Prodromal dementia with Lewy bodies in REM sleep behavior disorder: A multicenter study.

INTRODUCTION: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia. METHODS: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed-effect models determined the annual progression of neuropsychological testing. RESULTS: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes. DISCUSSION: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion. HIGHLIGHTS: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. Decline in episodic memory best distinguished dementia-first from parkinsonism-first phenoconversion.

Cross-sectional proteomic expression in Parkinson's disease-related proteins in drug-naïve patients vs healthy controls with longitudinal clinical follow-up.

There is an urgent need to find reliable and accessible blood-based biomarkers for early diagnosis of Parkinson's disease (PD) correlating with clinical symptoms and displaying predictive potential to improve future clinical trials. This led us to a conduct large-scale proteomics approach using an advanced high-throughput proteomics technology to create a proteomic profile for PD. Over 1300 proteins were measured in serum samples from a de novo Parkinson's (DeNoPa) cohort made up of 85 deep clinically phenotyped drug-naïve de novo PD patients and 93 matched healthy controls (HC) with longitudinal clinical follow-up available of up to 8 years. The analysis identified 73 differentially expressed proteins (DEPs) of which 14 proteins were confirmed as stable potential diagnostic markers using machine learning tools. Among the DEPs identified, eight proteins-ALCAM, contactin 1, CD36, DUS3, NEGR1, Notch1, TrkB, and BTK- significantly correlated with longitudinal clinical scores including motor and non-motor symptom scores, cognitive function and depression scales, indicating potential predictive values for progression in PD among various phenotypes. Known functions of these proteins and their possible relation to the pathophysiology or symptomatology of PD were discussed and presented with a particular emphasis on the potential biological mechanisms involved, such as cell adhesion, axonal guidance and neuroinflammation, and T-cell activation. In conclusion, with the use of advance multiplex proteomic technology, a blood-based protein signature profile was identified from serum samples of a well-characterized PD cohort capable of potentially differentiating PD from HC and predicting clinical disease progression of related motor and non-motor PD symptoms. We thereby highlight the need to validate and further investigate these markers in future prospective cohorts and assess their possible PD-related mechanisms.

Blood Markers of Inflammation, Neurodegeneration, and Cardiovascular Risk in Early Parkinson's Disease.

BACKGROUND: Recent studies point toward a significant impact of cardiovascular processes and inflammation on Parkinson's disease (PD) progression. OBJECTIVE: The aim of this study was to assess established markers of neuronal function, inflammation, and cardiovascular risk by high-throughput sandwich immune multiplex panels in deeply phenotyped PD. METHODS: Proximity Extension Assay technology on 273 markers was applied in plasma of 109 drug-naive at baseline (BL) patients with PD (BL, 2-, 4-, and 6-year follow-up [FU]) and 96 healthy control patients (HCs; 2- and 4-year FU) from the de novo Parkinson's cohort. BL plasma from 74 individuals (37 patients with PD, 37 healthy control patients) on the same platform from the Parkinson Progression Marker Initiative was used for independent validation. Correlation analysis of the identified markers and 6 years of clinical FU, including motor and cognitive progression, was evaluated. RESULTS: At BL, 35 plasma markers were differentially expressed in PD, showing downregulation of atherosclerotic risk markers, eg, E-selectin and ß2 -integrin. In contrast, we found a reduction of markers of the plasminogen activation system, eg, urokinase plasminogen activator. Neurospecific markers indicated increased levels of peripheral proteins of neurodegeneration and inflammation, such as fibroblast growth factor 21 and peptidase inhibitor 3. Several markers, including interleukin-6 and cystatin B, correlated with cognitive decline and progression of motor symptoms during FU. These findings were independently validated in the Parkinson Progression Marker Initiative. CONCLUSIONS: We identified and validated possible PD plasma biomarker candidates for state, fate, and disease progression, elucidating new molecular processes with reduced endothelial/atherosclerotic processes, increased thromboembolic risk, and neuroinflammation. Further investigations and validation in independent and larger longitudinal cohorts are needed. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Accurate Detection of α-Synuclein Seeds in Cerebrospinal Fluid from Isolated Rapid Eye Movement Sleep Behavior Disorder and Patients with Parkinson's Disease in the DeNovo Parkinson (DeNoPa) Cohort.

