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Background: Neurofilament light is a marker of axonal degeneration, whose measurement from peripheral blood was recently made possible by new assays. Objective: We aimed to determine whether plasma neurofilament light chain (NfL) concentration reflects brain white matter integrity in patients with early Parkinson’s disease (PD). Methods: 137 early PD patients and 51 healthy controls were included. Plasma NfL levels were measured using ultrasensitive single molecule array. 3T MRI including diffusion tensor imaging was acquired for voxelwise analysis of association between NfL and both fractional anisotropy (FA) and mean diffusivity (MD) in white matter tracts and subcortical nuclei. Results: A pattern of brain microstructural changes consistent with neurodegeneration was associated with increased plasma NfL in most of the frontal lobe and right internal capsule, with decreased FA and increased MD. The same clusters were also associated with poorer global cognition. A significant cluster in the left putamen was associated with increased NfL, with a significantly greater effect in PD than controls. Conclusion: Plasma NfL may be associated with brain microstructure, as measured using diffusion tensor imaging, in patients with early PD. Higher plasma NfL was associated with a frontal pattern of neurodegeneration that also correlates with cognitive performance in our cohort. This may support a future role for plasma NfL as an accessible biomarker for neurodegeneration and cognitive dysfunction in PD.

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 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.

Background: Lipid biomarkers have potential neuroprotective effects in Parkinson’s disease (PD) and there is limited evidence in the field. Objective: This study aims to investigate the association between comprehensive blood lipid biomarkers and PD. Methods: A total of 205 PD patients and 102 non-PD subjects were included from Early Parkinson’s disease Longitudinal Singapore (PALS) cohort. We investigated 6 serum lipid biomarkers including total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo A1), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B). PD patients were further classified into mild cognitive impairment (MCI) and normal cognition (NC) subgroups. We conducted a cross-sectionals study to examine the association between lipids and PD and further explored the relationship between lipids and PD-MCI. Results: PD patients had significantly lower level of lipid panel including TC, TG, HDL-C, Apo A1, LDL-C, and Apo B (all 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.

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: There is currently insufficient long-term data on costs of treatment in patients with Parkinson’s disease (PD), which is chronic and progressive, and associated with substantial healthcare costs. Identifying patterns in healthcare utilization and cost may illuminate further discussion on early intervention. Objective: To characterize long-term healthcare utilization and costs of PD in newly diagnosed patients managed by movement disorder specialists. Methods: Using a longitudinal matched-cohort study of linked data from the National Neuroscience Institute Parkinson’s disease and Movement Disorder and healthcare administrative databases in Singapore from 2008–2017, we compared healthcare utilization and costs between patients and controls matched on age, sex, race, and Charlson Comorbidity Index score. Results: 1,162 patients met study inclusion criteria and 1,157 matched controls were identified. The total mean annual healthcare cost (at 2017 costs) was significantly increased in patients compared to controls from years 1–9 post-diagnosis. The increased cost was observed 2 years before diagnosis (USD2322 vs. 2052; p

Freezing of Gait is the most disabling gait disturbance in Parkinson’s disease. For the past decade, there has been a growing interest in applying machine learning and deep learning models to wearable sensor data to detect Freezing of Gait episodes. In our study, we recruited sixty-seven Parkinson’s disease patients who have been suffering from Freezing of Gait, and conducted two clinical assessments while the patients wore two wireless Inertial Measurement Units on their ankles. We converted the recorded time-series sensor data into continuous wavelet transform scalograms and trained a Convolutional Neural Network to detect the freezing episodes. The proposed model achieved a generalisation accuracy of 89.2% and a geometric mean of 88.8%.

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 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.

Objective To investigate the impact of diabetes mellitus (DM) on cognitive performance and longitudinal volumetric brain changes in a cohort of cognitively normal mild PD patients. Methods Prospective study of idiopathic PD subjects who underwent baseline and follow-up MRI imaging and neuropsychological assessments at 6 month intervals for 3 years. Subjects were classified based on the presence (PD-DM) or absence of DM (PD-No DM) at baseline. Volumetric analysis was performed using FreeSurfer 5.3 image analysis suite. Brain volume and cognition were compared and analyzed cross-sectionally and longitudinally. Analyses were corrected for intracranial volume. Results There were 65 PD-no DM and 12 PD-DM subjects at baseline with comparable global cognition at baseline. PD-DM subjects had lower cortical grey matter (GM), amygdala, frontal white matter and temporal white matter volumes and higher total white matter hyperintensity and periventricular hyperintensities. After mean follow-up of 29.08 months, there were 51 PD-no DM and 11 PD-DM subjects. PD-DM subjects demonstrated greater decline in MMSE and MOCA scores compared to PD-No DM. PD-DM subjects had a higher rate of atrophy in the cortical WM, particularly in the parietal and occipital white matter. Conclusion Mild PD patients with DM have lower GM and WM volumes at baseline and higher WMH volumes, despite comparable cognitive scores. Longitudinally, DM in PD results in greater rate of cognitive decline, associated with higher WM atrophy.

