Clinical characteristics of PD patients carrying LRRK2 R1628P variant

Clinical characteristics of PD patients carrying LRRK2 R1628P variant | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Clinical characteristics of PD patients carrying LRRK2 R1628P variant Xiao Deng, Joshua Kuruvilla, Ebonne Yu-Lin Ng, Yew-long Lo, Zheyu Xu, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5321847/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Parkinson’s Disease (PD) presents devastating challenges for the aging society. Variations in the LRRK2 gene, including R1628P in Asian populations have been linked to PD risk yet remain under-explored in clinical presentations. We assessed clinical manifestations in R1628P carriers versus non-carriers in an Asian PD cohort. Our study found that LRRK2 R1628P carriers had significantly lower Non-Motor Symptom Scale (NMSS) Total score (10 vs 15 p=0.01) than non-carriers. Specifically, NMSS domain 2 score (sleep/fatigue) was lower in carriers compared to non-carriers (0 vs 1, p=0.02), with no significant differences in other NMSS domains. This study underscores the importance of analysing specific LRRK2 variants, to characterise accurately the influence of unique genetic variation of PD relevant gene and identify potential therapeutic target. Introduction Parkinson’s Disease (PD) is a complex and progressive neurodegenerative disorder with various genetic and environmental factors contributing to its development. It is characterised primarily by clinically recognised motor symptoms, including tremors, bradykinesia, rigidity, and postural instability [ 1 ]. Notably, a host of non-motor symptoms (NMS) significantly impact the quality-of-life for individuals suffering from PD. NMS covers a broad spectrum, ranging from cognitive and psychiatric symptoms (depression, anxiety), to autonomic dysfunction (constipation, urinary problems), sleep disturbances, sensory issues and fatigue [ 2 ]. Mutations in the leucine-rich repeat kinase 2 ( LRRK2 ) gene represent one of the most common monogenic forms of PD in Caucasian populations [ 3 , 4 ], whereas genetic variants in LRRK2 are associated with the risk of PD development in Asian population [ 5 , 6 ]. The study on LRRK2 protein also provides valuable insights in idiopathic PD [ 7 ] and it reveals the mechanisms involved in disease progression including neuronal death [ 8 ], kinase activity [ 9 ], and α-synuclein aggregation [ 10 ]. The association between a significant increase in risk of Parkinson's disease and G2385R carriers was first identified in an Asian population in 2006 [ 11 ]. R1628P was the second risk factor to be identified in Asian populations, with an increased PD risk in Chinese populations (Taiwan and Singapore) [ 12 , 13 ]. Evidence of clinical presentation of LRRK2 -related PD is conflicting, particularly regarding Asian-related LRRK2 variants ( G2385R and R1628P ). In this study, we investigated motor, non-motor symptoms and cognitive functions of LRRK2 R1628P variant carriers in a Asian PD cohort. Methods Participants PD patients diagnosed in accordance with the diagnostic criteria of the National Institute of Neurological Disorders and Stroke (NINDS), were recruited from two movement disorder outpatient clinics in Singapore. Approval for our study was obtained from the SingHealth Centralized Institutional Review Board (CIRB) under Ref 2019/2433 and the approval date was 2 August 2014. The written informed consent was obtained from all participating individuals. Data collection and assessments Demographic and comorbidity information was gathered from all participants. Motor performance was evaluated by the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), while non-motor symptoms were assessed by the non-motor symptom scale (NMSS). The overall cognitive change was assessed using the Montreal Cognitive Assessment (MoCA) score. Genetic analyses LRRK2 R1628P variant was genotyped by the Illumina Human OmniZhonghua-8 v1A BeadChip. All positive variants in our selected samples have been validated by Sanger sequencing. Patients with PD were categorised according to the genotyping results into carriers (LRRK2 R1628P GC allele) and non-carriers (LRRK2 R1628P GG allele). Statistical analysis Continuous variables were presented as either mean with standard deviation (SD) or median with first and third quartile. Categorical variables were summarized through frequencies and percentages. The comparison of categorical variables between LRRK2 R1628P carriers and non-carriers utilized the Chi-square or Fisher’s exact test. For continuous variables, a two-sample t-test or Mann–Whitney U test (depending on the tenability of the normality assumption) was conducted to compare the two groups. The significance level was set at p < 0.05. False discovery rate (FDR) method was performed to control for multiple testing comparison and q value was calculated. We set the threshold of q values as 0.15. Data processing and statistical analysis were conducted using Stata/SE version 16.1. Results In this cross-section study, a total of 206 Parkinson's disease (PD) patients were included in the analysis, comprising 20 LRRK2 R1628P carriers and 186 