BACKGROUND: Misfolded α-synuclein (αSyn) aggregates (αSyn-seeds) in cerebrospinal fluid (CSF) are biomarkers for synucleinopathies such as Parkinson's disease (PD). αSyn-seeds have been detected in prodromal cases with isolated rapid eye movement sleep behavior disorder (iRBD). OBJECTIVES: The objective of this study was to determine the accuracy of the αSyn-seed amplification assay (αS-SAA) in a comprehensively characterized cohort with a high proportion of PD and iRBD CSF samples collected at baseline. METHODS: We used a high-throughput αS-SAA to analyze 233 blinded CSF samples from 206 participants of the DeNovo Parkinson Cohort (DeNoPa) (113 de novo PD, 64 healthy controls, 29 iRBD confirmed by video polysomnography). Results were compared with the final diagnosis, which was determined after up to 10 years of longitudinal clinical evaluations, including dopamine-transporter-single-photon emission computed tomography (DAT-SPECT) at baseline, CSF proteins, Movement Disorder Society-Unified Parkinson's Disease Rating Scale, and various cognitive and nonmotor scales. RESULTS: αS-SAA detected αSyn-seeds in baseline PD-CSF with 98% accuracy. αSyn-seeds were detected in 93% of the iRBD cases. αS-SAA results showed higher agreement with the final than the initial diagnosis, as 14 patients were rediagnosed as non-αSyn aggregation disorder. For synucleinopathies, αS-SAA showed higher concordance with the final diagnosis than DAT-SPECT. Statistically significant correlations were found between assay parameters and disease progression. CONCLUSIONS: Our results confirm αS-SAA accuracy at the first clinical evaluation when a definite diagnosis is most consequential. αS-SAA conditions reported here are highly sensitive, enabling the detection of αSyn-seeds in CSF from iRBD just months after the first symptoms, suggesting that αSyn-seeds are present in the very early prodromal phase of synucleinopathies. Therefore, αSyn-seeds are clear risk markers for synuclein-related disorders, but not for time of phenoconversion. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Levodopa Dose Equivalency in Parkinson's Disease: Updated Systematic Review and Proposals.

BACKGROUND: To compare drug regimens across clinical trials in Parkinson's disease (PD) conversion formulae between antiparkinsonian drugs have been developed. These are reported in relation to levodopa as the benchmark drug in PD pharmacotherapy as 'levodopa equivalent dose' (LED). Currently, the LED conversion formulae proposed in 2010 by Tomlinson et al. based on a systematic review are predominantly used. However, new drugs with established and novel mechanisms of action and novel formulations of longstanding drugs have been developed since 2010. Therefore, consensus proposals for updated LED conversion formulae are needed. OBJECTIVES: To update LED conversion formulae based on a systematic review. METHODS: The MEDLINE, CENTRAL, and Embase databases were searched from January 2010 to July 2021. Additionally, in a standardized process according to the GRADE grid method, consensus proposals were issued for drugs with scarce data on levodopa dose equivalency. RESULTS: The systematic database search yielded 3076 articles of which 682 were eligible for inclusion in the systematic review. Based on these data and the standardized consensus process, we present proposals for LED conversion formulae for a wide range of drugs that are currently available for the pharmacotherapy of PD or are expected to be introduced soon. CONCLUSIONS: The LED conversion formulae issued in this Position Paper will serve as a research tool to compare the equivalence of antiparkinsonian medication across PD study cohorts and facilitate research on the clinical efficacy of pharmacological and surgical treatments as well as other non-pharmacological interventions in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies.

