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Parkinson's disease (PD) is a chronic, non-reversible neurodegenerative disorder, and freezing of gait (FOG) is one of the most disabling symptoms in PD as it is often the leading cause of falls and injuries that drastically reduces patients' quality of life. In order to monitor continuously and objectively PD patients who suffer from FOG and enable the possibility of on-demand cueing assistance, a sensor-based FOG detection solution can help clinicians manage the disease and help patients overcome freezing episodes. Many recent studies have leveraged deep learning models to detect FOG using signals extracted from inertial measurement unit (IMU) devices. Usually, the latent features and patterns of FOG are discovered from either the time or frequency domain. In this study, we investigated the use of the time-frequency domain by applying the Continuous Wavelet Transform to signals from IMUs placed on the lower limbs of 63 PD patients who suffered from FOG. We built convolutional neural networks to detect the FOG occurrences, and employed the Bayesian Optimisation approach to obtain the hyper-parameters. The results showed that the proposed subject-independent model was able to achieve a geometric mean of 90.7% and a F1 score of 91.5%.

The biological underpinnings of the PD clusters remain unknown as the existing PD clusters lacks biomarker characterization. We try to identify clinical subtypes of Parkinson Disease (PD) in an Asian cohort and characterize them by comparing clinical assessments, genetic status and blood biochemical markers. A total of 206 PD patients were included from a multi-centre Asian cohort. Hierarchical clustering was performed to generate PD subtypes. Clinical and biological characterization of the subtypes were performed by comparing clinical assessments, allelic distributions of Asian related PD gene (SNCA, LRRK2, Park16, ITPKB, SV2C) and blood biochemical markers. Hierarchical clustering method identified three clusters: cluster A (severe subtype in motor, non-motor and cognitive domains), cluster B (intermediate subtype with cognitive impairment and mild non-motor symptoms) and cluster C (mild subtype and young age of onset). The three clusters had significantly different allele frequencies in two SNPs (Park16 rs6679073 A allele carriers in cluster A B C: 67%, 74%, 89%, p = 0.015; SV2C rs246814 T allele distribution: 7%, 12%, 25%, p = 0.026). Serum homocysteine (Hcy) and C-reactive protein (CRP) levels were also significantly different among three clusters (Mean levels of Hcy and CRP among cluster A B C were: 19.4 ± 4.2, 18.4 ± 5.7, 15.6 ± 5.6, adjusted p = 0.005; 2.5 ± 5.0, 1.5 ± 2.4, 0.9 ± 2.1, adjusted p

Introduction Subjective cognitive complaints (SCC) and affective symptoms are highly prevalent in Parkinson's Disease (PD). In early PD, SCC prevalence and its affective correlates, using recommended Movement Disorders Society (MDS) Level II Criteria to define the underlying cognitive impairment, has not been previously explored. Methods We recruited 121 participants with early PD from two tertiary hospitals in Singapore. The presence of SCC was defined using a Non-Motor Symptoms Scale Domain-5 Score ≥1. Comprehensive neuropsychological testing was conducted with Mild Cognitive Impairment (PD-MCI) defined using recommended MDS Level II Criteria. Affective symptoms were assessed using the Hospital Anxiety Depression Scale (HADS), Geriatric Depression Scale (GDS) and Apathy Scale (AS). Analysis using multivariable linear regression model was performed. Results In our early PD cohort, SCC prevalence independent of underlying cognitive status was 38.8%. Prevalence of SCC in cognitively impaired and cognitively normal participants was 10.7% and 28.1% respectively (р = 0.241). In cognitively normal PD participants, multivariable linear regression analysis revealed that SCC was significantly associated with anxiety (β = 0.28, 95% CI = 0.09–0.79, p = 0.014), depression (β = 0.31, 95% CI = 0.10–0.59, p = 0.006) and apathy (β = 0.32, 95% CI = 1.15–5.98, p = 0.004). Such an association was not found in cognitively impaired PD participants. Conclusion SCC is highly prevalent even in early PD. Its implications in early PD differ depending on underlying cognitive status. SCC in cognitively impaired participants underestimates the true prevalence of PD-MCI. In contrast, SCC in cognitively normal participants is suggestive of an underlying affective disorder.

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.

