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1.
Mov Disord ; 37(5): 1028-1039, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35165920

RESUMO

BACKGROUND: Clinical diagnosis and monitoring of Parkinson's disease (PD) remain challenging because of the lack of an established biomarker. Neuromelanin-magnetic resonance imaging (NM-MRI) is an emerging biomarker of nigral depigmentation indexing the loss of melanized neurons but has unknown prospective diagnostic and tracking performance in multicenter settings. OBJECTIVES: The aim was to investigate the diagnostic accuracy of NM-MRI in early PD in a multiprotocol setting and to determine and compare serial NM-MRI changes in PD and controls. METHODS: In this longitudinal case-control 3 T MRI study, 148 patients and 97 controls were included from six UK clinical centers, of whom 140 underwent a second scan after 1.5 to 3 years. An automated template-based analysis was applied for subregional substantia nigra NM-MRI contrast and volume assessment. A point estimate of the period of prediagnostic depigmentation was computed. RESULTS: All NM metrics performed well to discriminate patients from controls, with receiver operating characteristic showing 85% accuracy for ventral NM contrast and 83% for volume. Generalizability using a priori volume cutoff was good (79% accuracy). Serial MRI demonstrated accelerated NM loss in patients compared to controls. Ventral NM contrast loss was point estimated to start 5 to 6 years before clinical diagnosis. Ventral nigral depigmentation was greater in the most affected side, more severe cases, and nigral NM volume change correlated with change in motor severity. CONCLUSIONS: We demonstrate that NM-MRI provides clinically useful diagnostic information in early PD across protocols, platforms, and sites. It provides methods and estimated depigmentation rates that highlight the potential to detect preclinical PD and track progression for biomarker-enabled clinical trials. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Doença de Parkinson , Biomarcadores , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Melaninas , Doença de Parkinson/diagnóstico , Estudos Prospectivos , Substância Negra/diagnóstico por imagem , Substância Negra/patologia
2.
Mov Disord ; 36(2): 424-433, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33111402

RESUMO

BACKGROUND: There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case-control genome-wide association studies have identified variants associated with disease risk, but not progression. The objective of the current study was to identify genetic variants associated with PD progression. METHODS: We analyzed 3 large longitudinal cohorts: Tracking Parkinson's, Oxford Discovery, and the Parkinson's Progression Markers Initiative. We included clinical data for 3364 patients with 12,144 observations (mean follow-up 4.2 years). We used a new method in PD, following a similar approach in Huntington's disease, in which we combined multiple assessments using a principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analyzed in linear regression in genome-wide association studies. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis. RESULTS: There was no overlap between variants associated with PD risk, from case-control studies, and PD age at onset versus PD progression. The APOE ε4 tagging variant, rs429358, was significantly associated with composite and cognitive progression in PD. Conditional analysis revealed several independent signals in the APOE locus for cognitive progression. No single variants were associated with motor progression. However, in gene-based analysis, ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (P = 5.3 × 10-6 ). CONCLUSIONS: We provide early evidence that this new method in PD improves measurement of symptom progression. We show that the APOE ε4 allele drives progressive cognitive impairment in PD. Replication of this method and results in independent cohorts are needed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Doença de Parkinson , Biomarcadores , Cognição , Progressão da Doença , Estudo de Associação Genômica Ampla , Humanos , Doença de Parkinson/genética
3.
Brain ; 142(9): 2828-2844, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31324919

