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Background: Isolated Rapid Eye Movement (REM) sleep Behavior Disorder (iRBD) requires quantitative tools to detect incipient Parkinson's disease (PD). Methods: A motor battery was designed and compared with the Movement Disorder Society‐Unified Parkinson's Disease Rating Scale part III (MDS‐UPDRS‐III) in people with iRBD and controls. This included two keyboard‐based tests (BRadykinesia Akinesia INcoordination tap test and Distal Finger Tapping) and two dual tasking tests (walking and finger tapping). Results: We included 33 iRBD patients and 29 controls. The iRBD group performed both keyboard‐based tapping tests more slowly (P < 0.001, P = 0.020) and less rhythmically (P < 0.001, P = 0.006) than controls. Unlike controls, the iRBD group increased their walking duration (P < 0.001) and had a smaller amplitude (P = 0.001) and slower (P = 0.007) finger tapping with dual task. The combination of the most salient motor markers showed 90.3% sensitivity for 89.3% specificity (area under the ROC curve [AUC], 0.94), which was higher than the MDS‐UPDRS‐III (minus action tremor) (69.7% sensitivity, 72.4% specificity; AUC, 0.81) for detecting motor dysfunction. Conclusion: Speed, rhythm, and dual task motor deterioration might be accurate indicators of incipient PD in iRBD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Summary: Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is a sleep disorder that is characterised by dream enactment episodes during REM sleep. It is the strongest known predictor of α‐synuclein‐related neurodegenerative disease (αNDD), such that >80% of people with iRBD will eventually develop Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy in later life. More research is needed to understand the trajectory of phenoconversion to each αNDD. Only five 'gold standard' prevalence studies of iRBD in older adults have been undertaken previously, with estimates ranging from 0.74% to 2.01%. The diagnostic recommendations for video‐polysomnography (vPSG) to confirm iRBD makes prevalence studies challenging, as vPSG is often unavailable to large cohorts. In Australia, there have been no iRBD prevalence studies, and little is known about the cognitive and motor profiles of Australian people with iRBD. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study will investigate the prevalence of iRBD in Tasmania, an island state of Australia, using validated questionnaires and home‐based vPSG. It will also explore several cognitive, motor, olfactory, autonomic, visual, tactile, and sleep profiles in people with iRBD to better understand which characteristics influence the progression of iRBD to αNDD. This paper details the ISLAND Sleep Study protocol and presents preliminary baseline results. [ABSTRACT FROM AUTHOR]

Objective: Parkinson's disease (PD) is a neurodegenerative disorder with complex etiology. Multiple genetic and environmental factors have been associated with PD, but most PD risk remains unexplained. The aim of this study was to test for statistical interactions between PD‐related genetic and environmental exposures in the 23andMe, Inc. research dataset. Methods: Using a validated PD polygenic risk score and common PD‐associated variants in the GBA gene, we explored interactions between genetic susceptibility factors and 7 lifestyle and environmental factors: body mass index (BMI), type 2 diabetes (T2D), tobacco use, caffeine consumption, pesticide exposure, head injury, and physical activity (PA). Results: We observed that T2D, as well as higher BMI, caffeine consumption, and tobacco use, were associated with lower odds of PD, whereas head injury, pesticide exposure, GBA carrier status, and PD polygenic risk score were associated with higher odds. No significant association was observed between PA and PD. In interaction analyses, we found statistical evidence for an interaction between polygenic risk of PD and the following environmental/lifestyle factors: T2D (p = 6.502 × 10−8), PA (p = 8.745 × 10−5), BMI (p = 4.314 × 10−4), and tobacco use (p = 2.236 × 10−3). Although BMI and tobacco use were associated with lower odds of PD regardless of the extent of individual genetic liability, the direction of the relationship between odds of PD and T2D, as well as PD and PA, varied depending on polygenic risk score. Interpretation: We provide preliminary evidence that associations between some environmental and lifestyle factors and PD may be modified by genotype. ANN NEUROL 2024;95:677–687 [ABSTRACT FROM AUTHOR]

Background: Rapid eye movement (REM) sleep behavior disorder (RBD) is an early feature of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Damaging coding variants in Glucocerebrosidase (GBA1) are a genetic risk factor for RBD. Recently, a population-specific non-coding risk variant (rs3115534) was found to be associated with PD risk and earlier onset in individuals of African ancestry. Objectives: We aimed to investigate whether the GBA1 rs3115534 PD risk variant is associated with RBD in persons with PD. Methods: We studied 709 persons with PD and 776 neurologically healthy controls from Nigeria. All DNA samples were genotyped and imputed, and the GBA1 rs3115534 risk variant was extracted. The RBD screening questionnaire (RBDSQ) was used to assess symptoms of possible RBD. Results: RBD was present in 200 PD (28.2%) and 51 (6.6%) controls. We identified that the non-coding GBA1 rs3115534 risk variant is associated with possible RBD in individuals of Nigerian origin (β, 0.3640; standard error [SE], 0.103, P = 4.093e(04), as well as in all samples after adjusting for PD status (β, 0.2542; SE, 0.108; P = 0.019) suggesting that although noncoding, this variant may have the same downstream consequences as GBA1 coding variants. Conclusions: Our results indicate that the non-coding GBA1 rs3115534 risk variant is associated with an increasing number of RBD symptoms in persons with PD of Nigerian origin. Further research is needed to assess if this variant is also associated with polysomnography-defined RBD and with RBD symptoms in DLB. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Clinical trials of disease‐modifying therapies in PD require valid and responsive primary outcome measures that are relevant to patients. Objectives: The objective is to select a patient‐centered primary outcome measure for disease‐modification trials over three or more years. Methods: Experts in Parkinson's disease (PD), statistics, and health economics and patient and public involvement and engagement (PPIE) representatives reviewed and discussed potential outcome measures. A larger PPIE group provided input on their key considerations for such an endpoint. Feasibility, clinimetric properties, and relevance to patients were assessed and synthesized. Results: Although initial considerations favored the Movement Disorder Society‐sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) Part III in Off, feasibility, PPIE input, and clinimetric properties supported the MDS‐UPDRS Part II. However, PPIE input also highlighted the importance of nonmotor symptoms, especially in the longer term, leading to the selection of the MDS‐UPDRS Parts I + II sum score. Conclusions: The MDS‐UPDRS Parts I + II sum score was chosen as the primary outcome for large 3‐year disease‐modification trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Finding low‐cost methods to detect early‐stage Alzheimer's disease (AD) is a research priority for neuroprotective drug development. Presymptomatic Alzheimer's is associated with gait impairment but hand motor tests, which are more accessible, have hardly been investigated. This study evaluated how home‐based Tasmanian (TAS) Test keyboard tapping tests predict episodic memory performance. METHODS: 1169 community participants (65.8 ± 7.4 years old; 73% female) without cognitive symptoms completed online single‐key and alternate‐key tapping tests and episodic memory, working memory, and executive function cognitive tests. RESULTS: All single‐key (R2adj = 8.8%, ΔAIC = 5.2) and alternate‐key (R2adj = 9.1%, ΔAIC = 8.8) motor features predicted episodic memory performance relative to demographic and mood confounders only (R2adj = 8.1%). No tapping features improved estimation of working memory. DISCUSSION: Brief self‐administered online hand movement tests predict asymptomatic episodic memory impairment. This provides a potential low‐cost home‐based method for stratification of enriched cohorts. Highlights: We devised two brief online keyboard tapping tests to assess hand motor function.1169 cognitively asymptomatic adults completed motor‐ and cognitive tests online.Impaired hand motor function predicted reduced episodic memory performance.This brief self‐administered test may aid stratification of community cohorts. [ABSTRACT FROM AUTHOR]

