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1.
Neurology ; 89(2): 138-143, 2017 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-28592451

RESUMO

OBJECTIVE: To identify the significance of baseline motor features to the lifelong prognostic motor subtypes in a Parkinson disease (PD) cohort. METHODS: In a previous study of 166 PD cases, we observed different prognosis in tremor-dominant, akinetic-rigid, and mixed subtypes. This study includes the same cases, but we excluded 10 cases with symptoms of ≥15 years duration at baseline. Relative severity of tremor, bradykinesia/akinesia, and rigidity at baseline were evaluated as predictors of the motor subtypes, which are known to have different prognosis. RESULTS: The most common motor subtype was mixed, followed by akinetic-rigid and then the tremor-dominant. Seventy cases were not receiving antiparkinsonian drugs at baseline. The prognostic subtypes could be predicted at baseline in 85% of all and in 91% of the treatment-naive cases. Sensitivity, specificity, and positive predictive values were strong for the mixed and the akinetic-rigid but weak for the tremor-dominant subtype. CONCLUSIONS: Our data show that motor profile at baseline can predict prognosis in most PD cases. These findings can be incorporated into clinical practice.


Assuntos
Progressão da Doença , Rigidez Muscular/diagnóstico , Doença de Parkinson/classificação , Doença de Parkinson/diagnóstico , Tremor/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Rigidez Muscular/etiologia , Rigidez Muscular/fisiopatologia , Doença de Parkinson/complicações , Doença de Parkinson/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Sensibilidade e Especificidade , Tremor/etiologia , Tremor/fisiopatologia
3.
Parkinsonism Relat Disord ; 21(10): 1232-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26372624

RESUMO

BACKGROUND: Definite diagnosis of idiopathic Parkinson's disease is based on histological findings of marked substantia nigra neuronal loss and Lewy body inclusions. Almost all cases with clinical diagnosis of idiopathic Parkinson's disease are treated with levodopa. Because there is no biological marker for the diagnosis, erroneous clinical diagnosis and treatment of such cases with levodopa are well known. There is very limited literature on levodopa treated cases that had normal substantia nigra at autopsy. METHODS: Patients seen at Movement Disorders Clinic Saskatchewan are offered autopsy at no cost to the family/estate of the patient. Autopsy studies are performed by certified neuropathologists. Notation on the status of substantia nigra is made in every autopsied case. RESULTS: Between 1968 and 2014, 21 cases treated with levodopa had normal substantia nigra at autopsy. Eleven patients continued levodopa until death and 9 received the drug for four years or longer. No objective motor symptom benefit, dyskinesia or motor response fluctuations on levodopa were observed in any case. The most common final diagnosis was essential tremor. CONCLUSION: Individuals with normal substantia nigra do not benefit from levodopa and do not manifest motor response fluctuations or dyskinesia. Long-term use of levodopa is not toxic to normal human substantia nigra.


Assuntos
Antiparkinsonianos/uso terapêutico , Tremor Essencial/diagnóstico , Levodopa/uso terapêutico , Doença de Parkinson/diagnóstico , Substância Negra/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Autopsia , Erros de Diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Substância Negra/patologia , Adulto Jovem
4.
Hum Mol Genet ; 23(7): 1794-801, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24218364

RESUMO

A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case-control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA. A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation, of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch-German-Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows that the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions. In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor-sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2 and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.


Assuntos
Corpos de Lewy/genética , Chaperonas Moleculares/genética , Mutação/genética , Doença de Parkinson/genética , Adulto , Idade de Início , Idoso , Sequência de Bases , Estudos de Casos e Controles , Células Cultivadas , Endocitose/genética , Endossomos/genética , Família , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença por Corpos de Lewy/genética , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares/imunologia , Linhagem , Proteínas Serina-Treonina Quinases/genética , Alinhamento de Sequência , Análise de Sequência de DNA , Proteínas de Transporte Vesicular/genética
5.
Neurobiol Aging ; 35(4): 935.e9-10, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24139280

RESUMO

A recent genome-wide association study of patients with essential tremor (ET) from Germany has nominated SLC1A2 rs3794087 as a novel risk factor for disease. This association was independently replicated in the Chinese population, albeit with an opposite direction of effect. To further define the role of SLC1A2 in ET, we genotyped rs3794087 in a North American series consisting of 1347 patients with ET and controls. Statistical analysis did not identify significant differences in genotype or allele frequencies between healthy controls and patients with ET (p > 0.36). These findings therefore do not support a role for SLC1A2 rs3794087 in susceptibility to ET in the North American population. Further studies in ethnically distinct populations of patients with ET are necessary to understand whether genetic variability in SLC1A2 affects disease risk for ET.


