Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 33
Filtrar
1.
Brain ; 146(5): 1873-1887, 2023 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-36348503

RESUMO

Parkinson's disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson's disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson's disease patients, and the genetic basis for this heterogeneity is incompletely understood. To explore the genetic factors associated with rate of progression to Parkinson's disease dementia, we performed a genome-wide survival meta-analysis of 3923 clinically diagnosed Parkinson's disease cases of European ancestry from four longitudinal cohorts. In total, 6.7% of individuals with Parkinson's disease developed dementia during study follow-up, on average 4.4 ± 2.4 years from disease diagnosis. We have identified the APOE ε4 allele as a major risk factor for the conversion to Parkinson's disease dementia [hazard ratio = 2.41 (1.94-3.00), P = 2.32 × 10-15], as well as a new locus within the ApoE and APP receptor LRP1B gene [hazard ratio = 3.23 (2.17-4.81), P = 7.07 × 10-09]. In a candidate gene analysis, GBA variants were also identified to be associated with higher risk of progression to dementia [hazard ratio = 2.02 (1.21-3.32), P = 0.007]. CSF biomarker analysis also implicated the amyloid pathway in Parkinson's disease dementia, with significantly reduced levels of amyloid ß42 (P = 0.0012) in Parkinson's disease dementia compared to Parkinson's disease without dementia. These results identify a new candidate gene associated with faster conversion to dementia in Parkinson's disease and suggest that amyloid-targeting therapy may have a role in preventing Parkinson's disease dementia.


Assuntos
Disfunção Cognitiva , Demência , Doença de Parkinson , Humanos , Doença de Parkinson/genética , Demência/complicações , Disfunção Cognitiva/etiologia , Apolipoproteínas E/genética , Biomarcadores , Receptores de LDL
2.
Molecules ; 28(4)2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36838815

RESUMO

Vitamin B12 deficiency can lead to oxidative stress, which is known to be involved in neurodegenerative diseases such as Alzheimer's disease (AD). Mogrosides are plant-derived triterpene glycosides that exhibit anti-inflammatory and antioxidant activity in animal cell lines and mouse models. Since amyloid-ß toxicity is known to cause oxidative stress and damage to brain cells, we hypothesized that mogrosides may have a protective effect against AD. In this study, we investigated the potential anti-AD effect of mogrosides in vitamin B12-deficient wild-type N2 and in transgenic CL2355 Caenorhabditis elegans expressing amyloid-ß peptide. Our data indicated that mogrosides have a beneficial effect on the lifespan and egg-laying rate of N2 and vitamin B12-deficient N2 worms. Additionally, the results revealed that mogrosides can effectively delay the paralysis of CL2355 worms as determined by serotonin sensitivity assay. Our analysis showed that mogrosides increase the expression of oxidative protective genes in N2 worms fed with vitamin B12-deficient OP50 bacterium. We conclude that mogrosides may exert preventative rather than curative effects that counteract the detrimental vitamin B12-deficient environment in N2 and CL2355 C. elegans by modulating oxidation-related gene expression.


Assuntos
Doença de Alzheimer , Proteínas de Caenorhabditis elegans , Camundongos , Animais , Caenorhabditis elegans , Animais Geneticamente Modificados , Vitamina B 12/metabolismo , Doença de Alzheimer/genética , Antioxidantes/farmacologia , Peptídeos beta-Amiloides/metabolismo , Estresse Oxidativo , Proteínas de Caenorhabditis elegans/metabolismo , Extratos Vegetais/farmacologia
3.
Mov Disord ; 36(12): 2821-2832, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34448251