non-carriers. Demographics of the two groups were comparable, including gender distribution [58.6% males in the non-carrier group and 65.0% in the LRRK2 R1628P carrier group (p = 0.64)]. Most participants were of Chinese descent [84.4% in the non-carrier group and 94.7% in the carrier group (p = 0.90)]. A higher proportion of individuals with a family history of PD was observed in the LRRK2 R1628P carrier group (13.3%) compared to the non-carrier group (5.2%) (p = 0.04). No significant differences were found while examining comorbidities (p > 0.05 for all comparisons). The analysis of non-motor symptoms revealed LRRK2 R1628P carriers exhibited notably reduced NMSS Total scores compared to non-carriers (10 vs. 15, p = 0.01, q = 0.13). Particularly, within the specific domain of sleep/fatigue (NMSS domain 2), carriers displayed significantly lower scores in contrast to non-carriers (0 vs. 1, p = 0.02, q = 0.13). NMSS total and NMSS domain 2 q values are both 0.13, which indicates that they are still significant after the adjustment for multiple comparison. No significant differences were found in the remaining NMSS domains (p > 0.05 for all comparisons). Table 1 Demographic and comorbidity between LRRK2 R1628P carriers and non-carriers Non-carriers LRRK2 R1628P carriers n = 186 n = 20 p-value ** Gender: male (%) 109 (58.6%) 13 (65.0%) 0.64 Race: Chinese 157 (84.4%) 18 (94.7%) 0.90 Family history (%) 7 (5.2%) 2 (13.3%) 0.04 Diabetes Mellitus (%) 8 (17.4%) 27 (17.1%) 1.00 Hypertension (%) 33 (17.7%) 2 (10.0%) 0.54 Hyperlipidaemia (%) 82 (44.1%) 13 (65.0%) 0.10 Gout (%) 84 (45.2%) 13 (65.0%) 0.10 Lipid medication 81 (43.5%) 12 (60.0%) 0.24 Hypertension medication 82 (44.1%) 12 (60.0%) 0.24 Categorical variables reported as frequency (%); Chi-square or Fisher exact test (where appropriate) for categorical variables; Table2: clinical characteristics between LRRK2 R1628P carriers and non-carriers Non-carriers LRRK2 R1628P carriers p-value q-value n=186 n=20 Age of diagnosis 63.5 (9.2) 63.3 (7.8) 0.91 0.91 MDS-UPDRS part III score 20 (15-26) 20.5 (18-28.5) 0.5 0.68 MoCA Total 26 (23-28) 27 (24.5-29) 0.11 0.36 NMSS Total score 15 (9-27) 10 (3-14.5) 0.01 * 0.13 ** NMSSD1Score (cardiovascular) 0 (0-0) 0 (0-0) 0.26 0.56 NMSSD2Score (sleep/fatigue) 1 (0-5) 0 (0-1.5) 0.02 * 0.13 ** NMSSD3Score (mood/apathy) 0 (0-2) 0 (0-1) 0.58 0.68 NMSSD4Score (perceptual problems) 0 (0-0) 0 (0-0) 0.53 0.68 NMSSD5Score (attention/memory) 0 (0-2) 0 (0-2) 0.6 0.68 NMSSD6Score (gastrointestinal) 0 (0-3) .5 (0-3) 0.63 0.68 NMSSD7Score (urinary) 4 (0-8) 1.5 (0-4) 0.07 0.3 NMSSD8Score (sexual function) 0 (0-0) 0 (0-0) 0.51 0.68 NMSSD9Score (miscellaneous) 0 (0-4) 0 (0-2.5) 0.23 0.56 Abbreviations: MDS-UPDRS: Movement Disorder Society-Unified Parkinson’s Disease Rating Scale; NMSS: Non-motor symptom scale C ontinuous variables reported as median and first and third quartile. Chi-square or Fisher exact test (where appropriate) for categorical variables; Two-sample t test or Mann Whitney U test (where appropriate) for continuous variables, respectively False discovery rate (FDR) method was performed to control for multiple testing comparison and q value was calculated. We set the threshold of q values as 0.15. Discussion Our cross-sectional study involved the assessment of 206 PD patients with clinical evaluations of motor, non-motor symptoms. The results revealed intriguing disparities between these two groups. Notably, LRRK2 R1628P carriers displayed significantly lower NMSS Total scores compared to non-carriers, implying milder NMS. In particular, within the non-motor domains, we observed significantly lower scores for the sleep and fatigue subdomain in LRRK2 R1628P carriers. Evidence of clinical presentation of PD carrying Asian related LRRK2 variants is limited and conflicting. Liang et al reported that LRRK2 G2385R and R1628P carriers had similar clinical features compared to idiopathic PD patients [14]. This all-or-none LRRK2 variant categorisation could at least partially explain the discrepancy that a study observed a lack of significant differences in non-motor characteristics between carriers and non-carriers [15] whereas another study observing a single LRRK2 variant ( G2385R ) identified that carriers are a risk factor for severe motor subtype and had more REM sleep behaviour disorder [16]. Our study examined a single LRRK2 variant ( R1628P ) to elucidate their clinical impact on PD. The observed differences in our study could be attributed to the unique genetic properties of the R1628P variant, thereby highlighting the need to analyse LRRK2 variants separately in clinical studies. Additionally, previous studies suggested there was no significant difference in NMS in either variant ( G2385R and R1628P ) compared to non-carriers [14] , [17]. However, these previous studies assessed NMS using a compilation of various evaluations for each NMS [14] or used Non-Motor Symptom Questionnaire (NMSQ) [17]. In contrast, our study conducted a structured interview employing NMSS specific for evaluation of NMS in PD, an evaluation capable of capturing a range of relevant NMS within a single scale and possessing strong correlation with advancing disease stages of PD since