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Background: Suppressor of tumorgenicity 2 (ST2) is highly expressed in brain tissue and is a receptor for interleukin 33 (IL-33). ST2 exists in two forms, a transmembrane receptor (ST2L) and a soluble decoy receptor (sST2). IL-33 binds to ST2L, triggering downstream signaling pathways involved in amyloid plaque clearance. Conversely, sST2 binds competitively to IL-33, attenuating its neuroprotective effects. High sST2 levels have been reported in mild cognitive impairment (MCI) and Alzheimer’s disease (AD), suggesting that the IL-33/ST2 signaling pathway may be implicated in neurodegenerative diseases. Objective: To investigate plasma sST2 levels in controls and patients with MCI, AD, frontotemporal dementia (FTD), and Parkinson’s disease (PD). Methods: Plasma sST2 levels were measured using ELISA in 397 subjects (91 HC, 46 MCI, 38 AD, 28 FTD, and 194 PD). Cerebrospinal fluid (CSF) levels of sST2 were measured in 22 subjects. Relationship between sST2 and clinical outcomes were analyzed. Results: Plasma sST2 levels were increased across all disease groups compared to controls, with highest levels seen in FTD followed by AD and PD. Dementia patients with higher sST2 had lower cross-sectional cognitive scores in Frontal Assessment Battery and Digit Span Backward. At baseline, PD-MCI patients had higher sST2, associated with worse attention. In the longitudinal PD cohort, higher sST2 significantly associated with decline in global cognition and visuospatial domains. Plasma sST2 levels correlated with CSF sST2 levels. Conclusion: Plasma sST2 is raised across neurodegenerative diseases and is associated with poorer cognition. Higher baseline sST2 is a potential biomarker of disease severity in neurodegeneration.

Background: Diffusion kurtosis imaging provides in vivo measurement of microstructural tissue characteristics and could help guide management of Parkinson’s disease. Objective: To investigate longitudinal diffusion kurtosis imaging changes on magnetic resonance imaging in the deep grey nuclei in people with early Parkinson’s disease over two years, and whether they correlate with disease progression. Methods: We conducted a longitudinal case-control study of early Parkinson’s disease. 262 people (Parkinson’s disease: n = 185, aged 67.5±9.1 years; 43% female; healthy controls: n = 77, aged 66.6±8.1 years; 53% female) underwent diffusion kurtosis imaging and clinical assessment at baseline and two-year timepoints. We automatically segmented five nuclei, comparing the mean kurtosis and other diffusion kurtosis imaging indices between groups and over time using repeated-measures analysis of variance, and Pearson correlation with the two-year change in Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part III. Results: At baseline, mean kurtosis was higher in Parkinson’s disease than controls in the substantia nigra, putamen, thalamus and globus pallidus when adjusting for age, sex, and levodopa equivalent daily dose (p < 0.027). These differences grew over two years, with mean kurtosis increasing for the Parkinson’s disease group while remaining stable for the control group; evident in significant “group ×time” interaction effects for the putamen, thalamus and globus pallidus ( η p 2 = 0.08–0.11, p < 0.015). However, we did not detect significant correlations between increasing mean kurtosis and declining motor function in the Parkinson’s disease group. Conclusion: Diffusion kurtosis imaging of specific grey matter structures shows abnormal microstructure in PD at baseline and abnormal progression in PD over two years.