Several studies have confirmed the α-synuclein real-time quaking-induced conversion (RT-QuIC) assay to have high sensitivity and specificity for Parkinson's disease. However, whether the assay can be used as a robust, quantitative measure to monitor disease progression, stratify different synucleinopathies and predict disease conversion in patients with idiopathic REM sleep behaviour disorder remains undetermined. The aim of this study was to assess the diagnostic value of CSF α-synuclein RT-QuIC quantitative parameters in regard to disease progression, stratification and conversion in synucleinopathies. We performed α-synuclein RT-QuIC in the CSF samples from 74 Parkinson's disease, 24 multiple system atrophy and 45 idiopathic REM sleep behaviour disorder patients alongside 55 healthy controls, analysing quantitative assay parameters in relation to clinical data. α-Synuclein RT-QuIC showed 89% sensitivity and 96% specificity for Parkinson's disease. There was no correlation between RT-QuIC quantitative parameters and Parkinson's disease clinical scores (e.g. Unified Parkinson's Disease Rating Scale motor), but RT-QuIC positivity and some quantitative parameters (e.g. Vmax) differed across the different phenotype clusters. RT-QuIC parameters also added value alongside standard clinical data in diagnosing Parkinson's disease. The sensitivity in multiple system atrophy was 75%, and CSF samples showed longer T50 and lower Vmax compared to Parkinson's disease. All RT-QuIC parameters correlated with worse clinical progression of multiple system atrophy (e.g. change in Unified Multiple System Atrophy Rating Scale). The overall sensitivity in idiopathic REM sleep behaviour disorder was 64%. In three of the four longitudinally followed idiopathic REM sleep behaviour disorder cohorts, we found around 90% sensitivity, but in one sample (DeNoPa) diagnosing idiopathic REM sleep behaviour disorder earlier from the community cases, this was much lower at 39%. During follow-up, 14 of 45 (31%) idiopathic REM sleep behaviour disorder patients converted to synucleinopathy with 9/14 (64%) of convertors showing baseline RT-QuIC positivity. In summary, our results showed that α-synuclein RT-QuIC adds value in diagnosing Parkinson's disease and may provide a way to distinguish variations within Parkinson's disease phenotype. However, the quantitative parameters did not correlate with disease severity in Parkinson's disease. The assay distinguished multiple system atrophy patients from Parkinson's disease patients and in contrast to Parkinson's disease, the quantitative parameters correlated with disease progression of multiple system atrophy. Our results also provided further evidence for α-synuclein RT-QuIC having potential as an early biomarker detecting synucleinopathy in idiopathic REM sleep behaviour disorder patients prior to conversion. Further analysis of longitudinally followed idiopathic REM sleep behaviour disorder patients is needed to better understand the relationship between α-synuclein RT-QuIC signature and the progression from prodromal to different synucleinopathies.

Blood DNA methylation provides an accurate biomarker of KMT2B-related dystonia and predicts onset.

Dystonia is a prevalent, heterogeneous movement disorder characterized by involuntarily abnormal postures. Biomarkers of dystonia are notoriously lacking. Here, a biomarker is reported for histone lysine methyltransferase (KMT2B)-deficient dystonia, a leading subtype among the individually rare monogenic dystonias. It was derived by applying a support vector machine to an episignature of 113 DNA CpG sites, which, in blood cells, showed significant epigenome-wide association with KMT2B deficiency and at least 1× log-fold change of methylation. This classifier was accurate both when tested on the general population and on samples with various other deficiencies of the epigenetic machinery, thus allowing for definitive evaluation of variants of uncertain significance and identifying patients who may profit from deep brain stimulation, a highly successful treatment in KMT2B-deficient dystonia. Methylation was increased in KMT2B deficiency at all 113 CpG sites. The coefficients of variation of the normalized methylation levels at these sites also perfectly classified the samples with KMT2B-deficient dystonia. Moreover, the mean of the normalized methylation levels correlated well with the age at onset of dystonia (P = 0.003)-being lower in samples with late or incomplete penetrance-thus serving as a predictor of disease onset and severity. Similarly, it may also function in monitoring the recently envisioned treatment of KMT2B deficiency by inhibition of DNA methylation.

Evidence for immune system alterations in peripheral biological fluids in Parkinson's disease.

Immune-related alterations in Parkinson's disease (PD) can be monitored by assessing peripheral biological fluids that show that specific inflammatory pathways contribute to a chronic pro-inflammatory status. This pro-inflammatory activity is hypothesized to be already present in the prodromal stages of PD. These pathways maintain and reinforce chronic neurodegeneration by stimulating cell activation and proliferation what triggers the pro-inflammatory status as well. The gut microbiome possibly contributes to inflammatory pathways and shows specific differences in fecal samples from PD compared to healthy controls. In PD, Bacteroides abundance correlates with inflammatory markers in blood and motor impairment. Increased pro-inflammatory and decreased anti-inflammatory bacterial colonization can lead to changes in the metabolic pathways of amino acids, inducing increased membrane permeability, described as a leaky gut, enabling advanced contact between immune cells and gut microbiome and potentially a spreading of neuroinflammation through the body via the blood. Increased cytokine blood levels in PD are correlated with disease severity, motor symptoms, and clinical phenotypes. α-synuclein is a central player in PD-associated inflammation, inducing specific T-cell activity and triggering microglial activation in the central nervous system (CNS). Misfolded α-synuclein propagation possibly results in the spreading of aggregated α-synuclein from neuron to neuron leading to a sustained neuroinflammation. This is supported by age-dependent defects of protein uptake in microglia and monocytes, so-called "inflammaging", including α-synuclein oligomers, as the key pathological protein in PD. Genetic risk markers and inherited forms of PD are also associated with inflammation, which is highly relevant for potential therapeutical targets. The documented associations of inflammatory markers and clinical phenotypes indicate a pro-inflammatory concept of specific PD pathophysiology here. An in-depth understanding of inflammatory mechanisms in PD from bottom (gut) to top (CNS) and vice versa is needed to design novel immunomodulatory approaches to delay or even stop PD. Future studies focusing on structured protocols in large patient cohorts with appropriate control groups and comparative analysis among studies will aid the discovery of novel candidate biomarkers.