Background and purpose Mild cognitive impairment (MCI) is associated with pronounced grey matter atrophy in various brain regions. However, the association between atrophy patterns and progression from no cognitive impairment (NCI) to Parkinson's disease (PD)-MCI is not clearly known. We investigated the pattern and progression of atrophy in subcortical structures and its impact on cognition in patients with mild PD. Methods Sixty-five patients with mild PD with baseline and longitudinal clinical and neuropsychological assessments, and structural magnetic resonance imaging scans were studied. Movement Disorder Society Task Force criteria were used to classify patients with PD into PD-NCI (n = 54) and PD-MCI (n = 11). Based on progression over time, those who remained without cognitive impairment were classified as PD-stable (n = 42) and those who converted to MCI over 18 months were classified as PD-converters (n = 12). FreeSurfer was used to measure cortical thickness and subcortical volumes at baseline and follow-up. Results Parkinson's disease-MCI showed baseline thalamus atrophy and progressive atrophy in the thalamus, caudate, presubiculum, cornu ammonis 1 and 2–3, and significant memory and executive dysfunction compared with PD-NCI. PD-converters had greater accumbens atrophy at baseline and progressive atrophy in the thalamus, caudate and accumbens with dysfunctions in memory and executive domains. Conclusions Progression of cognitive impairment in non-demented PD is associated with a specific pattern of subcortical atrophy. Findings from this study will allow future studies to investigate in the role of subcortical structures as a biomarker for PD dementia.

Background Anxiety is prevalent in patients with Parkinson's disease (PD) and may affect patients' quality of life. Yet, little is known about the neural basis of anxiety in PD, and none have used a longitudinal design. Methods 73 patients with mild PD were recruited and followed up for 18 months. A whole-brain analysis was first used to identify brain regions associated with anxiety symptoms, followed by a regional analysis focusing on a priori hypothesised regions at baseline. A multivariate generalized estimating equations analysis was then conducted to determine the longitudinal association between grey matter (GM) volumetric changes of these significant regions and changes of anxiety symptoms. Results At baseline, anxiety symptom severity was associated with decreased GM volumes in the bilateral precuneus and anterior cingulate cortex (ACC). Over 18 months, increased severity of anxiety symptoms was associated with decreased GM volume in the left precuneus and ACC, independent of age, gender, education, depressive symptom severity or use of psychiatric medication. Conclusions These results mainly implicate the precuneus and ACC in the pathogenesis of anxiety in PD. We speculate that these structural changes could reflect the disrupted default mode network due to PD pathology, contributing to spontaneous anxiety-related self-focused thoughts.

Background and purpose This study quantified the total brain and periventricular white matter hyperintensity (WMH) burdens in patients with early Parkinson's disease (PD) and explored their associations with cardiovascular risk factors and cognitive performance. Methods A total of 175 non-demented patients with early PD who had undergone baseline brain magnetic resonance imaging were included. Comprehensive neurocognitive testing was conducted to identify PD with mild cognitive impairment (PD-MCI) and to evaluate performances in individual cognitive domains. Cardiovascular risk was expressed as a modified Framingham 10-year cardiovascular risk score (mFRS). Results A total of 53.7% of this early PD cohort fulfilled the diagnostic criteria for PD-MCI. An increase in mFRS was significantly associated with increases in the total brain WMH (P = 0.015) and periventricular WMH (P = 0.040) burden, independent of age and gender. The periventricular WMH burden was significantly associated with PD-MCI (P = 0.046) in early PD, independent of cardiovascular risk factors. Patients in the 5th quintile of periventricular WMH burden were 8.6 times more likely to have PD-MCI compared with patients in the 1st quintile of periventricular WMH burden (P = 0.004). However, total brain WMH burden was not associated with PD-MCI (P = 0.158). In individual cognitive domains, heavier periventricular WMH burden was associated with worse executive function and visuospatial function independent of cardiovascular risk factors. Conclusion Periventricular WMHs are a useful imaging biomarker for cognitive impairment in early PD. Cardiovascular risk factors, although associated with periventricular WMHs, were unable to fully explain the association between periventricular WMHs and cognitive impairment in early PD.

