years (range 40-56), and the mean age at death was 52 years (range 44-64). In all patients, we identified TDP-43-positive neuronal inclusions, dystrophic neurites and axonal spheroids in a predominantly pallidonigral distribution, and we demonstrated changes in solubility and electrophoretic mobility of TDP-43 in brain tissue. The inclusions were highly pleomorphic and predominated in the extrapyramidal system, sparing the cortex, hippocampus and motor neurons. There were no mutations in GRN or TARDBP. INTERPRETATION: Perry syndrome displays unique TDP-43 pathology that is selective for the extrapyramidal system and spares the neocortex and motor neurons.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Depressão/patologia , Globo Pálido/metabolismo , Hipoventilação/patologia , Transtornos Parkinsonianos/patologia , Substância Negra/metabolismo , Redução de Peso , Proteínas de Ligação a DNA/genética , Depressão/complicações , Depressão/genética , Feminino , Humanos , Hipoventilação/complicações , Hipoventilação/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/genética , Progranulinas
3.
BMC Med Inform Decis Mak ; 4: 14, 2004 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-15361256

RESUMO

BACKGROUND: Although significant response time deficits (both reaction time and movement time) have been identified in numerous studies of patients with Parkinson's disease (PD), few attempts have been made to evaluate the use of these measures in screening for PD. METHODS: Receiver operator characteristic curves were used to identify cutoff scores for a unit-weighted composite of two choice response tasks in a sample of 40 patients and 40 healthy participants. These scores were then cross-validated in an independent sample of 20 patients and 20 healthy participants. RESULTS: The unit-weighted movement time composite demonstrated high sensitivity (90%) and specificity (90%) in the identification of PD. Movement time was also significantly correlated (r = 0.59, p < 0.025) with the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS). CONCLUSIONS: Measures of chronometric speed, assessed without the use of biomechanically complex movements, have a potential role in screening for PD. Furthermore, the significant correlation between movement time and UPDRS motor score suggests that movement time may be useful in the quantification of PD severity.


Assuntos
Programas de Rastreamento/métodos , Exame Neurológico/métodos , Doença de Parkinson/diagnóstico , Tempo de Reação/fisiologia , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Destreza Motora/fisiologia , Ontário , Doença de Parkinson/classificação , Doença de Parkinson/patologia , Projetos Piloto , Índice de Gravidade de Doença
4.
Motor Control ; 7(1): 71-81, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12536163

RESUMO

The effect of a precue on improving movement initiation (i.e., reaction time; RT) is well understood, whereas its influence on movement execution (i.e., movement time; MT) has rarely been examined. The current study investigated the influence of a directional precue (i.e., left vs. right) on the RT and MT of simple and discrete bi-directional movements in a large sample of Parkinson's disease patients and healthy control participants. Both patients and controls were tested twice, with testing sessions separated by 2 hours. Patients were tested first following an overnight levodopa withdrawal and again after they had taken their medication. Both patients and controls demonstrated a significant RT improvement when information was provided in advance. MT in both healthy participants and medicated patients was, however, slower with the provision of advance information, while unmedicated patients showed no significant MT effects. These results suggest that while the basal ganglia may not be involved in motor program selection, they may dynamically modulate movement execution.


Assuntos
Gânglios da Base/fisiopatologia , Atividade Motora/fisiologia , Doença de Parkinson/fisiopatologia , Tempo de Reação/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Motor/fisiopatologia , Estimulação Luminosa , Desempenho Psicomotor/fisiologia , Índice de Gravidade de Doença
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