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

Objectives To evaluate the utility of the splenial angle (SA), an axial angular index of lateral ventriculomegaly measured on diffusion tensor MRI color fractional anisotropy maps, in differentiating NPH from Alzheimer’s disease (AD), Parkinson’s disease (PD), and healthy controls (HC), and post-shunt changes in NPH, compared to Evans’ index and callosal angle. Methods Evans’ index, callosal angle, and SA were measured on brain MRI of 76 subjects comprising equal numbers of age- and sex-matched subjects from each cohort of NPH, AD, PD, and HC by two raters. Receiver operating characteristics (ROC) and multivariable analysis were used to assess the screening performance of each measure in differentiating and predicting NPH from non-NPH groups respectively. Temporal changes in the measures on 1-year follow-up MRI in 11 NPH patients (with or without ventriculoperitoneal shunting) were also assessed. Results Inter-rater and intra-rater reliability were excellent for all measurements (intraclass correlation coefficients > 0.9). Pairwise comparison showed that SA was statistically different between NPH and AD/PD/HC subjects (p < 0.0001). SA performed the best in predicting NPH, with an area under the ROC curve of > 0.98, and was the only measure left in the final model of the multivariable analysis. Significant (p < 0.01) change in SA was seen at follow-up MRI of NPH patients who were shunted compared to those who were not. Conclusions The SA is readily measured on axial DTI color FA maps compared to the callosal angle and shows superior performance differentiating NPH from neurodegenerative disorders and sensitivity to ventricular changes in NPH after surgical intervention. Key Points • The splenial angle is a novel simple angular radiological index proposed for idiopathic normal pressure hydrocephalus, measured in the ubiquitous axial plane on DTI color fractional anisotropy maps. • The splenial angle quantitates the compression and stretching of the posterior callosal commissural fibers alongside the distended lateral ventricles in idiopathic normal pressure hydrocephalus (NPH) using tools readily accessible in clinical practice and shows excellent test-retest reliability. • Splenial angle outperforms Evans’ index and callosal angle in predicting NPH from healthy, Parkinson’s disease, and Alzheimer’s disease subjects on ROC analysis with an area under the curve of > 0.98 and is sensitive to morphological ventricular changes in NPH patients after ventricular shunting.

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.

Background Despite experimental evidence implicating oxidative stress in the pathogenesis of PD, epidemiological studies have provided inconsistent associations between dietary antioxidants and risk of developing PD. Furthermore, no study has been done in any Asian population. Objectives We examined the associations for intake levels of dietary carotenoids (α‐carotene, β‐carotene, lycopene, β‐cryptoxanthin, and lutein) and vitamins (vitamin A, C and E) and the risk of developing PD. Methods We used data from the Singapore Chinese Health Study, a population‐based prospective cohort of 63,257 men and women aged 45 to 74 years during enrollment in 1993–1998. Antioxidant intake was derived from a validated semiquantitative food frequency questionnaire. Incident cases were identified through follow‐up interviews, hospital records, or PD registries through 31 July 2018. Hazard ratios and corresponding 95% confidence intervals were derived from multivariable Cox proportional hazard regression models with adjustment for other lifestyle and dietary factors. Results During an average 19.4 years of follow‐up, 544 incident PD cases were identified. No association was found for dietary carotenoids, individually or summed. Hazard ratio comparing highest to lowest quartile for total carotenoids was 0.98 (95% confidence interval: 0.76–1.28; P trend = 0.83). There were also no clear dose‐dependent associations of dietary vitamins A, C, and E with risk of developing PD (all P trend ≥ 0.10). Sensitive analyses with lag time and excluding supplement use did not materially alter results. Conclusions Intake of dietary antioxidants, such as carotenoids and vitamins, was not associated with the risk of developing PD in Singaporean Chinese. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Brain donations are imperative for research; understanding possible barriers to entry is required to improve brain donation rates. While a few surveys have studied attitudes towards brain banking in patients with neurodegenerative disorders, none have surveyed patients with chronic neurological disorders but without neurodegeneration. This cross-sectional study was conducted on 187 participants, with both neurodegenerative (n = 122) and non-neurodegenerative disorders (n = 65), to compare their attitudes and preferences towards brain donation. Encouragingly, patients with non-neurodegenerative disorders were just as likely to consider brain donation as those with neurodegenerative diseases. Approximately half of each group were willing to consider brain donation, and majority of participants across both groups would not be offended if asked to participate in brain donation (71%). Across both groups, altruistic reasons such as desire to advance medical knowledge and benefit to other patients were the main motivating factors for brain donation, while perceived stress for family members, fears of body disfigurement and religious reasons were the main reasons against brain donation. Of note, nearly two-thirds of all participants were agreeable to allow their family to decide on their behalf. Overall, participants with non-neurodegenerative disorders appeared equally likely to consider brain donation as participants with neurodegenerative disorders. This is an important finding as they represent a significant population seen in specialist neurology clinics who may be overlooked in brain donor recruitment and awareness efforts. Healthcare professionals involved in brain banking should consider actively approaching these potential donors and involving their family members in these discussions.