Histopathological examination of brain tissue is required for better understanding of neurodegenerative conditions such as Parkinson’s disease and related disorders. However, patient willingness remains the greatest hurdle hampering participation in brain donation for research. While there is extensive research being conducted on the subject in West, to the best of our knowledge, there are no studies done in this regard in Asia. This cross-sectional survey was conducted on 105 Parkinson’s disease patients to assess their knowledge, beliefs and attitude towards brain donation in an Asian population. The majority of the participants (78%) acknowledged the importance of donation of brain for research, and 70% believed that their donated brain samples would be handled professionally. Fifty percent participants were willing to consider donating their brain for research. Motivating factors for brain donation included altruism (87%) and contribution to advance medical knowledge (80%). Common reasons for unwillingness towards brain donation were stress for family (30%), disfigurement of body (25%), and having a conservative mindset (23%). About one-third of the participants preferred to be approached for brain donation after their first clinic visit. Most patients preferred either their treating neurologists (66%) or research staff (18%) to discuss brain donation with. Participation for brain donation may be increased further with greater patient and public education to overcome misconceptions and change mindsets.

Freezing of Gait (FoG) is a common motor-related impairment among Parkinson's disease patients, which substantially reduces their quality of life and puts them at risk of falls. These patients benefit from wearable FoG detection systems that provide timely biofeedback cues and hence help them regain control over their gait. Unfortunately, the systems proposed thus far are bulky and obtrusive when worn. The objective of this paper is to demonstrate the first integration of an FoG detection system into a single sensor node. To achieve such an integration, features with low computational load are selected and dedicated hardware is designed that limits area and memory utilization. Classification is achieved with a neural network that is capable of learning in real time and thus allows the system to adapt to a patient during run-time. A small form factor FPGA implements the feature extraction and classification, whereas a custom PCB integrates the system into a single node. The system fits into a 4.5 × 3.5 × 1.5 cm $^3$ housing case, weighs 32 g, and achieves 95.6% sensitivity and 90.2% specificity when adapted to a patient. Biofeedback cues are provided either through auditory or somatosensory means and the system can remain operational for longer than 9 h while providing cues. The proposed system is highly competitive in terms of classification performance and excels with respect to wearability and real-time patient adaptivity.

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.

Background Depression and anxiety are common in Parkinson's disease (PD) and contribute significantly to a reduced quality of life in PD patients. Though they often co-exist, it is unclear whether depression and anxiety result from a shared pathological process. We studied the longitudinal course and determinants of depression and anxiety in PD in order to understand which factors contribute to the development of these symptoms. Methods We conducted a prospective longitudinal study of 89 mild PD patients over 18 months, measuring depressive and anxiety symptoms at 6 monthly intervals using the Geriatric Depression Scale and Hospital Anxiety and Depression Scale – ‘Anxiety’ subscale. Univariate and multivariate Generalised Estimating Equations were used to investigate the course of depression and anxiety and their association with demographic factors, motor measures, non-motor symptoms, and pharmacological factors. Results Depression and anxiety were co-morbid in 13.5% of the sample. Depressive symptoms remained relatively stable while anxiety symptoms improved over the course of 18 months. Severity of depressive symptoms was associated with female gender, motor fluctuations, apathy, and anxiety, while severity of anxiety was associated with older age, higher educational attainment, shorter disease duration, younger age of disease onset, and excessive daytime sleepiness. Conclusions Although depression and anxiety are frequently co-morbid in PD, they were dissociable from each other. They had distinct trajectories and different longitudinal relationships with demographic, motor, and non-motor factors that were unique to each disorder.

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.

Dysphagia increases risk of pneumonia in patients with Parkinson’s disease (PD). However, no studies have investigated the association between objective measures of swallowing dysfunction and clinical outcomes. Therefore, we aimed to study the link between scores obtained on the modified barium swallow impairment scale profile (MBSImP) and hospital admissions for pneumonia and choking, in groups of patients with PD on different feeding modes. 157 patients who completed MBS studies were divided into three groups based on their feeding modes (oral, enteral, and rejected enteral feeding with oral feeding at own risk). Videos were analysed using the MBSImP. We evaluated the association of the oral, pharyngeal, and combined scores, with risk of admission for pneumonia and choking. Kaplan–Meier plots and log-rank tests were used to compare survival distributions among feeding groups. Cox regression models were generated to estimate hazard ratios (HRs) and 95% confidence intervals. Patients in the group that rejected enteral feeding scored the highest on the MBSImP, followed by enteral then oral feeding. Within the group that rejected enteral feeding, higher pharyngeal (HR = 3.73, p = 0.036) and combined scores (HR = 1.63, p = 0.034) significantly increased the risk of pneumonia and choking. In the enteral feeding group, higher oral subscores (HR = 2.16, p = 0.011) increased risk for the event, while higher pharyngeal (HR = 0.40, p = 0.004) subscores reduced risk for pneumonia and choking. This is the first study to analyse the association of MBSImP scores with clinical outcomes in PD patients. Patients who rejected enteral feeding had the highest risk for pneumonia and choking that could be predicted by their MBSImP scores. In the enteral feeding group, this risk was partially reversed. Compliance with feeding modes reduces the risk of pneumonia and choking.