RESUMO

Our objective was to define the prevalence and clinical features of genetic Parkinson's disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Unified Parkinson's Disease Rating Scale scores, and Montreal Cognitive Assessment scores. We analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, family history and clinical features. Of the 2262 participants recruited to the Tracking Parkinson's study, 424 had young-onset Parkinson's disease (age at onset ≤ 50) and 1799 had late onset Parkinson's disease. A range of methods were used to genotype 2005 patients: 302 young-onset patients were fully genotyped with multiplex ligation-dependent probe amplification and either Sanger and/or exome sequencing; and 1701 late-onset patients were genotyped with the LRRK2 'Kompetitive' allele-specific polymerase chain reaction assay and/or exome sequencing (two patients had missing age at onset). We identified 29 (1.4%) patients carrying pathogenic mutations. Eighteen patients carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplication in SNCA. In PRKN, we identified patients carrying deletions of exons 1, 4 and 5, and P113Xfs, R275W, G430D and R33X. In PINK1, two patients carried deletions in exon 1 and 5, and the W90Xfs point mutation. Eighteen per cent of patients with age at onset ≤30 and 7.4% of patients from large dominant families carried pathogenic Mendelian gene mutations. Of all young-onset patients, 10 (3.3%) carried biallelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an SNCA duplication. There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic and familial disease. In young-onset patients, dominant and recessive mutations were equally common. There were no differences in clinical features between LRRK2 carriers and non-carriers. However, we did find that PRKN and PINK1 mutation carriers have distinctive clinical features compared to young-onset non-carriers, with more postural symptoms at diagnosis and less cognitive impairment, after adjusting for age and disease duration. This supports the idea that there is a distinct clinical profile of PRKN and PINK1-related Parkinson's disease. We estimate that there are approaching 1000 patients with a known genetic aetiology in the UK Parkinson's disease population. A small but significant number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be targeted by new therapies, such as LRRK2 inhibitors.


Assuntos
Análise da Randomização Mendeliana/métodos , Mutação/genética , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , Vigilância da População/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Testes Genéticos/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Estudos Prospectivos , Reino Unido/epidemiologia
4.
Neuropathology ; 40(6): 611-619, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32830366

RESUMO

Fragile X-associated tremor ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG trinucleotide expansion from 55 to 200 repeats in the non-coding region of the fragile X mental retardation 1 (FMR1) gene (FMR1). Clinical features include cognitive decline, progressive tremor, and gait ataxia. Neuropathologically, FXTAS shows white matter changes, hippocampal and cerebellar involvement, and p62-positive eosinophilic intranuclear inclusions in astrocytes and neurons. Here, we document the neuropathological findings from a subject who developed cognitive impairment but not tremor and was proved to have genetically confirmed FMR1 premutation. Microscopically, typical p62-postive intranuclear inclusions were present in all the regions examined. Neocortical regions demonstrated gliosis of layer I and mild degree of neuronal loss and atrophy across the other layers. The molecular, Purkinje's cell, and granule cell layers of the cerebellar folia demonstrated mild gliosis, and cerebellar white matter was mildly affected. Aside from p62-positive inclusions, the hippocampus was spared. Arteries in the deep white matter often showed changes consistent with moderate small vessel disease (SVD). Reactive gliosis and severe SVD were features of basal ganglia. Florid reactive astrocytosis was found in the white matter of all regions. Axonal loss and features of axonal damage were found in the white matter of the centrum semiovale. Microglial activation was widespread and evenly seen in both the white matter and grey matter, although the grey matter appeared more severely affected. Pathology associated with Alzheimer's disease was limited. Similarly, no abnormal accumulations of α-synuclein were present. We postulate that age at death and disease duration may play a role in the extent of the pathological features associated with FXTAS. The present results suggest that immunohistochemical staining for p62 can help with the diagnosis of cases with atypical phenotype. In addition, it is likely that the cognitive impairment observed was a result of white matter changes.


Assuntos
Ataxia/patologia , Encéfalo/patologia , Síndrome do Cromossomo X Frágil/patologia , Tremor/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Substância Cinzenta/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Substância Branca/patologia
5.
J Neurol Neurosurg Psychiatry ; 89(7): 702-709, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29378790

