Disease Progression of Data-Driven Subtypes of Parkinson's Disease: 5-Year Longitudinal Study from the Early Parkinson's Disease Longitudinal Singapore (PALS) Cohort.

Background: The detailed trajectory of data-driven subtypes in Parkinson's disease (PD) within Asian cohorts remains undisclosed. Objective: To evaluate the motor, non-motor symptom (NMS) progression among the data-driven PD clusters. Methods: In this 5-year longitudinal study, NMS scale (NMSS), Hospital Anxiety Depression Scale (HADS), and Epworth sleepiness scale (ESS) were carried out annually to monitor NMS progression. H& Y staging scale, MDS-UPDRS part III motor score, and postural instability gait difficulty (PIGD) score were assessed annually to evaluate disease severity and motor progression. Five cognitive standardized scores were used to assess detailed cognitive progression. Linear mixed model was performed to assess the annual progression rates of the longitudinal outcomes. Results: Two hundred and six early PD patients, consisting of 43 patients in cluster A, 98 patients in cluster B and 65 subjects in cluster C. Cluster A (severe subtype) had significantly faster progression slope in NMSS Domain 3 (mood/apathy) score (p = 0.01), NMSS Domain 4 (perceptual problems) score (p = 0.02), NMSS Domain 7 (urinary) score (p = 0.03), and ESS Total Score (p = 0.04) than the other two clusters. Cluster A also progressed significantly in PIGD score (p = 0.04). For cognitive outcomes, cluster A deteriorated significantly in visuospatial domain (p = 0.002), while cluster C (mild subtype) deteriorated significantly in executive domain (p = 0.04). Conclusions: The severe cluster had significantly faster progression, particularly in mood and perceptual NMS domains, visuospatial cognitive performances, and postural instability gait scores. Our findings will be helpful for clinicians to stratify and pre-emptively manage PD patients by developing intervention strategies to counter the progression of these domains.

Parkinson's disease genome-wide association study-linked PARK16 variant is associated with a lower risk of cognitive impairment: A 4-year observational study.

BACKGROUND AND PURPOSE: A genome-wide association study-linked variant (PARK16 rs6679073) modulates the risk of Parkinson's disease (PD). We postulate that there may be differences in clinical characteristics between PARK16 rs6679073 carriers and noncarriers. In a prospective study, we investigate the clinical characteristics between PARK16 rs6679073 A allele carriers and noncarriers over 4 years. METHODS: A total of 204 PD patients, comprising 158 PARK16 rs6679073 A allele carriers and 46 noncarriers, were recruited. All patients underwent motor and nonmotor symptom and cognitive assessments yearly over 4 years. RESULTS: PARK16 rs6679073 carriers were less likely to have mild cognitive impairment (MCI) compared to noncarriers at both baseline (48.1% vs. 67.4%, p = 0.027) and 4-year follow-up (29.3% vs. 58.6%, p = 0.007). CONCLUSIONS: PD PARK16 rs6679073 carriers had significantly lower frequency of MCI in a 4-year follow-up study, suggesting that the variant may have a neuroprotective effect on cognitive functions.

Identifying clinical features and blood biomarkers associated with mild cognitive impairment in Parkinson disease using machine learning.

BACKGROUND AND PURPOSE: A broad list of variables associated with mild cognitive impairment (MCI) in Parkinson disease (PD) have been investigated separately. However, there is as yet no study including all of them to assess variable importance. Shapley variable importance cloud (ShapleyVIC) can robustly assess variable importance while accounting for correlation between variables. Objectives of this study were (i) to prioritize the important variables associated with PD-MCI and (ii) to explore new blood biomarkers related to PD-MCI. METHODS: ShapleyVIC-assisted variable selection was used to identify a subset of variables from 41 variables potentially associated with PD-MCI in a cross-sectional study. Backward selection was used to further identify the variables associated with PD-MCI. Relative risk was used to quantify the association of final associated variables and PD-MCI in the final multivariable log-binomial regression model. RESULTS: Among 41 variables analysed, 22 variables were identified as significantly important variables associated with PD-MCI and eight variables were subsequently selected in the final model, indicating fewer years of education, shorter history of hypertension, higher Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor score, higher levels of triglyceride (TG) and apolipoprotein A1 (ApoA1), and SNCA rs6826785 noncarrier status were associated with increased risk of PD-MCI (p < 0.05). CONCLUSIONS: Our study highlighted the strong association between TG, ApoA1, SNCA rs6826785, and PD-MCI by machine learning approach. Screening and management of high TG and ApoA1 levels might help prevent cognitive impairment in early PD patients. SNCA rs6826785 could be a novel therapeutic target for PD-MCI. ShapleyVIC-assisted variable selection is a novel and robust alternative to traditional approaches for future clinical study to prioritize the variables of interest.