Background: PREDICT‐PD is a United Kingdom population‐based study aiming to stratify individuals for future Parkinson's disease (PD) using a risk algorithm. Methods: A randomly selected, representative sample of participants in PREDICT‐PD were examined using several motor assessments, including the motor section of the Movement Disorder Society‐Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS‐UPDRS)‐III, at baseline (2012) and after an average of 6 years of follow‐up. We checked for new PD diagnoses in participants seen at baseline and examined the association between risk scores and incident sub‐threshold parkinsonism, motor decline (increasing ≥5 points in MDS‐UPDRS‐III) and single motor domains in the MDS‐UPDRS‐III. We replicated analyses in two independent datasets (Bruneck and Parkinson's Progression Markers Initiative [PPMI]). Results: After 6 years of follow‐up, the PREDICT‐PD higher‐risk group (n = 33) had a greater motor decline compared with the lower‐risk group (n = 95) (30% vs. 12.5%, P = 0.031). Two participants (both considered higher risk at baseline) were given a diagnosis of PD during follow‐up, with motor signs emerging between 2 and 5 years before diagnosis. A meta‐analysis of data from PREDICT‐PD, Bruneck, and PPMI showed an association between PD risk estimates and incident sub‐threshold parkinsonism (odds ratio [OR], 2.01 [95% confidence interval (CI), 1.55–2.61]), as well as new onset bradykinesia (OR, 1.69 [95% CI, 1.33–2.16]) and action tremor (OR, 1.61 [95% CI, 1.30–1.98]). Conclusions: Risk estimates using the PREDICT‐PD algorithm were associated with the occurrence of sub‐threshold parkinsonism, including bradykinesia and action tremor. The algorithm could also identify individuals whose motor examination experience a decline over time. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies suggested an association between Parkinson's disease (PD) and type 2 diabetes, but less is known about type 1 diabetes (T1D) and PD. Objective: This study sought to explore the association between T1D and PD. Methods: We used Mendelian randomization, linkage disequilibrium score regression, and multi‐tissue transcriptome‐wide analysis to examine the association between PD and T1D. Results: Mendelian randomization showed a potentially protective role of T1D for PD risk (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.94–0.99; P = 0.039), as well as motor (OR, 0.94; 95% CI, 0.88–0.99; P = 0.044) and cognitive progression (OR, 1.50; 95% CI, 1.08–2.09; P = 0.015). We further found a negative genetic correlation between T1D and PD (rg = −0.17; P = 0.016), and we identified eight genes in cross‐tissue transcriptome‐wide analysis that were associated with both traits. Conclusions: Our results suggest a potential genetic link between T1D and PD risk and progression. Larger comprehensive epidemiological and genetic studies are required to validate our findings. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Dementia is associated with a range of non‐cognitive features that can occur during the prodromal phase. Improved recognition of non‐cognitive presentations of dementia could reduce inequalities in dementia diagnosis, particularly if sociocultural factors influence rates of help‐seeking for cognitive symptoms. We aimed to investigate presentations to primary care in the years before dementia diagnosis in a deprived and ethnically diverse population with universal access to health care. Method: We conducted a nested case‐control study using electronic health care records on 1,016,277 individuals from primary care practices in East London, UK between 1990 and 2018. Individuals with a diagnosis of dementia were compared to controls without dementia. We ran a matched analysis (four controls matched to each person with dementia according to age and sex) using multivariable logistic regression to assess the associations between pre‐diagnostic presentations to primary care with subsequent diagnosis of dementia. We analysed three time periods (<2, 2‐5, 5‐10) before diagnosis. Result: We included 4,137 individuals and 15,754 controls in the matched analysis (51.8% White; 42.7% Black, South Asian and other ethnicities). Neuropsychiatric presentations including depression (odds ratio [OR] = 2.71; 95% CI: 2.33 to 3.16), anxiety (OR = 1.67; 95% CI: 1.46 to 1.92), initiation of antipsychotic medication (as a proxy for psychotic symptoms) (OR = 5.84; 95% CI: 4.80 to 7.11) and insomnia (OR = 1.69; 95% CI: 1.31 to 2.17) were more frequent in the years before dementia diagnosis. Associations were found for autonomic features including constipation (OR = 1.54; 95% CI: 1.39 to 1.71) and incontinence (OR = 2.63; 95% CI: 2.32 to 2.97) up to a decade, and hypotension (OR = 1.89; 95% CI: 1.35 to 2.63) up to five years before dementia diagnosis. Sensory features including hearing loss (OR = 1.36; 95% CI: 1.14 to 1.63), imbalance and dizziness were also associated with subsequent dementia diagnosis. Memory difficulty was more strongly associated with subsequent dementia diagnosis than any non‐cognitive presentation (OR = 51.00; 95% CI: 43.87 to 59.29). Conclusion: A range of non‐cognitive presentations are seen during the prodromal period of dementia in a diverse population. Improved recognition of these associations could increase access to dementia diagnosis, through improved recognition of potential presenting symptoms in people from different backgrounds. [ABSTRACT FROM AUTHOR]

Background: Isolated rapid eye movement sleep behavior disorder (iRBD) is associated with an increased risk of Parkinson's disease and other synucleinopathies. There is no consensus about disclosure of this risk to patients with iRBD. Objective: The objective of our study was to assess the experiences of risk disclosure in a group of patients with iRBD and their views on what, when, and how this should be done. Methods: A survey was administered to patients with iRBD to explore their experiences and views on risk disclosure. Results: Thirty‐one patients with iRBD (28 males; mean age, 70 [SD 8.7] years; mean disease duration, 8.7 [SD 6.4] years) were included. A third reported they had not been informed about the link between iRBD and other conditions by clinicians at diagnosis, but 90% would have liked to have received prognostic information, and 60% indicated that this should happen at the point that iRBD was diagnosed. Most participants wanted this information to come from the clinician diagnosing and treating iRBD (90.3%). Almost three‐quarters (72.2%) had searched for this information online. Conclusions: Patients with iRBD mostly wished to have received information regarding the potential implications of iRBD when the diagnosis was made. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Targeting modifiable risk factors may prevent or delay dementia. The mechanisms by which some risk factors influence dementia remain unclear and commonality between risk factors is often overlooked. We aimed to characterize the shared genetic architecture of modifiable risk factors for dementia, and use this to explore whether shared pathways influence dementia pathogenesis and brain health. Method: We performed two multivariate genome‐wide association studies (GWAS) to characterize the shared genetic architecture of 12 modifiable risk factors for dementia using genomic structural equation modeling (GSEM). One GWAS measured genetic associations with 3 latent subgroups of closely correlated risk factors, whereas our second GWAS measured genetic associations shared across all 12 risk factors (Figure 1). We tested whether the associated variants were enriched in neuronal/glial subtypes and epigenetic marks found in different brain regions using stratified‐GSEM and identified potentially causal genes for each of the latent factors using gene mapping techniques and summary‐data‐based Mendelian randomization. Pathway analysis was conducted to examine whether the prioritized genes were implicated in dementia‐related biological pathways. Result: We identified 305 genome‐wide significant loci for the 3‐factor model of modifiable dementia risk and 285 genome‐wide significant loci for the Common Factor. Thirty‐four of these loci were novel (not previously associated with any phenotype by GWAS). Post‐GWAS analyses uncovered multiple links between the shared risk factor loci and dementia pathogenesis. Stratified‐GSEM showed that shared risk factor variants are significantly enriched in regions of the brain that degenerate in dementia, including the hippocampus and prefrontal cortex. Gene mapping identified potentially shared causal genes between risk factor loci and Alzheimer's disease (AD) loci. Pathway analysis indicated that our prioritized genes were enriched in AD pathways, protein aggregation and neuronal cell signaling. Mendelian randomization provided evidence for a causal role of the shared risk factor variants in AD pathogenesis. Conclusion: We highlight multiple genomic regions where genetic overlap between modifiable risk factors seems to directly influence dementia‐related pathways in regions of the brain that are known to degenerate in dementia. Our findings provide novel insights into the potential biological mechanisms by which modifiable risk factors may increase risk for dementia. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) affects males more than females. The reasons for the gender differences in PD prevalence remain unclear. Objective: The objective of this systematic review and meta-analysis was to update the overall male/female prevalence ratios (OPR). Methods: We updated previous work by searching MEDLINE, SCOPUS, and OVID for articles reporting PD prevalence for both genders between 2011 and 2021. We calculated OPRs and investigated heterogeneity in effect estimates. Results: We included 19 new articles and 13 articles from a previously published meta-analysis. The OPR was 1.18, 95% CI, [1.03, 1.36]. The OPR was lowest in Asia and appeared to be decreasing over time. Study design, national wealth, and participant age did not explain OPR heterogeneity. Conclusion: Gender differences in PD prevalence may not be as stark as previously thought. Studies are needed to understand the role of other determinants of gender differences in PD prevalence. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a complex neurodegenerative condition in which genetic and environmental factors interact to contribute to its etiology. Remarkable progress has been made in deciphering disease etiology through genetic approaches, but there is limited data about how environmental and genetic factors interact to modify penetrance, risk, and disease severity. Here, we provide insights into environmental modifiers of PD, discussing precedents from other neurological and non‐neurological conditions. Based on these examples, we outline genetic and environmental factors contributing to PD and review potential environmental modifiers of penetrance and clinical variability in monogenic and idiopathic PD. We also highlight the potential challenges and propose how future studies might tackle these important questions. ANN NEUROL 2022;92:715–724 [ABSTRACT FROM AUTHOR]