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

Background: Various classifications have been proposed to subtype Parkinson's disease (PD) based on their motor phenotypes. However, the stability of these subtypes has not been properly evaluated.Objective: The goal of this study was to understand the distribution of PD motor subtypes, their stability over time, and baseline factors that predicted subtype stability.Methods: Participants (n = 170) from two prospective cohorts were included: the Early PD Longitudinal Singapore (PALS) study and the National Neuroscience Institute Movement Disorders Database. Early PD patients were classified into tremor-dominant (TD), postural instability and gait difficulty (PIGD), and indeterminate subtypes according to the Movement Disorder Society's Unified PD Rating Scale (MDS-UPDRS) criteria and clinically evaluated for three consecutive years.Results: At baseline, 60.6% patients were TD, 12.4% patients were indeterminate, and 27.1% patients were PIGD subtypes (p < 0.05). After 3 years, only 62% of patients in TD and 50% of patients in PIGD subtypes remained stable. The mean levodopa equivalent daily dose (LEDD) was higher in the PIGD subtype (276.92 ± 232.91 mg; p = 0.01). Lower LEDD [p < 0.05, odds ratio (OR) 0.99, 95% confidence interval (CI): 0.98–0.99] and higher TD/PIGD ratios (p < 0.05, OR 1.77, 95% CI: 1.29–2.43) were independent predictors of stability of TD subtype with an area under the curve (AUC) of 0.787 (95%CI: 0.669–0.876), sensitivity = 57.8%, and specificity = 89.7%.Conclusion: Only 50–62% of PD motor subtypes as defined by MDS-UPDRS remained stable over 3 years. TD/PIGD ratio and baseline LEDD were independent predictors for TD subtype stability over 3 years.

Objective: In a prospective study, we investigated the association between physical activity and various motor, non-motor outcomes, and quality of life in early Parkinson's disease (PD) participants in the PD Longitudinal Singapore Study.Background: Prospective studies that examined the association between physical activity and motor and non-motor domains in early PD are lacking.Methods: 121 PD participants were followed-up prospectively to evaluate the association of physical activity with various symptom domains. The Physical Activity Scale for the Elderly (PASE) was used to measure physical activity annually. PD-related symptoms were categorized by motor, non-motor, and quality of life measures. Multivariate regression with gain score analysis was performed to understand the association of baseline PASE scores with the change of each variable at 1-year follow-up.Results: Higher baseline PASE scores (greater activity) were associated with a younger age, lower MDS-UPDRS motor scores, a smaller levodopa equivalent daily dose, better attention and memory scores, and better QoL. Activity scores in early PD declined on follow-up. Multivariate analysis revealed higher baseline physical activity to be associated with decreased anxiety and apathy scores at 1-year follow-up, after adjusting for demographic variables and medications.Conclusion: We demonstrated that higher baseline physical activity was associated with improved anxiety and apathy symptoms in early PD over a 1-year period.

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 p 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.

Objective. The aim of this study is to compare Parkinson’s disease (PD) treatment practices by movement disorder (MD) specialists across a decade, and to determine the factors that influence drug choice for the motor symptoms of PD in newly diagnosed drug-naïve patients. Methods. This prospective temporal analysis included patients seen at the National Neuroscience Institute in Singapore and diagnosed with PD by MD specialists in the years 2007 and 2017. Primary outcomes were use of specific PD drugs and changes in drug-prescribing patterns. Descriptive analyses and multivariable logistic regression models determined the extent to which patient characteristics were associated with type of PD treatment. Results. Of 230 patients with PD (mean (SD) age, 66.7 (10.3) years), 131 (57.0%) were male. From 2007 to 2017, the use of ergot dopamine agonists and anticholinergics decreased from 19.3% to 2.0% (P<0.001) and from 12.0% to 2.7% (P=0.004), respectively. The use of monoamine oxidase B inhibitors (MAOBI) increased from 13.3% to 25.2% (P=0.033). The use of levodopa (LD)-sparing strategies decreased nonsignificantly from 33.7% to 24.5% (P=0.133). Overall, 196 (85.2%) patients were initiated on symptomatic monotherapy, with LD being the most commonly prescribed. MAOBI was the most common drug used in combination therapy. Age ≤70 (adjusted OR, 11.9; 95% CI, 4.5–31.5) and Hoehn and Yahr (HY) stage P=0.005). Conclusions. Drug-prescribing patterns in PD have changed significantly through the last decade, influenced by emerging evidence and reports of adverse drug effects. Choosing drugs based on the patient’s age and disease severity remain sound guiding principles across the years. It is important that international and national guidelines for pharmacotherapy in PD be updated consistently throughout different socioeconomic settings to optimize care.