RESUMO

OBJECTIVES: To examine the influence of the glucocerebrosidase (GBA) mutation carrier state on age at onset of Parkinson's disease (PD), the motor phenotype and cognitive function at baseline assessment in a large cohort of UK patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive function. METHODS: We prospectively recruited patients with PD in the Tracking Parkinson's study. We fully sequenced the GBA gene in all recently diagnosed patients (≤3.5 years). We examined cognitive (Montreal Cognitive Assessment) and motor (Movement Disorder Society Unified Parkinson's Disease Rating Scale part 3) function at a baseline assessment, at an average of 1.3 years after diagnosis. We used logistic regression to determine predictors of PD with mild cognitive impairment and PD with dementia. RESULTS: We studied 1893 patients with PD: 48 (2.5%) were heterozygous carriers for known Gaucher's disease (GD) causing pathogenic mutations; 117 (6.2%) had non-synonymous variants, previously associated with PD, and 28 (1.5%) patients carried variants of unknown significance in the GBA gene. L444P was the most common pathogenic GBA mutation. Patients with pathogenic GBA mutations were on average 5 years younger at disease onset compared with non-carriers (P=0.02). PD patients with GD-causing mutations did not have an increased family risk of PD. Patients with GBA mutations were more likely to present with the postural instability gait difficulty phenotype compared with non-carriers (P=0.02). Patients carrying pathogenic mutations in GBA had more advanced Hoehn and Yahr stage after adjustment for age and disease duration compared with non-carriers (P=0.005). There were no differences in cognitive function between GBA mutation carriers and non-carriers at this early disease stage. CONCLUSIONS: Our study confirms the influence of GBA mutations on the age of onset, disease severity and motor phenotype in patients with PD. Cognition did not differ between GBA mutation carriers and non-carriers at baseline, implying that cognitive impairment/dementia, reported in other studies at a later disease stage, is not present in recently diagnosed cases. This offers an important window of opportunity for potential disease-modifying therapy that may protect against the development of dementia in GBA-PD. CLINICAL TRIAL REGISTRATION: NCT02881099; Results.


Assuntos
Disfunção Cognitiva/epidemiologia , Demência/epidemiologia , Glucosilceramidase/genética , Heterozigoto , Mutação/genética , Doença de Parkinson/genética , Idade de Início , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/psicologia , Estudos Prospectivos , Reino Unido
6.
J Neurol Neurosurg Psychiatry ; 89(12): 1279-1287, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30464029

RESUMO

OBJECTIVES: To use a data-driven approach to determine the existence and natural history of subtypes of Parkinson's disease (PD) using two large independent cohorts of patients newly diagnosed with this condition. METHODS: 1601 and 944 patients with idiopathic PD, from Tracking Parkinson's and Discovery cohorts, respectively, were evaluated in motor, cognitive and non-motor domains at the baseline assessment. Patients were recently diagnosed at entry (within 3.5 years of diagnosis) and were followed up every 18 months. We used a factor analysis followed by a k-means cluster analysis, while prognosis was measured using random slope and intercept models. RESULTS: We identified four clusters: (1)  fast motor progression with symmetrical motor disease, poor olfaction, cognition and postural hypotension; (2) mild motor and non-motor disease with intermediate motor progression; (3) severe motor disease, poor psychological well-being and  poor sleep with an intermediate motor progression; (4) slow motor progression with tremor-dominant, unilateral disease. Clusters were moderately to substantially stable across the two cohorts (kappa 0.58). Cluster 1 had the fastest motor progression in Tracking Parkinson's at 3.2 (95% CI 2.8 to 3.6) UPDRS III points per year while cluster 4 had the slowest at 0.6 (0.1-1.1). In Tracking Parkinson's, cluster 2 had the largest response to levodopa 36.3% and cluster 4 the lowest 28.8%. CONCLUSIONS: We have found four novel clusters that replicated well across two independent early PD cohorts and were associated with levodopa response and motor progression rates. This has potential implications for better understanding disease pathophysiology and the relevance of patient stratification in future clinical trials.


Assuntos
Doença de Parkinson/classificação , Idoso , Progressão da Doença , Feminino , Humanos , Levodopa/uso terapêutico , Masculino , Testes Neuropsicológicos , Doença de Parkinson/tratamento farmacológico , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença
7.
Mov Disord ; 33(1): 75-87, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29193359

RESUMO

BACKGROUND: Consensus criteria for classifying tremor disorders were published by the International Parkinson and Movement Disorder Society in 1998. Subsequent advances with regard to essential tremor, tremor associated with dystonia, and other monosymptomatic and indeterminate tremors make a significant revision necessary. OBJECTIVES: Convene an international panel of experienced investigators to review the definition and classification of tremor. METHODS: Computerized MEDLINE searches in January 2013 and 2015 were conducted using a combination of text words and MeSH terms: "tremor", "tremor disorders", "essential tremor", "dystonic tremor", and "classification" limited to human studies. Agreement was obtained using consensus development methodology during four in-person meetings, two teleconferences, and numerous manuscript reviews. RESULTS: Tremor is defined as an involuntary, rhythmic, oscillatory movement of a body part and is classified along two axes: Axis 1-clinical characteristics, including historical features (age at onset, family history, and temporal evolution), tremor characteristics (body distribution, activation condition), associated signs (systemic, neurological), and laboratory tests (electrophysiology, imaging); and Axis 2-etiology (acquired, genetic, or idiopathic). Tremor syndromes, consisting of either isolated tremor or tremor combined with other clinical features, are defined within Axis 1. This classification scheme retains the currently accepted tremor syndromes, including essential tremor, and provides a framework for defining new syndromes. CONCLUSIONS: This approach should be particularly useful in elucidating isolated tremor syndromes and syndromes consisting of tremor and other signs of uncertain significance. Consistently defined Axis 1 syndromes are needed to facilitate the elucidation of specific etiologies in Axis 2. © 2017 International Parkinson and Movement Disorder Society.