RESUMO

BACKGROUND: Parkinson's disease (PD) comorbid with rapid eye movement sleep behavior disorder (RBD) may show more severe motor and nonmotor symptoms, suggesting a distinct PD subtype. OBJECTIVE: The aim of this study was to investigate the impact of RBD on the longitudinal change of motor and nonmotor symptoms in patients with PD. METHODS: Patients with early PD (diagnosed within 3.5 years) recruited from 2010 to 2019 were followed every 18 months in the Oxford Parkinson's Disease Centre Discovery cohort. At each visit, we used standard questionnaires and measurements to assess demographic features and motor and nonmotor symptoms (including RBD, daytime sleepiness, mood, autonomic symptoms, cognition, and olfaction). Data were analyzed with linear mixed effects and Cox regression models. Possible RBD (pRBD) was longitudinally determined according to RBD Screening Questionnaire scores. RESULTS: A total of 923 patients were recruited (mean age: 67.1 ± 9.59 years; 35.9% female), and 788 had follow-up assessment(s) (mean: 4.8 ± 1.98 years, range: 1.3-8.3). Among them, 33.3% were identified as pRBD (PD + pRBD). Patients with PD + pRBD had more severe baseline symptoms and showed faster progression on Movement Disorder Society-Unified Parkinson's Disease Rating Scale parts I and III, Purdue Pegboard test, and Beck Depression Inventory scores. Moreover, PD + pRBD was associated with an increased level of risk for mild cognitive impairment (hazard ratio [HR] = 1.36, 95% confidence interval [CI]: 1.01-1.83), freezing of gait (HR = 1.42, 95% CI: 1.10-1.86), and frequent falling (HR = 1.62, 95% CI: 1.02-2.60). CONCLUSIONS: Patients with PD + pRBD progress faster on motor, mood, and cognitive symptoms, confirming a more aggressive PD subtype that can be identified at baseline and has major clinical implications. © 2021 International Parkinson and Movement Disorder Society.


Assuntos
Transtornos Neurológicos da Marcha , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Idoso , Estudos de Coortes , Feminino , Transtornos Neurológicos da Marcha/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/psicologia , Transtorno do Comportamento do Sono REM/complicações , Transtorno do Comportamento do Sono REM/diagnóstico , Inquéritos e Questionários
4.
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
5.
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
6.
Mov Disord ; 34(8): 1174-1183, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31283854

RESUMO

OBJECTIVE: The objective of this study was to identify clinical predictors of motor complications (dyskinesia and motor fluctuations) of levodopa in a prospectively recruited PD cohort using longitudinal analysis. METHODS: An inception cohort (Oxford Discovery) of 734 patients was followed to a maximum of 10 years from diagnosis using a discrete-time survival analysis. A subset analysis was used to validate an online dyskinesia-risk calculator developed from the results of the Stalevo Reduction in Dyskinesia Evaluation PD trial. RESULTS: A total of 186 cases of dyskinesia and 254 cases of motor fluctuations were observed. Dyskinesia incidence increased with time (risk per 100 participants [95% confidence interval] 13 [11-16] <3.5 years, 16 [13-21] 3.5-5.0 years, 19 [14-26] 5-6.5 years, and 23 [16-33] >6.5 years from diagnosis). Motor complication predictors were grouped as medication predictors, disease predictors and patient predictors. Baseline nonmotor feature severity, low mood, anxiety, and age at symptom onset were associated with motor complications among a number of previously identified predictors. Replication of the Stalevo Reduction in Dyskinesia Evaluation PD calculator was reasonable with the area under the curve for dyskinesia risk score as a predictor of dyskinesia being 0.68 (95% confidence interval, 0.55-0.81). CONCLUSIONS: This study quantifies risk of motor complications, finds consistent predictors, and demonstrates the novel finding that nonmotor features of PD, particularly low mood and anxiety, are significant risk factors for motor complications. Further validation of dyskinesia risk scores are required as well as evidence to determine if the routine use of such scores can be clinically valuable in enhancing patient care and quality of life. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Antiparkinsonianos/efeitos adversos , Ansiedade/epidemiologia , Depressão/epidemiologia , Discinesia Induzida por Medicamentos/epidemiologia , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Discinesia Induzida por Medicamentos/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Doença de Parkinson/fisiopatologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Índice de Gravidade de Doença
7.
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
8.
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
9.
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
11.
Artigo em Inglês | MEDLINE | ID: mdl-38898616

RESUMO

BACKGROUND: Dopaminergic responsiveness is a defining feature of Parkinson's disease (PD). However, there is limited information on how this evolves over time. OBJECTIVES: To examine serial dopaminergic responses, if there are distinct patterns, and which factors predict these. METHODS: We analyzed data from the Parkinson's Progression Markers Initiative on repeated dopaminergic challenge tests (≥24.5% defined as a definite response). Growth-mixture modeling evaluated for different response patterns and multinomial logistic regression tested for predictors of these clusters. RESULTS: 1525 dopaminergic challenge tests were performed in 336 patients. At enrolment, mean age was 61.2 years (SD 9.6), 66.4% were male and disease duration was 0.5 years (SD 0.5). 1 to 2 years after diagnosis, 48.0% of tests showed a definite response, but this proportion increased with longer disease duration (51.1-74.3%). We identified 3 response groups: "Striking" (n = 29, 8.7%); "Excellent" (n = 110; 32.7%) and "Modest" (n = 197, 58.6%). Significant differences were as follows: striking responders commenced treatment earlier (P = 0.02), were less likely to be on dopamine agonist monotherapy (P = 0.01), and had better cognition (P < 0.01) and activities of daily living (P = 0.01). Excellent responders had higher challenge doses (P = 0.03) and were more likely to be on combination therapy (P < 0.01). CONCLUSION: Three distinct patterns of the dopaminergic response were observed. As the proportion of PD cases with definite dopa responsiveness increased over time, the initial treatment response may be an unreliable diagnostic aid.