Rapid eye movement sleep behaviour disorder: Past, present, and future.

This manuscript presents an overview of REM sleep behaviour disorder (RBD) with a special focus on European contributions. After an introduction examining the history of the disorder, we address the pathophysiological and clinical aspects, as well as the diagnostic issues. Further, implications of RBD diagnosis and biomarkers are discussed. Contributions of European researchers to this field are highlighted.

SEAweb: the small RNA Expression Atlas web application.

We present the Small RNA Expression Atlas (SEAweb), a web application that allows for the interactive querying, visualization and analysis of known and novel small RNAs across 10 organisms. It contains sRNA and pathogen expression information for over 4200 published samples with standardized search terms and ontologies. In addition, SEAweb allows for the interactive visualization and re-analysis of 879 differential expression and 514 classification comparisons. SEAweb's user model enables sRNA researchers to compare and re-analyze user-specific and published datasets, highlighting common and distinct sRNA expression patterns. We provide evidence for SEAweb's fidelity by (i) generating a set of 591 tissue specific miRNAs across 29 tissues, (ii) finding known and novel bacterial and viral infections across diseases and (iii) determining a Parkinson's disease-specific blood biomarker signature using novel data. We believe that SEAweb's simple semantic search interface, the flexible interactive reports and the user model with rich analysis capabilities will enable researchers to better understand the potential function and diagnostic value of sRNAs or pathogens across tissues, diseases and organisms.

Identification of Restless Legs Syndrome Genes by Mutational Load Analysis.

OBJECTIVE: Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes. METHODS: We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low-frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth. RESULTS: Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni-corrected significance by the other to show a differential burden of low-frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine-mapping potentially causative domains within these genes. INTERPRETATION: Differential burden with intragenic low-frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2020;87:184-193.

Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.

OBJECTIVE: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. METHODS: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis. RESULTS: A 5'-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5' risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3' of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3' variant rs356182) had an opposite direction of effect in iRBD compared to PD. INTERPRETATION: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3' of SNCA. Several 5' SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584-598.

Systematic Assessment of 10 Biomarker Candidates Focusing on α-Synuclein-Related Disorders.

BACKGROUND: Objective diagnostic biomarkers are needed to support a clinical diagnosis. OBJECTIVES: To analyze markers in various neurodegenerative disorders to identify diagnostic biomarker candidates for mainly α-synuclein (aSyn)-related disorders (ASRD) in serum and/or cerebrospinal fluid (CSF). METHODS: Upon initial testing of commercially available kits or published protocols for the quantification of the candidate markers, assays for the following were selected: total and phosphorylated aSyn (pS129aSyn), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), tau protein (tau), ubiquitin C-terminal hydrolase L1 (UCHL-1), glial fibrillary acidic protein (GFAP), calcium-binding protein B (S100B), soluble triggering receptor expressed on myeloid cells 2 (sTREM-2), and chitinase-3-like protein 1 (YKL-40). The cohort comprised participants with Parkinson's disease (PD, n = 151), multiple system atrophy (MSA, n = 17), dementia with Lewy bodies (DLB, n = 45), tau protein-related neurodegenerative disorders (n = 80, comprising patients with progressive supranuclear palsy (PSP, n = 38), corticobasal syndrome (CBS, n = 16), Alzheimer's disease (AD, n = 11), and frontotemporal degeneration/amyotrophic lateral sclerosis (FTD/ALS, n = 15), as well as healthy controls (HC, n = 20). Receiver operating curves (ROC) with area under the curves (AUC) are given for each marker. RESULTS: CSF total aSyn was decreased. NfL, pNfH, UCHL-1, GFAP, S100B, and sTREM-2 were increased in patients with neurodegenerative disease versus HC (P < 0.05). As expected, some of the markers were highest in AD (i.e., UCHL-1, GFAP, S100B, sTREM-2, YKL-40). Within ASRD, CSF NfL levels were higher in MSA than PD and DLB (P < 0.05). Comparing PD to HC, interesting serum markers were S100B (AUC: 0.86), sTREM2 (AUC: 0.87), and NfL (AUC: 0.78). CSF S100B and serum GFAP were highest in DLB. CONCLUSIONS: Levels of most marker candidates tested in serum and CSF significantly differed between disease groups and HC. In the stratification of PD versus other tau- or aSyn-related conditions, CSF NfL levels best discriminated PD and MSA. CSF S100B and serum GFAP best discriminated PD and DLB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Cerebrospinal α-Synuclein Oligomers Reflect Disease Motor Severity in DeNoPa Longitudinal Cohort.