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.

Objectives: In a longitudinal follow-up study, we compared the clinical features and motor progression of patients with Parkinson disease (PD) who are carriers of the leucine-rich repeat kinase 2 ( LRRK2 ) gene risk variants with patients who are noncarriers. Methods: We prospectively evaluated a cohort of patients with PD for their clinical characteristics, disease severity, and LRRK2 genotype. Carriers of risk variants (G2385R, R1628P, S1647T) and noncarriers were classified separately. A longitudinal, linear mixed model analysis of motor score progression was performed to compare motor progression between the 2 groups. Motor score progression was defined as the difference between Unified Parkinson9s Disease Rating Scale motor score at baseline and follow-up scores. Results: A total of 184 patients (122 risk variant carriers and 62 noncarriers) were evaluated and followed up for up to 6.5 years. No differences in demographics and baseline disease characteristics were found. In the longitudinal, linear mixed model analysis, risk variant carriers experienced greater rate of motor progression than noncarriers after 4 years from the date of diagnosis ( p ≤ 0.018). Conclusions: PD LRRK2 risk variant carriers showed greater motor progression after 4 years of disease duration compared with noncarrier patients, suggesting that these risk variants may facilitate neurodegeneration with increasing disease duration.

Introduction There are few large studies that have evaluated prognostic factors for mortality in Parkinson's disease (PD). This large study aimed to identify demographic and clinical features associated with early mortality in PD. Methods PD patients at the National Neuroscience Institute were identified from the Movement Disorders Database from which demographic information and prospectively collected baseline disease characteristics were obtained. All study patients were linked to the Singapore Registry of Birth and Death to obtain information on vital status through December 31, 2012. The prognostic variables analyzed include patient demographics, baseline disease characteristics, and type of PD medication used. Multivariate Cox regression analysis was carried out to identify factors associated with the risk of mortality in PD. Results Of the 1786 PD patients identified, 363 (20.3%) had died during the 11-year study period. Median survival time from diagnosis was 15.8 years (range 0.3–31). Factors associated with higher mortality (HR, 95% CI) were older age at diagnosis (1.06, 1.03–1.08), male gender (2.29, 1.57–3.35), Hoehn & Yahr (HY) stage ≥2.5 (1.54, 1.07–2.22), UPDRS motor score ≥30 (1.63, 1.13–2.35), higher bradykinesia subscores (1.05, 1.01–1.09) and cognitive impairment (2.30, 1.55–3.41). Conclusions In the largest study to date evaluating baseline disease characteristics prognostic of mortality risk in PD, we found that male gender, older age at diagnosis, higher baseline HY stage, higher baseline UPDRS motor scores, higher bradykinesia subscores and baseline cognitive impairment were associated with early mortality in PD.

Longitudinal neuroimaging studies could provide insights into pathophysiology of cognitive impairment in PD. We examined the role of hippocampal atrophy and cerebral white matter disease as risk factors for mild cognitive impairment and dementia in PD.Prospective longitudinal study of patients with mild PD in a tertiary neurology center. All subjects underwent baseline MRI brain and had baseline and 6 monthly cognitive evaluations. Cognitive impairment was diagnosed based on the Movement Disorder Society Criteria. The predictive role of hippocampal volume and white matter hyperintensity at baseline on progression of cognitive impairment was studied.97 subjects with mean age 65.3 years, mean education of 10.3 years and mean HoehnYahr of 1.9 were studied. Over 2 years, 16 subjects developed mild cognitive impairment and 8 subjects with mild cognitive impairment progressed to dementia. After adjusting for age and vascular risk factors, hippocampal volume was a significant predictor for mild cognitive impairment (OR 7.05, CI 1.5-34.1; p = 0.015) and dementia (OR 7.03, CI 2.39-25.2; p = 0.001). With Cox regression, hippocampal volume was a significant predictor for "time to cognitive impairment" (HR 7.67; CI 3.47-16.95, p 0.001). Difference between survival curves based on volume of white matter hyperintensity in predicting "time to mild cognitive impairment" was significant (p = 0.0295).Hippocampal volume is a major factor predicting the development of mild cognitive impairment and dementia in PD. White matter hyperintensity also contributes to the longitudinal cognitive status in PD.