Assuntos
Tremor Essencial/etnologia , Tremor Essencial/genética , Predisposição Genética para Doença/genética , Genótipo , Proteínas de Transporte de Glutamato da Membrana Plasmática/genética , Idoso , Idoso de 80 Anos ou mais , Transportador 2 de Aminoácido Excitatório , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte/etnologia , Fatores de Risco
6.
J Neurosurg ; 116(6): 1238-41, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22404675

RESUMO

OBJECT: Investigators conducting the International Study of Unruptured Intracranial Aneurysms, sponsored by the National Institutes of Health, sought to evaluate predictors of future hemorrhage in patients who had unruptured mirror aneurysms. These paired aneurysms in bilateral arterial positions mirror each other; their natural history is unknown. METHODS: Centers in the US, Canada, and Europe enrolled patients for prospective assessment of unruptured intracranial aneurysms. Central radiological review confirmed the presence or absence of mirror aneurysms in patients without a history of prior subarachnoid hemorrhage (SAH) (Group 1). Outcome at 1 and 5 years and aneurysm characteristics are compared. RESULTS: Of 3120 patients with aneurysms treated in 61 centers, 376 (12%) had mirror aneurysms, which are more common in women than men (82% [n = 308] vs 73% [n = 1992], respectively; p <0.001) and in patients with a family history of aneurysm or SAH (p <0.001). Compared with patients with nonmirror saccular aneurysms, a greater percentage of patients with mirror aneurysms had larger (>10 mm) aneurysms (mean maximum diameter 11.7 vs 10.4 mm, respectively; p <0.001). The most common distribution for mirror aneurysms was the middle cerebral artery (34% [126 patients]) followed by noncavernous internal carotid artery (32% [121]), posterior communicating artery (16% [60]), cavernous internal carotid artery (13% [48]), anterior cerebral artery/anterior communicating artery (3% [13]), and vertebrobasilar circulation (2% [8]). When these patients were compared with patients without mirror aneurysms, no statistically significant differences were found in age (mean age 54 years in both groups), blood pressure, smoking history, or cardiac disease. Aneurysm rupture rates were similar (3.0% for patients with mirror aneurysms vs 2.8% for those without). CONCLUSIONS: Overall, patients with mirror aneurysms were more likely to be women, to report a family history of aneurysmal SAH, and to have larger aneurysms. The presence of a mirror aneurysm was not an independent predictor of future SAHs.


Assuntos
Aneurisma Intracraniano/diagnóstico , Hemorragia Subaracnóidea/diagnóstico , Aneurisma Roto/diagnóstico , Aneurisma Roto/genética , Aneurisma Roto/mortalidade , Causas de Morte , Angiografia Cerebral , Distribuição de Qui-Quadrado , Estudos Transversais , Feminino , Seguimentos , Humanos , Aneurisma Intracraniano/genética , Aneurisma Intracraniano/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores Sexuais , Hemorragia Subaracnóidea/genética , Hemorragia Subaracnóidea/mortalidade
7.
Can J Neurol Sci ; 37(2): 235-9, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20437935

