Polygenic Risk Scores in a Prospective Parkinson's Disease Cohort.

BACKGROUND: Ethnic-specific genetic risk assessment framework for Parkinson's disease (PD) is lacking for the Asian population. OBJECTIVE: We investigated the association of a polygenic risk score (PRS) with PD incidence in a population-based Asian prospective cohort. METHODS: Genetic, dietary, and lifestyle information were prospectively collected from 25,646 participants within the Singapore Chinese Health Study cohort. PRS was constructed with Asian-specific and top genome-wide association study variants. The association between PRS and PD incidence was evaluated with multivariable Cox proportional hazard models, Kaplan-Meier survival analysis, and concordance statistics. RESULTS: A total of 333 incident cases were identified after a follow-up period of more than 20 years. Participants with PRS in the top tertile (hazard ratio [HR], 1.81; 95% confidence interval [CI], 1.37-2.39) and middle tertile (HR, 1.35; 95% CI, 1.00-1.83) are at higher risk of developing PD after adjusting for dietary and lifestyle risk factors, with a shorter time to PD event in a Kaplan-Meier survival analysis (P < 0.001). CONCLUSION: We identified a PRS that was significantly associated with PD incidence in a prospective Chinese cohort after adjusting for dietary and lifestyle factors. © 2021 International Parkinson and Movement Disorder Society.

The Modified Barium Swallow Impairment Profile as a Predictor of Clinical Outcomes of Admission for Pneumonia or Choking in Dysphagic Patients with Parkinson's Disease.

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.

Parkinson's Disease Risk Variant rs9638616 is Non-Specifically Associated with Altered Brain Structure and Function.

Background: A genome-wide association study (GWAS) variant associated with Parkinson's disease (PD) risk in Asians, rs9638616, was recently reported, and maps to WBSCR17/GALNT17, which is involved in synaptic transmission and neurite development. Objective: To test the association of the rs9638616 T allele with imaging-derived measures of brain microstructure and function. Methods: We analyzed 3-Tesla MRI and genotyping data from 116 early PD patients (aged 66.8±9.0 years; 39% female; disease duration 1.25±0.71 years) and 57 controls (aged 68.7±7.4 years; 54% female), of Chinese ethnicity. We performed voxelwise analyses for imaging-genetic association of rs9638616 T allele with white matter tract fractional anisotropy (FA), grey matter volume and resting-state network functional connectivity. Results: The rs9638616 T allele was associated with widespread lower white matter FA (t = -1.75, p = 0.042) and lower functional connectivity of the supplementary motor area (SMA) (t = -5.05, p = 0.001), in both PD and control groups. Interaction analysis comparing the association of rs9638616 and FA between PD and controls was non-significant. These imaging-derived phenotypes mediated the association of rs9638616 to digit span (indirect effect: ß= -0.21 [-0.42,-0.05], p = 0.031) and motor severity (indirect effect: ß= 0.15 [0.04,0.26], p = 0.045). Conclusions: We have shown that a novel GWAS variant which is biologically linked to synaptic transmission is associated with white matter tract and functional connectivity dysfunction in the SMA, supported by changes in clinical motor scores. This provides pathophysiologic clues linking rs9638616 to PD risk and might contribute to future risk stratification models.

Long-term outcomes of subthalamic nucleus deep brain stimulation for Parkinson's disease in Singapore.

Introduction: Subthalamic nucleus deep brain stimulation (STN-DBS) is a proven treatment modality for Parkinson's disease (PD), reducing dyskinesia and time spent in the "OFF" state. This study evaluates the long-term outcomes of STN-DBS in PD patients up to 10 years post-surgery in Singapore. Method: We conducted a retrospective review of Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores, activities of daily living (ADLs), disease milestones, dopaminergic drug prescriptions, and adverse events in patients before and after STN-DBS surgery. Results: A total of 94 PD patients who underwent bilateral STN-DBS were included. STN-DBS reduced time in the "OFF" state by 36.9% at 1 year (P=0.034) and 40.9% at 5 years (P=0.006). Time with dyskinesia did not significantly change. Levodopa equivalent daily dose was reduced by 35.1% by 5 years (P<0.001). MDS-UPDRS-II and III scores increased from 5 years post-DBS by 40.5% and 35.4%, respectively. Independence in ADLs decreased, though not significantly. The prevalence of frequent falls increased at 5 years. Surgery- and device-related adverse events were uncommon and generally mild. Conclusion: STN-DBS provides sustained relief from motor complications and reduced medication requirements in PD patients in Singapore. This study highlights STN-DBS as an effective treatment option, significantly enhancing the quality of life for those with PD.

