Relationship Between LRRK2 G2385R Variant And Subthalamic Deep Brain Stimulation Efficacy In Parkinson’s Disease

BackgroundParkinson’s disease(PD)is a common and chronic neurodegenerative disorder characterized clinically by movement impairments including resting tremor,bradykinesia,rigidity,and postural instability,as well as a variety of non-motor symptoms.The symptoms which mentioned above severely influenced the quality of life with PD.Due to the development of molecular biology technology,the role of genetic factors in the pathogenesis of PD has been paid more and more attention.At present,more than 20 PD related genes have been found,among which LRRK2(leucine-rich repeat kinase2)gene is the most common mutation in sporadic and familial PD.Of these,G2385R and R1628P are the two most common LRRK2 variants in Asian patients with PD.In particular,G2385R variation has been proved to be an important genetic risk factor for PD patients of han nationality,which may increases the risk of PD in the Han Chinese population by nearly two-fold.Deep brain stimulation(DBS)has become an effective treatment for advanced Parkinson’s disease.DBS can effectively improve resting tremor,bradykinesia,and rigidity,reduce the LEDD,motor fluctuations and dyskinesia,and significantly improve the quality of life of patients.The effect of DBS is closely related to preoperative evaluation,target accuracy and postoperative stimulation settings.Although many factors affect the outcome of DBS,there is still no consensus on the effect of genotype on DBS outcomes in PD.LRRK2 gene are the most common mutations in PD patients,and the variant rate of G2385R of LRRK2 gene is about 10%in Han Chinese population.Recent studies have confirmed its role in causing disease by altering the intensity and quality of LRRK2 protein interactions.Previous studies have confirmed that the improvement of DBS in PD patients with gene mutation is similar to sporadic PD.So far,no studies have focused on the effect of G2385R variant of LRRK2 gene on the efficacy of DBS.We retrospectively compared clinical outcomes of STN-DBS surgery between G2385R variant carriers and non-carriers in Han Chinese PD patients.ObjectiveCurrently,among the studies on the effect of genotype and DBS,no existing reports have focused on the outcomes of bilateral STN-DBS in Han Chinese PD patients positive for the G2385R variant.To test this,we retrospectively compared clinical outcomes of STN-DBS surgery between G2385R variant carriers and non-carriers in Han Chinese PD patients.Methods1.Research objectsA number of 61 PD patients of Han nationality who underwent bilateral STN-DBS surgery in the Department of Neurosurgery at Qilu Hospital of Shandong University between January 2015 and December 2017 agreed to participate in this study.All patients met the diagnostic criteria of PD and the indications for DBS surgery,and they volunteered to participate in this study.In order to exclude the influence of other common variant R1628P of LRRK2 gene,possible Parkin gene mutations and other hereditary genes,the exclusion criteria of this study were PD patients with R1628P positive,age at onset less than 40 years(onset age of PD patients with Parkin gene mutation is generally less than 40 years)and patients with a family history of PD(other hereditary PD).2.Research methodsLRRK2 G2385R and R1628P variants were detected in 61 PD patients by direct DNA sequencing.A total of 4 patients(2 patients with positive R1628P,1 patient with family history,and 1 patient onset age less than 40 years)were excluded.G2385R+/R1628P-patients were assigned to the positive G2385R group(G2385R+group)and G2385R-/R1628P-patients were assigned to the negative G2385R group(G2385R-group)in 57 PD patient.Clinical data of the two groups of patients were collected at the preoperative baseline and 12 months after surgery.Clinical data included the preoperative and post-DBS Mini-Mental State Examination Scale(MMSE),the Hamilton Depression Rating Scale(HAMD),the Unified Parkinson’s Disease Rating Scale(UPDRS-I:Cognition,Behavior,and Emotion;UPDRS-II:Daily Activity;UPDRS-III:Motor Function;UPDRS-IV:Levodopa-induced Motor Fluctuations and Dyskinesia),and levodopa equivalent daily dose(LEDD).Preoperative Hoehn and Yahr Scale,levodopa responsiveness and postoperative stimulation settings were also recorded.The following clinical data of PD patients in the two groups were analyzed and compared:l)The differences in age,gender,age at onset,disease duration,motor symptoms,levodopa responsiveness,Hoehn and Yahr Scale,and clinical symptoms between the two groups of PD patients at the preoperative baseline of STN-DBS;2)To compare the differences of clinical outcomes of STN-DBS surgery between G2385R+and G2385R-group;3)To analyze the improved clinical symptoms after STN-DBS of the two groups;4)Part of fllow-up datas of PD patients 24 months post-DBS and 36 months post-DBS were collected and compared with the preoperative baseline to observe the long-term follow-up results after STN-DBS;5)To compare the postoperative stimulation settings of the two groups.3.Statistical methods:Data were analyzed using SPSS 22.0.If