Although the clinical signs of prodromal Parkinson's disease (PD) have been identified, little is known about the neural features of the prodromal phase of PD (proPD). The aim of this study was to examine the structural network alterations from healthy aging to proPD and to early PD.181 non-demented and non-depressed participants comprising 55 healthy controls (HCs), 20 proPDs, and 106 de novo PD patients (dPDs) were included in the study and underwent clinical assessment and diffusion tensor imaging scanning. Graph-theoretical analysis and network-based statistics, with age and gender as nuisance covariates, were used.Compared with HCs and dPDs, proPD patients showed significantly elevated small-worldness and clustering coefficient (Ps 0.01) and greater local connectivity between regions relating to motor, olfactory and sleep functions (Ps 0.05). Although dPDs and HCs did not differ on all graph-theoretic metrics, dPD patients showed decreased connectivity within the prefrontal regions and between the left temporal and occipital lobes (P 0.05). The connectivity strength between these regions significantly distinguished between diagnostic groups. Connectivity between bilateral SMAs was correlated with UPSIT in HCs and with UPDRS-III in dPDs. Connectivity between the right SMA and putamen was correlated RBDSQ in proPDs.Increased network efficiency and connectivity of proPDs and decreased local connectivity of dPDs might suggest the emergence and dissipation of neural compensation in the prodromal phase and in early PD, respectively. Nonetheless, longitudinal studies are needed to follow up the long-term structural network changes of proPD patients.

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

The neuroanatomical substrates underlying cognitive impairment in Parkinson's disease (PD) remain poorly understood. To address this gap, we compared the grey matter atrophy patterns in PD patients with mild cognitive impairment (PD-MCI) with PD patients having no cognitive impairment (PD-NCI), and examined relationships between atrophic regions and cognitive performance in specific domains.90 non-demented PD patients (64.95±7.54 years, Hoehn and Yahr=1.88±0.39) were classified using formal diagnostic criteria as PD-MCI (n=23) or PD-NCI (n=67). Grey matter volume differences were examined using voxel-based morphometry on structural MRI, and multivariate linear regressions were employed to assess the relationships between cognitive performance in specific domains and atrophic regions.Patients with PD-MCI had lower global cognition scores compared with PD-NCI (Mini Mental State Examination: 26.9 vs. 28.4, p=0.011; Montreal Cognitive Assessment: 24.5 vs. 27.0, p0.001). The PD-MCI group demonstrated significantly poorer performance on executive function, attention, memory and language abilities. Patients with PD-MCI had reductions in grey matter volumes in the left insular, left superior frontal and left middle temporal areas compared to PD-NCI. Multiple regressions controlling for age, education and cardiovascular risk factors revealed significant positive correlations between left insular atrophy and executive-attention dysfunction.Domain specific cognitive impairment in mild PD is associated with distinct areas of grey matter atrophy. These regions of atrophy are demonstrable early in the disease course and may serve as a biomarker for dementia in PD.

Motor asymmetry in Parkinson's disease (PD) is evident clinically and on functional neuroimaging, but not reported in diffusion tensor imaging (DTI). We aim to determine if asymmetry in fractional anisotropy (FA) and apparent diffusion coefficient (ADC) can be detected in the substantia nigra (SN) of PD subjects.DTI scans were performed on 11 PD and 12 healthy subjects. Regions of interest (ROIs) were drawn by 2 independent raters at the caudal, middle and rostral SN on each side. FA and ADC were extracted from the ROIs.Significant asymmetry was observed in the FA (p0.005) and ADC (p0.00005) at the rostral SN of PD subjects. The differences in FA and ADC across the left and right rostral SN were significantly different between PD and healthy subjects, p0.05 and p0.02 respectively. PD subjects had significantly higher ADC at the left rostral SN than healthy subjects (p0.01). Significant correlation between the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and the FA was noted in the left rostral SN (r = 0.7, p0.03).Asymmetry in DTI indices was noted at the rostral SN of PD subjects. The relationship between FA in the SN and UPDRS motor score was studied. Our findings may provide a model for better understanding of the implication of FA reduction in the SN.