Objective: This study aimed to examine the relationship between covert cerebrovascular disease, comprised of covert brain infarction and white matter disease, discovered incidentally in routine care, and subsequent Parkinson disease.Methods: Patients were ≥50 years and received neuroimaging for non-stroke indications in the Kaiser Permanente Southern California system from 2009 to 2019. Natural language processing identified incidentally discovered covert brain infarction and white matter disease and classified white matter disease severity. The Parkinson disease outcome was defined as 2 ICD diagnosis codes.Results: 230,062 patients were included (median follow-up 3.72 years). A total of 1,941 Parkinson disease cases were identified (median time-to-event 2.35 years). Natural language processing identified covert cerebrovascular disease in 70,592 (30.7%) patients, 10,622 (4.6%) with covert brain infarction and 65,814 (28.6%) with white matter disease. After adjustment for known risk factors, white matter disease was associated with Parkinson disease (hazard ratio 1.67 [95%CI, 1.44, 1.93] for patients <70 years and 1.33 [1.18, 1.50] for those ≥70 years). Greater severity of white matter disease was associated with increased incidence of Parkinson disease(/1,000 person-years), from 1.52 (1.43, 1.61) in patients without white matter disease to 4.90 (3.86, 6.13) in those with severe disease. Findings were robust when more specific definitions of Parkinson disease were used. Covert brain infarction was not associated with Parkinson disease (adjusted hazard ratio = 1.05 [0.88, 1.24]).Interpretation: Incidentally discovered white matter disease was associated with subsequent Parkinson disease, an association strengthened with younger age and increased white matter disease severity. Incidentally discovered covert brain infarction did not appear to be associated with subsequent Parkinson disease. ANN NEUROL 2022;92:620-630. [ABSTRACT FROM AUTHOR]

Objective: The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual‐level genetic data available. Methods: We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership–Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome‐wide association study meta‐analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene‐based analyses and functional enrichment analyses. Results: A higher polygenic resilience score was associated with a lower risk for PD (β = −0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome‐wide significance, MAGMA gene‐based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow‐sense heritability associated with resilience to PD (h2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci. Interpretation: The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high‐risk genetic burden from developing PD. ANN NEUROL 2022;92:270–278 [ABSTRACT FROM AUTHOR]

Background: Human genetics research lacks diversity; over 80% of genome‐wide association studies have been conducted on individuals of European ancestry. In addition to limiting insights regarding disease mechanisms, disproportionate representation can create disparities preventing equitable implementation of personalized medicine. Objective: This systematic review provides an overview of research involving Parkinson's disease (PD) genetics in underrepresented populations (URP) and sets a baseline to measure the future impact of current efforts in those populations. Methods: We searched PubMed and EMBASE until October 2021 using search strings for "PD," "genetics," the main "URP," and and the countries in Latin America, Caribbean, Africa, Asia, and Oceania (excluding Australia and New Zealand). Inclusion criteria were original studies, written in English, reporting genetic results on PD from non‐European populations. Two levels of independent reviewers identified and extracted information. Results: We observed imbalances in PD genetic studies among URPs. Asian participants from Greater China were described in the majority of the articles published (57%), but other populations were less well studied; for example, Blacks were represented in just 4.0% of the publications. Also, although idiopathic PD was more studied than monogenic forms of the disease, most studies analyzed a limited number of genetic variants. We identified just nine studies using a genome‐wide approach published up to 2021, including URPs. Conclusion: This review provides insight into the significant lack of population diversity in PD research highlighting the immediate need for better representation. The Global Parkinson's Genetics Program (GP2) and similar initiatives aim to impact research in URPs, and the early metrics presented here can be used to measure progress in the field of PD genetics in the future. © 2022 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies have reported an association between Parkinson's disease (PD) and restless legs syndrome. Objectives: We aimed to use genetic data to study whether these 2 disorders are causally linked or share genetic architecture. Methods: We performed two‐sample Mendelian randomization and linkage disequilibrium score regression using summary statistics from recent genome‐wide meta‐analyses of PD and restless legs syndrome. Results: We found no evidence for a causal relationship between restless legs syndrome (as the exposure) and PD (as the outcome, inverse variance‐weighted; b = −0.003, SE = 0.031, P = 0.916; F statistic = 217.5). Reverse Mendelian randomization also did not demonstrate any causal effect of PD on restless legs syndrome (inverse variance‐weighted; b = −0.012, SE = 0.023, P = 0.592; F statistic = 191.7). Linkage disequilibrium score regression analysis demonstrated lack of genetic correlation between restless legs syndrome and PD (rg = −0.028, SE = 0.042, P = 0.507). Conclusions: There was no evidence for a causal relationship or genetic correlation between restless legs syndrome and PD. The associations observed in epidemiological studies could be attributed, in part, to confounding or nongenetic determinants. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

This article discusses the use of biological markers for the diagnosis and monitoring of nitrous oxide (N2O) abuse. The authors propose the use of vitamin B12 as a biomarker for N2O intoxication. They explain that N2O exposure leads to the functional inactivation of vitamin B12, resulting in a decrease in methionine synthase activity. The authors suggest that plasma homocysteine and plasma MMA can be used as markers for recent N2O consumption and the clinical severity of N2O abuse, respectively. They recommend a combination of biomarkers and emphasize the importance of excluding other causes of elevated homocysteine or MMA levels. [Extracted from the article]