RESUMO

INTRODUCTION: Idiopathic intracranial hypertension (IIH) can be an elusive diagnosis, and poor visual outcomes may occur. Currently, the only means of accurately diagnosing and following these patients is with repeated lumbar puncture. Previous work has shown that transcranial doppler measurements of pulsatility correlate accurately with elevated intracranial pressure (ICP). This study is designed to assess whether pulsatility index (PI) correlates with ICP in patients newly diagnosed with IIH. METHODS: Seven patients with clinical suspicion of IIH were included in this study. Clinical suspicion was based on history of recurrent headaches and papilledema. All patients had otherwise normal examinations and imaging. Middle cerebral arteries were insonated to obtain average PI values. Cerebrospinal fluid (CSF) was then withdrawn, and closing pressures were recorded. Pulsatility index values were then obtained again, within ten minutes after completing CSF withdrawal. PI values were correlated with ICP values, and pre and post CSF withdrawal values were compared. RESULTS: All seven patients had elevated opening pressures (average 39 cm H2O, range 27-70). The average closing pressure after approximately 30 cc of CSF withdrawal was 11.9 cm H2O. The average PI before CSF withdrawal was 0.95, which dropped to 0.70 after CSF withdrawal (p = 0.02). The change in ICP was found to be correlated with a change in PI (p = 0.004). CONCLUSIONS: These findings suggest that PI may be useful for following patients with IIH non-invasively. Further study with larger groups and blinded assessments should be useful in better characterizing the accuracy of this technique.


Assuntos
Pseudotumor Cerebral/diagnóstico por imagem , Ultrassonografia Doppler Transcraniana/métodos , Adolescente , Adulto , Humanos , Pessoa de Meia-Idade , Artéria Cerebral Média/fisiopatologia , Pseudotumor Cerebral/líquido cefalorraquidiano , Adulto Jovem
8.
Mov Disord ; 24(16): 2411-4, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19890971

RESUMO

Alpha-synuclein gene (SNCA) mutations cause familial Parkinsonism but the role of SNCA variability in idiopathic Parkinson's disease (PD) remains incompletely defined. We report a study of SNCA genetic variation in 452 idiopathic PD cases and 245 controls. SNCA copy number mutations were not associated with early-onset disease in this population. The minor allele "G" at rs356165 was associated with increased odds of PD (P = 0.013) and genetic variation in D4S3481 (Rep1) was associated with age of disease onset (P = 0.007). There was a trend toward association between variation at rs2583988 and rapid PD progression.


Assuntos
Predisposição Genética para Doença , Mutação/genética , Doença de Parkinson/genética , alfa-Sinucleína/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Saskatchewan/epidemiologia , Saskatchewan/etnologia
9.
Neurosci Lett ; 453(1): 9-11, 2009 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-19429005

RESUMO

Attempts at replicating the first genome-wide association study (GWAS) in Parkinson's disease (PD) have not successfully identified genetic risk factors. The present study reevaluates data from the first GWAS and focuses on the SNP (rs11155313, located in the Phactr2 gene) with the lowest P-value in the Tier 2 patient-control series. We employed four case-control series to examine the nominated SNP rs11155313 and identified association in US (OR: 1.39, P=0.032), Canadian (OR: 1.41, P=0.014) and Irish (OR: 1.44, P=0.034) patient-control series, but not in the Norwegian series (OR: 1.15, P=0.27). When combining all four series the observed trend was statistically significant (OR: 1.30, P<0.001). This study shows that reappraisal of publicly available results of GWAS may help nominate new risk factors for PD.


Assuntos
Proteínas dos Microfilamentos/genética , Proteínas do Tecido Nervoso/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá/epidemiologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Irlanda/epidemiologia , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Doença de Parkinson/epidemiologia , Fatores de Risco , Estados Unidos/epidemiologia , Adulto Jovem
11.
Parkinsonism Relat Disord ; 14(5): 431-5, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18321757

RESUMO

We report a retrospective multivariable analysis of the association between patient characteristics at first clinic visit and rapid disease progression in 1411 Parkinson's disease patients treated between 1985 and 2006. At first visit rapid progression was positively associated with age at onset > or = 70 years (OR=5.77), rigidity (OR=1.94), bradykinesia (OR=1.73), dementia (OR=2.61), and levodopa use (OR=1.74). Rapid progression was negatively associated with disease duration (OR=0.52), male sex (OR=0.49), and resting tremor at first visit (OR=0.44). Family history of movement disorders, while significant for univariable analysis, did not retain significance in multivariable analysis. This initial clinical profile may aid physicians in adjusting treatment and follow-up plans. Further prospective studies are needed to evaluate this relationship.


Assuntos
Doença de Parkinson/complicações , Doença de Parkinson/epidemiologia , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos
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