normally distributed,measurements were expressed as means ± standard deviations.Otherwise,percentiles(P25-P75)were used for non-normal distributions.For categorical data,data were described in the form of frequencies(percentages).Between-group pre-surgical measurements were compared using t-tests or non-parametric tests,while categorical data were compared with chi-squared or Fisher’ s exact probability tests for between-group comparisons.A linear mixed model was used for post-surgical group comparisons.Paired t-tests or Kruskal-Wallis non-parametric tests were used to compare preoperative and postoperative indexes.The chi-square test was used to compare stimulation settings.P<0.05 was used to detect statistical significance.Result1、Preoperative baseline clinical characteristics of the two groupsAccording to the inclusion and exclusion criteria of this study,a total of 57 PD patients with bilateral STN-DBS surgery were included,including 8 patients in group G2385R+and 49 patients in group G2385R-.There were no significant differences in age,gender,age at onset,disease duration,UPDRS-Ⅲ sores(off-medication/on-medication),levodopa responsiveness,or Hoehn and Yahr Scale between the groups.There were no significant differences in the preoperative UPDRS scores(part Ⅰ to Ⅳ)and the subscores of UPDRS-Ⅲ,nor in LEDD,MMSE or HAMD scores.2、Comparison of efficacy between the two groups 12 months post-DBSThe G2385R variant showed no significant difference in UPDRS-Ⅱ score and improvement rate,UPDRS-Ⅲ score and improvement rate and LEDD reduction 12 months post-DBS,indicating that the G2385R variant did not significantly influence the effects of DBS on PD symptoms.Compared to the G2385R-group,post-surgery rigidity in the G2385R+group was significantly improved(P=0.045),while there was no significant difference in the other outcomes between the two groups.3、Surgical effects 12 months post-DBS in G2385R+and G2385R-group:Compared with the preoperative baseline,the UPDRS-Ⅱ and Ⅲ scores of 49 PD patients in G2385R+group were significantly improved 12 months post-DBS(P<0.001).The improvement rates of UPDRS-Ⅱ and Ⅲ were 35.48%and 45.45%,respectively;LEDD decreased by 37.50%compared with the preoperative baseline,and there was a significant decrease of LEDD(P<0.001).Compared with the preoperative baseline,G2385R-group showed significant improvement in other outcomes,including UPDRS-Ⅰ and Ⅳ scores,subscores of UPDRS-Ⅲ,and HAMD.There was no significant difference between preoperative and postoperative MMSE scores.Compared with the preoperative baseline,8 PD patients in G2385R+group showed significant improvement in the UPDRS-Ⅱ and Ⅲ scores 12 months post-DBS(P<0.05).The improvement rates of UPDRS-Ⅱ and Ⅲ were 36.95%and 46.08%,respectively;LEDD was reduced by 41.95%compared with the preoperative amount,and there was a significant decrease of LEDD(P<0.05).Compared with the preoperative baseline,the G2385R+group improved on all scores except for the cognitive function,depression symptom,tremor,axial symptom,dyskinesias,and motor fluctuations.4、Surgical effects at 24 and 36 months after surgery:In the two follow-up sites of 12 months and 24 months,9 PD patients after the operation also improved significantly UPDRS-Ⅱ scores and UPDRS-Ⅲ scores and decreases in LEDD;the symptoms of rigidity were significantly improved compared with baseline.There was no significant improvement in other outcomes.Compared with the baseline at 36 months after the operation,except for the significant decrease in UPDRS-Ⅲ scores,there were no significant differences in other scores.5、Stimulation settingsThere were no statistically significant differences in proportional distributions of monopolar stimulation,bipolar stimulation,double monopolar stimulation,and interleaved stimulations between the two groups.The postoperative voltage used in PD patients in the G2385R+group was significantly higher than that used in G2385R-group patients(P=0.033).However,there was no significant difference in pulse width or frequency between the two groups.Conclusion1.There was no significant difference in age,gender,age at PD onset,age at DBS surgery,duration of disease,severity of disease and other clinical features between G2385R carriers and G2385R non-carriers;2.There was no significant difference in in motor function,activities of daily living,and LEDD reductions between G2385R carriers and G2385R non-carriers,indicating that G2385R variation did not significantly affect the outcome of DBS surgery;3.G2385R carriers and G2385R non-carriers significantly improved their motor function,activities of daily living,and LEDD reductions 12 months post-DBS.4.Follow-up of 9 PD patients 24 months after STN-DBS surgery showed that their motor function,activities of daily living,and LEDD reductions were significantly improved.Five PD patients were followed up for 36 months after STN-DBS,and only motor function improved significantly.5.The postoperative voltage used in PD patients in the G2385R+carriers was significantly higher than that used in G2385R non-carriers.However,there was no significant difference in pulse width or frequency between the two groups.