Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls.

BACKGROUND: Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls. METHODS: Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients. RESULTS: Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients. CONCLUSIONS: The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society.

Genetic markers of Restless Legs Syndrome in Parkinson disease.

INTRODUCTION: Several studies proposed that Restless Legs Syndrome (RLS) and Parkinson disease (PD) may be clinically and/or etiologically related. To examine this hypothesis, we aimed to determine whether the known RLS genetic markers may be associated with PD risk, as well as with PD subtype. METHODS: Two case-control cohorts from Tel-Aviv and New-York, including 1133 PD patients and 867 controls were genotyped for four RLS-related SNPs in the genes MEIS1, BTBD9, PTPRD and MAP2K5/SKOR1. The association between genotype, PD risk and phenotype was tested using multivariate regression models. RESULTS: None of the tested SNPs was significantly associated with PD risk, neither in any individual cohort nor in the combined analysis after correction for multiple comparisons. The MAP2K5/SKOR1 marker rs12593813 was associated with higher frequency of tremor in the Tel-Aviv cohort (61.0% vs. 46.5%, p = 0.001, dominant model). However, the risk allele for tremor in this gene has been associated with reduced RLS risk. Moreover, this association did not replicate in Tremor-dominant PD patients from New-York. CONCLUSION: RLS genetic risk markers are not associated with increased PD risk or subtype in the current study. Together with previous genetic, neuropathological and epidemiologic studies, our results further strengthen the notion that RLS and PD are likely to be distinct entities.

Higher frequency of certain cancers in LRRK2 G2019S mutation carriers with Parkinson disease: a pooled analysis.

IMPORTANCE: Patients with Parkinson disease (PD) who harbor LRRK2 G2019S mutations may have increased risks of nonskin cancers. However, the results have been inconsistent across studies. OBJECTIVES: To analyze pooled data from 5 centers to further examine the association between LRRK2 G2019S mutation and cancer among patients with PD and to explore factors that could explain discrepancies. DESIGN, SETTING, AND PARTICIPANTS: Clinical, demographic, and genotyping data as well as cancer outcomes were pooled from 1549 patients with PD recruited across 5 movement disorders clinics located in Europe, Israel, and the United States. Associations between LRRK2 G2019S mutation and the outcomes were examined using mixed-effects logistic regression models to estimate odds ratios (ORs) and 95% CIs. Models were adjusted for age and ethnicity (Ashkenazi Jewish vs others) as fixed effects and study center as a random effect. MAIN OUTCOMES AND MEASURES: All cancers combined, nonskin cancers, smoking-related cancers, hormone-related cancers, and other types of cancer. RESULTS: The overall prevalence of the LRRK2 G2019S mutation was 11.4% among all patients with PD. Mutation carriers were younger at PD diagnosis and more likely to be women (53.1%) and of Ashkenazi Jewish descent (76.8%) in comparison with individuals who were not mutation carriers. The LRRK2 G2019S mutation carriers had statistically significant increased risks for nonskin cancers (OR, 1.62; 95% CI, 1.04-2.52), hormone-related cancers (OR, 1.87; 95% CI, 1.07-3.26) and breast cancer (OR, 2.34; 95% CI, 1.05-5.22) in comparison with noncarriers. There were no associations with other cancers. There were no major statistically significant differences in the results when the data were stratified by Ashkenazi Jewish ethnicity; however, there was some evidence of heterogeneity across centers. CONCLUSIONS AND RELEVANCE: This multinational study from 5 centers demonstrates that LRRK2 G2019S mutation carriers have an overall increased risk of cancer, especially for hormone-related cancer and breast cancer in women. Larger prospective cohorts or family-based studies investigating associations between LRRK2 mutations and cancer among patients with PD are warranted to better understand the underlying genetic susceptibility between PD and hormone-related cancers.

Olfactory identification in LRRK2 G2019S mutation carriers: a relevant marker?

OBJECTIVE: Olfactory impairment is a potential marker for impending phenoconversion to Parkinson disease (PD) that may precede the development of disease by several years. Because of low specificity, it may be of greater predictive value in those with genetic mutations and its potential as a marker for developing LRRK2 PD should be evaluated. METHODS: We examined olfactory identification in 126 LRRK2 G2019S mutation carriers with PD, 125 mutation carriers not manifesting PD, 126 noncarriers with idiopathic PD, 106 noncarrier family members without PD, and 35 unrelated controls. We compared olfactory performance and performed mixture modeling to identify possible subgroups of olfactory performance in LRRK2 PD and nonmanifesting carriers. RESULTS: Adjusting for sex, age, cognitive score, site, and smoking history, LRRK2 PD had better olfactory scores compared to idiopathic PD (mean olfaction difference: -3.7, P < 0.001), and both LRRK2 PD and idiopathic PD had worse olfaction than controls (-12.8, -9.1, both P < 0.001). LRRK2 PD were less likely to be hyposmic than idiopathic PD (54.8% vs. 80.2%, P < 0.001). Nonmanifesting carriers and noncarrier family members did not differ. Mixture model analysis identified three classes in the LRRK2 PD and nonmanifesting carriers, suggesting that there are subgroups with poor olfactory identification in both LRRK2 PD and nonmanifesting carriers. INTERPRETATION: Therefore, olfactory identification deficit is less likely to be an obligate feature in LRRK2 PD than idiopathic PD, and while a relevant marker in some, a subset of carriers who eventually phenoconvert may proceed directly to PD without prior impaired olfaction.