Analysis Of Gastrointestinal Dysfunctions In Parkinson’s Disease

ObjectivesParkinson’s disease(PD)is the second common neurodegenerative disease.In addition to the motor symptoms,gastrointestinal(GI)dysfunctions are commonly experienced in PD patients,such as constipation and gastric emptying disorder.Recently,evidences have been reported that α-synuclein aggregates are found in the GI tract of PD cases.Furthermore,PD patients exhibit GI inflammation and altered compositions of GI microbiome when compared to healthy controls(HC).The involvement of GI tract in the pathogenesis and progression of PD is further reinforced by observations showing that PD and inflammatory bowel disease(IBD)are genetically and epidemiologically linked.Therefore,we analyzed the associations between GI dysfunctions and PD progression,and further evaluated the effect of genetic and serologic factors related to GI dysfunctions in PD.In the present study,we aimed to investigate the genetic basis of GI dysfunctions in PD,search for candidate biomarkers related to GI functions for PD early diagnosis,and provide views and methods to explore the underlying mechanisms of PD related GI dysfunctions.MethodsExperiment 1:We analyzed the baseline and follow-up clinical data of 414 PD patients from the Parkinson Progression Marker Initiative(PPMI)database.Mixed linear models were performed to assess the associations between GI dysfunctions and the progression of motor symptoms,disease severity and motor complications in PD patients.We further analyzed the differences in the reductions of striatal dopaminergic transporter and the baseline cerebrospinal fluid(CSF)protein levels between PD patients with high or low GI dysfunctions.Experiment 2:The Genome-wide sequencing data of PD and HC cohorts were acquired from PPMI database and 20 single nucleotide polymorphisms(SNPs)of IL23R and NOD2 were selected after quality control.We compared the frequency of these SNPs between PD patients and HC to search for risk or protective factors in PD.Furthermore,we evaluated the effects of these SNPs on GI dysfunctions and disease progression in PD.Experiment 3:We recruited 140 PD patients,105 essential tremor(ET)patients and 130 HC.Clinical assessment was performed and the levels of serum antibodies related to GI inflammation were tested,such as Anti-saccharomyces cerevisiae antibody(ASCA).We compared the positivity and concentrations of serum antibodies in 3 groups and evaluated the diagnostic accuracy of these antibodies in differentiating PD patients from ET patients or from HC.Furthermore,we analyzed the associations between serum antibodies and clinical characteristics in PD patients.ResultsExperiment 1:The associations between GI dysfunctions and disease progression in PDThe burden of GI dysfunctions was positively related to the progression of motor symptoms and Hoehn-Yahr stage in PD.PD patients who experienced more GI symptoms were likely to have earlier occurrence and faster development in motor complications,which is to some degree also related to disease progression.Consistent with the clinical phenotype,we found the burden of GI dysfunction was positively associated with the reductions of striatal dopaminergic transporter.Furthermore,significant relationship between GI dysfunctions and baseline CSF Aβ1-42 levels was indicated in the present study,while no evidences was found regarding the associations between GI dysfunctions and CSF α-Syn,Tau or p-Tau.Experiment 2:The associations between IBD-related SNPs and PDOverall,we selected 14 SNPs of IL23R and 6 SNPs of NOD2 for the present study.We found the A allele of IL23R-rs10889667 was related to increased risk of PD.We further analyzed the associations between these SNPs and GI dysfunctions in PD and found the IL23R-rs10889667,IL23R-rs72676073 and NOD2-rs8061960 were related to the GI autonomous dysfunctions in PD.Interestingly,this effect was not found in HC cohort.Additionally,no relationship between 20 SNPs and motor progression was found in PD.Experiment 2:The associations between IBD-related serum antibodies and PDBoth ASCAIgG and IgAlevels were significantly higher in the serum of PD patients in comparison with those of ET patients or HC.Serum ASCA levels were positively correlated with age.Corrected for age and gender,serum ASCA IgG and IgA levels could discriminate PD patients from HC or from ET patients.Combining ASCA IgG and IgA levels,a composite marker generated by using logistic regression analysis was able to distinguish PD patients from HC or from ET patients as well.Additionally,ASCA IgG levels were significantly related to constipations and ASCA IgA was positively correlated with UPDRS part Ⅱ scores in PD patents.ConclusionsIn the present study,we analyzed the associations between GI dysfunctions and disease progression in PD and found the burden of GI symptoms was positively related to the development of motor symptoms,Hoehn-Yahr stage and motor complications,which indicated that GI dysfunctions may serve as a prognostic factor in PD pathological progression.We further identified some SNPs of IL23R and NOD2 being significantly related to the GI symptoms in PD,suggesting the genetic factors may be involved in the development of GI dysfunctions in PD.Besides,IL23R and NOD2 may become potential targets for the treatment of PD-related GI symptoms.Then we identified the A allele of IL23R-rs10889667 which may serve as a risk factor in PD for the first time,providing new ideas for the pathogenesis of PD.Additionally,we found elevated serum ASCA levels in PD patients for the first time and evaluated it as a potential biomarker for PD diagnosis.The originality of the present study is that we investigated the roles of GI dysfunctions in PD pathogenesis and progression from multiple perspectives,including symptomology,genetics and serology.For the first time we identified certain SNPs of IL23R and NOD2 as risk factors of PD and PD-related GI dysfunctions,and evaluated the potential of serum ASCA level to be a biomarker for PD diagnosis.This study could provide new views for further researches in PD.