Predicting atrial fibrillation after ischemic stroke: clinical, genetics and electrocardiogram modelling.

INTRODUCTION: Detection of atrial fibrillation (AF) is challenging in patients after ischemic stroke due to its paroxysmal nature. We aim to determine the utility of a combined clinical, electrocardiographic and genetic variables model to predict AF in a post-stroke population. MATERIALS AND METHODS: We performed a cohort study at a single comprehensive stroke centre from 09/11/2009 to 31/10/2017. All patients recruited were diagnosed with acute ischemic stroke or transient ischemic attacks. Electrocardiographic variables including p-wave terminal force (PWTF), corrected QT interval (QTc) and genetic variables including single nucleotide polymorphisms (SNP) at the 4q25 (rs2200733) were evaluated. Clinical, electrocardiographic and genetic variables of patients without AF and those who developed AF were compared. Multiple logistic regression analysis and receiver operating characteristics were performed to identify parameters and determine their ability to predict the occurrence of AF. RESULTS: Out of 709 patients (median age of 59 years, IQR 52-67) recruited, sixty (8.5%) were found to develop AF on follow-up. Age (odds ratio (OR): 3.49, 95% confidence interval (CI): 2.03-5.98, p<0.0001), hypertension (OR: 2.76, 95% CI: 1.36-5.63, p=0.0052) and valvular heart disease (OR: 8.49, 95% CI: 2.62-27.6, p<0.004 were the strongest predictors of AF, with area under receiver operating value of 0.76 (95% CI: 0.70-0.82), and 0.82 (95% CI: 0.77-0.87) when electrocardiographic variables (PWTF and QTc) were added. SNP did not improve prediction modelling. CONCLUSION: We demonstrated that a model combining clinical and electrocardiographic variables provided robust prediction of AF in our post-stroke population. Role of SNP in prediction of AF was limited.

Longitudinal Study of SNCA Rep1 Polymorphism on Executive Function in Early Parkinson's Disease.

The alpha-synuclein gene promoter (SNCA-Rep1) is associated with Parkinson's disease (PD), but its relationship with performance across individual cognitive domains in early PD is unknown. This study aims to investigate Rep1 polymorphism and longitudinal change in cognition in early PD. In this longitudinal study, Rep1 allele lengths ("long" and "short") were determined in 204 early PD patients. All participants underwent annual neuropsychological assessments and followed up for 3 years. Linear-mixed model was performed to investigate the association of Rep1 status and longitudinal change in individual cognitive domains. At 3 years, significant decline in executive function was observed in long Rep1 allele carriers vs short allele carriers, controlling for potential confounders. This is the first longitudinal study demonstrating that long Rep1 allele carriers are at higher risk for executive dysfunction in early PD.

Case-control study of hypertension and Parkinson's disease.

We evaluate the association of hypertension with PD in an Asian population and performed a meta-analysis on similar studies to address the effect of hypertension on PD risk. A matched case-control study involving 1342 Chinese subjects (671 PD and 671 age and gender-matched controls (with a mean age of 63.9 ± 9.7 and 63.5 ± 9.8 years, and identical proportion of gender distribution) was conducted. Hypertension increases PD risk by 1.9 times [OR 1.86 (1.46-2.38)]. The literature search identified 618 studies initially; however, only three matched case-control studies (all in Caucasians) met the inclusion criteria for meta-analysis. Overall analysis showed that hypertension decreases PD risk by 0.2 times [OR 0.80 (0.66-0.96)]. Hypertension increases PD risk by 1.9 times in our Asian population. However, a meta-analysis comprising of Caucasian populations showed a protective effect of hypertension suggesting that ethnic differences or other genetic or environmental factors may contribute to the divergent observation. Early diagnosis and treatment of hypertension may potentially reduce the risk of PD, at least in our population.

Association study of MCCC1/LAMP3 and DGKQ variants with Parkinson's disease in patients of Malay ancestry.