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

Objective: Sleep–wake disturbances, such as excessive daytime somnolence (EDS), are nonmotor symptoms of Parkinson's disease (PD) and significantly affect the quality of life. This study aimed to examine the relationship between EDS and motor and nonmotor symptoms of PD. Methods: Eighty-two patients with idiopathic mild PD were followed up twice a year for 2 years and assessed on sleep, mood, anxiety, cognition, function, and disease severity. Data were analyzed retrospectively, comparing motor and nonmotor outcomes between those with EDS and those without. Results: At baseline, 27.9% had EDS and were similar in demographic and clinical characteristics to those without; 10% had persistent EDS during the first year of follow-up. Excessive daytime somnolence had a significant main effect on mood and anxiety as shown by consistently higher scores on the Geriatric Depression Scale ( P = .022) and Hospital Anxiety and Depression Scale-Anxiety subscale scores ( P = .011) throughout duration of follow-up. The group with persistent EDS showed greater rate of worsening Frontal Assessment Battery scores by the end of first-year follow-up ( P = .025) and greater rate of worsening Apathy Scale scores by the end of 2-year follow-up ( P = .002). No significant effects of EDS on motor symptoms and disease severity were found. Conclusions: In a Southeast Asian cohort of patients with PD, EDS had a negative longitudinal impact on mood, anxiety, apathy, and cognitive function but no impact on motor symptoms and disease severity. Excessive daytime somnolence is thus a potential therapeutic target to improve nonmotor outcomes.

Graphical abstract, Highlights • Putamen susceptibility value was higher in PD than controls one year into diagnosis. • Putamen susceptibility value was associated with clinical motor scores in early PD. • Mean diffusivity revealed greater cellular loss in the lateral substantial nigra. • Putamen and caudate microstructural degradation were driven by radial diffusivity. • A composite putamen-caudate DKI-QSM marker classified early PD from controls., Objective To investigate the utility of quantitative susceptibility mapping (QSM) and diffusion kurtosis imaging (DKI) as complementary tools in characterizing pathological changes in the deep grey nuclei in early Parkinson’s disease (PD) and their clinical correlates to aid in diagnosis of PD. Method Patients with a diagnosis of PD made within a year and age-matched healthy controls were recruited. All participants underwent clinical evaluation using the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS III) and Hoehn & Yahr stage (H&Y), and brain 3 T MRI including QSM and DKI. Regions-of-interest (ROIs) in the caudate nucleus, putamen, globus pallidus, and medial and lateral substantia nigra (SN) were manually drawn to compare the mean susceptibility (representing iron deposition) and DKI indices (representing restricted water diffusion) between PD patients and healthy controls and in correlation with MDS-UPDRS III and H&Y, focusing on susceptibility value, mean diffusivity (MD) and mean kurtosis (MK). Results There were forty-seven PD patients (aged 68.7 years, 51% male, disease duration 0.78 years) and 16 healthy controls (aged 67.4 years, 63% male). Susceptibility value was increased in PD in all ROIs except the caudate, and was significantly different after multiple comparison correction in the putamen (PD: 64.75 ppb, HC: 44.61 ppb, p = 0.004). MD was significantly higher in PD in the lateral SN, putamen and caudate, the regions with the lowest susceptibility value. In PD patients, we found significant association between the MDS-UPDRS III score and susceptibility value in the putamen after correcting for age and sex (β = 0.21, p = 0.003). A composite DKI-QSM diagnostic marker based on these findings successfully differentiated the groups (p

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 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.