it’s conception [18]. A previous study on PD utilising both NMSQ and NMSS has also highlighted apparent discrepancies, noting the methodology of NMSS assessing the severity or frequency of NMS being in contrast to NMSQ which uses a “yes” or “no" scoring system [19]. Interestingly, correlation was found in a study exploring the common etiology between sporadic Alzheimer’s disease (SAD) and PD with LRRK2 , which observed a neuroprotective effect of LRRK2 R1628P variant through lower risk of developing SAD in an Asian population subset (Han Chinese population), particularly among APOE e4 allele carriers. In contrast, another LRRK2 variant G2385R failed to emulate a similar result, further reinstating the importance of studying specific LRRK2 variant individually [20]. Consistently, this neuroprotective observation aligns with our clinical characterisation of decreased NMS in R1628P carriers. Our study underscores the significance of conducting analyses for specific LRRK2 variants separately in clinical studies, particularly among different ethnicities. In existing studies, G2019S mutation, a well-known LRRK2 mutation which primarily affects individuals of Caucasian descent among PD patients was identified to have more behavioural abnormalities (depression, hallucinations) and sleep disorders compared to non-carriers [21, 22] although some studies have found less conclusive results on NMS impact [23-25]. Our study’s results, based on PD of Asian populations, provide insights into the clinical characteristics of PD patients with LRRK2 R1628P variant. The observed reduction in NMS symptoms associated with LRRK2 R1628P variant emphasises not only the importance of targeted analysis among different demographics carrying PD-relevant variants, but also has the potential impact on development of neuroprotective strategy given the finding of our study and others that R1628P may confer neuroprotection in NMS including cognitive functions. Future research to elucidate the underlying mechanisms and explore further clinical implication of R1628P variant on translational PD models is warranted. Declarations Funding: This study was supported by the Singapore Ministry of Health’s National Medical Research Council under its Open Fund Large Collaborative Grant (MOH-OFLCG18May-0002). Acknowledgments: We would like to thank the support from Singapore Ministry of Health’s National Medical Research Council under its Open Fund Large Collaborative Grant (MOH-OFLCG18May-0002). Author Contributions Statement: XD, XB: Review concept, design, drafting, revising the manuscript; JK and YLN: Data collection, helping draft and revise the manuscript; Y-L L, ZYX, K-Y T, W-L A: revising manuscript; E-K T and LCS T: Study supervision, revising manuscript. Data Availability Statements: The datasets generated during and/or analysed during the current study are not publicly available due to ethical restrictions, but are available from the corresponding author on reasonable request. Competing interests: No competing interests. References DeMaagd G, Philip A (2015). Parkinson's Disease and Its Management: Part 1: Disease Entity, Risk Factors, Pathophysiology, Clinical Presentation, and Diagnosis. P t, 40:504-532. Seppi K, Ray Chaudhuri K, Coelho M, Fox SH, Katzenschlager R, Perez Lloret S , et al. (2019). Update on treatments for nonmotor symptoms of Parkinson's disease-an evidence-based medicine review. Mov Disord, 34:180-198. Tolosa E, Vila M, Klein C, Rascol O (2020). LRRK2 in Parkinson disease: challenges of clinical trials. Nat Rev Neurol, 16:97-107. Trinh J, Zeldenrust FMJ, Huang J, Kasten M, Schaake S, Petkovic S , et al. (2018). 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LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson's disease patients. Nat Commun, 10:5570. Volpicelli-Daley LA, Abdelmotilib H, Liu Z, Stoyka L, Daher JP, Milnerwood AJ , et al. (2016). G2019S-LRRK2 Expression Augments alpha-Synuclein Sequestration into Inclusions in Neurons. J Neurosci, 36:7415-7427. Di Fonzo A, Wu-Chou YH, Lu CS, van Doeselaar M, Simons EJ, Rohé CF , et al. (2006). A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan. Neurogenetics, 7:133-138. Tan EK, Tan LC, Lim HQ, Li R, Tang M, Yih Y , et al. (2008). LRRK2 R1628P increases risk of Parkinson's disease: replication evidence. Hum Genet, 124:287-288. Ross OA, Wu Y-R, Lee M-C, Funayama M, Chen M-L, Soto AI , et al. (2008). Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease. Annals of Neurology, 64:88-92. Liang D, Shu L, Pan H, Xu Q, Guo J, Yan X , et al. (2018). Clinical characteristics of PD patients with LRRK2 G2385R and R1628P variants. Neurosci Lett, 685:185-189. Wang C, Cai Y, Gu Z, Ma J, Zheng Z, Tang BS , et al. (2014). Clinical profiles of Parkinson's disease associated with common leucine-rich repeat kinase 2 and glucocerebrosidase genetic variants in Chinese individuals. Neurobiol Aging, 35:725 e721-726. Sun Q, Wang T, Jiang TF, Huang P, Li DH, Wang Y , et al. (2016). Effect of a Leucine-rich Repeat Kinase 2 Variant on Motor and Non-motor Symptoms in Chinese Parkinson's Disease Patients. Aging Dis, 7:230-236. Li DW, Gu Z, Wang C, Ma J, Tang BS, Chen SD , et al. (2015). Non-motor symptoms