Background: Type 2 diabetes (T2DM) and Parkinson's disease (PD) are prevalent diseases that affect an aging population. Previous systematic reviews and meta‐analyses have explored the relationship between diabetes and the risk of PD, but the results have been conflicting. Objective: The objective was to investigate T2DM as a determinant of PD through a meta‐analysis of observational and genetic summary data. Methods: A systematic review and meta‐analysis of observational studies was undertaken by searching 6 databases. We selected the highest‐quality studies investigating the association of T2DM with PD risk and progression. We then used Mendelian randomization (MR) to investigate the causal effects of genetic liability toward T2DM on PD risk and progression, using summary data derived from genome‐wide association studies. Results: In the observational part of the study, pooled effect estimates showed that T2DM was associated with an increased risk of PD (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.07–1.36), and there was some evidence that T2DM was associated with faster progression of motor symptoms (standardized mean difference [SMD] 0.55, 95% CI 0.39–0.72) and cognitive decline (SMD −0.92, 95% CI −1.50 to −0.34). Using MR, we found supportive evidence for a causal effect of diabetes on PD risk (inverse‐variance weighted method [IVW] OR 1.08, 95% CI 1.02–1.14; P = 0.010) and some evidence of an effect on motor progression (IVW OR 1.10, 95% CI 1.01–1.20; P = 0.032) but not on cognitive progression. Conclusions: Using meta‐analyses of traditional observational studies and genetic data, we observed convincing evidence for an effect of T2DM on PD risk and new evidence to support a role in PD progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objectives: Patients with established Parkinson's disease (PD) display differences in peripheral blood markers of immune function, including leukocyte differential counts, compared with controls. These differences may be useful biomarkers to predict PD and may shed light on pathogenesis. We sought to identify whether peripheral immune dysregulation was associated with increased risk of subsequent PD diagnosis. Methods: We examined the relationship between incident PD, baseline differential leukocyte count and other blood markers of acute inflammation in UK Biobank (UKB), a longitudinal cohort with ~500,000 participants. We used a range of sensitivity analyses and Mendelian randomization (MR) to further explore the nature of associations. Results: After excluding individuals with comorbidities which could influence biomarkers of inflammation, 465 incident PD cases and 312,125 controls remained. Lower lymphocyte count was associated with increased risk of subsequent PD diagnosis (per 1‐SD decrease in lymphocyte count odds ratio [OR] = 1.18, 95% confidence interval [CI] = 1.07–1.32, padjusted = 0.01). There was some evidence that reductions in eosinophil counts, monocyte counts and C‐reactive protein (CRP) were associated with increased PD risk, and that higher neutrophil count was also associated. Only the association between lower lymphocyte count and increased PD risk remained robust to sensitivity analyses. MR suggested that the effect of lower lymphocyte count on PD risk may be causal (per 1‐SD decrease in lymphocyte count; ORMR = 1.09, 95% CI = 1.01–1.18, p = 0.02). Interpretation: We provide converging evidence from observational analyses in UKB and MR that lower lymphocyte count is associated with an increased risk of subsequent PD. ANN NEUROL 2021;89:803–812 [ABSTRACT FROM AUTHOR]

Background: Many countries have implemented drastic measures to fight the COVID‐19 pandemic. Restrictions and diversion of resources may have negatively affected patients with Parkinson's disease (PD). Our aim was to examine whether COVID‐19 had an impact on access to PD medication by region and income. Methods: This study was conducted as part of a survey sent to members of the Movement Disorders Society focusing on access to PD medication globally. Results: Of 346 responses, 157 (45.4%) agreed that COVID‐19 had affected access to PD medication, while 189 (54.6%) disagreed. 22.8% of high‐income and 88.9% of low‐income countries' respondents agreed that access to PD medication was affected by COVID‐19. 59% of all 'yes' respondents reported increased disability of patients as an impact. Conclusions: Access to PD medication is likely to have been affected by COVID‐19 and result in deterioration of patients' symptomatic control. Resource‐poor countries appear to be disproportionately affected compared to more affluent countries. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Long‐term exposure to lipid‐lowering drugs might affect Parkinson's disease (PD) risk. We conducted Mendelian randomization analyses where genetic variants indexed expected effects of modulating lipid‐lowering drug targets on PD. Statin exposure was not predicted to increase PD risk, although results were not precise enough to support benefits for prevention clearly (odds ratio [OR] = 0.83; 95% confidence interval [CI] = 0.65, 1.07). Other target results were null, except for variants indicating Apolipoprotein‐A5 or Apolipoprotein‐C3 inhibition might confer protection. These findings suggest peripheral lipid variation may not have a prominent role in PD etiology, but some related drug targets could influence PD via alternate pathways. ANN NEUROL 2020;88:1043–1047 [ABSTRACT FROM AUTHOR]

Background: Identifying individuals at risk of developing Parkinson's disease (PD) is critical to define target populations for future neuroprotective trials.Objective: The objective of this study was to apply the PREDICT-PD algorithm of risk indicators for PD in a prospective community-based study (the Bruneck study), representative of the general elderly population.Methods: PREDICT-PD risk scores were calculated based on risk factor assessments obtained at baseline (2005, n = 574 participants). Cases of incident PD were identified at 5-year and 10-year follow-ups. Participants with PD or secondary parkinsonism at baseline were excluded (n = 35). We analyzed the association of log-transformed risk scores with the presence of well-established markers as surrogates for PD risk at baseline and with incident PD at follow-up.Results: A total of 20 participants with incident PD were identified during follow-up (11 after 5 years and 9 after 10 years). Baseline PREDICT-PD risk scores were associated with incident PD with odds ratios of 2.09 (95% confidence interval, 1.35-3.25; P = 0.001) after 5 years and of 1.95 (1.36-2.79; P < 0.001) after 10 years of follow-up per doubling of risk scores. In addition, higher PREDICT-PD scores were significantly correlated with established PD risk markers (olfactory dysfunction, signs of rapid eye movement sleep behavior disorder and motor deficits) and significantly associated with higher probability for prodromal PD according to the Movement Disorder Society research criteria at baseline.Conclusions: The PREDICT-PD score was associated with an increased risk for incident PD in our sample and may represent a useful first screening step in future algorithms aiming to identify cases of prodromal PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Although the leucine-rich repeat kinase 2 p.G2019S mutation has been demonstrated to be a strong risk factor for PD, factors that contribute to penetrance among carriers, other than aging, have not been well identified.Objectives: To evaluate whether a cumulative genetic risk identified in the recent genome-wide study is associated with penetrance of PD among p.G2019S mutation carriers.Methods: We included p.G2019S heterozygote carriers with European ancestry in three genetic cohorts in which the mutation carriers with and without PD were selectively recruited. We also included the carriers from two data sets: one from a case-control setting without selection of mutation carriers and the other from a population sampling. Associations between polygenic risk score constructed from 89 variants reported recently and PD were tested and meta-analyzed. We also explored the interaction of age and PRS.Results: After excluding eight homozygotes, 833 p.G2019S heterozygote carriers (439 PD and 394 unaffected) were analyzed. Polygenic risk score was associated with a higher penetrance of PD (odds ratio: 1.34; 95% confidence interval: [1.09, 1.64] per +1 standard deviation; P = 0.005). In addition, associations with polygenic risk score and penetrance were stronger in the younger participants (main effect: odds ratio 1.28 [1.04, 1.58] per +1 standard deviation; P = 0.022; interaction effect: odds ratio 0.78 [0.64, 0.94] per +1 standard deviation and + 10 years of age; P = 0.008).Conclusions: Our results suggest that there is a genetic contribution for penetrance of PD among p.G2019S carriers. These results have important etiological consequences and potential impact on the selection of subjects for clinical trials. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Hyposmia is an early feature in neurodegenerative diseases, most notably Parkinson's disease (PD). Using abbreviated smell tests could provide a cost‐effective means for large‐scale hyposmia screening. It is unclear whether short smell tests can effectively detect hyposmia in patient populations. Objectives: To test the ability of short smell combinations to "prescreen" for probable hyposmia in people with PD and target administration of more extensive tests, such as the University of Pennsylvania Smell Identification Test. Methods: We assessed the screening performance of a short 4‐smell combination previously derived from use of the 40‐item University of Pennsylvania Smell Identification Test in healthy older people and its ability to detect hyposmia in a large cohort of PD patients. Results: The novel 4‐smell combination included menthol, clove, onion, and orange and had a sensitivity of 87.1% (95% confidence interval, 84.9%–89.2%) and specificity of 69.7% (63.3%–75.5%) for detecting hyposmia in patients with PD. A different (also novel) 4‐item combination developed using a data‐driven approach in PD patients only achieved 81.3% (78.2%–84.4%) sensitivity for equivalent specificity. Conclusions: A short 4‐smell combination derived from a healthy population demonstrated high sensitivity to detect those with hyposmia and PD. [ABSTRACT FROM AUTHOR]