Objective. The success of clinical research and tissue donation programs are highly dependent on recruitment of willing volunteers. A comprehensive survey of patient preferences and attitudes can help identify and address barriers hindering the recruitment for research. Method. This is a cross-sectional study on 105 Parkinson’s disease patients who completed an interviewer-administered questionnaire. Results. Out of 105 respondents, 48% of patients had either already participated in clinical research or were keen to participate. About 80% believed clinical research to be safe for their health and privacy. More than 70% of participants were willing to donate blood, urine, or stool, while 16% were agreeable for cerebrospinal fluid sample donation. Motivating factors for clinical research included altruism (64%) and contribution to advance medical knowledge (64%). Common reasons for unwillingness towards clinical research included the risks involved (43%), time constraints (33%), and mobility challenges (24%). Conclusion. The attitude of Singaporean Parkinson patients toward clinical research and tissue donation is encouraging with about half of the participants willing to support clinical research. Three-quarters of patients would support tissue donations. Participation in research may be further increased with greater patient and public education to overcome misconceptions and also by limiting the demands of studies.

Background Few studies have been performed on palliative care in Parkinson's disease (PD). This study was undertaken to understand treatment preferences of PD patients toward end-of-life care. Methods A questionnaire modified from the Willingness to Accept Life-Sustaining Treatment instrument was administered to participants. Four different scenarios based on the burden of care and outcome of the treatment were presented in detail to obtain decisions for end-of-life care. The responses in each scenario were compared between PD patients and controls. Further analyses were performed to identify factors that influenced treatment preferences among PD patients. Results In total, 136 PD patients and 60 controls were recruited. Parkinson's disease patients and controls were demographically similar, except that PD patients had more previous hospital admissions (P = 0.0195). Parkinson's disease patients were more likely to opt for high-burden care with poor outcome than controls (odds ratio [OR] = 2.11, P = 0.04). In the subgroup analysis for PD patients, the factors that influenced treatment preference toward end-of-life care were belief in religion (OR: 7.43, 95% confidence interval:1.97–28.07), higher Unified Parkinson's Disease Rating Scale (UPDRS) motor score (2.51, 1.14–5.50) in scenario B; belief in religion (6.93, 2.23–21.43), married patients (6.93, 2.23–21.43) in scenario C; and Chinese patients (0.29, 0.10–0.79), better PD knowledge (0.37, 0.17–0.80), and higher UPDRS motor scores (3.05, 1.35–6.9) in scenario D. Conclusion Parkinson's disease patients were more likely to agree to high-burden care with a poor outcome compared to controls. Among PD patients, race, marital status, religious status, knowledge about PD, and severity of motor impairment significantly influenced their end-of-life treatment preferences.

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 (SV2CandWBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association forSV2C(rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21;P = 1.17 × 10−10in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity atWBSCR17(rs9638616;I2=67.1%;P = 3.40 × 10−3for 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.

A recent meta-analysis of Parkinson's disease (PD) genome-wide association studies has identified 17 novel risk loci in the European population. We aim to assess if these reported novel risk loci are similarly implicated in PD risk within the East Asian population by analyzing the reported risk single nucleotide polymorphism or proxy single nucleotide polymorphism in 14,006 East Asian samples (779 patients and 13,227 controls). We found that 9 of the 17 reported novel PD risk loci showed very similar effects in Europeans and East Asians (I2 = 0 to 10.7%), of which 2 loci ITPKB and ZNF184 were significantly associated with PD in our samples. Two of the reported risk loci, ANK2/CAMK2D and CTSB, were non-polymorphic in East Asians and therefore not implicated in PD risk in the East Asian population. Given the small effect sizes of these risk loci, further validation is needed in additional Asian samples. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore) Accepted version

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.

Co-existence of Parkinson’s disease (PD) and essential tremor (ET) may reflect overlapping pathophysiology underlying both conditions. Furthermore, PD patients with leucine-rich repeat kinase-2 (LRRK2) mutations may present with ET-like features, suggesting the possibility of common genetic underpinnings. Two common LRRK2 variants, R1398H and N551K, have been shown to be protective in multiple PD cohorts. We hypothesized that R1398H and N551K may show a similar effect in ET. In a case-control study involving 3198 subjects (2680 controls and 518 ET cases), R1398H was detected in 16.6% of ET cases compared to 18.0% in controls (OR = 0.91, 95% CI = 0.71–1.17, p = 0.46); while N551K was detected in 16.5% of ET cases compared to 18.0% of controls (OR = 0.89, 95% CI = 0.69–1.15, p = 0.37). While these results suggest that LRRK2 R1398H or N551K do not appear to modulate the risk of ET, it remains possible that a protective trend for both variants may be present in ET and a much larger sample size is required to identify this.

