Fractures in the prodromal period of Parkinson disease.

OBJECTIVE: To examine the association between fractures and Parkinson disease (PD) during the 5-year prodromal phase as compared to controls. METHODS: We performed a population-based case-control study of Medicare beneficiaries in the United States from 2004 to 2009. We identified 89,632 incident PD cases and 117,760 comparable controls 66-90 years of age in 2009. PD case status was the outcome, and noncranial fracture the independent variable. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for association between fracture and PD in yearly time intervals prior to PD diagnosis/control reference date, after adjusting for covariates. RESULTS: There were 39,606 total fractures (25.4% cases, 14.3% controls) over the 5 years prior to the PD diagnosis/control reference date. PD was positively associated with fractures even after adjusting for age, sex, race/ethnicity, Charlson comorbidity index, alcohol use, tobacco use, and osteoporosis. The association between PD and fracture was evident at yearly time windows prior to PD diagnosis/control reference date. The association between PD and each type of fracture strengthened as the PD diagnosis/control reference date approached (all time interaction p values ≤0.02). Among beneficiaries with a mechanism of injury, the majority were attributed to falls (74.6% cases, 72.8% controls). CONCLUSION: Fractures occur more commonly during the prodromal period of PD compared to controls, especially as diagnosis date approached, suggesting that patients with PD may experience unrecognized motor and nonmotor symptoms.

ß2-adrenoreceptor medications and risk of Parkinson disease.

OBJECTIVE: A recent study observed a 2-fold greater risk of Parkinson disease (PD) in relation to the ß2-adrenoreceptor antagonist propranolol and a markedly lower risk of PD for the ß2-adrenoreceptor agonist salbutamol. We examined whether confounding by clinical indication for these medications, that is, tremor and smoking-related pulmonary conditions, explained these associations. METHODS: In a large, population-based case-control study of United States Medicare beneficiaries in 2009 with diagnosis codes, procedure codes, and prescription data (48,295 incident PD cases, 52,324 controls), we examined the risk of PD in relation to use of selected ß antagonists (propranolol, carvedilol, metoprolol), the ß2 agonist salbutamol, and other medications used for the same clinical indications (primidone, inhaled corticosteroids). We adjusted for demographics, smoking, and overall use of medical care. We then examined the effect of also adjusting for clinical indication and applying medication exposure lagging. RESULTS: Propranolol appeared to increase PD risk (odds ratio [OR] = 3.62, 95% confidence interval [CI] = 3.31-3.96). When we adjusted for tremor or abnormal involuntary movement prior to the PD diagnosis/reference date and lagged propranolol exposure, the association was 0.97 (95% CI = 0.80-1.18). Primidone, also used for tremor, was similarly sensitive to this adjustment and lagging. ß Antagonists not indicated for tremor appeared to reduce PD risk (carvedilol: OR = 0.77, 95% CI = 0.73-0.81; metoprolol: OR = 0.94, 95% CI = 0.91-0.97) and were insensitive to adjustment for indications and lagging. Neither salbutamol nor inhaled corticosteroids were consistently associated with PD risk. INTERPRETATION: ß2-adrenoreceptor agonists and antagonists do not appear to alter PD risk. Ann Neurol 2018;84:691-701.

Use of medical care biases associations between Parkinson disease and other medical conditions.

OBJECTIVE: To examine how use of medical care biases the well-established associations between Parkinson disease (PD) and smoking, smoking-related cancers, and selected positively associated comorbidities. METHODS: We conducted a population-based, case-control study of 89,790 incident PD cases and 118,095 randomly selected controls, all Medicare beneficiaries aged 66 to 90 years. We ascertained PD and other medical conditions using ICD-9-CM codes from comprehensive claims data for the 5 years before PD diagnosis/reference. We used logistic regression to estimate age-, sex-, and race-adjusted odds ratios (ORs) between PD and each other medical condition of interest. We then examined the effect of also adjusting for selected geographic- or individual-level indicators of use of care. RESULTS: Models without adjustment for use of care and those that adjusted for geographic-level indicators produced similar ORs. However, adjustment for individual-level indicators consistently decreased ORs: Relative to ORs without adjustment for use of care, all ORs were between 8% and 58% lower, depending on the medical condition and the individual-level indicator of use of care added to the model. ORs decreased regardless of whether the established association is known to be positive or inverse. Most notably, smoking and smoking-related cancers were positively associated with PD without adjustment for use of care, but appropriately became inversely associated with PD with adjustment for use of care. CONCLUSION: Use of care should be considered when evaluating associations between PD and other medical conditions to ensure that positive associations are not attributable to bias and that inverse associations are not masked.

