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Constipation is a common but not a universal feature in early PD, suggesting that gut involvement is heterogeneous and may be part of a distinct PD subtype with prognostic implications. We analysed data from the Parkinson’s Incidence Cohorts Collaboration, composed of incident community-based cohorts of PD patients assessed longitudinally over 8 years. Constipation was assessed with the MDS-UPDRS constipation item or a comparable categorical scale. Primary PD outcomes of interest were dementia, postural instability and death. PD patients were stratified according to constipation severity at diagnosis: none (n = 313, 67.3%), minor (n = 97, 20.9%) and major (n = 55, 11.8%). Clinical progression to all three outcomes was more rapid in those with more severe constipation at baseline (Kaplan–Meier survival analysis). Cox regression analysis, adjusting for relevant confounders, confirmed a significant relationship between constipation severity and progression to dementia, but not postural instability or death. Early constipation may predict an accelerated progression of neurodegenerative pathology.

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 ofGBAon phenotypes.GBAvariants 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 ofGBAvariants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant nearLRRK2and 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 inPMVKand the development of wearing-off effects (HR 1.66 [1.19–2.31] for the C allele of rs114138760). Age at onset was associated withTMEM175variant p.M393T (−0.72 [−1.21 to −0.23] in years), the C allele of rs199347 (intronic region ofGPNMB, 0.70 [0.27–1.14]), and G allele of rs1106180 (intronic region ofCCDC62, 0.62 [0.21–1.03]).ConclusionsThis study provides evidence that alleles associated with Parkinson disease risk, in particularGBAvariants, 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.