BACKGROUND: Suicide is a potentially preventable event. Suicidal ideation is common in Parkinson's disease (PD), but literature on completed suicides is scarce. In this case‐control study, we compared the clinical characteristics of PD subjects who completed suicide (case) with those who died from natural causes (control). METHODS: PD patients from the National Neurosciences Institute's movement disorders database from 2002 till 2012 were identified. The database was linked to the Singapore National Registry of Disease Office for mortality information, and suicide deaths were confirmed with the coroner's office. The demographic and clinical variables were compared between the cases and controls and the significant factors were further analyzed using logistic regression analysis. RESULTS: During the study period, 366 deaths were recorded and suicide accounted for 11 deaths. Ten subjects with suicide deaths with complete clinical information were compared with randomly selected 30 PD subjects who had died from natural causes. PD suicide patients were younger (65.9 vs. 74.48 years), had less comorbidities (CWI: 2.6 vs. 4.63), better cognition (MMSE: 25.75 vs. 21.36), lower ‘ON’ UPDRS motor scores (20.83 vs. 41.63), lower H &Y stage (2.16 vs. 3.86), and higher use of Entacapone than the PD non‐suicide group. CONCLUSION: Suicide is potentially preventable tragedy. PD patients with the identified clinical characteristics should be closely monitored for suicide ideations. Motor fluctuation is a treatable factor in such patients and should be aggressively managed.

Background Deviation in gait performance from normative data of healthy cohorts is used to quantify gait ability. However, normative data is influenced by anthropometry and such differences among subjects impede accurate assessment. De-correlation of anthropometry from gait parameters and mobility measures is therefore desirable. Methods 87 (42 male) healthy subjects varying form 21 to 84 years of age were assessed on gait parameters (cadence, ankle velocity, stride time, stride length) and mobility measures (the 3-meter/7-meter Timed Up-and-Go, 10-meter Walk Test). Multiple linear regression models were derived for each gait parameter and mobility measure, with anthropometric measurements (age, height, body mass, gender) and self-selected walking speed as independent variables. The resulting models were used to normalize the gait parameters and mobility measures. The normalization’s capability in de-correlating data and reducing data dispersion were evaluated. Results Gait parameters were predominantly influenced by height and walking speed, while mobility measures were affected by age and walking speed. Normalization de-correlated data from anthropometric measurements from |rs| < 0.74 to |rs| < 0.23, and reduced data dispersion by up to 69%. Conclusion Normalization of gait parameters and mobility measures through linear regression models augment the capability to compare subjects with varying anthropometric measurements.

To evaluate the contribution of non-synonymous-coding variants of known familial and genome-wide association studies (GWAS)-linked genes for Parkinson's disease (PD) to PD risk in the East Asian population, we sequenced all the coding exons of 39 PD-related disease genes and evaluated the accumulation of rare non-synonymous-coding variants in 375 early-onset PD cases and 399 controls. We also genotyped 782 non-synonymous-coding variants of these genes in 710 late-onset PD cases and 9046 population controls. Significant enrichment of LRRK2 variants was observed in both early- and late-onset PD (odds ratio = 1.58; 95% confidence interval = 1.29-1.93; P = 8.05 × 10(-6)). Moderate enrichment was also observed in FGF20, MCCC1, GBA and ITGA8. Half of the rare variants anticipated to cause loss of function of these genes were present in healthy controls. Overall, non-synonymous-coding variants of known familial and GWAS-linked genes appear to make a limited contribution to PD risk, suggesting that clinical sequencing of these genes will provide limited information for risk prediction and molecular diagnosis.

Objective Hippocampal atrophy has been associated with mild cognitive impairment (MCI) in Parkinson's disease (PD). However, literature on how hippocampal atrophy affects the pathophysiology of cognitive impairment in PD has been limited. Previous studies assessed the hippocampus as an entire entity instead of their individual subregions. We studied the progression of cognitive status in PD subjects over 18 in relation to hippocampal subfields atrophy. Methods 65 PD subjects were included. Using the MDS task force criteria, PD subjects were classified as either having no cognitive impairment (PD-NCI) or PD-MCI. We extended the study by investigating the hippocampal subfields atrophy patterns in those who converted from PD-NCI to PD-MCI (PD-converters) compared to those who remained cognitively stable (PD-stable) over 18 months. Freesurfer 6.0 was used to perform the automated segmentation of the hippocampus into thirteen subregions. Results PD-MCI showed lower baseline volumes in the left fimbria, right CA1, and right HATA; and lower global cognition scores compared to PD-NCI. Baseline right CA1 was also correlated with baseline attention. Over 18 months, decline in volumes of CA2–3 and episodic memory were also seen in PD-converters compared to PD-stable. Baseline volumes of GC-DG, right CA4, left parasubiculum, and left HATA were predictive of the conversion from PD-NCI to PD-MCI. Conclusion The findings from this study add to the anatomical knowledge of hippocampal subregions in PD, allowing us to understand the unique functional contribution of each subfield. Structural changes in the hippocampus subfields could be early biomarkers to detect cognitive impairment in PD., Highlights • Hippocampal subfields atrophy could detect cognitive impairment in PD. • Each hippocampal subfields has a unique functional contribution. • Baseline hippocampal subfields volumes predicted conversion to from NCI to MCI.