Assuntos
Consenso , Cooperação Internacional , Sociedades Médicas/normas , Tremor/classificação , Tremor/diagnóstico , Humanos , MEDLINE/estatística & dados numéricos
8.
Brain ; 140(5): 1204-1211, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28334938

RESUMO

Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carried out whole exome sequencing on the remaining negative cases including four family trios, but could not identify any further potentially disease-causing mutations, confirming the equivalence of focused and whole exome sequencing in the diagnosis of genetic leukoencephalopathies. Here we provide an overview of the clinical and genetic features of these disorders in adults.


Assuntos
Exoma/genética , Predisposição Genética para Doença/genética , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Adolescente , Adulto , Feminino , Humanos , Masculino , Mutação , Análise de Sequência de DNA , Adulto Jovem
9.
Radiology ; 283(3): 789-798, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27820685

RESUMO

Purpose To investigate the pattern of neuromelanin signal intensity loss within the substantia nigra pars compacta (SNpc), locus coeruleus, and ventral tegmental area in Parkinson disease (PD); the specific aims were (a) to study regional magnetic resonance (MR) quantifiable depigmentation in association with PD severity and (b) to investigate whether imaging- and platform-dependent signal intensity variations can be normalized. Materials and Methods This prospective case-control study was approved by the local ethics committee and the research department of Nottingham University Hospitals. Written informed consent was obtained from all participants before enrollment in the study. Sixty-nine participants (39 patients with PD and 30 control subjects) were investigated with neuromelanin-sensitive MR imaging by using two different 3-T platforms and three differing protocols. Neuromelanin-related volumes of the anterior and posterior SNpc, locus coeruleus, and ventral tegmental area were determined, and normalized neuromelanin volumes were assessed for protocol-dependent effects. Diagnostic test performance of normalized neuromelanin volume was investigated by using receiver operating characteristic analyses, and correlations with the Unified Parkinson's Disease Rating Scale scores were tested. Results Reduction of normalized neuromelanin volume in PD was most pronounced in the posterior SNpc (median, -83%; P < .001), followed by the anterior SNpc (-49%; P < .001) and the locus coeruleus (-37%; P < .05). Normalized neuromelanin volume loss of the posterior and whole SNpc allowed the best differentiation of patients with PD and control subjects (area under the receiver operating characteristic curve, 0.92 and 0.88, respectively). Normalized neuromelanin volume of the anterior, posterior, and whole SNpc correlated with Unified Parkinson's Disease Rating Scale scores (r2 = 0.25, 0.22, and 0.28, respectively; all P < .05). Conclusion PD-induced neuromelanin loss can be quantified across imaging protocols and platforms by using appropriate adjustment. Depigmentation in PD follows a distinct spatial pattern, affords high diagnostic accuracy, and is associated with disease severity. ©RSNA, 2016 Online supplemental material is available for this article.


Assuntos
Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/patologia , Imageamento por Ressonância Magnética , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Tronco Encefálico/química , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Melaninas/análise , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Doença de Parkinson/diagnóstico , Estudos Prospectivos , Índice de Gravidade de Doença
10.
J Neurol Neurosurg Psychiatry ; 87(5): 512-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-25935893

RESUMO

BACKGROUND: Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a hereditary, adult onset leukodystrophy which is characterised by the presence of axonal loss, axonal spheroids and variably present pigmented macrophages on pathological examination. It most frequently presents in adulthood with dementia and personality change. HDLS has recently been found to be caused by mutations in the colony stimulating factor-1 receptor (CSF1R) gene. METHODS: In this study, we sequenced the CSF1R gene in a cohort of 48 patients from the UK, Greece and Ireland with adult onset leukodystrophy of unknown cause. RESULTS: Five pathogenic mutations were found, including three novel mutations. The presentations ranged from suspected central nervous system (CNS) vasculitis to extrapyramidal to cognitive phenotypes. The case histories and imaging are presented here, in addition to neuropathological findings from two cases with novel mutations. CONCLUSION: We estimate that CSF1R mutations account for 10% of idiopathic adult onset leukodystrophies and that genetic testing for CSF1R mutations is essential in adult patients presenting with undefined CNS vasculitis or a leukodystrophy with prominent neuropsychiatric signs or dementia.