in Chinese Parkinson's disease patients with and without LRRK2 G2385R and R1628P variants. J Neural Transm (Vienna), 122:661-667. Chaudhuri KR, Martinez-Martin P, Brown RG, Sethi K, Stocchi F, Odin P , et al. (2007). The metric properties of a novel non-motor symptoms scale for Parkinson's disease: Results from an international pilot study. Mov Disord, 22:1901-1911. Mendorf S, Witte OW, Zipprich H, Prell T (2020). Association Between Nonmotor Symptoms and Nonadherence to Medication in Parkinson's Disease. Front Neurol, 11:551696. Li HL, Lu SJ, Sun YM, Guo QH, Sadovnick AD, Wu ZY (2013). The LRRK2 R1628P variant plays a protective role in Han Chinese population with Alzheimer's disease. CNS Neurosci Ther, 19:207-215. Belarbi S, Hecham N, Lesage S, Kediha MI, Smail N, Benhassine T , et al. (2010). LRRK2 G2019S mutation in Parkinson's disease: a neuropsychological and neuropsychiatric study in a large Algerian cohort. Parkinsonism Relat Disord, 16:676-679. Mirelman A, Alcalay RN, Saunders-Pullman R, Yasinovsky K, Thaler A, Gurevich T , et al. (2015). Nonmotor symptoms in healthy Ashkenazi Jewish carriers of the G2019S mutation in the LRRK2 gene. Mov Disord, 30:981-986. Mestre TA, Pont-Sunyer C, Kausar F, Visanji NP, Ghate T, Connolly BS , et al. (2018). Clustering of motor and nonmotor traits in leucine-rich repeat kinase 2 G2019S Parkinson's disease nonparkinsonian relatives: A multicenter family study. Mov Disord, 33:960-965. Alcalay RN, Mirelman A, Saunders-Pullman R, Tang MX, Mejia Santana H, Raymond D , et al. (2013). Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations. Mov Disord, 28:1966-1971. Gatto EM, Parisi V, Converso DP, Poderoso JJ, Carreras MC, Marti-Masso JF , et al. (2013). The LRRK2 G2019S mutation in a series of Argentinean patients with Parkinson's disease: clinical and demographic characteristics. Neurosci Lett, 537:1-5. Additional Declarations No competing interests reported. Supplementary Files GA.png Graphical abstract: Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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01:23:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5321847/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5321847/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":70468681,"identity":"907aae47-7f29-4d50-8488-553311787bc0","added_by":"auto","created_at":"2024-12-03 12:54:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":384167,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5321847/v1/8b5b56b2-e187-4787-bd10-9cbda00cd2eb.pdf"},{"id":68269403,"identity":"300afc60-3749-4618-9836-e5da45fdd6df","added_by":"auto","created_at":"2024-11-05 13:26:06","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21249,"visible":true,"origin":"","legend":"\u003cp\u003eGraphical abstract:\u003c/p\u003e","description":"","filename":"GA.png","url":"https://assets-eu.researchsquare.com/files/rs-5321847/v1/3018d323f05394aa56a6930a.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical characteristics of PD patients carrying LRRK2 R1628P variant","fulltext":[{"header":"Introduction","content":"\u003cp\u003eParkinson\u0026rsquo;s Disease (PD) is a complex and progressive neurodegenerative disorder with various genetic and environmental factors contributing to its development. It is characterised primarily by clinically recognised motor symptoms, including tremors, bradykinesia, rigidity, and postural instability [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Notably, a host of non-motor symptoms (NMS) significantly impact the quality-of-life for individuals suffering from PD. NMS covers a broad spectrum, ranging from cognitive and psychiatric symptoms (depression, anxiety), to autonomic dysfunction (constipation, urinary problems), sleep disturbances, sensory issues and fatigue [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Mutations in the leucine-rich repeat kinase 2 (\u003cem\u003eLRRK2\u003c/em\u003e) gene represent one of the most common monogenic forms of PD in Caucasian populations [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], whereas genetic variants in \u003cem\u003eLRRK2\u003c/em\u003e are associated with the risk of PD development in Asian population [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The study on LRRK2 protein also provides valuable insights in idiopathic PD [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and it reveals the mechanisms involved in disease progression including neuronal death [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], kinase activity [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and α-synuclein aggregation [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The association between a significant increase in risk of Parkinson's disease and \u003cem\u003eG2385R\u003c/em\u003e carriers was first identified in an Asian population in 2006 [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. \u003cem\u003eR1628P\u003c/em\u003e was the second risk factor to be identified in Asian populations, with an increased PD risk in Chinese populations (Taiwan and Singapore) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Evidence of clinical presentation of \u003cem\u003eLRRK2\u003c/em\u003e-related PD is conflicting, particularly regarding Asian-related \u003cem\u003eLRRK2\u003c/em\u003e variants (\u003cem\u003eG2385R and R1628P\u003c/em\u003e). In this study, we investigated motor, non-motor symptoms and cognitive functions of \u003cem\u003eLRRK2 R1628P\u003c/em\u003e variant carriers in a Asian PD cohort.