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

Objective Cerebral small-vessel disease (SVD) is a risk factor for dementia in Parkinson’s disease (PD), however the pathophysiological role of SVD in PD-dementia is unclear. We investigated the impact of baseline and progression of SVD on cortical thickness and the correlation to cognition. Methods Seventy-three mild PD patients with baseline and follow-up structural MRI scans, serial clinical and neuropsychological assessments were studied. SVD included the load of white matter hyperintensities (WMH), lacunes and perivascular spaces (PVS). WMH progression was assessed using the modified Rotterdam Progression scale, while for lacunes and PVS, development of new lesions was considered as lesion progression. Patients were classified as having SVD-progression and SVD-no-progression based on the longitudinal changes in their SVD measures. Freesurfer was used to measure baseline and follow-up regional cortical thickness and subcortical volumes and correlated to cognitive performance. Results Fourteen patients were classified as SVD-progression and 59 as SVD-no-progression. Over 18 months, PD SVD-progression demonstrated significant cortical thinning in the left frontal and bilateral parietal regions with associated decline in memory, executive function, and motor functions. PD SVD-progression also had reduced volumes in the nucleus accumbens and amygdala at baseline and greater atrophy in the caudate nucleus over 18 months. Discussion The extent and progression of SVD is associated with focal cerebral atrophy and domain-specific cognitive dysfunction. Measures to retard SVD may be potentially useful in preventing dementia in PD.

To evaluate the time to hospitalisation and baseline factors associated with pneumonia/choking in Parkinson's Disease (PD) patients.Although dysphagia and pneumonia are common problems in PD, scarce research has been performed.A total of 194 PD patients who underwent a VFS evaluation were retrospectively selected. The mode of feeding and admissions for pneumonia/choking were analyzed. Baseline clinical and demographic variables were compared between feeding groups. Kaplan-Meier survival analysis was performed to estimate time to pneumonia/choking. Clinical variables significantly associated with pneumonia/choking free survival were identified using Cox regression.Hospitalisation for pneumonia/choking occurred in 89 out of 194 patients, with the highest admission rate in rejected enteral feeding group (66.7%), followed by enteral feeding (61.8%) and oral feeding (38.8%) groups. The estimates of median time to event were 11, 14, and 47 months for rejected enteral feeding, enteral and oral feeding groups respectively (log-rank test p 0.001). The rejected enteral feeding group had the highest risk of pneumonia/choking (HR 4.61, 95%CI:2.33-9.08, p 0.001), followed by enteral feeding group (HR 2.29, 95%CI:1.25-4.19, p = 0.007), when compared to oral feeding group after adjusting for possible confounders. A stepwise Cox regression showed that the rejected enteral feeding (HR 4.89, 95%CI:2.19-10.88, p 0.001), enteral mode of feeding (HR 2.43, 95%CI:1.11-5.32, p = 0.026), and Charlson weighted index of co-morbidity (HR 1.27, 95%CI:1.03-1.58, p = 0.028) were independently associated with higher hazard of pneumonia/choking.Compliance to feeding recommendations is important to reduce the risk of hospitalisation for pneumonia/choking. The recommended mode of feeding and comorbidity index was significantly associated with pneumonia/choking risk.

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.

Objective: To investigate in vivo the impact of age on nigrostriatal dopamine dysfunction in Parkinson's disease (PD). Methods: PD patients (n = 78) and healthy control subjects (n = 35) underwent longitudinal positron emission tomography assessments using 3 presynaptic dopamine markers: (1) [11C](±)dihydrotetrabenazine (DTBZ), to estimate the density of the vesicular monoamine transporter type 2; (2) [11C]d-threo-methylphenidate, to estimate the density of the plasma membrane dopamine transporter; and (3) 6-[18F]-fluoro-L-dopa, to estimate the activity of the enzyme dopa-decarboxylase. Results: The study comprised 438 PD scans and 241 control scans (679 scans in total). At symptom onset, the loss of putamen DTBZ binding was substantially greater in younger compared to older PD patients (p = 0.015). Remarkably, however, the rate of progression of DTBZ binding loss was significantly slower in younger patients (p< 0.05). The estimated presymptomatic phase of the disease spanned more than 2 decades in younger patients, compared to 1 decade in older patients. Interpretation: Our results suggest that, compared to older patients, younger PD patients progress more slowly and are able to endure more damage to the dopaminergic system before the first motor symptoms appear. These observations suggest that younger PD patients have more efficient compensatory mechanisms. Ann Neurol 2011

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.

People with Parkinson’s disease (PD) have difficulty performing dual tasks or simultaneous movements, even if the same movements can be easily performed individually. This has particular significance clinically, as for example falling injuries may occur if care is not taken to perform tasks one at a time. We investigated whether this difficultyx results from impaired dopamine-modulated connectivity. We recorded the EEG in PD subjects off and on l -dopa medication performing simultaneous and unimanual tracking tasks. To deal with the inherent non-stationarity of the EEG during motor tasks, we segmented the data into task-related sections based on transient synchronisation between independent components of the data, before assessing the mutual information (MI) between each EEG channel pair. In both tasks, PD subjects off-medication demonstrated enhanced fronto-central and decreased occipital synchronisation within theta and alpha bands, and widespread increased beta-band synchronisation, compared to controls. Synchronisation changes in theta and beta bands were partially normalised by l -dopa, but l -dopa had relatively little effect on alpha band synchronisation. When comparing simultaneous movements to unimanual tracking, PD subjects off-medication demonstrated synchronisation changes within theta and beta bands, however alpha connectivity was largely unchanged. These results suggest that downstream influences of impaired basal ganglia function on cortico-cortical connectivity may result in difficulties with dual task performance in PD.