Outcomes after deep brain stimulation for elderly versus non-elderly patients with Parkinson's disease.

INTRODUCTION: The decision to offer deep brain stimulation (DBS) to elderly patients with Parkinson's disease (PD) presents challenges due to higher perceived risks and uncertain long-term benefits. Here, we aimed to compare the outcomes after DBS for elderly versus non-elderly patients with PD. METHODS: We analyzed data from our institutional cohort and retrieved publicly available data through a systematic review. The exposure was age at DBS electrode insertion, which was defined as elderly (≥70 years old) and non-elderly (<70 years old). The outcomes examined were changes in the Movement Disorders Society-Parkinson's Disease Rating Scale (MDS-UPDRS) or UPDRS part III total score, levodopa-equivalent daily dose (LEDD), and adverse events. RESULTS: The included studies and our cohort comprised a total of 527 patients, with 111 (21.1 %) classified as elderly. There was no statistically significant difference in the change in MDS-UPDRS or UPDRS part III total score and generally no statistically significant difference in the change in LEDD between the elderly and non-elderly patients. Elderly patients had a higher incidence of wound infection (elderly 5.4 % vs non-elderly 1.9 %; p = 0.087) and inadequate wound healing (elderly 3.6 % vs non-elderly 1.4 %; p = 0.230), but this difference was not statistically significant. There was no significant difference in the incidence of mortality (elderly 0 % vs non-elderly 0 %; p = 1.000), stroke (elderly 0 % vs non-elderly 0.2 %; p = 1.000), and cognitive decline between the age groups. CONCLUSIONS: Notwithstanding the trend towards a higher risk of wound infection and inadequate wound healing, elderly patients have similar motor outcomes and levels of PD medication reduction as non-elderly patients after DBS for PD. Hence, age should not be used as the sole criterion for determining eligibility for DBS, and the decision to offer DBS to elderly patients should be personalized and made in a multidisciplinary setting, taking into consideration patient- and disease-related factors.

Using the consolidated framework for implementation research to guide a pilot of implementing an institution level patient informed consent process for clinical research at an outpatient setting.

BACKGROUND: In Singapore, research teams seek informed patient consent on an ad hoc basis for specific clinical studies and there is typically a role separation between operational and research staff. With the enactment of the Human Biomedical Research Act, there is increased emphasis on compliance with consent-taking processes and research documentation. To optimize resource use and facilitate long-term research sustainability at our institution, this study aimed to design and pilot an institution level informed consent workflow (the "intervention") that is integrated with clinic operations. METHODS: We used the Consolidated Framework for Implementation Research (CFIR) as the underpinning theoretical framework and conducted the study in three stages: Stage 1, CFIR constructs were used to systematically identify barriers and facilitators of intervention implementation, and a simple time-and-motion study of the patient journey was used to inform the design of the intervention; Stage 2, implementation strategies were selected and mapped to the Expert Recommendations for Implementing Change (ERIC) taxonomy; Stage 3, we piloted and adapted the implementation process at two outpatient clinics and evaluated implementation effectiveness through patient participation rates. RESULTS: We identified 15 relevant CFIR constructs. Implementation strategies selected to address these constructs were targeted at three groups of stakeholders: institution leadership (develop relationships, involve executive boards, identify and prepare champions), clinic management team (develop relationships, identify and prepare champions, obtain support and commitment, educate stakeholders), and clinic operations staff (develop relationships, assess readiness, conduct training, cyclical tests of change, model and simulate change, capture and share local knowledge, obtain and use feedback). Time-and-motion study in clinics identified the pre-consultation timepoint as the most appropriate for the intervention. The implementation process was adapted according to clinic operations staff and service needs. At the conclusion of the pilot, 78.3% of eligible patients provided institution level informed consent via the integrated workflow implemented. CONCLUSIONS: Our findings support the feasibility of implementing an institution level informed consent workflow that integrates with service operations at the outpatient setting to optimize healthcare resources for research. The CFIR provided a useful framework to identify barriers and facilitators in the design of the intervention and its implementation process.

Psychosis in Parkinson's disease in a Southeast Asian cohort: prevalence and clinical correlates.