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

1·8 billion people of diverse ethnicities and cultures live in the Western Pacific Region. The increasing longevity of populations in this region is a major contributor to the exponential increase in Parkinson's disease prevalence worldwide. Differences exist between Parkinson's disease in the Western Pacific Region and in Europe and North America that might provide important insights into our understanding of the disease and approaches to management. For example, some genetic factors (such as LRRK2 mutations or variants) differ, environmental exposures might play differential roles in modulating the risk of Parkinson's disease, and fewer dyskinesias are reported, with some differences in the profile of non-motor symptoms and comorbidities. Gaps in awareness of the disease and inequitable access to treatments pose challenges. Further improvements in infrastructure, clinical governance, and services, and concerted collaborative efforts in training and research, including greater representation of the Western Pacific Region in clinical trials, will improve care of patients with Parkinson's disease in this region and beyond.

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

Highlights • COVID-19 has significant impact on PD research and education activities. • Country-specific restrictions may pose challenges to PD research and require careful adaptations. • Neurological Symptoms of COVID-19 may overlap with PD.

IMPORTANCE: The presence of Notch homolog 2 N-terminal-like C (NOTCH2NLC) repeat expansions are associated with neuronal intranuclear inclusion body disease (NIID), with varied neurological signs, including neuropathy, ataxia, parkinsonism, and tremor. To date, genetic screening of NOTCH2NLC GGC repeats in a cohort with typical Parkinson disease (PD) appears not to have been reported. OBJECTIVE: To investigate if NOTCH2NLC GGC expansions are present in a cohort of patients with PD and controls. DESIGN, SETTING, AND PARTICIPANTS: This case-control study was conducted in 2 tertiary movement disorder centers in Singapore. Participants were recruited and followed up from January 2005 to January 2020. The presence of NOTCH2NLC GGC expansion repeats was screened using polymerase chain reaction tests, and representative samples were verified with long-read genome sequencing. MAIN OUTCOMES AND MEASURES: Qualitative and quantitative comparisons between participants with sporadic PD, healthy control participants, and individuals with NIID. RESULTS: A total of 2076 participants, including 1000 with sporadic PD (600 men [60.0%]; mean age at onset, 62.6 [7.7] years) and 1076 healthy controls (581 men [54.0%]; mean age at study recruitment, 54.9 [9.4] years) were recruited. A total of 13 patients with PD and no healthy control participants were identified as carrying NOTCH2NLC GGC repeat expansions of more than 40 units; the frequency of more than 40 repeat expansions was higher in participants with PD than controls (P

BackgroundApathy is common in Parkinson's disease (PD) but its underlying white matter (WM) architecture is not well understood. Moreover, how apathy affects cognitive functions in PD remains unclear. We investigated apathy-related WM network alterations and the impact of apathy on cognition in the context of PD.MethodsApathetic PD patients (aPD), non-apathetic PD patients (naPD), and matched healthy controls (HCs) underwent brain scans and clinical assessment. Graph-theoretical and network-based analyses were used for group comparisons of WM features derived from diffusion spectrum imaging (DSI). Path analysis was used to determine the direct and indirect effects of apathy and other correlates on different cognitive functions.ResultsThe aPD group was impaired on neural integration measured by global efficiency (p = 0.009) and characteristic path length (p = 0.04), executive function (p < 0.001), episodic memory (p < 0.001) and visuospatial ability (p = 0.02), and had reduced connectivity between the bilateral parietal lobes and between the putamen and temporal regions (p < 0.05). In PD, executive function was directly impacted by apathy and motor severity and indirectly influenced by depression; episodic memory was directly and indirectly impacted by apathy and depression, respectively; conversely, visuospatial ability was not related to any of these factors. Neural integration, though being marginally correlated with apathy, was not associated with cognition.ConclusionsOur results suggest compromised neural integration and reduced structural connectivity in aPD. Apathy, depression, and motor severity showed distinct impacts on different cognitive functions with apathy being the most influential determinant of cognition in PD.