BACKGROUND: Genome-wide association studies (GWAS) have shown that variants in the 3-methylcrotonyl-CoA carboxylase (MCCC1)/lysosome-associated membrane protein 3 (LAMP3) loci (rs10513789, rs12637471, rs12493050) reduce the risk of Parkinson's disease (PD) in Caucasians, Chinese and Ashkenazi-Jews while the rs11248060 variant in the diacylglycerol kinase theta (DGKQ) gene increases the risk of PD in Caucasian and Han Chinese cohorts. However, their roles in Malays are unknown. Therefore, this study aims to investigate the association of these variants with the risk of PD in individuals of Malay ancestry. METHODS: A total of 1114 subjects comprising of 536 PD patients and 578 healthy controls of Malay ancestry were recruited and genotyped using Taqman® allelic discrimination assays. RESULTS: The G allele of rs10513789 (OR = 0.83, p = 0.001) and A allele of rs12637471 (OR = 0.79, p = 0.007) in the MCCC1/LAMP3 locus were associated with a protective effect against developing PD in the Malay population. A recessive model of penetrance showed a protective effect of the GG genotype for rs10513789 and the AA genotype for rs12637471. No association with PD was found with the other MCCC1/LAMP3 rs12493050 variant or with the DGKQ (rs11248060) variant. No significant associations were found between the four variants with the age at PD diagnosis. CONCLUSION: MCCC1/LAMP3 variants rs10513789 and rs12637471 protect against PD in the Malay population.

SNCA Rep1 microsatellite length influences non-motor symptoms in early Parkinson's disease.

Long alpha-synuclein gene (SNCA) promoter (Rep1) allele-carriers are linked to higher risk for Parkinson's disease (PD) and faster motor progression. Non-motor symptoms including autonomic, neuropsychiatric, and sleep disorders are common in PD. However, the relationship between SNCA Rep1 microsatellite lengths and non-motor symptoms in early PD remains to be elucidated. 171 consecutive early PD patients were recruited from tertiary clinics and genotyped for Rep1. Multivariable regression analyses were performed to examine associations between Rep1 alleles and non-motor outcome scores. Longer Rep1 alleles significantly associated with higher total Non-Motor Symptom Scale (NMSS) scores (p=.006) and Hospital Anxiety and Depression Scale (HADS) depression subscale scores (p=.002), after adjusting for covariates and Bonferroni correction. We demonstrated that SNCA Rep1 allele length influences overall non-motor symptom burden and depression in early PD patients. Further functional studies to evaluate the role of Rep1 in non-dopaminergic systems may unravel new therapeutic targets for non-motor symptoms in PD.

Association of NOTCH2NLC Repeat Expansions With Parkinson Disease.

Importance: The presence of Notch homolog 2 N-terminal-like C (NOTCH2NLC) repeat expansions are associated with neuronal intranuclear inclusion body disease (NIID), with varied neurological signs, including neuropathy, ataxia, parkinsonism, and tremor. To date, genetic screening of NOTCH2NLC GGC repeats in a cohort with typical Parkinson disease (PD) appears not to have been reported. Objective: To investigate if NOTCH2NLC GGC expansions are present in a cohort of patients with PD and controls. Design, Setting, and Participants: This case-control study was conducted in 2 tertiary movement disorder centers in Singapore. Participants were recruited and followed up from January 2005 to January 2020. The presence of NOTCH2NLC GGC expansion repeats was screened using polymerase chain reaction tests, and representative samples were verified with long-read genome sequencing. Main Outcomes and Measures: Qualitative and quantitative comparisons between participants with sporadic PD, healthy control participants, and individuals with NIID. Results: A total of 2076 participants, including 1000 with sporadic PD (600 men [60.0%]; mean age at onset, 62.6 [7.7] years) and 1076 healthy controls (581 men [54.0%]; mean age at study recruitment, 54.9 [9.4] years) were recruited. A total of 13 patients with PD and no healthy control participants were identified as carrying NOTCH2NLC GGC repeat expansions of more than 40 units; the frequency of more than 40 repeat expansions was higher in participants with PD than controls (P < .001). None of the patients with PD were carriers of known PD-associated genes. Ten patients with PD carried a GGC expansion of between 41 and 64 repeats (1% of patients with sporadic PD; mean [SD], 49.4 [9.2] repeats). The other 3 patients carried GGC repeats of 79 or more units, 2 with 122 and 79 repeats, respectively, exhibited typical parkinsonism and were responsive to small dosages of levodopa over many years, with no clinical or imaging features of NIID. The other patient with PD, who had 130 repeats, only developed cognitive impairment before death. Within the GGC expansions, there was no GGA interruptions (mean [SD] GGA percentage in the 3 patients with PD vs patients with NIID, 0% vs 12% [9%]), and the frequency of AGC interruptions was 3 times higher in these patients with PD than patients with NIID (mean [SD], 25% [12%] vs 8% [8%]). Conclusions and Relevance: This study demonstrated that individuals with sporadic PD who carried pathogenic NOTCH2NLC GGC repeat expansions can present with typical parkinsonism, requiring only low dosages of levodopa, without displaying other clinical or imaging features of NIID even after several years of follow-up. None of the patients with PD had GGA interruptions within their GGC expansions, and the frequency of AGC interruptions was much higher than that of patients with NIID. The functional significance of a higher moderate repeat expansion in patients with PD compared with healthy controls needs to be further investigated.