Introduction: Psychosis is a prominent neuropsychiatric symptom of Parkinson's disease (PD) and is associated with negative outcomes, such as poorer quality of life and greater rate of functional impairment. Early identification of patients with PD at risk of developing psychosis facilitates appropriate management to improve outcomes. However, this phenomenon has not been examined locally. This study aimed to examine the prevalence of PD-associated psychosis in the local setting, identify any associated risk factors, as well as characterise the cognitive trajectory of patients with PD with psychosis. Methods: A retrospective cohort of 336 patients with PD, who presented to the National Neuroscience Institute, Singapore, in 2006 and 2007 and attended follow-up visits through to 2013 was analysed. The data analysed included scores from clinician assessments of cognitive function, disease severity and presence of psychotic symptoms, conducted when clinically appropriate during patients' medical visits. Survival analysis and logistic and linear regression analysis were performed. Results: Psychosis was diagnosed in 63 patients with PD, indicating a prevalence of 18.8% for PD-associated psychosis. Incidence of psychosis in PD was calculated to be 40 per 1,000 person-years. No significant association was found between demographic variables and the odds of developing psychosis in PD. Regression analyses found that the presence of psychosis significantly predicted greater cognitive decline and disease severity. Conclusion: Psychosis has a significant presence among the PD population in Singapore, possibly serving as an indicator of more rapid cognitive decline and progression of PD severity.

Longitudinal Healthcare Utilization and Costs in Parkinson's Disease: Pre-Diagnosis to 9 Years After.

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 < 0.001). Mean annual cost attributable to PD increased from USD1854 at 1-year post-diagnosis to USD2652 at 9 years. Over 9 years, average costs were significantly higher across all domains of healthcare utilization except primary care-cost of intermediate and long-term care was increased by a factor of 2.5, specialist care by 2.3, emergency department visits by 1.6, and hospital admissions by 1.3. CONCLUSION: PD results in higher healthcare utilization and costs. Pre-diagnosis increase in healthcare utilization observed in patients supports the presence of prodromal PD symptoms and may present an opportunity for early diagnosis.

Poor sleep quality is associated with fatigue and depression in early Parkinson's disease: A longitudinal study in the PALS cohort.

Background: Sleep disorders are common in Parkinson's disease (PD). However, the longitudinal relationship between sleep quality and the other non-motor symptoms of PD has not been well characterized, especially in early PD. Objective: To explore the value of baseline sleep quality in predicting the progression of other non-motor symptoms in early PD. Methods: 109 early PD patients were recruited to the study. Patients were stratified into good and poor sleepers using the Pittsburgh Sleep Quality Index (PSQI). Assessments performed at baseline and 1 year follow-up included the Epworth Sleepiness Scale, Fatigue Severity Scale, Non-Motor Symptom Scale, Geriatric Depression Scale, Hospital Anxiety and Depression Scale, Apathy Scale, Montreal Cognitive Assessment and detailed neuropsychological assessments. Multivariable linear regression was performed at baseline to investigate differences in clinical scores between poor and good sleepers, while multivariable regression models were used to investigate associations between sleep quality and progression of test scores at 1 year follow-up. Results: 59 poor sleepers and 50 good sleepers were identified. At baseline, poor sleepers had greater HADS anxiety scores (p = 0.013) [2.99 (95% CI 2.26, 3.73)] than good sleepers [1.59 (95% CI 0.75, 2.42)]. After 1 year, poor sleepers had greater fatigue (FSS scores +3.60 as compared to -2.93 in good sleepers, p = 0.007) and depression (GDS scores +0.42 as compared to -0.70, p = 0.006). Conclusion: This study shows a longitudinal association between sleep quality, fatigue, and depression in early PD patients, independent of medication effect and disease severity, this may support the hypothesis that a common serotonergic pathway is implicated in these non-motor symptoms.

Subjective cognitive Complaints in early Parkinson's disease patients with normal cognition are associated with affective symptoms.

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 (ß = 0.28, 95% CI = 0.09-0.79, p = 0.014), depression (ß = 0.31, 95% CI = 0.10-0.59, p = 0.006) and apathy (ß = 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.

Evolution of Initial Pharmacologic Treatment of Newly Diagnosed Parkinson's Disease Patients over a Decade in Singapore.