Assuntos
Axônios/patologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Transtornos Parkinsonianos/patologia , Receptores de Fator Estimulador de Colônias/genética , Vasculite do Sistema Nervoso Central/patologia , Adulto , Feminino , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/complicações , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Humanos , Leucoencefalopatias/complicações , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/genética , Fenótipo , Vasculite do Sistema Nervoso Central/complicações , Vasculite do Sistema Nervoso Central/genética
11.
J Neurol Neurosurg Psychiatry ; 87(11): 1183-1190, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27671901

RESUMO

BACKGROUND: Cardiovascular disease (CVD) influences phenotypic variation in Parkinson's disease (PD), and is usually an indication for statin therapy. It is less clear whether cardiovascular risk factors influence PD phenotype, and if statins are prescribed appropriately. OBJECTIVES: To quantify vascular risk and statin use in recent-onset PD, and examine the relationship between vascular risk, PD severity and phenotype. METHODS: Cardiovascular risk was quantified using the QRISK2 calculator (high ≥20%, medium ≥10 and <20%, low risk <10%). Motor severity and phenotype were assessed using the Movement Disorder Society Unified PD Rating Scale (UPDRS) and cognition by the Montreal cognitive assessment. RESULTS: In 2909 individuals with recent-onset PD, the mean age was 67.5 years (SD 9.3), 63.5% were men and the mean disease duration was 1.3 years (SD 0.9). 33.8% of cases had high vascular risk, 28.7% medium risk, and 22.3% low risk, while 15.2% of cases had established CVD. Increasing vascular risk and CVD were associated with older age (p<0.001), worse motor score (p<0.001), more cognitive impairment (p<0.001) and worse motor phenotype (p=0.021). Statins were prescribed in 37.2% with high vascular risk, 15.1% with medium vascular risk and 6.5% with low vascular risk, which compared with statin usage in 75.3% of those with CVD. CONCLUSIONS: Over 60% of recent-onset PD patients have high or medium cardiovascular risk (meriting statin usage), which is associated with a worse motor and cognitive phenotype. Statins are underused in these patients, compared with those with vascular disease, which is a missed opportunity for preventive treatment. TRIAL REGISTRATION NUMBER: GN11NE062, NCT02881099.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Uso de Medicamentos/estatística & dados numéricos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/epidemiologia , Fatores Etários , Idoso , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/diagnóstico , Comorbidade , Estudos Transversais , Inglaterra , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Fenótipo , Medição de Risco
12.
Mov Disord ; 31(10): 1518-1526, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27324570

