Study On Clinical Characteristics And Disease Progression Of CPDR And CPD-LRRK2R Cohorts

Background:Parkinson’s disease(PD)is the second most common neurodegenerative disorder after Alzheimer’s disease.The prevalence of PD increases gradually with age,with an approximate prevalence of 2% in individuals over 65 years old,and a prevalence of about 4% in those over85 years of age.The clinical manifestations of PD are very heterogeneous,and the progression of the disease can vary greatly among patients.The LRRK2 gene is a pathogenic/risk gene for PD.There has been much debate over whether the clinical phenotype and disease progression of LRRK2-associated PD(LRRK2-PD)differ from that of idiopathic PD(IPD).The scientific question addressed in this thesis is: what are the clinical features and disease progression characteristics of PD patients and LRRK2-PD patients in China.Objective: To investigate the clinical features and disease progression of PD in China,and to explore the clinical characteristics,disease progression and differences between LRRK2-PD and IPD.Methods:(1)To establish the Chinese Parkinson’s Disease Registry(CPDR)research cohort,abbreviated as “CPDR cohort”;To establish the Chinese Parkinson’s Disease with LRRK2 Variants Registry(CPD-LRRK2R)research cohort,abbreviated as “CPD-LRRK2 R cohort”.(2)To complete the basic information collection,baseline clinical symptom evaluation,and relevant assessment scales of the CPDR and CPD-LRRK2 R cohorts.To complete the first 2-year follow-up of the CPDR and CPD-LRRK2 R cohorts.(3)Utilizing multivariate analysis methods such as multiple linear regression,logistic regression,and generalized linear models to analyze the clinical characteristics and disease progression of the CPDR and CPDLRRK2 R cohorts.Results:(1)A total of 3,148 clinically established or clinically probable PD patients with complete baseline data were included in the CPDR,including1,623 males and 1,525 females,897 early-onset PD and 2,251 late-onset PD,respectively.(2)In the CPDR cohort,we found that 1)patients with late-onset PD had more severe motor and non-motor symptoms than those with earlyonset PD,but the incidence of motor complications was significantly lower in the late-onset group.2)Patients with late-onset PD experienced faster progression of both motor and non-motor symptoms than those with earlyonset PD,but had a lower risk of developing motor complications.(3)In the CPDR cohort,1)female PD patients exhibited milder motor symptoms than male PD patients,but had higher incidence of dyskinesia,depression and cognitive impairment.In contrast,male PD patients had a higher proportion of autonomic dysfunction,excessive daytime sleepiness,and olfactory dysfunction.2)Additionally,female PD patients progressed slower in terms of tremors,rigidity,and autonomic dysfunction,but faster in terms of cognitive dysfunction and had a higher risk of developing dyskinesia than male patients.(4)Clinical subtypes in the CPDR cohort: 1)The mild motorpredominant subtype was characterized by mild motor and non-motor symptoms,with a relatively low proportion of probable rapid eye movement sleep behavior disorder(RBD),cognitive impairment,and motor complications.The diffuse malignant subtype was characterized by more severe motor and non-motor symptoms,with a relatively high proportion of probable RBD,cognitive impairment,and motor complications.The characteristics of the intermediate subtype were between the above two types.2)The diffuse malignant subtype had the fastest progression of both motor and non-motor symptoms,while the intermediate subtype had a moderate progression rate that was slightly higher than the mild motor-dominant subtype.(5)LRRK2 gene variation analysis(3,879 PD patients and 2,931 healthy controls): Analysis of variation in LRRK2 coding region found that the burden of rare variants in Chinese PD patients was similar to that in the control group;In the analysis of all common variants in LRRK2 transcription region and its flanking sequences,LRRK2 G2385 R,R1628P and A419 V were significantly correlated with PD after multiple test corrections.(6)Clinical features and disease progression were analyzed in the CPD-LRRK2 R cohort(649 cases)and the IPD cohort(1,407 cases),and the following findings were obtained: 1)CPD-LRRK2 R patients had similar motor symptoms to IPD patients,but a higher proportion of dyskinesia.The occurrence rate of fatigue and excessive daytime sleepiness was lower in CPD-LRRK2 R patients,while other non-motor symptoms were similar.2)The disease progression in terms of motor symptoms and motor complications was similar between CPD-LRRK2 R and IPD patients,with a lower risk of developing fatigue and sleep disturbances.3)The risk of developing dyskinesia in A419 V LRRK2-PD patients in the CPD-LRRK2 R cohort was higher than that in IPD patients and G2385 R LRRK2-PD patients.Conclusion:(1)The age at onset,gender,and clinical subtype of PD patients are correlated with the clinical phenotype and disease severity of PD,as well as disease progression.(2)LRRK2-PD patients exhibit similarities with IPD patients concerning motor symptoms,but there are differences in the proportion of dyskinesia,fatigue,and excessive daytime sleepiness.(3)LRRK2-PD patients have a lower risk of fatigue and sleep disturbances compared to IPD patients,while A419 V LRRK2-PD patients have a relatively higher risk of dyskinesia.