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 <2 (adjusted OR, 3.4; 95% CI, 1.5-7.7) were independent factors for LD-sparing strategies. Non-LD prescriptions (13 of 92; 14.1%) were more likely to be discontinued compared to LD ones (6 of 149; 4.0%) (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.

Physical Activity Improves Anxiety and Apathy in Early Parkinson's Disease: A Longitudinal Follow-Up Study.

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.

Corrigendum: Increased Activation of Default Mode Network in Early Parkinson's With Excessive Daytime Sleepiness.

[This corrects the article DOI: 10.3389/fnins.2019.01334.].

Patient-Centric Care for Parkinson's Disease: From Hospital to the Community.

Parkinson's disease (PD) is a chronic neurodegenerative disease with complex motor and non-motor symptoms often leading to significant caregiver burden. An integrated, multidisciplinary care setup involving different healthcare professionals is the mainstay in the holistic management of PD. Many challenges in delivering multidisciplinary team (MDT) care exist, such as insufficient expertise among different healthcare professionals, poor interdisciplinary collaboration, and communication. The need to attend different clinics, incurring additional traveling and waiting time for allied health therapies can also make MDT care more burdensome. By shifting MDT care to local community settings and into patients' homes, patient-centered care can be achieved. In Singapore, the National Neuroscience Institute created the Community Care Partners Programme in 2007 to bring the allied MDT team to the community and nurse-led Integrated Community Care Programme for Parkinson's Disease in 2012 to provide care in community and at patient's home. However, attaining MDT care in the community setting is difficult to achieve where there is a shortage of PD-trained professionals. As such, interdisciplinary and transdisciplinary management would be other best practice options to deliver patient-centric care in PD. Telemedicine could be another viable option to bring the MDT closer to the patient.

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

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

Mild Parkinsonian Signs in a Community Ambulant Population.

BACKGROUND: Mild parkinsonian signs (MPS) are common in the older adult and associated with a wide range of adverse health outcomes. There is limited data on the prevalence of MPS and its significance. OBJECTIVE: To determine the prevalence of MPS in the community ambulant population and to evaluate the relationship of MPS with prodromal features of Parkinson's disease (PD) and cognition. METHODS: This cross-sectional community-based study involved participants aged ≥50 years. Parkinsonian signs were assessed using the modified Unified Parkinson's Disease Rating Scale (mUPDRS) and cognition using the Montreal Cognitive Assessment (MoCA). Premotor symptoms of PD were screened using a self-reported questionnaire. Linear regression was used to assess the association of MPS with premotor symptoms of PD and cognitive impairment. RESULTS: Of 392 eligible participants, MPS was present in 105 (26.8%). Mean age of participants with MPS was 68.8±6.9 years and without MPS was 66.1±5.9 years (p < 0.001). Multivariate analysis revealed that MoCA scores were significantly lower in the MPS group (ß= -0.152, 95% CI = -0.009, -0.138, p < 0.05). A significant correlation between the presence of REM sleep behavior disorder (RBD) and total MPS scores (ß= 0.107, 95% CI = 0.053, 1.490, p < 0.05) was also found. Neither vascular risk factors nor other premotor symptoms were significantly associated with MPS. CONCLUSION: MPS is common and closely related to cognitive impairment and increasing age. Presence of RBD is predictive of higher MPS scores. This study highlights the necessity of other investigations or sensitive risk markers to identify subjects at future risk of PD.

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

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

Increased Activation of Default Mode Network in Early Parkinson's With Excessive Daytime Sleepiness.

BACKGROUND AND OBJECTIVES: The underlying neuropathology of excessive daytime sleepiness (EDS) remains elusive in Parkinson's disease (PD). We aim to investigate neural network changes that underlie EDS in PD. METHODS: Early PD patients comprising eighty-one patients without EDS (EDS-) and seventeen patients with EDS (EDS+) received a resting state functional MRI scan and the Epworth Sleepiness Scale (ESS). Connectivities within the default mode network (DMN), motor and basal ganglia networks were compared between the EDS+ and EDS- groups. Correlations between network connectivity and the severity of EDS were investigated through linear regression. RESULTS: EDS+ patients displayed a trend of increased network connectivity of the posterior DMN (pDMN). A significant positive correlation was found between connectivity of the ventromedial prefrontal cortex in the pDMN and ESS. CONCLUSION: EDS+ patients are likely to display increased activation in the DMN, suggesting neural compensation in early PD or impaired attentiveness due to mechanisms such as mind-wandering.

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

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