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003ePD patients diagnosed in accordance with the diagnostic criteria of the National Institute of Neurological Disorders and Stroke (NINDS), were recruited from two movement disorder outpatient clinics in Singapore. Approval for our study was obtained from the SingHealth Centralized Institutional Review Board (CIRB) under Ref 2019/2433 and the approval date was 2 August 2014. The written informed consent was obtained from all participating individuals.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection and assessments\u003c/h3\u003e\n\u003cp\u003eDemographic and comorbidity information was gathered from all participants. Motor performance was evaluated by the Movement Disorder Society-Unified Parkinson\u0026rsquo;s Disease Rating Scale (MDS-UPDRS), while non-motor symptoms were assessed by the non-motor symptom scale (NMSS). The overall cognitive change was assessed using the Montreal Cognitive Assessment (MoCA) score.\u003c/p\u003e\n\u003ch3\u003eGenetic analyses\u003c/h3\u003e\n\u003cp\u003eLRRK2 \u003cem\u003eR1628P\u003c/em\u003e variant was genotyped by the Illumina Human OmniZhonghua-8 v1A BeadChip. All positive variants in our selected samples have been validated by Sanger sequencing. Patients with PD were categorised according to the genotyping results into carriers (LRRK2 \u003cem\u003eR1628P\u003c/em\u003e GC allele) and non-carriers (LRRK2 \u003cem\u003eR1628P\u003c/em\u003e GG allele).\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were presented as either mean with standard deviation (SD) or median with first and third quartile. Categorical variables were summarized through frequencies and percentages. The comparison of categorical variables between LRRK2 \u003cem\u003eR1628P\u003c/em\u003e carriers and non-carriers utilized the Chi-square or Fisher\u0026rsquo;s exact test. For continuous variables, a two-sample t-test or Mann\u0026ndash;Whitney U test (depending on the tenability of the normality assumption) was conducted to compare the two groups. The significance level was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. False discovery rate (FDR) method was performed to control for multiple testing comparison and q value was calculated. We set the threshold of q values as 0.15. Data processing and statistical analysis were conducted using Stata/SE version 16.1.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eIn this cross-section study, a total of 206 Parkinson's disease (PD) patients were included in the analysis, comprising 20 LRRK2 \u003cem\u003eR1628P\u003c/em\u003e carriers and 186 non-carriers. Demographics of the two groups were comparable, including gender distribution [58.6% males in the non-carrier group and 65.0% in the LRRK2 \u003cem\u003eR1628P\u003c/em\u003e carrier group (p\u0026thinsp;=\u0026thinsp;0.64)]. Most participants were of Chinese descent [84.4% in the non-carrier group and 94.7% in the carrier group (p\u0026thinsp;=\u0026thinsp;0.90)]. A higher proportion of individuals with a family history of PD was observed in the LRRK2 \u003cem\u003eR1628P\u003c/em\u003e carrier group (13.3%) compared to the non-carrier group (5.2%) (p\u0026thinsp;=\u0026thinsp;0.04). No significant differences were found while examining comorbidities (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all comparisons). The analysis of non-motor symptoms revealed LRRK2 \u003cem\u003eR1628P\u003c/em\u003e carriers exhibited notably reduced NMSS Total scores compared to non-carriers (10 vs. 15, p\u0026thinsp;=\u0026thinsp;0.01, q\u0026thinsp;=\u0026thinsp;0.13). Particularly, within the specific domain of sleep/fatigue (NMSS domain 2), carriers displayed significantly lower scores in contrast to non-carriers (0 vs. 1, p\u0026thinsp;=\u0026thinsp;0.02, q\u0026thinsp;=\u0026thinsp;0.13). NMSS total and NMSS domain 2 q values are both 0.13, which indicates that they are still significant after the adjustment for multiple comparison. No significant differences were found in the remaining NMSS domains (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all comparisons).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and comorbidity between LRRK2 \u003cem\u003eR1628P\u003c/em\u003e carriers and non-carriers\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-carriers\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eLRRK2 R1628P\u003c/em\u003e carriers\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;186\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003cem\u003e**\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender: male (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e109 (58.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (65.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRace: Chinese\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e157 (84.