RESUMO

OBJECTIVE: The purpose of this study was to examine the relationship between vascular disease (and vascular risk factors), cognition and motor phenotype in Parkinson's disease (PD). METHODS: Recently diagnosed PD cases were enrolled in a multicenter prospective observational longitudinal cohort study. Montreal cognitive assessment (normal >23, mild cognitive impairment 22 to 23 or lower but without functional impairment, and dementia 21 or less with functional impairment) and Movement Disorder Society Unified PD Rating Scale part 3 (UPDRS 3) scores were analyzed in relation to a history of vascular events and risk factors. RESULTS: In 1759 PD cases, mean age 67.5 (standard deviation 9.3) years, mean disease duration 1.3 (standard deviation 0.9) years, 65.2% were men, 4.7% had a history of prior stroke or transient ischemic attack, and 12.5% had cardiac disease (angina, myocardial infarction, heart failure). In cases without a history of vascular disease, hypertension was recorded in 30.4%, high cholesterol 27.3%, obesity 20.7%, diabetes 7.2%, and cigarette smoking in 4.6%. Patients with prior stroke or transient ischemic attack were more likely to have cognitive impairment (42% vs 25%) and postural instability gait difficulty (53.5% vs 39.5%), but these findings were not significant after adjustment for age, sex, and disease duration (P = .075). The presence of more than 2 vascular risks was associated with worse UPDRS 3 motor scores (beta coefficient 4.05, 95% confidence interval 1.48, 6.61, p = .002) and with cognitive impairment (ordinal odds ratio 2.24, 95% confidence interval 1.34, 3.74, p = .002). In 842 patients (47.8%) with structural brain imaging, white matter leukoaraiosis, but not lacunar or territorial infarction, was associated with impaired cognition (p = .006) and postural instability gait difficulty (p = .010). CONCLUSION: Vascular comorbidity is significantly associated with cognitive and gait impairment in patients with early PD, which may have prognostic and treatment implications. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Disfunção Cognitiva/fisiopatologia , Demência/fisiopatologia , Transtornos Neurológicos da Marcha/fisiopatologia , Doença de Parkinson/fisiopatologia , Doenças Vasculares/fisiopatologia , Idoso , Disfunção Cognitiva/epidemiologia , Comorbidade , Demência/epidemiologia , Feminino , Transtornos Neurológicos da Marcha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Estudos Prospectivos , Fatores de Risco , Reino Unido/epidemiologia , Doenças Vasculares/epidemiologia
13.
Mov Disord ; 31(9): 1327-36, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27273470

RESUMO

The International Parkinson and Movement Disorder Society established a task force on tremor that reviewed the use of transducer-based measures in the quantification and characterization of tremor. Studies of accelerometry, electromyography, activity monitoring, gyroscopy, digitizing tablet-based measures, vocal acoustic analysis, and several other transducer-based methods were identified by searching PubMed.gov. The availability, use, acceptability, reliability, validity, and responsiveness were reviewed for each measure using the following criteria: (1) used in the assessment of tremor; (2) used in published studies by people other than the developers; and (3) adequate clinimetric testing. Accelerometry, gyroscopy, electromyography, and digitizing tablet-based measures fulfilled all three criteria. Compared to rating scales, transducers are far more sensitive to changes in tremor amplitude and frequency, but they do not appear to be more capable of detecting a change that exceeds random variability in tremor amplitude (minimum detectable change). The use of transducer-based measures requires careful attention to their limitations and validity in a particular clinical or research setting. © 2016 International Parkinson and Movement Disorder Society.


Assuntos
Técnicas e Procedimentos Diagnósticos/normas , Transdutores/normas , Tremor/diagnóstico , Humanos
14.
NPJ Parkinsons Dis ; 10(1): 113, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849413

RESUMO

There are 90 independent genome-wide significant genetic risk variants for Parkinson's disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1, ASNS, PDE5A, and XPO1. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD.

15.
J Neurol Neurosurg Psychiatry ; 84(11): 1288-95, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23486993

RESUMO

The diagnosis of movement disorders including Parkinson's disease (PD) and essential tremor is determined through clinical assessment. The difficulty with diagnosis of early PD has been highlighted in several recent clinical trials. Studies have suggested relatively high clinical diagnostic error rates for PD and essential tremor. This review was undertaken to clarify the utility of DaT-SPECT imaging with ((123)I)ioflupane (DaTSCAN or DaTscan or ((123)I)FP-CIT) in assisting practitioners in their clinical decision making by visualising the dopamine transporter in parkinsonian cases. In some patients with suspected parkinsonian syndromes, SPECT imaging with ((123)I)ioflupane is useful to assist in the diagnosis and to help guide prognosis and treatment decisions, including avoiding medications that are unlikely to provide benefit. Clinicians ordering ((123)I)ioflupane SPECT should be aware of its limitations and pitfalls and should order scans when there is diagnostic uncertainty or when the scan will be helpful in clinical decision making.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/fisiologia , Nortropanos , Transtornos Parkinsonianos/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único , Antiparkinsonianos/uso terapêutico , Encéfalo/diagnóstico por imagem , Técnicas de Apoio para a Decisão , Diagnóstico Diferencial , Tremor Essencial/diagnóstico por imagem , Tremor Essencial/fisiopatologia , Humanos , Exame Neurológico , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/fisiopatologia , Valor Preditivo dos Testes , Incerteza
16.
Neurodegener Dis ; 11(1): 22-32, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-22571977