BACKGROUND: Tangible efforts have been made to identify biomarkers for Parkinson's disease (PD) diagnosis and progression, with α-synuclein (α-syn) related biomarkers being at the forefront. OBJECTIVES: The objectives of this study were to explore whether cerebrospinal fluid (CSF) levels of total, oligomeric, phosphorylated Ser 129 α-synuclein, along with total tau, phosphorylated tau 181, and ß-amyloid 1-42 are (1) informative as diagnostic markers for PD, (2) changed over disease progression, and/or (3) correlated with motor and cognitive indices of disease progression in the longitudinal De Novo Parkinson cohort. METHODS: A total of 94 de novo PD patients and 52 controls at baseline and 24- and 48-month follow-up were included, all of whom had longitudinal lumbar punctures and clinical assessments for both cognitive and motor functions. Using our in-house enzymelinked immunosorbent assays and commercially available assays, different forms of α-synuclein, tau, and ß-amyloid 1-42 were quantified in CSF samples from the De Novo Parkinson cohort. RESULTS: Baseline CSF total α-synuclein was significantly lower in early de novo PD compared with healthy controls, whereas the ratio of oligomeric/total and phosphorylated/total were significantly higher in the PD group. CSF oligomeric-α-synuclein longitudinally increased over the 4-year follow-up in the PD group and correlated with PD motor progression. Patients at advanced stages of PD presented with elevated CSF oligomeric-α-synuclein levels compared with healthy controls. CONCLUSIONS: Longitudinal transitions of CSF biomarkers over disease progression might not occur linearly and are susceptible to disease state. CSF oligomeric-α-synuclein levels appear to increase with diseases severity and reflect PD motor rather than cognitive trajectories. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Longitudinal Analysis of Multiple Neurotransmitter Metabolites in Cerebrospinal Fluid in Early Parkinson's Disease.

BACKGROUND: Cerebrospinal fluid (CSF) levels of monoamine metabolites may represent biomarkers of Parkinson's disease (PD). OBJECTIVE: The aim of this study was quantification of multiple metabolites in CSF from PD versus healthy control subjects (HCs), including longitudinal analysis. METHODS: Absolute levels of multiple monoamine metabolites in CSF were quantified by liquid chromatography coupled with tandem mass spectrometry from 161 individuals with early PD and 115 HCs from the Parkinson's Progression Marker Initiative and de novo PD (DeNoPA) studies. RESULTS: Baseline levels of homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were lower in individuals with PD compared with HCs. HVA levels correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale total scores (P < 0.01). Both HVA/dopamine and DOPAC/dopamine levels correlated with caudate nucleus and raw DOPAC with putamen dopamine transporter single-photon emission computed tomography uptake ratios (P < 0.01). No metabolite changed over 2 years in drug-naive individuals, but some changed on starting levodopa treatment. CONCLUSIONS: HVA and DOPAC CSF levels mirrored nigrostriatal pathway damage, confirming the central role of dopaminergic degeneration in early PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Comprehensive Analysis of Familial Parkinsonism Genes in Rapid-Eye-Movement Sleep Behavior Disorder.

BACKGROUND: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD). OBJECTIVE: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD. METHODS: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests. RESULTS: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls. CONCLUSION: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.

Elemental fingerprint: Reassessment of a cerebrospinal fluid biomarker for Parkinson's disease.