Recent whole-exome sequencing studies in European patients with Parkinson's disease (PD) have identified potential risk variants across 33 novel PD candidate genes. We aim to determine if these reported candidate genes are similarly implicated in Asians by assessing common, rare, and novel nonsynonymous coding variants by sequencing all 33 genes in 198 Chinese samples and genotyping coding variants in an independent set of 9756 Chinese samples. We carried out further targeted sequencing of CD36 in an additional 576 Chinese and Korean samples. We found that only 8 of 43 reported risk variants were polymorphic in our Chinese samples. We identified several heterozygotes for rare loss-of-function mutations, including the reported CD36 p.Gln74Ter variant, in both cases and controls. We also observed 2 potential compound heterozygotes among PD cases for rare loss-of-function mutations in CD36 and SSPO. The other reported variants were common in East Asians and not associated with PD, completely absent, or only found in controls. Therefore, the 33 reported candidate genes and associated variants are unlikely to confer significant PD risk in the East Asian population. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore) Accepted version

Genome-wide association studies (GWAS) on Parkinson’s disease (PD) have mostly been done in Europeans and Japanese. No study has been done in Han Chinese, which make up nearly a fifth of the world population. We conducted the first Han Chinese GWAS analysing a total of 22,729 subjects (5,125 PD cases and 17,604 controls) from Singapore, Hong Kong, Malaysia, Korea, mainland China and Taiwan. We performed imputation, merging and logistic regression analyses of 2,402,394 SNPs passing quality control filters in 779 PD cases, 13,227 controls, adjusted for the first three principal components. 90 SNPs with association P 1.45) on PD risk. Our results also demonstrate some differences in the genetic contribution to PD between Europeans and Asians. Further pan-ethnic meta-analysis with European GWAS cohorts may unravel new PD loci. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore) Accepted version

A variant (rs3129882) in the genome-wide association study (GWAS)-linked variant [in the human leukocyte antigen (HLA) gene region] has been reported to associate with an increased risk of Parkinson's disease (PD) in Caucasian population. Studies among Chinese are limited. To address this, we analysed rs3129882 in a total of 1312 subjects of Chinese ethnicity from independent Asian centers comprising of 675 controls and 637 PD cases. The rs3129882 variant was associated with a decreased risk in our ethnic Chinese PD patients. Logistic regression analysis taking into consideration variables of age, gender and race showed that allele A reduced the risk of PD via a dominant model [odds ratio (OR) = 0.77, 95% confidence interval (CI) = 0.62, 0.96, p = 0.018]. As HLA is a highly polymorphic region, it is possible that ethnic-specific effect or environmental agents may modulate the effect of this GWAS-linked locus in influencing the risk of PD.

r r Abstract: Objective: To study the interaction between levodopa and the feedback process on set-shifting in Parkinson's disease (PD). Methods: Functional magnetic resonance imaging (fMRI) studies were per- formed on 13 PD subjects and 17 age-matched healthy controls while they performed a modified card- sorting task. Experimental time periods were defined based on the types of feedback provided. PD subjects underwent the fMRI experiment twice, once during ''off'' medication (PDoff) and again after levodopa replacement (PDon). Results: Compared with normal subjects, the cognitive processing times were prolonged in PDoff but not in PDon subjects during learning through positive outcomes. The ability to set-shift through negative outcomes was not affected in PD subjects, even when ''off'' medica- tion. Intergroup comparisons showed the lateral prefrontal cortex was deactivated in PDoff subjects during positive feedback learning, especially following internal feedback cues. The cortical activations were increased in the posterior brain regions in PDoff subjects following external feedback learning, especially when negative feedback cues were provided. Levodopa replacement did not completely restore the activation patterns in PD subjects to normal although activations in the corticostriatal loops were restored. Conclusion: PD subjects showed differential ability to set-shift, depending on the dopa- mine status as well as the types of feedback cues provided. PD subjects had difficulty performing set- shift tasks through positive outcomes when ''off'' medication, and showed improvement after levodopa replacement. The ability to set-shift through negative feedback was not affected in PD subjects even when ''off'' medication, possibly due to compensatory changes outside the nigrostriatal dopaminergic pathway. Hum Brain Mapp 33:27-39, 2012. V C 2011 Wiley Periodicals, Inc.