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.

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

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

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

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

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.

BACKGROUND AND PURPOSE The aim of this study was to examine non-motor symptoms in different Parkinson's disease (PD) motor subtypes and their associations with quality of life (QoL). METHODS A total of 132 patients with early PD with comprehensive motor examinations and non-motor symptom assessments were included. Motor subtypes were classified based on Stebbins' method. Non-motor symptoms were assessed by the Non-Motor Symptom Scale (NMSS) and validated by more comprehensive instruments, including the Pittsburgh Sleep Quality Index (PSQI) and Fatigue Severity Scale (FSS). QoL was measured by the Parkinson's Disease Questionnaire-8. RESULTS We identified 66 patients (50%) with tremor-dominant (TD) subtype, 47 (35.6%) with postural instability and gait disorder (PIGD) subtype and 19 (14.4%) with Intermediate subtype. By comparing NMSS scores, patients with the PIGD subtype had more severe sleep impairment and fatigue (domain 2 score: 5.64 vs. 2.52, P < 0.001), urinary symptoms (domain 7 score: 6.96 vs. 3.48, P = 0.005) and overall more severe non-motor symptoms (NMSS total score: 25.89 vs. 17.27, P = 0.031), compared with patients with the TD subtype. Validation using the PSQI and FSS again suggested that patients with the PIGD subtype had independently and significantly more severe sleep impairment (PSQI score: 5.57 vs. 4.29, P = 0.020) and fatigue (FSS score: 34.81 vs. 25.85, P = 0.003) compared with patients with the TD subtype. Several non-motor symptoms had significant associations with QoL, among which sleep impairment and fatigue (P < 0.0001, partial r2 = 0.273) explained the largest proportion of QoL variability in patients with PD. CONCLUSIONS Patients with the PIGD subtype had more severe sleep impairment, fatigue and urinary disturbance compared with patients with the TD subtype. Sleep impairment and fatigue were the most important factors affecting QoL independent of motor subtypes. Prompt identification and treatment of these non-motor symptoms may improve patients' QoL.

Background The cause of PD at present remains unknown. A number of epidemiological studies have been conducted across the globe to ascertain the disease burden and the possible risk factors. In this review, we analyze the various studies from East and West with an aim to observe the important similarities and differences in the disease occurrence and risk factor profile. Methods A comprehensive search of descriptive and analytical epidemiological studies was undertaken. The descriptive studies and meta-analysis providing the standardised population rates were selected. The demographics, ethnicity and geographical differences between East and West were analysed. In analytical epidemiology, more established and well-studied non-genetic risk factors for PD were reviewed utilising the prospective cohort studies, case control studies and meta-analysis where available. Results and conclusion PD is more common with increasing age and shows male predominance, which is more obvious in Western studies. The PD prevalence and incidence rates are slightly lower in the East compared to the West. Incidence studies on different ethnic populations in the same country have also found a lower occurrence of PD amongst Easterners compared to Westerners. Setting methodological differences aside, studies from East and West suggest a role for both environmental and genetic risk factors in PD causation. Smoking, caffeine intake and pesticide exposure are well-established risk factors across regions. There is a robust data for dairy product consumption, urate levels and physical activity in the West while studies on certain risk factors like head injury and alcohol show conflicting and mixed results.

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.

Recent advancements in next-generation sequencing (NGS) have enabled techniques such as whole exome sequencing (WES) and whole genome sequencing (WGS) to be used to study paroxysmal movement disorders (PMDs). This review summarizes how the recent genetic advances have altered our understanding of the pathophysiology and treatment of the PMDs. Recently described disease entities are also discussed. With the recognition of the phenotypic and genotypic heterogeneity that occurs amongst the PMDs, an increasing number of gene mutations are now implicated to cause the disorders. PMDs can also occur as part of a complex phenotype. The increasing complexity of PMDs challenges the way we view and classify them. The identification of new causative genes and their genotype-phenotype correlation will shed more light on the underlying pathophysiology and will facilitate development of genetic testing guidelines and identification of novel drug targets for PMDs.