12.
Mov Disord Clin Pract ; 11(6): 686-697, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38587023

RESUMO

BACKGROUND: Motor complications are well recognized in Parkinson's disease (PD), but their reported prevalence varies and functional impact has not been well studied. OBJECTIVES: To quantify the presence, severity, impact and associated factors for motor complications in PD. METHODS: Analysis of three large prospective cohort studies of recent-onset PD patients followed for up to 12 years. The MDS-UPDRS part 4 assessed motor complications and multivariable logistic regression tested for associations. Genetic risk score (GRS) for Parkinson's was calculated from 79 single nucleotide polymorphisms. RESULTS: 3343 cases were included (64.7% male). Off periods affected 35.0% (95% CI 33.0, 37.0) at 4-6 years and 59.0% (55.6, 62.3) at 8-10 years. Dyskinesia affected 18.5% (95% CI 16.9, 20.2) at 4-6 years and 42.1% (38.7, 45.5) at 8-10 years. Dystonia affected 13.4% (12.1, 14.9) at 4-6 years and 22.8% (20.1, 25.9) at 8-10 years. Off periods consistently caused greater functional impact than dyskinesia. Motor complications were more common among those with higher drug doses, younger age at diagnosis, female gender, and greater dopaminergic responsiveness (in challenge tests), with associations emerging 2-4 years post-diagnosis. Higher Parkinson's GRS was associated with early dyskinesia (0.026 ≤ P ≤ 0.050 from 2 to 6 years). CONCLUSIONS: Off periods are more common and cause greater functional impairment than dyskinesia. We confirm previously reported associations between motor complications with several demographic and medication factors. Greater dopaminergic responsiveness and a higher genetic risk score are two novel and significant independent risk factors for the development of motor complications.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/genética , Doença de Parkinson/epidemiologia , Doença de Parkinson/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Índice de Gravidade de Doença , Discinesias/epidemiologia , Discinesias/etiologia , Discinesias/genética , Estudos Prospectivos , Distonia/epidemiologia , Distonia/genética , Antiparkinsonianos/uso terapêutico , Antiparkinsonianos/efeitos adversos , Seguimentos
13.
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.

14.
J Alzheimers Dis Rep ; 7(1): 213-225, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36994115

RESUMO

Background: Depression in individuals with Alzheimer's disease (AD) is common, distressing, difficult to treat, and inadequately understood. It occurs more frequently in AD than in older adults without dementia. The reasons why some patients develop depression during AD and others do not remain obscure. Objective: We aimed to characterize depression in AD and to identify risk factors. Methods: We used data from three large dementia focused cohorts: ADNI (n = 665 with AD, 669 normal cognition), NACC (n = 698 with AD, 711 normal cognition), and BDR (n = 757 with AD). Depression ratings were available using the GDS and NPI and in addition for BDR the Cornell. A cut-off of≥8 was used for the GDS and the Cornell Scale for Depression in Dementia,≥6 for the NPI depression sub-scale, and≥2 for the NPI-Q depression sub-scale. We used logistic regression to examine potential risk factors and random effects meta-analysis and an interaction term to look for interactions between each risk factor and the presence of cognitive impairment. Results: In individual studies there was no evidence of a difference in risk factors for depressive symptoms in AD. In the meta-analysis the only risk factor which increased the risk of depressive symptoms in AD was previous depression, but information on this was only available from one study (OR 7.78 95% CI 4.03-15.03). Conclusion: Risk factors for depression in AD appear to differ to those for depression per se supporting suggestions of a different pathological process, although a past history of depression was the strongest individual risk factor.