Tremor is defined as the involuntary rhythmic or quasi-rhythmic oscillation of a body part, resulting from alternating or simultaneous contractions of antagonistic muscle groups. While tremor may be physiological, those who have disabling pathological tremors find that performing typical activities for daily living to be physically challenging and emotionally draining. Detecting the presence of tremor and its proper identification are crucial in prescribing the appropriate therapy to lessen its deleterious physical, emotional, psychological, and social impact. While diagnosis relies heavily on clinical evaluation, pattern analysis of surface electromyogram (sEMG) signals can be a useful diagnostic aid for an objective identification of tremor types. Using sEMG system attached to several parts of the patient's body while performing several tasks, this research aims to develop a classifier system that automates the process of tremor types recognition. Finding the optimal model and its corresponding parameters is not a straightforward process. The resulting workflow, however, provides valuable information in understanding the interplay and impact of the different features and their parameters to the behavior and performance of the classifier system. The resulting model analysis helps identify the necessary locations for the placement of sEMG electrodes and relevant features that have significant impact in the process of classification. These information can help clinicians in streamlining the process of diagnosis without sacrificing its accuracy.

Objective: A genome-wide association study (GWAS) in the Japanese population identified 2 new Parkinson disease (PD) susceptibility loci on 1q32 (PARK16) (OMIM 613164) and BST1. We analyzed single nucleotide polymorphism (SNPs) located at the GWAS-linked loci (PARK16, PARK8, PARK1, and BST1) in a Chinese population and also conducted a meta-analysis in Asians by pooling 2 independent replication studies from Japan. Methods: We conducted an analysis of 13 SNPs associated with PD GWAS-linked loci in 2 case-control cohorts comprised of 1,349 ethnic Chinese subjects. Results:PARK16, PARK8, and PARK1 loci but not BST1 were found to be associated with PD. PARK16 SNPs were associated with a decreased risk while PARK1 and PARK8 SNPs were associated with an increased risk of PD. A pooled analysis of our Chinese cohorts and 2 Japanese replication cohorts involving 1,366 subjects with PD and 16,669 controls revealed robust association with these 3 loci and also BST1. There was a trend toward a stronger protective effect of SNPs at the PARK16 locus in sporadic PD compared to familial cases and in older compared to younger subjects. Conclusions: Our study reaffirms the role of GWAS-linked loci in PD in Asian subjects and the strength of association is similar between Chinese and Japanese subjects. Efforts to elucidate the associated gene within PARK16 locus are warranted.

The purpose of this study was to evaluate the responsiveness of the EQ-5D and the Parkinson’s Disease Questionnaire (PDQ-8) to deterioration in health-related quality of life (HRQoL) in patients with Parkinson’s disease (PD). HRQoL and clinical data collected from 31 patients with PD (male: 74.2%, mean age: 61 years) who were surveyed with the EQ-5D and the PDQ-8 questionnaires in 2002 and 2006/2007 were analyzed. Responsiveness of the EQ-5D, PDQ-8, and Hoehn and Yahr (H&Y) staging were assessed according to Cohen’s effect size (ES) and standardized response mean (SRM). The mean (standard deviation) EQ-5D index and PDQ-8 summary index (PDQ-8SI) scores were 0.76 (0.23) and 17.7 (14.2) at baseline and 0.52 (0.33) and 35.1 (17.4) at year four. Based on both ES and SRM indices, the rank order of responsiveness of the studied measures, from high to low, was PDQ-8SI (ES = 1.22), EQ-5D index score (ES = 1.06), H&Y score (ES = 0.82), and the EQ-VAS score (ES = 0.24). Both the EQ-5D and PDQ-8 are responsive to changes in health burden of the Parkinson’s disease over a 4-year period.