Inflammatory bowel disease and risk of Parkinson's disease in Medicare beneficiaries.

INTRODUCTION: Gastrointestinal (GI) dysfunction precedes the motor symptoms of Parkinson's disease (PD) by several years. PD patients have abnormal aggregation of intestinal α-synuclein, the accumulation of which may be promoted by inflammation. The relationship between intestinal α-synuclein aggregates and central nervous system neuropathology is unknown. Recently, we observed a possible inverse association between inflammatory bowel disease (IBD) and PD as part of a predictive model of PD. Therefore, the objective of this study was to examine the relationship between PD risk and IBD and IBD-associated conditions and treatment. METHODS: Using a case-control design, we identified 89,790 newly diagnosed PD cases and 118,095 population-based controls >65 years of age using comprehensive Medicare data from 2004-2009 including detailed claims data. We classified IBD using International Classification of Diseases version 9 (ICD-9) diagnosis codes. We used logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between PD and IBD. Covariates included age, sex, race/ethnicity, smoking, Elixhauser comorbidities, and health care use. RESULTS: PD was inversely associated with IBD overall (OR = 0.85, 95% CI 0.80-0.91) and with both Crohn's disease (OR = 0.83, 95% CI 0.74-0.93) and ulcerative colitis (OR = 0.88, 95% CI 0.82-0.96). Among beneficiaries with ≥2 ICD-9 codes for IBD, there was an inverse dose-response association between number of IBD ICD-9 codes, as a potential proxy for IBD severity, and PD (p-for-trend = 0.006). CONCLUSION: IBD is associated with a lower risk of developing PD.

A screening tool to detect clinical manganese neurotoxicity.

Manganese (Mn) over-exposure in occupational settings is associated with basal ganglia toxicity and a movement disorder characterized by parkinsonism (i.e., the signs and symptoms of Parkinson disease). A simple test to help non-neurologists identify workers with clinical Mn neurotoxicity represents an unmet need. In a cohort of Mn-exposed workers from welding worksites, with extensive clinical data, we developed a linear regression model to predict the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3) score. We primarily considered factors easily obtained in a primary care or occupational medicine clinic, specifically easily assessed signs of parkinsonism and factors likely to be associated with UPDRS3 such as age, timed motor task results, and selected symptoms/conditions. Secondarily we considered other demographic variables and welding exposure. We based the model on 596 examined workers age≤65years and with timed motor task data. We selected the model based on simplicity for clinical application, biologic plausibility, and statistical significance and magnitude of regression coefficients. The model contained age, timed motor task scores for each hand, and indicators of action tremor, speech difficulty, anxiety, depression, loneliness, pain and current cigarette smoking. When we examined how well the model identified workers with clinically significant parkinsonism (UPDRS3≥15) the receiver operating characteristic area under the curve (AUC) was 0.72 (95% confidence interval [CI] 0.67, 0.77). With a cut point that provided 80% sensitivity, specificity was 52%, the positive predictive value in our cohort was 29%, and the negative predictive value was 92%. Using the same cut point for predicted UPDRS3, the AUC was nearly identical for UPDRS3≥10, and was 0.83 (95% CI 0.76, 0.90) for UPDRS3≥20. Since welding exposure data was not required after including its putative effects, this model may help identify workers with clinically significant Mn neurotoxicity in a variety of settings, as a first step in a tiered occupational screening program.