RESUMO

BACKGROUND: An accurate diagnosis is important for timely and adequate treatment in patients with clinically uncertain parkinsonian syndrome (CUPS). OBJECTIVE: The objective of this study was to assess safety and changes in clinical management, diagnosis and quality of life (QoL) at 4 and 12 weeks following DaTscan (ioflupane [(123)I] injection) imaging in patients with CUPS. METHODS: This randomized, open-label, single-dose, multicenter trial was carried out in patients with CUPS who were randomized to either a DaTscan imaging group or to a control group without imaging. The main outcome measures were the proportions of patients with changes in clinical management and diagnosis from baseline through to 12 weeks after DaTscan. A total of 19 university hospital centers in Europe and the USA participated in the study. There were 267 patients enrolled and randomized (131 DaTscan, 136 control). RESULTS: Significantly more DaTscan patients had changes in clinical management after 12 weeks (p = 0.004) compared to the control group, and significantly more DaTscan patients had changes in diagnosis at 4 weeks and at 12 weeks (both p < 0.001) compared to control patients. No significant difference in total score for QoL was observed between groups during the study duration. DaTscan was safe and well-tolerated. No deaths, serious adverse events (AEs) or withdrawals due to AEs occurred during the study. One patient had a headache following treatment with a suspected relationship to DaTscan. CONCLUSION: DaTscan imaging significantly affected the clinical management and diagnosis of patients with CUPS. DaTscan is safe and well-tolerated and is a useful adjunct to differential diagnosis of CUPS.


Assuntos
Antiparkinsonianos/uso terapêutico , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/tratamento farmacológico , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Iofetamina , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/psicologia , Qualidade de Vida , Compostos Radiofarmacêuticos , Índice de Gravidade de Doença , Método Simples-Cego , Fatores de Tempo , Adulto Jovem
17.
J Neurol Neurosurg Psychiatry ; 83(6): 620-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22492213

RESUMO

BACKGROUND: This study assessed the impact of DaTscan on clinical management, diagnosis, confidence of diagnosis (CoD), quality of life (QoL), health resource use (HRU) and safety during a 1-year follow-up in patients with clinically uncertain parkinsonian syndromes (CUPS). METHODS: A total of 19 university hospital centres in Europe and the USA participated in this open-label, single-dose, prospective, clinical trial in patients with CUPS who were randomised to a DaTscan imaging group or to a no-imaging (control) group. The proportion of patients with changes in clinical management, diagnosis, CoD, QoL and HRU from baseline through 1 year post-DaTscan was compared between groups. RESULTS: There were 273 patients randomised (135 DaTscan, 138 control). Significantly more patients in the DaTscan imaging group had at least one change in their actual clinical management after 12 weeks (p=0.002) and after 1 year (p<0.001) compared with patients in the control group. In addition, significantly more DaTscan patients had changes in diagnosis and an increased CoD at 4 weeks, 12 weeks and 1 year (all p<0.001) compared with control patients. No significant differences in total score for QoL or HRU were observed between groups during the 1-year follow-up period. DaTscan was safe and well tolerated. One patient in the imaging group had an adverse event (headache) with suspected relationship to DaTscan post-administration. CONCLUSIONS: DaTscan had a significant impact on clinical management, diagnosis and CoD in patients with CUPS. DaTscan is safe and well tolerated, and is a useful adjunct to differentiate a diagnosis of CUPS. Trial registration number http://ClinicalTrials.gov Identifier: NCT00382967.


Assuntos
Gerenciamento Clínico , Radioisótopos do Iodo , Nortropanos , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Qualidade de Vida/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/diagnóstico por imagem , Valor Preditivo dos Testes , Estudos Prospectivos , Segurança/estatística & dados numéricos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tomografia Computadorizada de Emissão de Fóton Único/psicologia
18.
J Magn Reson Imaging ; 35(1): 48-55, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21987471

RESUMO

PURPOSE: To determine if tissue magnetic susceptibility is a more direct marker of tissue iron content than other MR markers of iron. This study presents the first quantitative, in vivo measurements of the susceptibility of the substantia nigra in patients with Parkinson's disease. MATERIALS AND METHODS: Nine patients and 11 controls were studied at 7 Tesla. Susceptibility maps were created by inverting the filtered phase maps associated with T2* weighted images. RESULTS: On average, patients showed an increase in susceptibility of the pars compacta compared with controls, which correlates with the predicted increase in brain iron in Parkinson's disease. A rostral-caudal gradient in susceptibility was also observed in controls and patients. CONCLUSION: Susceptibility mapping may provide a new tool for studying the development of Parkinson's disease.


Assuntos
Mapeamento Encefálico/métodos , Ferro/metabolismo , Imageamento por Ressonância Magnética/métodos , Doença de Parkinson/patologia , Substância Negra/patologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional , Ferro/química , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico
19.
Mov Disord ; 26(4): 699-704, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21370257

RESUMO

BACKGROUND: Previous studies have compared the accuracy of spiral analysis in distinguishing essential tremor (ET) from PD. In this study, we have used this technique to distinguish cases of tremulous PD (TDPD) (N = 24) from tremulous parkinsonian subjects without evidence of dopaminergic deficit (N = 41). METHODS: All patients were characterized on clinical and (123)I-N-ω-fluoro-propyl-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane ([(123)I] FP-CIT) SPECT scan data, which were concordant in every case. All analyses were carried out by observers blinded to the clinical details and supplied with just the spiral drawings, from which tremor severity (TS), 3-turn spiral diameter (3TD), and spiral density (SD) were measured. RESULTS: The spirals drawn by TDPD cases had significantly smaller 3TD (P = 0.029) and greater SD (P = 0.0082) than those with normal FP-CIT scans. There was no significant difference in the TS between the two groups (P = 0.11). The sensitivity and specificity of TS were 62.5% and 65.0%, 3TD were 75% and 56.7%, and SD were 30.4% and 82.5%, respectively, in predicting the correct classification. Further analyses combining these factors into pairs, showed that the respective sensitivities and specificities of (1) TS × 3TD were 75.0% and 40.0%, (2) TS/SD were 56% and 70.0%, and (3) 3TD/SD were 87.0% and 40.0%. DISCUSSION: There are significant differences in the 3TD and SD of spirals drawn by tremulous patients with normal versus abnormal FP-CIT scans. Spiral analysis may have some clinical value in helping to distinguish tremulous parkinsonian patients with normal presynaptic dopaminergic imaging from tremulous PD patients, providing results similar to those reported for expert movement disorder neurologists using standardized videotaped examinations.


Assuntos
Tremor Essencial/diagnóstico por imagem , Radioisótopos do Iodo , Transtornos Parkinsonianos/diagnóstico por imagem , Tropanos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Tomografia Computadorizada de Emissão de Fóton Único/métodos
20.
Mov Disord ; 26(9): 1633-8, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21491489

RESUMO

Depigmentation of the substantia nigra is a conspicuous pathological feature of Parkinson's disease and related to a loss of neuromelanin. Similar to melanin, neuromelanin has paramagnetic properties resulting in signal increase on specific T1-weighted magnetic resonance imaging. The aim of this study was to assess signal changes in the substantia nigra in patients with Parkinson's disease using an optimized neuromelanin-sensitive T1 scan. Ten patients with Parkinson's disease and 12 matched controls underwent high-resolution T1-weighted magnetic resonance imaging with magnetization transfer effect at 3T. The size and signal intensity of the substantia nigra pars compacta were determined as the number of pixels with signal intensity higher than background signal intensity+3 standard deviations and regional contrast ratio. Patients were subclassified as early stage (n=6) and late stage (n=4) using the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr Parkinson's disease staging scale. The T1 hyperintense area in the substantia nigra was substantially smaller in patients compared with controls (-60%, P<.01), and contrast was reduced (-3%, P<.05). Size reduction was even more pronounced in more advanced disease (-78%) than in early-stage disease (-47%). We present preliminary findings using a modified T1-weighted magnetic resonance imaging technique showing stage-dependent substantia nigra signal reduction in Parkinson's disease as a putative marker of neuromelanin loss. Our data suggest that reduction in the size of neuromelanin-rich substantia nigra correlates well with postmortem observations of dopaminergic neuron loss. Further validation of our results could potentially lead to development of a new biomarker of disease progression in Parkinson's disease.


Assuntos
Imageamento por Ressonância Magnética , Doença de Parkinson/patologia , Substância Negra/patologia , Idoso , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/métodos , Masculino , Melaninas/metabolismo , Pessoa de Meia-Idade , Substância Negra/metabolismo
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