Objective. COQ2 mutations have been reported in Japanese multiple system atrophy (MSA) patients. We examined the role of COQ2 in patients with dementia and essential tremor (ET), two common neurodegenerative conditions.Materials & Methods. A total of 2064 subjects, including 560 patients with dementia, 466 patients with ET, and 1038 healthy controls, were included. Genotyping for the COQ2 V393A (T>C) was carried out. Odds ratio (OR) adjusted by age and gender, together with 95% confidence interval (CI), was reported by means of logistic regression.Results. The frequency of the polymorphic variant V393A heterozygous (T/C) was 2.7% in dementia, 1.1% in ET, and 2.5% in controls (OR = 0.70, 95% confidence interval is 0.29–1.72 for dementia, and OR = 0.47, 95% confidence interval is 0.17–1.31,p=0.1217for ET). There was no significant association between V393A variant with dementia and ET.Conclusion. There was no significant association between V393A variant with dementia and ET. COQ2 gene is unlikely to play a significant role in patients with dementia or ET in our population.

Background Prospective studies on lipids and risk of Parkinson9s disease (PD) in Asian populations are sparse. This study prospectively examined the associations between dietary cholesterol and major fatty acids, and risk of PD among the Chinese in Singapore. Methods This study used data from the Singapore Chinese Health Study, a population-based prospective cohort of 63 257 men and women aged 45–74 years in Singapore enrolled in 1993–1998. Dietary intakes of cholesterol and fatty acids were derived from a validated semiquantitative food frequency questionnaire and the Singapore Food Composition Table. Incident PD cases were identified either through follow-up interviews or record linkage analysis with hospital discharge and PD outpatient registries. Results After an average of 14.6 years, 218 men and 193 women in the cohort developed PD. Dietary cholesterol was associated with statistically significantly lower risk of PD in a dose–dependent manner among men after adjustment for established risk factors for PD and intakes of major fatty acids. Compared to the lowest quartile, HR (95% CI) for the highest quartile was 0.53 (95% CI 0.33 to 0.84) (P for trend=0.006). Among women, dietary monounsaturated fatty acid was inversely associated with PD risk (P for trend=0.033). Compared to the lowest quartile, HR for the highest quartile was 0.44 (95% CI 0.22 to 0.88). There was no statistically significant association between dietary saturated, n-3 and n-6 fatty acids and PD risk. Conclusions Higher intakes of cholesterol and monounsaturated fatty acids may reduce risk of PD in men and women, respectively.

Essential tremor has a high heritability, but its molecular genetic determinants remain unknown. Müller et al. conduct a genome-wide association study in more than 2800 patients with essential tremor and more than 6800 controls of European descent, and identify three new loci associated with the disease., We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.

Essential tremor (ET) and Parkinson's disease (PD) are two of the most common adult onset movement disorders with overlapping clinical features. PD patients with leucine-rich repeat kinase-2 (LRRK2) mutations may present initially with an ET phenotype. To address the possibility of a common genetic link between ET and PD, we examined the association between a common LRRK2 R1628P gene variant and ET. The LRRK2 R1628P was genotyped in ET cases and matched healthy controls. A total of 1277 subjects comprising of 450 ET cases and 827 controls were included. There were 40 heterozygote (GG to CG) variant out of 450 ET cases (genotypic frequency 8.9%) and 36 heterozygote variant (GG to CG, genotypic frequency 4.3%) and one homozygote variant (GG to CC) out of 827 controls. Subjects carrying the R1628P variant had a twofold increased risk of ET (p = 0.0035, OR = 2.20 and 95% confidence interval is 1.30–3.73). Using a case control methodology, we demonstrated an association between a known PD risk variant, LRRK2 R1628P, with ET. Subjects carrying the R1628P variant had twice the risk of developing ET. The sharing of a similar gene risk variant suggests a possible pathophysiologic link between PD and ET.

It has been suggested that a common LRRK2 polymorphic variant (A419V (rs34594498 C >T)) may be a risk factor among Asians (especially in Taiwan). In this study, we examined this variant in a larger and independent Taiwan cohort. We found the frequency of the variant (A419V) to be very rare in our Taiwan PD and controls (?0.6%). Further studies were conducted in two other Chinese populations (Singapore and China), comprising of a total of 3004 subjects including 1517 PD patients and 1487 control subjects. However, our multi-center Chinese study revealed that the frequency of the variant was rare (?0.4%) and was not associated with risk of PD, suggesting that the variant is not a major risk factor for PD among Chinese, at least in our study population.

