Erratum: Genetic risk of Parkinson disease and progression: An analysis of 13 longitudinal cohorts.
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PROVIDER: S-EPMC6705618 | biostudies-literature | 2019 Aug
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Erratum: Genetic risk of Parkinson disease and progression: An analysis of 13 longitudinal cohorts.
Neurology. Genetics 20190815 4
[This corrects the article on p. e348 in vol. 5, PMID: 31404238.]. ...[more]
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Project description:ObjectiveTo determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression.MethodsWe evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed.ResultsWe confirmed the importance of GBA on phenotypes. GBA variants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69-6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04-20.60]). We also replicated previously reported associations of GBA variants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16-1.52] for the C allele of rs76904798) and an intronic variant in PMVK and the development of wearing-off effects (HR 1.66 [1.19-2.31] for the C allele of rs114138760). Age at onset was associated with TMEM175 variant p.M393T (-0.72 [-1.21 to -0.23] in years), the C allele of rs199347 (intronic region of GPNMB, 0.70 [0.27-1.14]), and G allele of rs1106180 (intronic region of CCDC62, 0.62 [0.21-1.03]).ConclusionsThis study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.
| S-EPMC6659137 | biostudies-literature
Project description:ImportanceParkinson disease dementia dramatically increases mortality rates, patient expenditures, hospitalization risk, and caregiver burden. Currently, predicting Parkinson disease dementia risk is difficult, particularly in an office-based setting, without extensive biomarker testing.ObjectiveTo appraise the predictive validity of the Montreal Parkinson Risk of Dementia Scale, an office-based screening tool consisting of 8 items that are simply assessed.Design, setting, and participantsThis multicenter study (Montreal, Canada; Tottori, Japan; and Parkinson Progression Markers Initiative sites) used 4 diverse Parkinson disease cohorts with a prospective 4.4-year follow-up. A total of 717 patients with Parkinson disease were recruited between May 2005 and June 2016. Of these, 607 were dementia-free at baseline and followed-up for 1 year or more and so were included. The association of individual baseline scale variables with eventual dementia risk was calculated. Participants were then randomly split into cohorts to investigate weighting and determine the scale's optimal cutoff point. Receiver operating characteristic curves were calculated and correlations with selected biomarkers were investigated.Main outcomes and measuresDementia, as defined by Movement Disorder Society level I criteria.ResultsOf the 607 patients (mean [SD] age, 63.4 [10.1]; 376 men [62%]), 70 (11.5%) converted to dementia. All 8 items of the Montreal Parkinson Risk of Dementia Scale independently predicted dementia development at the 5% significance level. The annual conversion rate to dementia in the high-risk group (score, >5) was 14.9% compared with 5.8% in the intermediate group (score, 4-5) and 0.6% in the low-risk group (score, 0-3). The weighting procedure conferred no significant advantage. Overall predictive validity by the area under the receiver operating characteristic curve was 0.877 (95% CI, 0.829-0.924) across all cohorts. A cutoff of 4 or greater yielded a sensitivity of 77.1% (95% CI, 65.6-86.3) and a specificity of 87.2% (95% CI, 84.1-89.9), with a positive predictive value (as of 4.4 years) of 43.90% (95% CI, 37.76-50.24) and a negative predictive value of 96.70% (95% CI, 95.01-97.85). Positive and negative likelihood ratios were 5.94 (95% CI, 4.08-8.65) and 0.26 (95% CI, 0.17-0.40), respectively. Scale results correlated with markers of Alzheimer pathology and neuropsychological test results.Conclusions and relevanceDespite its simplicity, the Montreal Parkinson Risk of Dementia Scale demonstrated predictive validity equal or greater to previously described algorithms using biomarker assessments. Future studies using head-to-head comparisons or refinement of weighting would be of interest.
| S-EPMC5885166 | biostudies-literature
Project description:ObjectiveThe goal of this study was to refine our understanding of disease risk attributable to common genetic variation in SNCA, a major locus in Parkinson disease, with potential implications for clinical trials targeting α-synuclein. We aimed to dissect the multiple independent association signals, stratify individuals by SNCA-specific risk profiles, and explore expression quantitative trait loci.MethodsWe analyzed participant-level data from 12,503 patients and 12,502 controls, optimizing a risk model and assessing SNCA-specific risk scores and haplotypes as predictors of individual risk. We also explored hypotheses about functional mechanisms and correlated risk variants to gene expression in human brain and protein levels in cerebrospinal fluid.ResultsWe report and replicate a novel, third independent association signal at genome-wide significance level downstream of SNCA (rs2870004, p = 3.0*10-8 , odds ratio [OR] = 0.88, 95% confidence interval [CI] = 0.84-0.92). SNCA risk score stratification showed a 2-fold difference in disease susceptibility between top and bottom quintiles (OR = 1.99, 95% CI = 1.78-2.23). Contrary to previous reports, we provide evidence supporting top variant rs356182 as functional in itself and associated with a specific SNCA 5' untranslated region transcript isoform in frontal cortex.InterpretationThe SNCA locus harbors a minimum of 3 independent association signals for Parkinson disease. We demonstrate a fine-grained stratification of α-synuclein-related genetic burden in individual patients of potential future clinical relevance. Further efforts to pinpoint the functional mechanisms are warranted, including studies of the likely causal top variant rs356182 and its role in regulating levels of specific SNCA mRNA transcript variants. Ann Neurol 2018;83:117-129.
| S-EPMC6192521 | biostudies-literature
Project description:ObjectiveTo investigate the longitudinal dose-effect relationship between dopamine replacement therapy and impulse control disorders (ICDs) in Parkinson disease (PD).MethodsWe used data from a multicenter longitudinal cohort of consecutive patients with PD with ≤5 years' disease duration at baseline followed up annually up to 5 years. ICDs were evaluated during face-to-face semistructured interviews with movement disorder specialists. Generalized estimating equations and Poisson models with robust variance were used to study the association between several time-dependent definitions of dopamine agonist (DA) use, taking dose and duration of treatment into account, and ICDs at each visit. Other antiparkinsonian drugs were also examined.ResultsAmong 411 patients (40.6% women, mean age 62.3 years, average follow-up 3.3 years, SD 1.7 years), 356 (86.6%) took a DA at least once since disease onset. In 306 patients without ICDs at baseline, the 5-year cumulative incidence of ICDs was 46.1% (95% confidence interval [CI] 37.4-55.7, DA ever users 51.5% [95% CI 41.8-62.1], DA never users 12.4% [95% CI 4.8-30.0]). ICD prevalence increased from 19.7% at baseline to 32.8% after 5 years. ICDs were associated with ever DA use (prevalence ratio 4.23, 95% CI 1.78-10.09). Lifetime average daily dose and duration of treatment were independently associated with ICDs with significant dose-effect relationships. Similar analyses for levodopa were not in favor of a strong association. ICDs progressively resolved after DA discontinuation.ConclusionIn this longitudinal study of patients with PD characterized by a high prevalence of DA treatment, the 5-year cumulative incidence of ICDs was ≈46%. ICDs were strongly associated with DA use with a dose-effect relationship; both increasing duration and dose were associated with ICDs. ICDs progressively resolved after DA discontinuation.Clinicaltrialsgov identifierNCT01564992.
| S-EPMC6059034 | biostudies-literature
Project description:Background and objectivesThe genetic basis of Parkinson disease (PD) motor progression is largely unknown. Previous studies of the genetics of PD progression have included small cohorts and shown a limited overlap with genetic PD risk factors from case-control studies. Here, we have studied genomic variation associated with PD motor severity and early-stage progression in large longitudinal cohorts to help to define the biology of PD progression and potential new drug targets.MethodsWe performed a GWAS meta-analysis of early PD motor severity and progression up to 3 years from study entry. We used linear mixed-effect models with additive effects, corrected for age at diagnosis, sex, and the first 5 genetic principal components to assess variability in axial, limb, and total Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III scores.ResultsWe included 3,572 unrelated European ancestry patients with PD from 5 observational cohorts and 1 drug trial. The average AAO was 62.6 years (SD = 9.83), and 63% of participants were male. We found an average increase in the total MDS-UPDRS III score of 2.3 points/year. We identified an association between PD axial motor progression and variation at the GJA5 locus at 1q12 (β = -0.25, SE = 0.04, p = 3.4e-10). Exploration of the regulation of gene expression in the region (cis-expression quantitative trait loci [eQTL] analysis) showed that the lead variant was associated with expression of ACP6, a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTL p-values in blood and brain RNA expression data sets: <10-14 in eQTLGen and 10-7 in PsychEncode).DiscussionOur study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets that might modify disease progression.
| S-EPMC10409573 | biostudies-literature
Project description:Orofacial symptoms are common in Parkinson's disease (PD) both as initial manifestations and late markers of disease complications. We aimed to investigate the evolution of orofacial manifestations and their prognostic value throughout PD progression.Data was obtained from "Jönköping Parkinson Registry" database on routine care visits of 314 people with idiopathic PD in southern Sweden. Information on baseline symptomatology, orofacial features, UPDRS, and medications was recorded at baseline and during each follow-up visit within an average of 4.2 (range: 1-12) years.Hypomimia, affected speech, drooling, and impaired swallowing were present in 37.3%/91.6%, 14.1%/65.5%, 11.7%/55.3%, and 10.2%/34.5% at baseline/follow-up, respectively. Male sex [OR = 2.4 (95% CI: 1.0-5.9)], UPDRS motor scores [OR = 1.2 (95% CI: 1.1-1.3)], dominant rigidity [OR = 5.2 (95% CI: 1.4-19.1)], and autonomic disturbance [OR = 3.4 (95% CI: 1.1-10.9)] were risk factors for drooling. Individuals with more severe orofacial burden at baseline had shorter median time to develop UPDRS-Part III > 28 [3rd tertile = 4.7 yr, 2nd tertile = 6.2 yr, and 1st tertile = 7.8 yr; p = 0.014].Majority of people with PD manifest orofacial manifestations at either early or late stages of the disease. PD severity, symmetry of motor disturbances, and autonomic disorders correlate with orofacial symptoms. Individuals with more severe orofacial burden at baseline progressed faster to more advanced stages.
| S-EPMC5534316 | biostudies-other
Project description:BackgroundCognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease.MethodsIn this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population.Findings3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6-4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and β-glucocerebrosidase (GBA) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1-7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82-0·90) and replication (95% CI 0·78-0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 [95% CI 9·4-36·1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79-0·94) and a negative predictive value of 0·92 (95% 0·88-0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets.InterpretationOur predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis.FundingNational Institutes of Health, US Department of Defense.
| S-EPMC5761650 | biostudies-literature
Project description:Currently, there are no reported genetic predictors of motor symptom progression in Parkinson's disease (PD). In familial PD, disease severity is associated with higher α-synuclein (SNCA) expression levels, and in postmortem studies expression varies with SNCA genetic variants. Furthermore, SNCA is a well-known risk factor for PD occurrence. We recruited Parkinson's patients from the communities of three central California counties to investigate the influence of SNCA genetic variants on motor symptom progression in idiopathic PD. We repeatedly assessed this cohort of patients over an average of 5.1 years for motor symptom changes employing the Unified Parkinson's Disease Rating Scale (UPDRS). Of 363 population-based incident PD cases diagnosed less than 3 years from baseline assessment, 242 cases were successfully re-contacted and 233 were re-examined at least once. Of subjects lost to follow-up, 69% were due to death. Adjusting for covariates, risk of faster decline of motor function as measured by annual increase in motor UPDRS exam score was increased 4-fold in carriers of the REP1 263bp promoter variant (OR 4.03, 95%CI:1.57-10.4). Our data also suggest a contribution to increased risk by the G-allele for rs356165 (OR 1.66; 95%CI:0.96-2.88), and we observed a strong trend across categories when both genetic variants were considered (p for trend = 0.002). Our population-based study has demonstrated that SNCA variants are strong predictors of faster motor decline in idiopathic PD. SNCA may be a promising target for therapies and may help identify patients who will benefit most from early interventions. This is the first study to link SNCA to motor symptom decline in a longitudinal progression study.
| S-EPMC3352914 | biostudies-literature
Project description:BackgroundAlzheimer's disease and related dementia (ADRD) are characterized by multiple and progressive anatomo-clinical changes including accumulation of abnormal proteins in the brain, brain atrophy and severe cognitive impairment. Understanding the sequence and timing of these changes is of primary importance to gain insight into the disease natural history and ultimately allow earlier diagnosis. Yet, modeling changes over disease course from cohort data is challenging as the usual timescales (time since inclusion, chronological age) are inappropriate and time-to-clinical diagnosis is available on small subsamples of participants with short follow-up durations prior to diagnosis. One solution to circumvent this challenge is to define the disease time as a latent variable.MethodsWe developed a multivariate mixed model approach that realigns individual trajectories into the latent disease time to describe disease progression. In contrast with the existing literature, our methodology exploits the clinical diagnosis information as a partially observed and approximate reference to guide the estimation of the latent disease time. The model estimation was carried out in the Bayesian Framework using Stan. We applied the methodology to the MEMENTO study, a French multicentric clinic-based cohort of 2186 participants with 5-year intensive follow-up. Repeated measures of 12 ADRD markers stemmed from cerebrospinal fluid (CSF), brain imaging and cognitive tests were analyzed.ResultsThe estimated latent disease time spanned over twenty years before the clinical diagnosis. Considering the profile of a woman aged 70 with a high level of education and APOE4 carrier (the main genetic risk factor for ADRD), CSF markers of tau proteins accumulation preceded markers of brain atrophy by 5 years and cognitive decline by 10 years. However we observed that individual characteristics could substantially modify the sequence and timing of these changes, in particular for CSF level of A[Formula: see text].ConclusionBy leveraging the available clinical diagnosis timing information, our disease progression model does not only realign trajectories into the most homogeneous way. It accounts for the inherent residual inter-individual variability in dementia progression to describe the long-term anatomo-clinical degradations according to the years preceding clinical diagnosis, and to provide clinically meaningful information on the sequence of events.Trial registrationclinicaltrials.gov, NCT01926249. Registered on 16 August 2013.
| S-EPMC10478286 | biostudies-literature
Project description:ObjectiveThe aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available.MethodsWe calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership-Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses.ResultsA higher polygenic resilience score was associated with a lower risk for PD (β = -0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci.InterpretationThe present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD. ANN NEUROL 2022;92:270-278.
| S-EPMC9329258 | biostudies-literature