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.

Parkinson's disease preferentially affects internally generated movements, e.g., movements recalled from memory, while externally cued movements are relatively preserved. However, L-dopa may have effects on visually guided movements as well as error-related processing. Fourteen Parkinson's disease (PD) subjects (on and off L-dopa medication) as well as ten normal controls performed a tracking task using a joystick. During discrete 30 s blocks, the visual feedback of the actual tracking errors were attenuated, amplified or unaltered. Second order dynamical system models, with the desired trajectory as the input and the actual motor performance as the output, were used to characterize the motor performance by the each subject under each condition. Although the overall root-mean-square tracking error did not significantly differ between groups, the nature of the motor performance differed significantly across groups. A clear dissociation was made between manipulations of error feedback--which altered the natural frequency of the models--and the effects of L-dopa, which affected damping. Compared to normal controls, PD subjects were significantly overdamped before medication and underdamped after medication. We interpret our results as being suggestive of L: -dopa normalization of compensatory overactive cerebellar activity in PD.

Previous validation studies on the PDQ-8, a brief disease-specific quality of life instrument, were performed with the PDQ-8 nested in the original PDQ-39. Such an approach may influence patient responses and the psychometric properties of the PDQ-8. We therefore undertook this study to validate the PDQ-8 when administered independently in English and Chinese and found good item-to-scale correlations (correlation coefficient: 0.44-0.68) and internal consistency (Cronbach's alpha: 0.81, 0.87). Factor analyses yielded a component on which all 8 questions were substantially loaded (loading range: 0.55-0.77). Scree plots also showed the one-factor solution thereby validating the PDQ-8 summary index. Construct validation against the Hoehn and Yahr stage and UPDRS motor scores showed significant correlations between higher PDQ-8 summary index and increased disease severity in both English and Chinese versions. Our results show the PDQ-8 to be a valid and reliable disease-specific HRQoL instrument for PD when used independently of the PDQ-39.

Introduction Apathy is one of the most common behavioural disorders in Parkinson's disease (PD) and contributes significantly to a reduced quality of life in PD patients. Methods We conducted a prospective longitudinal study of 89 mild PD patients over 18 months, measuring apathy symptoms at 6-monthly intervals using the Starkstein Apathy Scale, as well as measures of motor and non-motor symptoms, cognitive function, and functional disability at baseline. Mixed-effects models were used to characterise the individual trajectories of apathy symptom severity, and linear regression with stepwise elimination procedure was used to select significant baseline predictors. Results Clinically significant levels of apathy were present in 42.7% of our sample at baseline, with symptom severity remaining relatively stable on average over the course of 18 months. Male gender, lower educational attainment, higher depression symptom severity, more severe functional disability, and the presence of dyskinesias at study entry predicted increasing apathy over the subsequent 18 months. Conclusions Patients with these factors are at risk for progression of apathy, which may be prevented by treating depression and functional disability. Further studies are needed to address both the specific neurobiological pathways and psychosocial factors underpinning apathy in PD.

Genome-wide association studies have identified several loci associated with Parkinson's disease (PD). Whole-exome sequencing detects rare coding variants, but their links with PD genome-wide association study loci are unknown. Our objective was to investigate whether nonsynonymous variants in LRRK2 can explain associations at the PD-associated locus tagged by rs1994090.We sequenced all coding exons of LRRK2 in 453 East Asian samples and evaluated linkage disequilibrium between each nonsynonymous variant and rs1994090. We then tested selected variants and haplotypes for association with PD in 13,581 East Asian samples.Of all the nonsynonymous variants, only p.Gly2385Arg was in moderate linkage disequilibrium with rs1994090 and was observed on haplotypes tagged by the rs1994090-C risk allele. Conditional analyses showed that associations at these 2 variants are not independent.LRRK2 p.Gly2385Arg can explain most if not all of the PD association at rs1994090 in East Asians, but other nonsynonymous variants are independent. © 2015 International Parkinson and Movement Disorder Society.