Objective: Epidemiological research in multiple sclerosis (MS) has mainly been performed in socioeconomically and ethnically limited populations; influences on MS risk have not been studied in prospectively collected non-White populations. We set out to study the influence of previously described MS risk factors in an ethnically diverse population.Methods: A nested case-control study was created using primary care records of >1 million individuals, >50% of whom identify as Black, Asian, and Minority Ethnic (BAME). MS cases were compared to an age- and sex-matched control cohort (1:4), and to a large unmatched cohort. Odds ratios (ORs) of disease were determined according to exposure of interest, and a multivariate model including all exposures was created. Potential pairwise interactions were considered where both indicated a significant effect.Results: A total of 1,344 confirmed MS cases were included. MS OR in blacks aged <40 years was 1.15 (95% confidence interval [CI] = 0.81-1.62) compared to whites. MS odds in BAME current (OR = 1.71, 95% CI = 1.24-2.31) and ex-smokers (OR = 2.83, 95% CI = 2.14-3.72) were considerably higher than in Whites (OR = 1.09, 95% CI = 0.88-1.34; OR = 1.44, 95% CI = 1.19-1.74, respectively). Prior infectious mononucleosis was associated with increased odds of MS in Blacks (OR = 4.94, 95% CI = 1.23-17.89). An increase in MS odds was seen in the least-deprived quintile (OR = 2.46, 95% CI = 1.40-4.24), but no effect across deprived quintiles was seen.Interpretation: This cohort provides novel data on factors potentially driving MS susceptibility in a diverse population, one-third of whom live in poverty. Environmental exposures have differential risk across ethnicity. ANN NEUROL 2020;87:599-608. [ABSTRACT FROM AUTHOR]

Background: Mendelian randomization is a method for exploring observational associations to find evidence of causality.Objective: To apply Mendelian randomization between risk factors/phenotypic traits (exposures) and PD in a large, unbiased manner, and to create a public resource for research.Methods: We used two-sample Mendelian randomization in which the summary statistics relating to single-nucleotide polymorphisms from 5,839 genome-wide association studies of exposures were used to assess causal relationships with PD. We selected the highest-quality exposure genome-wide association studies for this report (n = 401). For the disease outcome, summary statistics from the largest published PD genome-wide association studies were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted method, followed by a range of sensitivity analyses. We used a false discovery rate of 5% from the inverse variance weighted analysis to prioritize exposures of interest.Results: We observed evidence for causal associations between 12 exposures and risk of PD. Of these, nine were effects related to increasing adiposity and decreasing risk of PD. The remaining top three exposures that affected PD risk were tea drinking, time spent watching television, and forced vital capacity, but these may have been biased and were less convincing. Other exposures at nominal statistical significance included inverse effects of smoking and alcohol.Conclusions: We present a new platform which offers Mendelian randomization analyses for a total of 5,839 genome-wide association studies versus the largest PD genome-wide association studies available (https://pdgenetics.shinyapps.io/MRportal/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: The BRadykinesia Akinesia INcoordination (BRAIN) tap test is an online keyboard tapping task that has been previously validated to assess upper limb motor function in Parkinson's disease (PD). Objectives: To develop a new parameter that detects a sequence effect and to reliably distinguish between PD patients on and off medication. In addition, we sought to validate a mobile version of the test for use on smartphones and tablet devices. Methods: The BRAIN test scores in 61 patients with PD and 93 healthy controls were compared. A range of established parameters captured number and accuracy of alternate taps. The new velocity score recorded the intertap speed. Decrement in the velocity score was used as a marker for the sequence effect. In the validation phase, 19 PD patients and 19 controls were tested using different hardware including mobile devices. Results: Quantified slopes from the velocity score demonstrated bradykinesia (sequence effect) in PD patients (slope cut‐off −0.002) with 58% sensitivity and 81% specificity (discovery phase of the study) and 65% sensitivity and 88% specificity (validation phase). All BRAIN test parameters differentiated between on and off medication states in PD. Differentiation between PD patients and controls was possible on all hardware versions of the test. Conclusion: The BRAIN tap test is a simple, user‐friendly, and free‐to‐use tool for the assessment of upper limb motor dysfunction in PD, which now includes a measure of bradykinesia. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown.Objectives: To identify the genetic determinants of PD age at onset.Methods: Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset.Results: We estimated that the heritability of PD age at onset attributed to common genetic variation was ∼0.11, lower than the overall heritability of risk for PD (∼0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in α-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD.Conclusions: Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: PD is a complex polygenic disorder. In recent years, several genes from the endocytic membrane-trafficking pathway have been suggested to contribute to disease etiology. However, a systematic analysis of pathway-specific genetic risk factors is yet to be performed.Objectives: To comprehensively study the role of the endocytic membrane-trafficking pathway in the risk of PD.Methods: Linkage disequilibrium score regression was used to estimate PD heritability explained by 252 genes involved in the endocytic membrane-trafficking pathway including genome-wide association studies data from 18,869 cases and 22,452 controls. We used pathway-specific single-nucleotide polymorphisms to construct a polygenic risk score reflecting the cumulative risk of common variants. To prioritize genes for follow-up functional studies, summary-data based Mendelian randomization analyses were applied to explore possible functional genomic associations with expression or methylation quantitative trait loci.Results: The heritability estimate attributed to endocytic membrane-trafficking pathway was 3.58% (standard error = 1.17). Excluding previously nominated PD endocytic membrane-trafficking pathway genes, the missing heritability was 2.21% (standard error = 0.42). Random heritability simulations were estimated to be 1.44% (standard deviation = 0.54), indicating that the unbiased total heritability explained by the endocytic membrane-trafficking pathway was 2.14%. Polygenic risk score based on endocytic membrane-trafficking pathway showed a 1.25 times increase of PD risk per standard deviation of genetic risk. Finally, Mendelian randomization identified 11 endocytic membrane-trafficking pathway genes showing functional consequence associated to PD risk.Conclusions: We provide compelling genetic evidence that the endocytic membrane-trafficking pathway plays a relevant role in disease etiology. Further research on this pathway is warranted given that critical effort should be made to identify potential avenues within this biological process suitable for therapeutic interventions. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Diagnosis of Parkinson's disease (PD) is typically preceded by nonspecific presentations in primary care.Objectives: The objective of this study was to develop and validate a prediction model for diagnosis of PD based on presentations in primary care.Setting: The settings were general practices providing data for The Health Improvement Network UK primary care database.Methods: Data from 8,166 patients aged older than age 50 years with incident diagnosis of PD and 46,755 controls were analyzed. Likelihood ratios, sensitivity, specificity, and positive and negative predictive values for individual symptoms and combinations of presentations were calculated. An algorithm for risk of diagnosis of PD within 5 years was calculated using multivariate logistic regression analysis. Split sample analysis was used for model validation with a 70% development sample and a 30% validation sample.Results: Presentations independently and significantly associated with later diagnosis of PD in multivariate analysis were tremor, constipation, depression or anxiety, fatigue, dizziness, urinary dysfunction, balance problems, memory problems and cognitive decline, hypotension, rigidity, and hypersalivation. The discrimination and calibration of the risk algorithm were good with an area under the curve of 0.80 (95% confidence interval 0.78-0.81). At a threshold of 5%, 37% of those classified as high risk would be diagnosed with PD within 5 years and 99% of those who were not classified as high risk would not be diagnosed with PD.Conclusion: This risk algorithm applied to routine primary care presentations can identify individuals at increased risk of diagnosis of PD within 5 years to allow for monitoring and earlier diagnosis of PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