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (94.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily history (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (5.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (13.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes Mellitus (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (17.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (17.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (17.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (10.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperlipidaemia (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82 (44.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (65.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGout (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84 (45.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (65.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLipid medication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81 (43.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (60.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension medication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82 (44.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (60.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eCategorical variables reported as frequency (%); Chi-square or Fisher exact test (where appropriate) for categorical variables;\u003c/em\u003e \u003c/p\u003e \u003cp\u003eTable2: clinical characteristics between LRRK2\u003cem\u003e\u0026nbsp;R1628P\u003c/em\u003e carriers and non-carriers\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"621\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.868%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.1965%;\"\u003e\n \u003cp\u003eNon-carriers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.1031%;\"\u003e\n \u003cp\u003e\u003cem\u003eLRRK2 R1628P\u003c/em\u003e carriers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003ep-value\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003eq-value\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.868%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.1965%;\"\u003e\n \u003cp\u003en=186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.1031%;\"\u003e\n \u003cp\u003en=20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.868%;\"\u003e\n \u003cp\u003eAge of diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.1965%;\"\u003e\n \u003cp\u003e63.5 (9.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.1031%;\"\u003e\n \u003cp\u003e63.3 (7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.868%;\"\u003e\n \u003cp\u003eMDS-UPDRS part III score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.1965%;\"\u003e\n \u003cp\u003e20 (15-26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.1031%;\"\u003e\n \u003cp\u003e20.5 (18-28.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.868%;\"\u003e\n \u003cp\u003eMoCA Total\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.1965%;\"\u003e\n \u003cp\u003e26 (23-28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.1031%;\"\u003e\n \u003cp\u003e27 (24.5-29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.868%;\"\u003e\n \u003cp\u003eNMSS Total score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.1965%;\"\u003e\n \u003cp\u003e15 (9-27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.1031%;\"\u003e\n \u003cp\u003e10 (3-14.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.01\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.13\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.868%;\"\u003e\n \u003cp\u003eNMSSD1Score (cardiovascular)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.1965%;\"\u003e\n \u003cp\u003e0 (0-0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.1031%;\"\u003e\n \u003cp\u003e0 (0-0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.868%;\"\u003e\n \u003cp\u003eNMSSD2Score (sleep/fatigue)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.1965%;\"\u003e\n \u003cp\u003e1 (0-5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.1031%;\"\u003e\n \u003cp\u003e0 (0-1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.02\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.13\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.868%;\"\u003e\n \u003cp\u003eNMSSD3Score (mood/apathy)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.1965%;\"\u003e\n \u003cp\u003e0 (0-2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.1031%;\"\u003e\n \u003cp\u003e0 (0-1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.868%;\"\u003e\n \u003cp\u003eNMSSD4Score (perceptual problems)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.1965%;\"\u003e\n \u003cp\u003e0 (0-0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.1031%;\"\u003e\n \u003cp\u003e0 (0-0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.868%;\"\u003e\n \u003cp\u003eNMSSD5Score (attention/memory)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.1965%;\"\u003e\n \u003cp\u003e0 (0-2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.1031%;\"\u003e\n \u003cp\u003e0 (0-2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.868%;\"\u003e\n \u003cp\u003eNMSSD6Score (gastrointestinal)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.1965%;\"\u003e\n \u003cp\u003e0 (0-3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.1031%;\"\u003e\n \u003cp\u003e.5 (0-3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.868%;\"\u003e\n \u003cp\u003eNMSSD7Score (urinary)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.1965%;\"\u003e\n \u003cp\u003e4 (0-8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.1031%;\"\u003e\n \u003cp\u003e1.5 (0-4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.868%;\"\u003e\n \u003cp\u003eNMSSD8Score (sexual function)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.1965%;\"\u003e\n \u003cp\u003e0 (0-0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.1031%;\"\u003e\n \u003cp\u003e0 (0-0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.868%;\"\u003e\n \u003cp\u003eNMSSD9Score (miscellaneous)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.1965%;\"\u003e\n \u003cp\u003e0 (0-4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.1031%;\"\u003e\n \u003cp\u003e0 (0-2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.9163%;\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations: MDS-UPDRS: Movement Disorder Society-Unified Parkinson\u0026rsquo;s Disease Rating Scale; NMSS: Non-motor symptom scale\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eC\u003c/em\u003e\u003cem\u003eontinuous variables reported as median and first and third quartile. Chi-square or Fisher exact test (where appropriate) for categorical variables; Two-sample t test or Mann Whitney U test (where appropriate) for continuous variables, respectively\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFalse discovery rate (FDR) method was performed to control for multiple testing comparison and q value was calculated. We set the threshold of q values as 0.15.\u0026nbsp;\u003c/em\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur cross-sectional study involved the assessment of 206 PD patients with clinical evaluations of motor, non-motor symptoms. The results revealed intriguing disparities between these two groups. Notably, \u003cem\u003eLRRK2\u003c/em\u003e \u003cem\u003eR1628P\u003c/em\u003e carriers displayed significantly lower NMSS Total scores compared to non-carriers, implying milder NMS. In particular, within the non-motor domains, we observed significantly lower scores for the sleep and fatigue subdomain in \u003cem\u003eLRRK2\u003c/em\u003e \u003cem\u003eR1628P\u003c/em\u003e carriers.\u003c/p\u003e\n\u003cp\u003eEvidence of clinical presentation of PD carrying Asian related \u003cem\u003eLRRK2\u003c/em\u003e variants is limited and conflicting. Liang \u003cem\u003eet al \u003c/em\u003ereported that \u003cem\u003eLRRK2\u003c/em\u003e \u003cem\u003eG2385R\u003c/em\u003e and \u003cem\u003eR1628P\u003c/em\u003e carriers had similar clinical features compared to idiopathic PD patients [14]. This all-or-none \u003cem\u003eLRRK2\u003c/em\u003e variant categorisation could at least partially explain the discrepancy that a study observed a lack of significant differences in non-motor characteristics between carriers and non-carriers [15] whereas another study observing a single LRRK2 variant (\u003cem\u003eG2385R\u003c/em\u003e) identified that carriers are a risk factor for severe motor subtype and had more REM sleep behaviour disorder [16]. Our study examined a single \u003cem\u003eLRRK2\u003c/em\u003e variant (\u003cem\u003eR1628P\u003c/em\u003e) to elucidate their clinical impact on PD. The observed differences in our study could be attributed to the unique genetic properties of the \u003cem\u003eR1628P\u003c/em\u003e variant, thereby highlighting the need to analyse \u003cem\u003eLRRK2\u003c/em\u003e variants separately in clinical studies. Additionally, previous studies suggested there was no significant difference in NMS in either variant (\u003cem\u003eG2385R\u003c/em\u003e and \u003cem\u003eR1628P\u003c/em\u003e) compared to non-carriers [14]\u003csup\u003e,\u003c/sup\u003e[17]. However, these previous studies assessed NMS using a compilation of various evaluations for each NMS [14] or used Non-Motor Symptom Questionnaire (NMSQ) [17]. In contrast, our study conducted a structured interview employing NMSS specific for evaluation of NMS in PD, an evaluation capable of capturing a range of relevant NMS within a single scale and possessing strong correlation with advancing disease stages of PD since it’s conception [18]. A previous study on PD utilising both NMSQ and NMSS has also highlighted apparent discrepancies, noting the methodology of NMSS assessing the severity or frequency of NMS being in contrast to NMSQ which uses a “yes” or “no\" scoring system [19]. Interestingly, correlation was found in a study exploring the common etiology between sporadic Alzheimer’s disease (SAD) and PD with \u003cem\u003eLRRK2\u003c/em\u003e, which observed a neuroprotective effect of \u003cem\u003eLRRK2\u003c/em\u003e \u003cem\u003eR1628P\u003c/em\u003e variant through lower risk of developing SAD in an Asian population subset (Han Chinese population), particularly among APOE e4 allele carriers. In contrast, another \u003cem\u003eLRRK2\u003c/em\u003e variant \u003cem\u003eG2385R\u003c/em\u003e failed to emulate a similar result, further reinstating the importance of studying specific \u003cem\u003eLRRK2\u003c/em\u003e variant individually [20]. Consistently, this neuroprotective observation aligns with our clinical characterisation of decreased NMS in\u003cem\u003e R1628P \u003c/em\u003ecarriers.