15.
Mov Disord Clin Pract ; 10(4): 539-546, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37070042

RESUMO

Background: Neuropathological studies, based on small samples, suggest that symptoms of Parkinson's disease (PD) emerge when dopamine/nigrostriatal loss is around 50-80%. Functional neuroimaging can be applied in larger numbers during life, which allows analysis of the extent of dopamine loss more directly. Objective: To quantify dopamine transporter (DaT) activity by neuroimaging in early PD. Methods: Systematic review and novel analysis of DaT imaging studies in early PD. Results: In our systematic review, in 423 unique cases from 27 studies with disease duration of less than 6 years, mean age 58.0 (SD 11.5) years, and mean disease duration 1.8 (SD 1.2) years, striatal loss was 43.5% (95% CI 41.6, 45.4) contralaterally, and 36.0% (95% CI 33.6, 38.3) ipsilaterally. For unilateral PD, in 436 unique cases, mean age 57.5 (SD 10.2) years, and mean disease duration 1.8 (SD 1.4) years, striatal loss was 40.6% (95% CI 38.8, 42.4) contralaterally, and 31.6% (95% CI 29.4, 33.8) ipsilaterally. In our novel analysis of the Parkinson's Progressive Marker Initiative study, 413 cases had 1436 scans performed. For a disease duration of less than 1 year, age was 61.8 (SD 9.8) years, and striatal loss was 51.2% (95% CI 49.1, 53.3) contralaterally and 39.5% (36.9, 42.1) ipsilaterally, giving an overall striatal loss of 45.3% (43.0, 47.6). Conclusions: Loss of striatal DaT activity in early PD is less at 35-45%, rather than the 50-80% striatal dopamine loss estimated to be present at the time of symptom onset, based on backwards extrapolation from autopsy studies.

16.
medRxiv ; 2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-37987016

RESUMO

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be key to understanding disease pathways and ultimately therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7,804 patients of European ancestry from Tracking Parkinson's (PRoBaND), The Oxford Discovery Cohort, and AMP-PD. We conducted a discrete phenotype genome-wide association studies comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk alleles rs429358 tagging APOEe4 and rs7668531 near the MMRN1 and SNCA-AS1 genes, increase the odds of developing dementia and that an intronic variant rs17442721 tagging LRRK2 G2019S, on chromosome 12 is protective against dementia. These results should be validated in autopsy confirmed cases in future studies.

17.
Plant Sci ; 322: 111361, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35760158

RESUMO

Fusarium head blight (FHB) caused by Fusarium graminearum (Fg) severely affects cereal crops, especially wheat and barley. FHB results in significant yield loss, reduces grain quality and contaminates grains with mycotoxin. The development of FHB-resistant cereal cultivars can be expedited through CRISPR gene editing. The Arabidopsis ethylene insensitive 2 (AtEIN2) plays a key role in ethylene signaling pathway and is critical for monitoring plant growth and defense responses. RNAi down-regulation of the wheat homolog TaEIN2 has been shown to enhance wheat FHB resistance. Here we generated site-specific mutations in AtEIN2 by CRISPR-editing. Detached inflorescence infection assays revealed that AtEIN2 knock-out (KO) mutants displayed enhanced Fg resistance and substantially reduced Fg spore production in planta. Gene expression profiling of defense genes revealed that impairment of AtEIN2 resulted in down-regulation of the ethylene signaling pathway while the salicylic acid signaling pathway was unaffected. Complementation of AtEIN2-KO plants with a barley orthologue, HvEIN2, restored Fg susceptibility, indicating that HvEIN2 is functionally equivalent to its Arabidopsis counterpart and, hence, may have a similar role in conditioning barley Fg susceptibility. These results provide insight into the defense role of EIN2 and a molecular and functional foundation for manipulating HvEIN2 to enhance FHB resistance in barley.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Fusarium , Hordeum , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Resistência à Doença/genética , Grão Comestível/metabolismo , Etilenos/metabolismo , Fusarium/fisiologia , Regulação da Expressão Gênica de Plantas , Hordeum/metabolismo , Doenças das Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Receptores de Superfície Celular/metabolismo , Triticum/genética
18.
Psychoneuroendocrinology ; 135: 105577, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34823140