LINGO2, a member of LRR gene family, has been linked with both Essential tremor (ET) and Parkinson’s disease (PD). However, there is a lack of conclusive evidence regarding the etiologic role of LINGO2 genetic variants. We investigated the association of LINGO2 variants with ET and PD in two independent Asian countries. A total of 1,262 subjects comprising 499 controls, 436 PD patients, and 327 ET patients were included. Eight LINGO2 variants, including four single-nucleotide polymorphisms (SNPs) and four coding variants, were initially analyzed in one Asian population. SNPs that showed positive association were then replicated in the second independent Asian population, and a pooled analysis was carried out. Out of the eight variants, two SNPs (rs7033345 and rs10812774) revealed significant or strong positive trend in the first Asian population, and these were analyzed in the second Asian population. In the pooled analysis, the CC genotype at rs7033345 had a higher risk of developing PD (OR = 1.67, 95% CI = 1.18, 2.35, p = 0.003) and ET (OR = 1.50, 95% CI = 1.02, 2.20, p = 0.04) under a recessive model. The C allele at rs10812774 increased the risk of ET (OR = 1.56 95% CI = 1.10, 2.22, p = 0.01) via a recessive model. The effect size and direction of trend were in the same direction in each of the two populations. Our study demonstrated for the first time that rs7033345 is associated with PD and ET and rs10812774 with ET among Asians, suggesting that LINGO2 might act as a susceptibility gene for both conditions.

To develop a function for mapping the eight-item Parkinson's Disease Questionnaire (PDQ-8) to the EuroQol Group's EQ-5D utility index.Data from two surveys of 324 patients with Parkinson's disease was divided into two groups. One was used to estimate the mapping functions by regression methods and the other was used to validate the mapping functions.A regression model with a non-linear trend explained 55% of the variation in EQ-5D utility values and had a mean absolute deviation (MAD) of 0.083. A regression model assuming a linear trend explained 52% of the variation and had an MAD of 0.085. In the validation sample, predicted values based on the aforementioned models respectively explained 42 and 44% of the variation in the observed EQ-5D utility values and both had MADs of about 0.1. The confidence intervals of the mean difference between these predicted values and the observed values totally fell within the pre-defined equivalence margin of 0.03 points. These predicted values were also similar to the observed EQ-5D utility values in terms of their association with clinical variables.At the group level, but not at the individual level, the mapping functions can accurately map the PDQ-8 outcomes to the EQ-5D utility index.

Data from Asian populations on dietary and lifestyle factors associated with Parkinson's disease are sparse. In 1993-2005, the authors examined these factors in relation to Parkinson's disease in the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese men and women. Baseline data were collected through in-person interviews using structured questionnaires. All 157 incident Parkinson's disease cases were identified either through follow-up interviews or via linkage with hospital discharge databases and Parkinson's disease outpatient registries and were confirmed by review of medical records. Current versus never smokers exhibited a reduced risk of Parkinson's disease (relative risk = 0.29, 95% confidence interval: 0.16, 0.52). Total caffeine intake was inversely related to Parkinson's disease risk (p for trend = 0.002); the relative risk for the highest versus lowest quartile was 0.55 (95% confidence interval: 0.35, 0.88). Black tea, a caffeine-containing beverage, showed an inverse association with Parkinson's disease risk that was not confounded by total caffeine intake or tobacco smoking (p for trend = 0.0006; adjusted relative risk for the highest vs. lowest tertile of intake = 0.29, 95% confidence interval: 0.13, 0.67). Green tea drinking was unrelated to Parkinson's disease risk. Diet had no strong influence on risk. Ingredients of black tea other than caffeine appear to be responsible for the beverage's inverse association with Parkinson's disease.

Background Adult-onset type II citrullinemia is an inborn error of urea cycle metabolism that can lead to hyperammonemic encephalopathy and coma. However, type II citrullinemia is rare outside Japan, and diagnosis and treatment can be delayed. Magnetic resonance spectroscopy may be a useful adjunct to magnetic resonance imaging, and has been applied to noninvasively study chemical metabolism in the human brain. Patients We describe 2 patients with type II citrullinemia who presented with episodic postprandial somnolence and coma. Diffusion-weighted magnetic resonance imaging showed bilaterally symmetrical signal abnormalities of the insular cortex and cingulate gyrus. On magnetic resonance spectroscopy, glutamine and glutamate levels were elevated, and choline and myo-inositol levels were decreased. The diagnosis of citrullinemia was confirmed based on elevated plasma ammonia and citrulline levels. Conclusion Characteristic features found at the time of magnetic resonance imaging and magnetic resonance spectroscopy may be helpful for early diagnosis of type II citrullinemia in adult patients who present with hyperammonemic encephalopathy and coma.