\u003c/p\u003e\n\u003cp\u003eOur study underscores the significance of conducting analyses for specific \u003cem\u003eLRRK2\u003c/em\u003e variants separately in clinical studies, particularly among different ethnicities. In existing studies, G2019S mutation, a well-known \u003cem\u003eLRRK2\u003c/em\u003e mutation which primarily affects individuals of Caucasian descent among PD patients was identified to have more behavioural abnormalities (depression, hallucinations) and sleep disorders compared to non-carriers [21, 22] although some studies have found less conclusive results on NMS impact [23-25]. Our study’s results, based on PD of Asian populations, provide insights into the clinical characteristics of PD patients with \u003cem\u003eLRRK2\u003c/em\u003e\u003cem\u003eR1628P \u003c/em\u003evariant. The observed reduction in NMS symptoms associated with \u003cem\u003eLRRK2\u003c/em\u003e\u003cem\u003eR1628P\u003c/em\u003e variant emphasises not only the importance of targeted analysis among different demographics carrying PD-relevant variants, but also has the potential impact on development of neuroprotective strategy given the finding of our study and others that \u003cem\u003eR1628P\u003c/em\u003e may confer neuroprotection in NMS including cognitive functions. Future research to elucidate the underlying mechanisms and explore further clinical implication of \u003cem\u003eR1628P\u003c/em\u003e variant on translational PD models is warranted.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This study was supported by the Singapore Ministry of Health’s National Medical Research Council under its Open Fund Large Collaborative Grant (MOH-OFLCG18May-0002).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e We would like to thank the support from Singapore Ministry of Health’s National Medical Research Council under its Open Fund Large Collaborative Grant (MOH-OFLCG18May-0002).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions Statement:\u003c/strong\u003e XD, XB: Review concept, design, drafting, revising the manuscript; JK and YLN: Data collection, helping draft and revise the manuscript; \u0026nbsp;Y-L L, ZYX, K-Y T, W-L A: revising manuscript; E-K T and LCS T: Study supervision, revising manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statements:\u0026nbsp;\u003c/strong\u003eThe datasets generated during and/or analysed during the current study are not publicly available due to ethical restrictions, but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e No competing interests.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDeMaagd G, Philip A (2015). 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Mov Disord, 28:1966-1971.\u003c/li\u003e\n\u003cli\u003eGatto EM, Parisi V, Converso DP, Poderoso JJ, Carreras MC, Marti-Masso JF\u003cem\u003e, et al.\u003c/em\u003e (2013). The LRRK2 G2019S mutation in a series of Argentinean patients with Parkinson\u0026apos;s disease: clinical and demographic characteristics. Neurosci Lett, 537:1-5.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5321847/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5321847/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eParkinson’s Disease (PD) presents devastating challenges for the aging society. Variations in the \u003cem\u003eLRRK2\u003c/em\u003e gene, including \u003cem\u003eR1628P\u003c/em\u003ein Asian populations have been linked to PD risk yet remain under-explored in clinical presentations. We assessed clinical manifestations in \u003cem\u003eR1628P\u003c/em\u003e carriers versus non-carriers in an Asian PD cohort. Our study found that \u003cem\u003eLRRK2\u003c/em\u003e \u003cem\u003eR1628P\u003c/em\u003ecarriers had significantly lower Non-Motor Symptom Scale (NMSS) Total score (10 vs 15 p=0.01) than non-carriers. Specifically, NMSS domain 2 score (sleep/fatigue) was lower in carriers compared to non-carriers (0 vs 1, p=0.02), with no significant differences in other NMSS domains. This study underscores the importance of analysing specific \u003cem\u003eLRRK2\u003c/em\u003e variants, to characterise accurately the influence of unique genetic variation of PD relevant gene and identify potential therapeutic target.\u003c/p\u003e","manuscriptTitle":"Clinical characteristics of PD patients carrying LRRK2 R1628P variant","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-05 13:26:02","doi":"10.21203/rs.3.rs-5321847/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5a5895ac-84cc-45dd-9b9e-7d0e802ad2d5","owner":[],"postedDate":"November 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-03T12:53:56+00:00","versionOfRecord":[],"versionCreatedAt":"2024-11-05 13:26:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5321847","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5321847","identity":"rs-5321847","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}