RESUMO

INTRODUCTION: Associations between measures of socio-economic position and cortisol remain controversial. We examined the association between social class and cortisol reactivity in an aging male population. METHODS: The Speedwell cohort study recruited 2348 men aged 45-59 years from primary care between 1979 and 1982 (phase I) where occupational social class was used to classify socioeconomic position. Men were seen on four more occasions, the last being between 1997 and 1999 (phase 5) when salivary samples were obtained capturing cortisol reactivity to stressors (cognitive test and venepuncture) and circadian variations (awakening and night-time cortisol levels, circadian slope and area under curve) at morning and afternoon clinic sessions. Longitudinal association between social class at phase 3 and log-transformed salivary cortisol measures at phase 5 was assessed using multivariable linear regression adjusted for variables associated with sampling time and age as a potential confounder, stratified by time of clinic session. We also explored possible mediation by psychosocial factors (e.g. work dislike) and health-related factors (e.g. waist-to-hip ratio and high-density lipoprotein cholesterol). RESULTS: From 1768 living men, 1003 men (57%) attended a clinic at phase five, 854 participants (85% of attendees) returned home cortisol samples (mean age 71.7 years). We found little evidence of association between social class and baseline cortisol (i.e. prior to stress), cortisol response to stressors, and cortisol diurnal variation. However, we found lower social class was associated with higher and delayed post-stress recovery cortisol for participants that visited the clinic in the morning (adjusted ß coefficient for manual versus non-manual 0.25 ng/ml; 95% CI: 0.06-0.48; P = 0.008). This association did not appear to be mediated by any of the measured psychosocial or health-related factors. CONCLUSION: Our data did not show an overall association between social class and cortisol variability either diurnal or in response to a stressor. Lower social class was associated with a slower time to recover from exposure to stress in the morning, thereby increasing overall cortisol exposure. These findings provide some evidence for a mechanism that may contribute to the association between lower social class and a higher risk of adverse health outcomes.


Assuntos
Hidrocortisona , Estresse Psicológico , Humanos , Hidrocortisona/análise , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Psicologia , Saliva/química , Fatores Sociodemográficos , Estresse Psicológico/metabolismo
19.
Front Genome Ed ; 3: 629769, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34713253

RESUMO

Sweet basil (Ocimum basilicum L.) downy mildew disease (DM) caused by Peronospora belbahrii is a worldwide threat to the basil industry due to the lack of natural genetic resistance in sweet basil germplasm collections. In this study, we used CRISPR-gene editing to modify the sweet basil DM susceptibility gene homoserine kinase (ObHSK). Gene-edited plants challenged with P. belbahrii displayed a significantly reduced susceptibility to DM, based on phenotypic disease indices and on in planta pathogen load. These results suggest that ObHSK plays a role in conditioning DM susceptibility, similar to that observed for the AtHSK gene in Arabidopsis. These results demonstrate the utility of CRISPR-gene editing in enhancing DM resistance and contributing to sweet basil breeding programs.

20.
Brain Behav ; 11(8): e2258, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34190430

RESUMO

OBJECTIVES: Hyposmia is a common feature of Parkinson's disease (PD), yet there is no standard method to define it. A comparison of four published methods was performed to explore and highlight differences. MATERIALS AND METHODS: Olfactory testing was performed in 2097 cases of early PD in two prospective studies. Olfaction was assessed using various cut-offs, usually corrected by age and/or gender. Control data were simulated based on the age and gender structure of the PD cases and published normal ranges. Association with age, gender, and disease duration was explored by method and study cohort. Prevalence of hyposmia was compared with the age and gender-matched simulated controls. Between method agreement was measured using Cohen's kappa and Gwet's AC1. RESULTS: Hyposmia was present in between 69.1% and 97.9% of cases in Tracking Parkinson's cases, and between 62.2% and 90.8% of cases in the Parkinson's Progression Marker Initiative, depending on the method. Between-method agreement varied (kappa 0.09-0.80, AC1 0.55-0.86). The absolute difference between PD cases and simulated controls was similar for men and women across methods. Age and male gender were positively associated with hyposmia (p < .001, all methods). Odds of having hyposmia increased with advancing age (OR:1.06, 95% CI:1.03, 1.10, p < .001). Longer disease duration had a negative impact on overall olfactory performance. CONCLUSIONS: Different definitions of hyposmia give different results using the same dataset. A standardized definition of hyposmia in PD is required, adjusting for age and gender, to account for the background decline in olfactory performance with ageing, especially in men.


Assuntos
Transtornos do Olfato , Doença de Parkinson , Anosmia , Feminino , Humanos , Masculino , Transtornos do Olfato/epidemiologia , Transtornos do Olfato/etiologia , Doença de Parkinson/complicações , Doença de Parkinson/epidemiologia , Estudos Prospectivos , Olfato
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa