Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and ...online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD-rs6812193 near SCARB2 (p = 7.6 × 10(-10), OR = 0.84) and rs11868035 near SREBF1/RAI1 (p = 5.6 × 10(-8), OR = 0.85)-both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%-7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered.
Summary Background Multiple system atrophy is a rare, fatal neurodegenerative disorder with symptoms of autonomic failure plus parkinsonism, cerebellar ataxia, or both. We report results of the first ...prospective natural history study of multiple system atrophy in the USA, and the effects of phenotype and autonomic failure on prognosis. Methods We recruited participants with probable multiple system atrophy—of either the parkinsonism subtype (MSA-P) or the cerebellar ataxia subtype (MSA-C)—at 12 neurology centres in the USA specialising in movement or autonomic disorders. We followed up patients every 6 months for 5 years and assessed them with the Unified Multiple System Atrophy Rating Scale part I (UMSARS I; a functional score of symptoms and ability to undertake activities of daily living), UMSARS II (neurological motor evaluation), and the Composite Autonomic Symptoms Scale (COMPASS)-select (a measure of autonomic symptoms and autonomic functional status). We assessed potential predictors of outcome. We used Cox proportional hazards models to calculate univariate hazard ratios for shorter survival using age at disease onset as a continuous variable and sex, clinical phenotype, and early development of neurological and autonomic manifestations as categorical variables. Findings We recruited 175 participants. Mean age at study entry was 63·4 years (SD 8·6). Median survival from symptom onset was 9·8 years (95% CI 8·8–10·7) and median survival from enrolment was 1·8 years (0·9–2·7). Participants with severe symptomatic autonomic failure (symptomatic orthostatic hypotension, urinary incontinence, or both) at diagnosis (n=62) had a worse prognosis than those without severe disease (n=113; median survival 8·0 years, 95% CI 6·5–9·5 vs 10·3 years, 9·3–11·4; p=0·021). At baseline, patients with MSA-P (n=126) and MSA-C (n=49) had much the same symptoms and functional status: mean UMSARS I 25·2 (SD 8·08) versus 24·6 (8·34; p=0·835); mean UMSARS II 26·4 (8·8) versus 25·4 (10·5; p=0·764); COMPASS-select 43·5 (18·7) versus 42·8 (19·6; p=0·835). Progression over 5 years, assessed by change in UMSARS I, UMSARS II, and COMPASS-select, was modest. Interpretation Probable multiple system atrophy is a late-stage disease with short survival. The natural histories of MSA-P and MSA-C are similar and severe symptomatic autonomic failure at diagnosis is associated with worse prognosis. Funding US National Institutes of Health, Mayo Clinic, and Kathy Shih Memorial Foundation.
Objective
Traumatic brain injury (TBI) is thought to be a risk factor for Parkinson disease (PD), but results are conflicting. Many studies do not account for confounding or reverse causation. We ...sought to address these concerns by quantifying risk of PD after TBI compared to non‐TBI trauma (NTT; defined as fractures).
Methods
Using inpatient/emergency department (ED) International Classification of Disease, Ninth Revision code data for California hospitals from 2005–2006, we identified patients aged ≥55 years with TBI (n = 52,393) or NTT (n = 113,406) and without baseline PD or dementia who survived hospitalization. Using Kaplan–Meier estimates and Cox proportional hazards models (adjusted for age, sex, race/ethnicity, income, comorbidities, health care use, and trauma severity), we estimated risk of PD after TBI during follow‐up ending in 2011. We also assessed interaction with mechanism of injury (fall vs nonfall) and effect of TBI severity (mild vs moderate/severe) and TBI frequency (1 TBI vs >1 TBI).
Results
TBI patients were significantly more likely to be diagnosed with PD compared to NTT patients (1.7% vs 1.1%, p < 0.001, adjusted hazard ratio HR = 1.44, 95% confidence interval CI = 1.31–1.58). Risk of PD was similar for TBI sustained via falls versus nonfalls (interaction p = 0.6). Assessment by TBI severity (mild TBI: HR = 1.24, 95% CI = 1.04–1.48; moderate/severe TBI: HR = 1.50, 95% CI = 1.35–1.66) and TBI frequency (1 TBI: HR = 1.45, 95% CI = 1.30–1.60; >1 TBI: HR = 1.87, 95% CI = 1.58–2.21) revealed a dose response.
Interpretation
Among patients aged ≥55 years presenting to inpatient/ED settings with trauma, TBI is associated with a 44% increased risk of developing PD over 5 to 7 years that is unlikely to be due to confounding or reverse causation. Ann Neurol 2015;77:987–995
Trial of Cinpanemab in Early Parkinson’s Disease Lang, Anthony E.; Siderowf, Andrew D.; Macklin, Eric A. ...
New England journal of medicine/The New England journal of medicine,
08/2022, Volume:
387, Issue:
5
Journal Article
Peer reviewed
Open access
In a phase 2 trial in early Parkinson’s disease, treatment with cinpanemab, a monoclonal antibody to α-synuclein, did not affect clinical or imaging progression over a period of 72 weeks.
Parkinson disease, the second-most-common neurodegenerative disorder, affects approximately 1 million individuals in the United States, and this number is projected to increase to 1.2 million by ...2030. Characterized pathologically by degeneration of dopaminergic neurons, with widespread pathology in nondopaminergic systems, Parkinson disease leads to an array of motor and nonmotor symptoms that can significantly impact an affected individual's quality of life. Treatments for Parkinson disease typically focus on controlling the motor symptoms of the disease, including treating OFF periods when motor symptoms return. OFF periods can occur for many individuals with Parkinson disease, especially as the disease progresses, and can pose a substantial burden to those with the disease and their caregivers. Available treatments for OFF periods may help alleviate this burden.
ObjectiveTo examine the baseline prevalence and longitudinal evolution in non-motor symptoms (NMS) in a prospective cohort of, at baseline, patients with de novo Parkinson’s disease (PD) compared ...with healthy controls (HC).MethodsParkinson’s Progression Markers Initiative (PPMI) is a longitudinal, ongoing, controlled study of de novo PD participants and HC. NMS were rated using the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part I score and other validated NMS scales at baseline and after 2 years. Biological variables included cerebrospinal fluid (CSF) markers and dopamine transporter imaging.Results423 PD subjects and 196 HC were enrolled and followed for 2 years. MDS-UPDRS Part I total mean (SD) scores increased from baseline 5.6 (4.1) to 7.7 (5.0) at year 2 in PD subjects (p<0.001) versus from 2.9 (3.0) to 3.2 (3.0) in HC (p=0.38), with a significant difference between the groups (p<0.001). In the multivariate analysis, higher baseline NMS score was associated with female sex (p=0.008), higher baseline MDS-UPDRS Part II scores (p<0.001) and more severe motor phenotype (p=0.007). Longitudinal increase in NMS severity was associated with the older age (0.008) and lower CSF Aβ1–42 (0.005) at baseline. There was no association with the dose or class of dopaminergic therapy.ConclusionsThis study of NMS in early PD identified clinical and biological variables associated with both baseline burden and predictors of progression. The association of a greater longitudinal increase in NMS with lower baseline Aβ1–42 level is an important finding that will have to be replicated in other cohorts.Trial registrationClinicalTrials.gov identifier: NCT01141023.
Parkinson's disease (PD) is one of the world's fastest growing neurological disorders. Much is unknown about PD-associated economic burdens in the United States (U.S.) and other high-income nations. ...This study provides a comprehensive analysis of the economic burdens of PD in the U.S. (2017) and projections for the next two decades. Multiple data sources were used to estimate the costs of PD, including public and private administrative claims data, Medicare Current Beneficiary Survey, Medical Expenditure Panel Survey, and a primary survey (n = 4,548) designed for this study. We estimated a U.S. prevalence of approximately one million individuals with diagnosed Parkinson's disease in 2017 and a total economic burden of $51.9 billion. The total burden of PD includes direct medical costs of $25.4 billion and $26.5 billion in indirect and non-medical costs, including an indirect cost of $14.2 billion (PWP and caregiver burden combined), non-medical costs of $7.5 billion, and $4.8 billion due to disability income received by PWPs. The Medicare program bears the largest share of excess medical costs, as most PD patients are over age 65. Projected PD prevalence will be more than 1.6 million with projected total economic burden surpassing $79 billion by 2037. The economic burden of PD was previously underestimated. Our findings underscore the substantial burden of PD to society, payers, patients, and caregivers. Interventions to reduce PD incidence, delay disease progression, and alleviate symptom burden may reduce the future economic burden of PD.
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