The aim of the study was to validate a predictive biomarker machine learning model for the classification of Parkinson's disease (PD) and age-matched controls (AMC), based on bioelement abundance in the cerebrospinal fluid (CSF). For this multicentric trial, participants were enrolled from four different centers. CSF was collected according to standardized protocols. For bioelement determination, CSF samples were subjected to inductively coupled plasma mass spectrometry. A predefined Support Vector Machine (SVM) model, trained on a previous discovery cohort was applied for differentiation, based on the levels of six different bioelements. 82 PD patients, 68 age-matched controls and 7 additional Normal Pressure Hydrocephalus (NPH) patients were included to validate a predefined SVM model. Six differentiating elements (As, Fe, Mg, Ni, Se, Sr) were quantified. Based on their levels, SVM was successfully applied to a new local cohort (AUROC 0.76, Sensitivity 0.80, Specificity 0.83), without taking any additional features into account. The same model did not discriminate PD and AMCs / NPH from three external cohorts, likely due to center effects. However, discrimination was possible in cohorts with a full elemental data set, now using center-specific discovery cohorts and a cross validated approach (AUROC 0.78 and 0.88, respectively). Pooled PD CSF iron levels showed a clear correlation with disease duration (p = .0001). In summary, bioelemental CSF patterns, obtained by mass spectrometry and integrated into a predictive model yield the potential to facilitate the differentiation of PD and AMC. Center-specific biases interfere with application in external cohorts. This must be carefully addressed using center-defined, local reference values and models.

Clinical trials in REM sleep behavioural disorder: challenges and opportunities.

The rapid eye movement sleep behavioural disorder (RBD) population is an ideal study population for testing disease-modifying treatments for synucleinopathies, since RBD represents an early prodromal stage of synucleinopathy when neuropathology may be more responsive to treatment. While clonazepam and melatonin are most commonly used as symptomatic treatments for RBD, clinical trials of symptomatic treatments are also needed to identify evidence-based treatments. A comprehensive framework for both disease-modifying and symptomatic treatment trials in RBD is described, including potential treatments in the pipeline, cost-effective participant recruitment and selection, study design, outcomes and dissemination of results. For disease-modifying treatment clinical trials, the recommended primary outcome is phenoconversion to an overt synucleinopathy, and stratification features should be used to select a study population at high risk of phenoconversion, to enable more rapid clinical trials. For symptomatic treatment clinical trials, objective polysomnogram-based measurement of RBD-related movements and vocalisations should be the primary outcome measure, rather than subjective scales or diaries. Mobile technology to enable objective measurement of RBD episodes in the ambulatory setting, and advances in imaging, biofluid, tissue, and neurophysiological biomarkers of synucleinopathies, will enable more efficient clinical trials but are still in development. Increasing awareness of RBD among the general public and medical community coupled with timely diagnosis of these diseases will facilitate progress in the development of therapeutics for RBD and associated neurodegenerative disorders.

Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson's Disease Progression.

BACKGROUND: The objective of this study was to assess neurofilament light chain as a Parkinson's disease biomarker. METHODS: We quantified neurofilament light chain in 2 independent cohorts: (1) longitudinal cerebrospinal fluid samples from the longitudinal de novo Parkinson's disease cohort and (2) a large longitudinal cohort with serum samples from Parkinson's disease, other cognate/neurodegenerative disorders, healthy controls, prodromal conditions, and mutation carriers. RESULTS: In the Parkinson's Progression Marker Initiative cohort, mean baseline serum neurofilament light chain was higher in Parkinson's disease patients (13 ± 7.2 pg/mL) than in controls (12 ± 6.7 pg/mL), P = 0.0336. Serum neurofilament light chain increased longitudinally in Parkinson's disease patients versus controls (P < 0.01). Motor scores were positively associated with neurofilament light chain, whereas some cognitive scores showed a negative association. CONCLUSIONS: Neurofilament light chain in serum samples is increased in Parkinson's disease patients versus healthy controls, increases over time and with age, and correlates with clinical measures of Parkinson's disease severity. Although the specificity of neurofilament light chain for Parkinson's disease is low, it is the first blood-based biomarker candidate that could support disease stratification of Parkinson's disease versus other cognate/neurodegenerative disorders, track clinical progression, and possibly assess responsiveness to neuroprotective treatments. However, use of neurofilament light chain as a biomarker of response to neuroprotective interventions remains to be assessed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Rare Variants in Specific Lysosomal Genes Are Associated With Parkinson's Disease.

OBJECTIVE: Impaired lysosomal degradation of α-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD. METHODS: We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes. RESULTS: We confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C. CONCLUSION: Rare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome-wide association studies are associated with PD. © 2020 International Parkinson and Movement Disorder Society.