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.

Depression, anxiety and apathy are common mood disturbances in Parkinson's disease (PD) but their pathophysiology is unclear. Advanced neuroimaging has been increasingly used to unravel neural substrates linked to these disturbances. A systematic review is provided of neuroimaging findings in depression, anxiety and apathy in PD. A PubMed, MEDLINE and EMBASE search of peer‐reviewed original research articles on these mood disturbances in PD identified 38 studies on depression, eight on anxiety and 14 on apathy in PD. Most of the imaging studies used either position emission tomography or single‐photon emission computed tomography techniques. These studies generally suggest increased neural activity in the prefrontal regions and decreased functional connectivity between the prefrontal−limbic networks in depressed patients. Functional imaging studies revealed an inverse correlation between dopaminergic density in the caudate and putamen with the severity of anxiety in PD. There was no consistent correlation between dopaminergic density of thalamus and anxiety. Studies demonstrated both positive and inverse correlations between apathy and metabolism or activity in the striatum, amygdalar, prefrontal, temporal and parietal regions. The clinical variability of study subjects and differences in image pre‐processing and analytical strategies may contribute to discrepant findings in these studies. Both nigrostriatal and extra‐nigrostriatal pathways (in particular the frontal region and its connecting areas) are affected in mood disorders in PD. Identifying the relative contributions of these neural pathways in PD patients with overlapping motor and mood symptoms could provide new pathophysiological clues for the development of better therapeutic targets for affected patients.

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.

Importance Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian). Objectives To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts. Design Setting, and Participants Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31 575 individuals passing quality control of 35 994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1 926 361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson’s Disease Society Brain Bank Criteria. Main Outcomes and Measures Genotypes of common variants, association with disease status, and polygenic risk scores. Results Of 31 575 samples identified, 6724 PD cases (mean [SD] age, 64.3 [10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24 851 controls (age, 59.4 [11.4] years; 11 030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2CandWBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association forSV2C(rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21;P = 1.17 × 10−10in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity atWBSCR17(rs9638616;I2=67.1%;P = 3.40 × 10−3for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%;P = 6.81 × 10−12). Conclusions and Relevance This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta–genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.

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

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

BackgroundGlobal hippocampal atrophy is a hallmark of Alzheimer’s dementia and has been similarly reported in Parkinson’s disease dementia (PDD). However, there is limited literature on the differential involvement of hippocampal subfields in predicting conversion to PDD. This study is an extension of previous findings on progression to mild cognitive impairment in Parkinson’s disease (PD).MethodsThis cohort study recruited 73 non-demented participants with idiopathic PD (age 65.80±8.17, 75.3% male) from an outpatient neurology clinic. All participants underwent clinical assessment, neuropsychological testing and 3T MRI scans at baseline and 18 months while on prescribed dopaminergic medication. Hippocampal subfield volumes were obtained using automatic segmentation in FreeSurfer V.6.0. Participants who progressed to PDD and those who did not were compared on hippocampal subfield atrophy and cognitive change (episodic memory, attention, executive functions, language, visuospatial abilities). Subfields were further examined for their abilities to predict PDD conversion and distinguish PDD from non-demented PD using receiver operating characteristic analysis.ResultsSmaller baseline global hippocampal volume, cornu ammonis (CA) subfield CA1, subiculum and presubiculum volumes were observed in participants who went on to develop dementia, and predicted PDD conversion. Those who progressed to PDD saw greater decline in global hippocampal volume, granule cell layer of the dentate gyrus, presubiculum, parasubiculum and fimbria. Decline in subiculum and fimbria volume corresponded to cognitive decline in attention and executive functions, respectively.ConclusionsEarly atrophy of CA1, subiculum and presubiculum preceded, and predicted, PDD conversion. Differential patterns of subfield atrophy were also observed among those who progressed to PDD and were associated with impaired executive functions.

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

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