(C) Where the assumptions are upheld, the change in outcome for a given change in the exposure can be calculated using the GRS in a one-sample setting or meta-analysis of the effects from independent SNPs in a two-sample setting. In truth, violations of assumption 3 (that there are no pleiotropic effects of exposure SNPs) are common and frequently bias the pooled effect estimate (red line). AD = Alzheimer's disease; GRS = genetic risk score; GSMR = generalized summary Mendelian randomization; GWAS = genomewide association study; MR = Mendelian randomization; SNP = single nucleotide polymorphism. [Extracted from the article]

Whilst the diagnosis of Parkinson's disease (PD) relies on the motor triad of bradykinesia, rigidity and tremor, the underlying pathological process starts many years before these signs are overt. In this prodromal phase of PD, a diverse range of non‐motor and motor features can occur. Individually they do not allow a diagnosis of PD, but when considered together, they reflect the gradual development of the clinical syndrome. Different subgroups within the prodromal phase may exist and reflect different underlying pathology. Here, we summarise the evidence on the prodromal phase of PD in patient groups at increased risk of PD with well described prodromal features: patients with idiopathic rapid eye movement sleep behaviour disorder, patients with idiopathic anosmia and families with monogenic mutations that are closely linked to PD pathology. In addition, we discuss the information on prodromal features from ongoing studies aimed at detecting prodromal PD in the general population. It is likely that better delineation of the clinical prodromes of PD and their progression in these high‐risk groups will improve understanding of the underlying pathophysiology. [ABSTRACT FROM AUTHOR]

Objective: Observational studies have shown that increased plasma urate is associated with lower risk of Parkinson's disease (PD), but these studies were not designed to test causality. If a causal relationship exists, then modulating plasma urate levels could be a potential preventive avenue for PD. We used a large two-sample Mendelian randomization (MR) design to assess for a causal relationship between plasma urate and PD risk.Methods: We used a genetic instrument consisting of 31 independent loci for plasma urate on a case-control genome-wide association study data set, which included 13,708 PD cases and 95,282 controls. Individual effect estimates for each SNP were combined using the inverse-variance weighted (IVW) method. Two additional methods, MR-Egger and a penalized weighted median (PWM)-based approach, were used to assess potential bias attributed to pleiotropy or invalid instruments.Results: We found no evidence for a causal relationship between urate and PD, with an effect estimate from the IVW method of odds ratio (OR) 1.03 (95% confidence interval [CI], 0.88-1.20) per 1-standard-deviation increase in plasma urate levels. MR Egger and PWM analyses yielded similar estimates (OR, 0.99 [95% CI, 0.83-1.17] and 0.99 [95% CI, 0.86-1.14], respectively).Interpretation: We did not find evidence for a linear causal protective effect by urate on PD risk. The associations observed in previous observational studies may be, in part, attributed to confounding or reverse causality. In the context of the present findings, strategies to elevate circulating urate levels may not reduce overall PD risk. Ann Neurol 2018;84:191-199. [ABSTRACT FROM AUTHOR]

Background: People with Parkinson's disease (PD) who develop visuo-perceptual deficits are at higher risk of dementia, but we lack tests that detect subtle visuo-perceptual deficits and can be performed by untrained personnel. Hallucinations are associated with cognitive impairment and typically involve perception of complex objects. Changes in object perception may therefore be a sensitive marker of visuo-perceptual deficits in PD.Objective: We developed an online platform to test visuo-perceptual function. We hypothesised that (1) visuo-perceptual deficits in PD could be detected using online tests, (2) object perception would be preferentially affected, and (3) these deficits would be caused by changes in perception rather than response bias.Methods: We assessed 91 people with PD and 275 controls. Performance was compared using classical frequentist statistics. We then fitted a hierarchical Bayesian signal detection theory model to a subset of tasks.Results: People with PD were worse than controls at object recognition, showing no deficits in other visuo-perceptual tests. Specifically, they were worse at identifying skewed images (P < .0001); at detecting hidden objects (P = .0039); at identifying objects in peripheral vision (P < .0001); and at detecting biological motion (P = .0065). In contrast, people with PD were not worse at mental rotation or subjective size perception. Using signal detection modelling, we found this effect was driven by change in perceptual sensitivity rather than response bias.Conclusions: Online tests can detect visuo-perceptual deficits in people with PD, with object recognition particularly affected. Ultimately, visuo-perceptual tests may be developed to identify at-risk patients for clinical trials to slow PD dementia. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Isolated REM sleep behaviour disorder (iRBD) is a prodrome to dementia with Lewy bodies (DLB) and other neurodegenerative disease (NDD) such that over 90% of people with iRBD (pwRBD) will develop a NDD within 10 years of diagnosis. Disrupted sleep and dream‐enactment episodes are frequently observed by bed partners of pwRBD but it is unclear whether pwRBD perceive reduced sleep quality themselves, as previous studies show inconsistent results. This research aims to investigate sleep quality in iRBD and we hypothesise that people with probable iRBD (pwpRBD) will report poorer sleep quality, compared to healthy controls. Method: Adults aged 50+ years in the Tasmanian ISLAND Sleep Study, Australia, completed the single REM Sleep Behaviour Disorder Screening Question (RBD1Q) and the Pittsburgh Sleep Quality Index (PSQI) online. The PSQI includes a 'total sleep quality' score as well as 7 subscales: duration of sleep, sleep disturbance, sleep latency, day dysfunction due to sleepiness, sleep efficiency, overall sleep quality, and need meds to sleep. Result: 2,905 participants were recruited (mean (SD) age 64 (7.7) years; 26% male) and 273 (9.4%) screened positive for pRBD (45% male). In the pRBD group, 66% had poor total sleep quality, compared to 57% of controls (p = 0.001). pRBD was associated with a greater prevalence of sleep disturbance (67% vs 54%) and daytime dysfunction due to sleepiness (24% vs 11%). There was no difference in sleep duration, sleep latency, or sleep efficiency between pRBD and controls. Conclusion: We found that pwpRBD report more sleep disturbance, daytime sleepiness and overall poorer sleep quality compared to those without pRBD. This suggests that pwpRBD may suffer from greater sleepiness than has previously been reported in the literature and highlights the importance of sleep enquiries in those with suspected prodromal NDD who drive or operate machinery. [ABSTRACT FROM AUTHOR]