NOTCH2NLC GGC Repeat Expansions Are Associated with Sporadic Essential Tremor: Variable Disease Expressivity on Long-Term Follow-up.

We screened 662 subjects comprising 462 essential tremor (ET) subjects (285 sporadic, 125 with family history, and 52 probands from well-characterized ET pedigrees) and 200 controls and identified pathogenic NOTCH2NLC GGC repeat expansions in 4 sporadic ET patients. Two patients were followed up for >1 decade; one with 90 repeats remained an ET phenotype that did not evolve after 40 years, whereas another patient with 107 repeats developed motor symptoms and cognitive impairment after 8 to 10 years. Neuroimaging in this patient revealed severe leukoencephalopathy; diffusion-weighted imaging hyperintensity in the corticomedullary junction and skin biopsy revealed intranuclear inclusions suggestive of intranuclear inclusion body disease (NIID). No GGC repeats of >60 units were detected in familial ET cases and controls, although 4 ET patients carried 47 to 53 "intermediate" repeats. NOTCH2NLC GGC repeat expansions can be associated with sporadic ET. Carriers presenting with a pure ET phenotype may or may not convert to NIID up to 4 decades after initial tremor onset. ANN NEUROL 2020;88:614-618.

Utility of plasma Neurofilament light as a diagnostic and prognostic biomarker of the postural instability gait disorder motor subtype in early Parkinson's disease.

BACKGROUND: The main motor subtypes of Parkinson's disease (PD) include tremor-dominant (TD) and postural instability gait disorder (PIGD), with varying disease course that warrant the development of biomarkers capable of predicting progression according to motor subtype. The PIGD subtype is associated with a poorer prognosis, hence identification of a biomarker associated with PIGD is clinically relevant. Neurofilament light (NfL) chain is a potential biomarker of disease severity in neurological disorders including PD. However, no study has investigated NfL and PD motor subtypes. Here, we aimed to investigate the diagnostic and prognostic utility of plasma NfL for PD motor subtypes in early Parkinson's disease. Given the higher risk for cognitive and motor decline in PIGD, we hypothesized that plasma NfL is a potential biomarker for PIGD. METHODS: Plasma NfL was measured in 199 participants (149 PD and 50 healthy controls, HC) using an ultrasensitive single molecule array. Patients were classified into TD or PIGD based on MDS-UPDRS components. After 2 years, 115 patients were reassessed. Association between NfL and clinical measures in PIGD and TD at baseline and at 2-year follow-up were analysed. RESULTS: At baseline, plasma NfL levels were higher in PD than HC (8.8 ± 3.4 vs 16.2 ± 7.6 pg/ml, p < 0.0001), and differentiated PD from HC with a good diagnostic accuracy (AUC = 0.833, p < 0.001). At 2 years, NfL was higher in PIGD than TD (18.4 ± 14.5 vs 12.6 ± 4.4 pg/ml, p = 0.039). Within the PIGD group, higher NfL associated significantly with worse global cognition and UPDRS motor scores at baseline, and was able to predict motor and cognitive decline at a mean follow-up duration of 1.9 years, controlled for age, sex and disease duration. CONCLUSIONS: In this longitudinal study, we demonstrated for the first time the potential utility of plasma NfL as a diagnostic and prognostic biomarker in PIGD even at early stages of PD. These important novel findings will require further confirmation in larger, longitudinal PD cohorts.

Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans: A Genome-Wide Association Study.

Importance: Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian). Objectives: To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts. Design Setting, and Participants: Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31 575 individuals passing quality control of 35 994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1 926 361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson's Disease Society Brain Bank Criteria. Main Outcomes and Measures: Genotypes of common variants, association with disease status, and polygenic risk scores. Results: Of 31 575 samples identified, 6724 PD cases (mean [SD] age, 64.3 [10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24 851 controls (age, 59.4 [11.4] years; 11 030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10-10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P = 3.40 × 10-3 for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P = 6.81 × 10-12). Conclusions and Relevance: This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta-genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.

Plasma ubiquitin C-terminal hydrolase L1 levels reflect disease stage and motor severity in Parkinson's disease.

Parkinson's disease (PD) is characterized by Lewy bodies containing α-synuclein and ubiquitin aggregates, their co-occurrence possibly linked to a failure of the ubiquitin proteasome system. Ubiquitin C-terminal hydrolase L1 (UCHL1) plays an important role in maintenance of nervous system integrity, and overexpression of UCHL1 has been shown to increase ubiquitin levels within neurons. While cerebrospinal fluid ubiquitin levels were reported to be lower in PD vs controls, plasma UCHL1 levels and their relationship with clinical measures in PD has not been reported. We measured plasma UCHL1 levels using single molecule array (Simoa) in 291 subjects (242 PD and 49 healthy controls, HC). We found that UCHL1 levels were significantly higher in PD patients at moderate stages (Hoehn and Yahr, H&Y stage >2) vs milder PD (H&Y ≤2, p<0.001) and HC (p=0.001). There was no significant difference in UCHL1 levels between PD patients at H&Y stages ≤2 vs HC. Across all PD patients, UCHL1 correlated significantly with UPDRS Part III motor scores (ß=3.87, 95% CI=0.43-7.31, p=0.028), but not with global cognition. Overall, we found that UCHL1 correlates with motor function in PD, with higher levels seen in later disease stages. These findings will be validated in longitudinal studies.

SNCA Rep1 promoter variability influences cognition in Parkinson's disease.

BACKGROUND: While the association between alpha-synuclein gene promoter (Rep1) variability and risk of PD is well established, its association with cognition is unclear. OBJECTIVES: To investigate the association between Rep1 and motor and cognitive outcomes in PD. METHODS: Rep1 allele lengths were determined in 172 PD patients who were grouped into "long" and "short" carriers according to previous methods. Multivariable regression analysis was performed to investigate the effect of Rep1 length on cognitive and motor scores. RESULTS: Long Rep1 allele carriers had significantly lower MMSE (P = 0.010) and higher UPDRS Part III (P = 0.026) and H & Y (P = 0.008) scores compared to short allele carriers (controlled for age, sex, and disease duration). Interaction analyses of Rep1 with apolipoprotein 4 revealed no significant effect on clinical outcomes. CONCLUSIONS: PD patients carrying long Rep1 alleles are more impaired on cognitive and motor function independent of apolipoprotein 4 genotype. © 2019 International Parkinson and Movement Disorder Society.

Plasma alpha-synuclein detected by single molecule array is increased in PD.

We utilized ultrasensitive single molecule technology to measure plasma alpha-synuclein in 221 subjects (51 controls, 170 PD). Plasma alpha-synuclein levels were significantly higher in PD than controls (15506.3 vs. 13057.0 pg/mL, P = 0.037), adjusting for age and gender. In PD, alpha-synuclein levels did not vary by H&Y stage or UPDRS motor scores but were significantly higher in PD patients with poorer cognition (MMSE ≤ 25) than controls (P = 0.016, Bonferroni corrected P = 0.047). Alpha-synuclein levels quantified using ultrasensitive single molecule technology discriminate PD from controls and correlate with cognitive severity. These preliminary findings require independent validation to determine the utility of this assay.

Parkinson's disease GWAS-linked Park16 carriers show greater motor progression.