The clinical implications of white matter hyperintensities (WMH) in non-demented Parkinson's disease (PD) have not been thoroughly examined. To address this, we investigated the spatial distribution of WMH and their regional predilection in non-demented patients with mild PD.Cognitive assessments classified the sample into patients with mild cognitive impairment (PD-MCI, n = 25) and patients with no cognitive impairment (PD-NCI, n = 65) based on the recent formal Movement Disorder Task Force diagnostic criteria. The mean age was 65.1 ± 7.7 years, disease duration was 5.3 ± 3.9 years, and Hoehn and Yahr stage was 1.9 ± .4. WMHs were outlined on T2-weighted imaging using a semi-automated technique. The spatial distribution of WMHs were compared between PD-MCI and PD-NCI using voxel-wise lesion probability maps (LPM). General linear models examined the associations between spatially specific WMHs and cognitive domains.LPM analyses showed significant differences in the spatial distribution of WMH in PD-MCI compared to PD-NCI in widespread regions of the brain (P.05). PD-MCI demonstrated significantly greater total and periventricular WMHs compared to PD-NCI (P ≤ .02). Spatial distribution of WMHs was also significantly associated with global cognition, performance on the Frontal Assessment Battery and Fruit Fluency (P.05).Voxel-wise LPM analysis revealed differences in the spatial distribution of WMH between PD-MCI and PD-NCI patients, particularly in the periventricular regions. A more widespread extent of WMH might be indicative of cognitive deterioration. Our findings warrant further longitudinal investigation into the importance of WMH spatial distribution as a predictor for conversion from PD to PD with dementia.

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.

Over the past two decades, positron emission tomography (PET) has provided valuable insights into the mechanisms of nigrostriatal degeneration in Parkinson's disease (PD). Furthermore, it allows the in vivo assessment of disease progression and the evaluation of treatment interventions. In this review, we shall discuss some of the issues and concerns that arise with the use of PET as a surrogate marker of disease progression in Parkinson's disease.

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.

Introduction Existing literature on brain volumetric alterations in patients with Parkinson's disease (PD) have mainly focused on gray matter (GM) and are largely cross-sectional. Little is known about white matter (WM) volumetric features and their impact on cognitive symptoms in PD. Therefore, the present study aims to examine both GM and WM volumes of cognitively asymptomatic PD patients with a longitudinal design. Methods A total of 42 cognitively asymptomatic patients with early stage PD were recruited and followed up for 1.5 years. At follow-up, 12 patients progressed to mild cognitive impairment (MCI) and were classified as “converters” while the remaining 30 patients remained cognitively asymptomatic and were classified as “non-converters”. All patients underwent clinical and neuropsychological assessments as well as MRI scans at baseline and at follow-up. Results At baseline, non-converters and converters had comparable cognitive scores. At follow-up, converters showed more deficits in frontal-related cognitive function than non-converters. Volumetric analyses revealed that converters had more longitudinal reduction in WM, but not GM, volume compared to non-converters. The decreased volumes among converters were mainly localized in the frontal areas. Moreover, baseline global WM volume significantly predicted conversion to PD-MCI, while baseline GM and WM volumes of the frontal and parietal regions were associated with frontal cognitive changes across time. Conclusion PD patients who develop MCI demonstrate longitudinal reduction in WM volume, especially in the frontal areas. While both regional GM and WM volumes associate with frontal cognitive decline, baseline global WM volume may be a neuroimaging marker of conversion to PD-MCI.

Early diagnosis of cognitive impairment in PD would allow appropriate monitoring and timely intervention to reduce the progression to dementia (PDD).To study the usefulness of the Montreal Cognitive Assessment (MoCA) in the screening for mild cognitive impairment (PD-MCI) and its predictive utility in determining longitudinal cognitive decline in PD.Prospective longitudinal study of patients with mild PD. PD-MCI and PDD was diagnosed based on the Movement Disorder taskforce (MDS) criteria. Receiver Operating Characteristic analyses and Cox regression analyses were performed.95 patients; mean age 66.37 (SD 7.86); mean HY score of 1.99 (SD 0.45) were studied. At baseline, 34 patients fulfilled the MDS criteria for PD-MCI. MoCA, compared to the MMSE had a high discriminatory power in detecting PD-MCI [Area Under Curve (AUC) of 0.912, p 0.001]. A MoCA score of ≤26 provided a sensitivity of 93.1% for the diagnosis of PD-MCI. In the longitudinal cohort over 2 years, baseline MOCA was useful in predicting cognitive decline (AUC of 0.707, p = 0.05). With Cox regression analyses, a 1-point lower score on baseline MoCA was associated with a 34% increased risk of cognitive decline [Hazard ratio (HR) 1.34; 95% CI: 1.03-1.74: p = 0.029]. A baseline MoCA ≤26 was highly predictive of progressive cognitive decline (HR 3.47, 95% CI: 2.38-5.07; p 0.01).MoCA is a reliable tool in predicting cognitive decline in early PD. A MoCA score of ≤26 significantly increases the risk for progressive cognitive decline.