Background: Identifying people with isolated REM sleep behaviour disorder (iRBD) provides important opportunities for targeted dementia prevention as iRBD is a prodrome of Lewy Body dementia (LBD) and other neurodegenerative diseases (NDD). There have been no prevalence studies of iRBD in Australia and little is known about whether associated motor, cognitive, olfactory and circadian features influence the progression to different NDD. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study aims to identify the iRBD prevalence in Tasmania and determine how different iRBD profiles predict progression to dementia and other NDD. Method: Adults aged 50+ years in Tasmania completed online questionnaires including the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ), RBD single question screen (RBD1Q), Pittsburgh Sleep Quality Index (PSQI), and questions regarding dreaming, autonomic, motor s, and pain symptoms. Result: 2,905 participants have been recruited (mean (SD) age 64 (7.7) years; 26% male). 273 (9.4%) have 'probable' iRBD (pRBD) based on the RBDQ1. Compared to those without pRBD, the pRBD group have poorer sleep quality (66% vs 57%), greater autonomic dysfunction (median score 18 vs 13), more pain (particularly stabbing and itching pain), higher risk for sleep apnoea (30% vs 13%), more intense dreams (21% vs 8%), and more motor symptoms, including shaky limbs (16% vs 6%) and slurred speech (12% vs 6%). Conclusion: 2905 participants have been recruited (mean (SD) age 64 (7.7) years; 26% male). 273 (9.4%) have 'probable' iRBD (pRBD) based on the RBDQ1. Compared to those without pRBD, the pRBD group have poorer sleep quality (66% vs 57%), greater autonomic dysfunction (median score 18 vs 13), more pain (particularly stabbing and itching pain), higher risk for sleep apnoea (30% vs 13%), more intense dreams (21% vs 8%), and more motor symptoms, including shaky limbs (16% vs 6%) and slurred speech (12% vs 6%). [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to examine whether prediagnostic features of Parkinson's disease (PD) were associated with changes in dopamine reuptake transporter-single-photon emission computed tomography and transcranial sonography.Methods: Prediagnostic features of PD (risk estimates, University of Pennsylvania Smell Identification Test, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire, and finger-tapping scores) were assessed in a large cohort of older U.K. residents. A total of 46 participants were included in analyses of prediagnostic features and MDS-UPDRS scores with the striatal binding ratio on dopamine reuptake transporter-single-photon emission computed tomography and nigral hyperechogenicity on transcranial sonography.Results: The striatal binding ratio was associated with PD risk estimates (P = .040), University of Pennsylvania Smell Identification Test (P = .002), Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire scores (P = .024), tapping speed (P = .024), and MDS-UPDRS motor scores (P = .009). Remotely collected assessments explained 26% of variation in the striatal binding ratio. The inclusion of MDS-UPDRS motor scores did not explain additional variance. The size of the nigral echogenic area on transcranial sonography was associated with risk estimates (P < .001) and MDS-UPDRS scores (P = .03) only.Conclusions: The dopamine reuptake transporter-single-photon emission computed tomography results correlated with motor and nonmotor features of prediagnostic PD, supporting its potential use as a marker in the prodromal phase of PD. Transcranial sonography results also correlated with risk scores and motor signs. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: A number of early features can precede the diagnosis of Parkinson's disease (PD).Objective: To test an online, evidence-based algorithm to identify risk indicators of PD in the UK population.Methods: Participants aged 60 to 80 years without PD completed an online survey and keyboard-tapping task annually over 3 years, and underwent smell tests and genotyping for glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) mutations. Risk scores were calculated based on the results of a systematic review of risk factors and early features of PD, and individuals were grouped into higher (above 15th centile), medium, and lower risk groups (below 85th centile). Previously defined indicators of increased risk of PD ("intermediate markers"), including smell loss, rapid eye movement-sleep behavior disorder, and finger-tapping speed, and incident PD were used as outcomes. The correlation of risk scores with intermediate markers and movement of individuals between risk groups was assessed each year and prospectively. Exploratory Cox regression analyses with incident PD as the dependent variable were performed.Results: A total of 1323 participants were recruited at baseline and >79% completed assessments each year. Annual risk scores were correlated with intermediate markers of PD each year and baseline scores were correlated with intermediate markers during follow-up (all P values < 0.001). Incident PD diagnoses during follow-up were significantly associated with baseline risk score (hazard ratio = 4.39, P = .045). GBA variants or G2019S LRRK2 mutations were found in 47 participants, and the predictive power for incident PD was improved by the addition of genetic variants to risk scores.Conclusions: The online PREDICT-PD algorithm is a unique and simple method to identify indicators of PD risk. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Parkinson's disease has multiple determinants and is associated with a wide range of exposures that appear to modify risk in traditional observational studies, including numerous lifestyle and environmental factors. Across other fields of medicine, Mendelian randomization has emerged as a powerful method to examine whether associations between exposures and disease outcomes are causal. Here we discuss the concept of Mendelian randomization, its potential relevance to Parkinson's disease, and suggest avenues through which the method could be employed to further understanding of the causal basis of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Chorea-acanthocytosis (ChAc) is a neurodegenerative condition predominantly manifesting with chorea and often acanthocytes on peripheral blood film. Abnormal appearances with 123I- FP- CIT single-photon emission computed tomography ( SPECT) have not previously been reported in ChAc. We describe 2 cases with typical presentations of ChAc and late development of parkinsonism with asymmetric reduction in presynaptic striatal uptake on 123I- FP- CIT SPECT. Case 1, a 50-year-old male, developed micrographia and limb bradykinesia 14 years after initial presentation at the age of 30. Case 2, a 42-year-old female presenting with vocal tics and generalized dystonia at the age of 25, developed tremor, bradykinesia, and rigidity 11 years into the disease course. These cases represent the best description to date of the natural history of ChAc, in which the early hyperkinetic clinical syndromes give way to a parkinsonian phenotype. This is consistent with a gradual deterioration of presynaptic nigrostriatal projections, reflected in the clinical parkinsonism and abnormal 123I FP- CIT SPECT. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association between diagnosis of Parkinson disease (PD) and risk factors or early symptoms amenable to population-based screening. Methods: A systematic review and meta-analysis of risk factors for PD. Results: The strongest associations with later diagnosis of PD were found for having a first-degree or any relative with PD (odds ratio [OR], 3.23; 95% confidence interval [CI], 2.65-3.93 and OR, 4.45; 95% CI, 3.39-5.83) or any relative with tremor (OR, 2.74; 95% CI, 2.10-3.57), constipation (relative risk [RR], 2.34; 95% CI, 1.55-3.53), or lack of smoking history (current vs never: RR, 0.44; 95% CI, 0.39-0.50), each at least doubling the risk of PD. Further positive significant associations were found for history of anxiety or depression, pesticide exposure, head injury, rural living, beta-blockers, farming occupation, and well-water drinking, and negative significant associations were found for coffee drinking, hypertension, nonsteroidal anti-inflammatory drugs, calcium channel blockers, and alcohol, but not for diabetes mellitus, cancer, oral contraceptive pill use, surgical menopause, hormone replacement therapy, statins, acetaminophen/paracetamol, aspirin, tea drinking, history of general anesthesia, or gastric ulcers. In the systematic review, additional associations included negative associations with raised serum urate, and single studies or studies with conflicting results. Interpretation: The strongest risk factors associated with later PD diagnosis are having a family history of PD or tremor, a history of constipation, and lack of smoking history. Further factors also but less strongly contribute to risk of PD diagnosis or, as some premotor symptoms, require further standardized studies to demonstrate the magnitude of risk associated with them. ANN NEUROL 2012 [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE Pre-menopausal females have a lower incidence of cardiovascular disease compared with age-matched males, implying differences in the mechanisms and pathways regulating vasoactivity. In small arteries, myogenic tone (constriction in response to raised intraluminal pressure) is a major determinant of vascular resistance. Endothelium-derived dilators, particularly NO, tonically moderate myogenic tone and, because the endothelium is an important target for female sex hormones, we investigated whether NO-mediated moderation of myogenic tone differed between the sexes. EXPERIMENTAL APPROACH Pressure-diameter or relaxation concentration-response curves to the NO donor spermine-NO or soluble guanylate cyclase (sGC) stimulation (BAY41-2272) were constructed before and following drug intervention in murine mesenteric resistance arteries. Hypotensive responses to activators of the NO-sGC pathway were determined. Quantitative PCR and Western blotting were used for expression analysis. KEY RESULTS NO synthase inhibition enhanced myogenic tone of arteries of both sexes while block of endothelium-derived hyperpolarizing factor (EDHF) enhanced responses in arteries of females only. Spermine-NO concentration-dependently relaxed mesenteric arteries isolated from either sex. However, while inhibition of sGC activity attenuated responses of arteries from male mice only, endothelial denudation attenuated responses of arteries from females only. BAY41-2272 and spermine-NO-induced vasodilatation and hypotension were greater in males than in females. CONCLUSIONS AND IMPLICATIONS NO moderated myogenic tone in arteries of male mice by a sGC-dependent pathway while EDHF was the predominant endothelial regulator in arteries of females. This is a potentially important sexual dimorphism in NO-mediated reactivity and further implicates EDHF as the predominant endothelial vasodilator in female resistance arteries. [ABSTRACT FROM AUTHOR]