BACKGROUND: Data on the long-term motor outcomes of genome-wide association study (GWAS)-linked Parkinson disease (PD) carriers are useful for clinical management. OBJECTIVES: To characterise the association between GWAS-linked PARK16 gene variant and disease progression in PD over a 9-year time frame. METHODS: Over a 9-year period, carriers of PARK16 rs11240572 variant and non-carriers were followed up and evaluated using the modified Hoehn and Yahr (H&Y) staging scale and Unified Parkinson's Disease Rating Scale (UPDRS) part III. A longitudinal, linear mixed model was performed to compare the changes of H&Y staging scale, UPDRS motor score and UPDRS subscores between the two groups. RESULTS: A total of 156 patients (41 PARK16 carriers and 115 non-carriers) were evaluated and followed up for up to 9 years. Using longitudinal linear mixed model analysis, there was a greater rate of deterioration in the motor function as measured by the UPDRS scores compared with non-carriers after 5 years from the date of diagnosis (p=0.009). In addition, we demonstrated that PARK16 variant carriers had worse gait scores (p=0.043) and greater motor progression than non-carriers after 6 years based on the modified H&Y staging scale (p=0.040). CONCLUSIONS: In a 9-year longitudinal study, we demonstrated that PD PARK16 variant carriers exhibited greater motor progression after 5 years of disease compared with non-carriers, suggesting that GWAS-linked gene variants may influence disease progression over time. Closer monitoring and management of these higher risk patients can facilitate a better quality of life.

Four-Year Longitudinal Study of Motor and Non-motor Symptoms in LRRK2-Related Parkinson's Disease.

Objectives: In a prospective 4-year study, we evaluated the progression of motor and non-motor symptoms in Parkinson's disease (PD) patients with Asian-specific LRRK2 risk variants and non-carriers. Methods: A total of 202 patients with PD, including 133 risk variant carriers and 69 non-carriers, were followed up and evaluated using the Modified Hoehn and Yahr staging scale, Unified Parkinson's Disease Rating Scale part III, Non-motor Symptom Scale, Parkinson's disease Questionnaire-39 item version. Means of generalized estimating equation model was performed to compare the differences from baseline between LRRK2 risk variant carriers and non-carriers. Results: Our longitudinal analysis revealed that risk variant carriers exhibited greater progression than non-carriers after 4 years based on the modified Hoehn and Yahr staging scale (risk variants carriers, 0.65; non-carriers, 0.06; P = 0.041). Meanwhile, Unified Parkinson's Disease Rating Scale gait and posture score in risk variant carriers also showed greater increase than that in non-carriers, although the difference was not statistically significant. Non-carriers experienced a transient improvement in non-motor symptoms at the early stage of PD, as scores at visit two significantly reduced compared to baseline in Non-motor Symptom Scale domain 3 (mood/apathy), Parkinson's disease Questionnaire-39 item version domain 3 (emotional well-being), and frequency of NMS in non-carriers but not in risk variants carriers. Conclusions: PD gene risk variant carriers were more likely to progress faster in their motor severity than non-carriers. There were transient differences in certain non-motor symptoms and quality of life in carriers. However, more studies are warranted to assess the association of PD risk variants and progression of non-motor symptoms.

Serum uric acid level and its association with motor subtypes and non-motor symptoms in early Parkinson's disease: PALS study.

OBJECTIVE: Uric acid has been found to be potentially neuroprotective in Parkinson's disease (PD). We investigated the relationship between serum uric acid levels and both motor and non-motor features in a prospective early PD cohort study. METHODS: Fasting serum uric acid levels were measured from 125 early PD patients. Demographic, clinical characteristics, motor and non-motor assessments were performed. Patients were categorized into three motor subtypes: tremor-dominant (TD), postural instability/gait difficulty (PIGD), and mixed. Non-motor symptoms were classified as present or absent based on the appropriate cut-offs for each non-motor instrument. RESULTS: Most patients had TD (n = 51, 40.8%) and mixed (n = 63, 50.4%) motor subtypes, while a minority had PIGD (n = 11, 8.8%) motor subtype. The mean serum uric acid levels were significantly different between the three motor subtypes (p = 0.0106), with the mixed subtype having the lowest serum uric acid levels. Using the TD subtype as reference, patients with higher serum uric acid levels were less likely to have the mixed (OR = 0.684; p = 0.0312) subtype as opposed to the TD subtype. Uric acid levels were not significantly different between the TD and PIGD subtypes. For non-motor symptoms, higher serum uric acid levels were significantly associated with less fatigue (OR = 0.693; p = 0.0408). CONCLUSION: Higher serum uric acid levels were associated with TD motor subtype and less fatigue in early PD, which could be related to its anti-oxidative properties. Uric acid could be an important biomarker for specific motor features and symptoms of fatigue in PD.