Background: The mechanisms by which modifiable risk factors influence Alzheimer's disease (AD) remain incompletely understood. Previous work using linkage disequilibrium score regression (LDSC) indicates that many of the modifiable risk factors have high genetic correlation with one another. Modelling this shared genetic architecture between risk factors, associated endophenotypes and AD could yield important insights into shared aetiological pathways. Method: We used genomic structural equation modelling (SEM) to model the shared genetic architecture between potentially modifiable risk factors (including anxiety, depression, diabetes, education, hearing loss, hypertension, obesity, sleep, smoking) and related endophenotypes (including inflammatory markers and metabolites). Genomic SEM uses summary statistics from genome‐wide association studies (downloaded from leading consortia, the Neale lab group, CTG lab group and UK Biobank) to calculate the genetic covariance between traits using multivariable LDSC. We then used exploratory factor analysis (EFA) to model the patterns of shared genetic architecture into latent constructs. Result: Multivariable LDSC showed multiple correlations between traits. EFA showed that AD shares genetic covariance with circulating metabolites and cytokines, but not modifiable risk factors. A second factor showed loadings of age‐related hearing loss with cytokines and metabolites distinct from their variance with Alzheimer's disease. A third factor comprised the majority of other risk factors including depression, insomnia and smoking, but not diabetes or obesity, which did not share significant covariance with any other AD‐related traits. Conclusion: We found high levels of shared genetic architecture between AD risk factors that were not shared with AD itself. This could suggest that rather than a direct causal effect on AD, risk factors exert their influence via a common intermediary (e.g. pro‐inflammatory states and/or cognitive reserve). Further work is required to establish model fit statistics, identify common SNPs related to these factors and conduct multivariable Mendelian randomisation to measure causal pathways that could lead to AD. This approach could provide important biological insights into the mechanisms underpinning the shared genetic architecture of AD risk factors, and explore how variation at these loci functionally impacts on AD pathophysiology, elucidating aetiological pathways, and ultimately prioritising targets for drug discovery and efforts to prevent AD. [ABSTRACT FROM AUTHOR]

Background: Early detection of Alzheimer’s disease (AD) is critical for the development of interventions that delay or prevent neurodegeneration. Previous studies suggest that genetic liability to AD may be associated with structural brain changes that start 20‐30 years before symptoms manifest. Method: We derived an optimised AD polygenic risk score (AD‐PRS) using imputed genotype data from 488,377 participants in UK Biobank. We examined the structural brain correlates of AD‐PRS in 27,496 healthy UK Biobank participants using voxel‐based morphometry (VBM) with multiple regression and additionally performed regression analyses using image‐derived phenotypes (IDPs) from T1‐weighted and diffusion‐weighted magnetic resonance images. Result: VBM revealed that high AD‐PRS was associated with reduced grey matter volume (GMV) in bilateral hippocampus and putamen (family wise error correction, p<0.05). IDP analysis further revealed GMV deficits in a bihemispheric limbic network incorporating hippocampus, parahippocampal gyrus, ventral striatum, orbitofrontal cortex, and thalamus, as well as reduced white matter integrity in the major white matter tracts of this network (fornix, cingulum hippocampus, and thalamic radiation). Conclusion: Genetic liability to AD is associated with preclinical neurodegeneration in grey and white matter components of the limbic system. Integrity of this network could serve as a marker of preclinical AD and an outcome measure in prevention trials. [ABSTRACT FROM AUTHOR]

Background: Central auditory function is affected early in the course of Alzheimer's disease, and may be useful as a prodromal disease marker. Speech‐in‐noise perception is a simple test of central auditory function. Method: We used Speech Reception Threshold (SRT) as a measure of speech‐in‐noise perception in 160,905 healthy subjects in UK Biobank. We assessed odds ratios for incident Alzheimer's disease by SRT quintile at a mean follow up of 10 years. In a subgroup of 37,082 healthy subjects with contemporaneous cognitive testing and brain imaging we assessed the relationships of SRT with cognitive performance and structural neuroanatomy using voxel‐based morphometry (VBM). Result: Poorer (higher) SRT was associated with greater odds of incident Alzheimer's disease (odds ratio for quintile 5 relative to quintile 1: 2.91 (95%CI 1.92‐4.57); p=0.000001). Worse SRT was associated with poorer cognitive performance in multiple domains. VBM revealed symmetrical grey matter correlates of SRT in a distributed network of auditory and speech perception areas, as well as medial temporal lobe structures. Conclusion: Speech‐in‐noise perception is a simple non‐invasive assay of cognition, brain structure and risk of incident Alzheimer's disease, and as such may be readily translatable as a cost‐effective tool for dementia risk stratification at large‐scale. [ABSTRACT FROM AUTHOR]

Background: The influence of ethnicity and socioeconomic status on dementia risk, and the extent to which this is mediated by known risk factors remain incompletely understood. We addressed this issue using health records data from the diverse and deprived population of East London (<50% White and >50% in the most deprived quintile of the UK). Method: We performed a nested case‐control study in over 1,000,000 East London inhabitants. We identified 4137 cases of all cause dementia, and matched on age and gender to controls with ratio 1:4. Logistic regression was used to calculated odds ratios (ORs) for exposures of ethnicity and UK Index of Multiple Deprivation (IMD), before and after inclusion in the model of established modifiable risk factors (type II diabetes, hypertension, smoking, body mass index, depression and hearing loss). In order to reflect the relative importance of known modifiable risk factors in this deprived multiracial population, we calculated weighted population attributable fractions (PAF) for each factor. Result: Risk of dementia was higher in the Black and South Asian groups relative to White (ORs (95%CI) Black 1.43 (1.31, 1.56), South Asian 1.17 (1.06, 1.29)). Risk of dementia was reduced in all IMD quintiles relative to the most deprived (ORs (95%CI) 2nd 0.71 (0.66, 0.77), 3rd 0.52 (0.44, 0.60), 4th 0.71 (0.53, 0.94), 5th 0.59 (0.38, 0.87)). The effects of ethnicity and deprivation persisted after adjusting for known risk factors. Weighted PAFs for modifiable risk factors were notably higher in this population for depression (9.2%) and diabetes (6.2%) than those estimated in the Lancet Commission meta‐analyses (4% and 1.2% respectively). Conclusion: Membership of non‐White ethnic groups and socioeconomic deprivation are important determinants of dementia risk, with effects larger than many of the more established risk factors. These effects cannot be completely accounted for by known modifiable risk factors and further work is required to establish the responsible mechanisms. Depression and diabetes are of greater relative importance, and should be prioritised as targets for dementia prevention in more diverse and deprived populations. [ABSTRACT FROM AUTHOR]