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ObjectivesWe aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD.MethodsThe consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA]).ResultsSix inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies.ConclusionsThe IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report.

Background and purpose: Our objective was to study the association between the presence of a neurological disease and the comorbidity burden as well as healthcare utilization (HCU). Methods: Using baseline data from the Canadian Longitudinal Study on Aging (CLSA), we examined the burden of five neurological conditions. The CLSA is a population‐based study of approximately 50 000 individuals, aged 45–85 years at baseline. We used multivariable Poisson regression to identify correlates of comorbidity burden and HCU. Results: The lifetime prevalence of five neurological diseases is presented: epilepsy, Parkinson's disease/parkinsonism, stroke/transient ischaemic attack, multiple sclerosis and migraine. We found the somatic and psychiatric comorbidity burden to be higher in those individuals with a neurological disease (an 18–45% mean increase in the number of chronic conditions) as compared with the comparison group without a neurological disease, except for Parkinson's disease/parkinsonism. The presence of a neurological disease was associated with only a modest increase in the probability of visiting a general practitioner but was associated with a greatly increased probability of visiting a medical specialist (up to 68% more likely) or an emergency department (up to 79% more likely) and an overnight hospitalization (up to 108% more likely). Conclusions: We found striking associations between our neurological diseases and increased comorbidity burdens and HCU. These findings are important for informing public policy planning as well as driving avenues for future research. The present study established the CLSA as an important research platform for the study of neurological conditions in an aging general population. [ABSTRACT FROM AUTHOR]

Biallelic GBA mutations cause Gaucher disease (GD), and heterozygous carriers are at risk for synucleinopathies. No founder GBA mutations in French‐Canadians are known. GBA was fully sequenced using targeted next generation and Sanger sequencing in French‐Canadian Parkinson disease (PD) patients (n = 436), rapid eye movement (REM)‐sleep behavior disorder (RBD) patients (n = 189) and controls (n = 891). Haplotype, identity‐by‐descent (IBD) and principal component analyses (PCA) were performed using single nucleotide polymorphism‐chip data. Data on GD patients from Toronto and Montreal were collected from patients' files. A GBA p.Trp378Gly mutation was identified in two RBD and four PD patients (1% of all patients combined), and not in controls. The two RBD patients had converted to DLB within 3 years of their diagnosis. Haplotype, IBD and PCA analysis demonstrated that this mutation is from a single founder. Out of 167 GD patients screened, 15 (9.0%) carried the p.Trp378Gly mutation, all in trans with p.Asn370Ser. Three (20%) of the GD patients with the p.Trp378Gly mutation had developed Parkinsonism, and 11 patients had family history of PD. The p.Trp378Gly mutation is the first French‐Canadian founder GBA mutation to be described, which leads to synucleinopathies and to GD type 1 when in compound heterozygosity with p.Asn370Ser. [ABSTRACT FROM AUTHOR]

Diarrhoea and perianal excoriation occur frequently after the endorectal pull-through operation for Hirschsprung's disease. A new method of faecal analysis was performed on 3-day stool collections in 17 postoperative Hirschsprung patients and in 14 normal children, in order to define the faecal abnormality and to establish the cause of perianal excoriation in these patients. Loose stools in postoperative patients were deficient in dry solid content and contained an excess of extractable faecal water. This also had a raised electrolyte concentration, particularly with respect to sodium. Total daily output of faecal water was normal. Formed stools from postoperative patients were also deficient in drysolids but had a normal extractable water content. Excess extractable faecal water, the main abnormality of loose stools in these patients, is the result of abnormal water absorption from the distal colon. Perianal excoriation in these patients is most closely associated with the concentration of sodium in faecal water. [ABSTRACT FROM AUTHOR]

BACKGROUND Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson’s disease. The monoclonal antibody prasinezumab, directed at aggregated α-synuclein, is being studied for its effect on Parkinson’s disease. METHODS In this phase 2 trial, we randomly assigned participants with early-stage Parkinson’s disease in a 1:1:1 ratio to receive intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every 4 weeks for 52 weeks. The primary end point was the change from baseline to week 52 in the sum of scores on parts I, II, and III of the Movement Disorder Society–sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS; range, 0 to 236, with higher scores indicating greater impairment). Secondary end points included the dopamine transporter levels in the putamen of the hemisphere ipsilateral to the clinically more affected side of the body, as measured by 123I-ioflupane single-photon-emission computed tomography (SPECT). RESULTS A total of 316 participants were enrolled; 105 were assigned to receive placebo, 105 to receive 1500 mg of prasinezumab, and 106 to receive 4500 mg of prasinezumab. The baseline mean MDS-UPDRS scores were 32.0 in the placebo group, 31.5 in the 1500-mg group, and 30.8 in the 4500-mg group, and mean (±SE) changes from baseline to 52 weeks were 9.4±1.2 in the placebo group, 7.4±1.2 in the 1500-mg group (difference vs. placebo, –2.0; 80% confidence interval [CI], –4.2 to 0.2; P=0.24), and 8.8±1.2 in the 4500-mg group (difference vs. placebo, –0.6; 80% CI, –2.8 to 1.6; P=0.72). There was no substantial difference between the active-treatment groups and the placebo group in dopamine transporter levels on SPECT. The results for most clinical secondary end points were similar in the active-treatment groups and the placebo group. Serious adverse events occurred in 6.7% of the participants in the 1500-mg group and in 7.5% of those in the 4500-mg group; infusion reactions occurred in 19.0% and 34.0%, respectively. CONCLUSIONS Prasinezumab therapy had no meaningful effect on global or imaging measures of Parkinson’s disease progression as compared with placebo and was associated with infusion reactions. (Funded by F. Hoffmann–La Roche and Prothena Biosciences; PASADENA ClinicalTrials.gov number. [ABSTRACT FROM AUTHOR]

Background: Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease.Methods: In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks. The primary end points were the changes from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (range, 0 to 236, with higher scores indicating worse performance) at weeks 52 and 72. Secondary end points included MDS-UPDRS subscale scores and striatal binding as assessed on dopamine transporter single-photon-emission computed tomography (DaT-SPECT).Results: Of the 357 enrolled participants, 100 were assigned to the control group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to the 3500-mg group. The trial was stopped after the week 72 interim analysis owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8 points in the control group, 10.5 points in the 250-mg group, 11.3 points in the 1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference vs. control, -0.3 points [95% confidence interval {CI}, -4.9 to 4.3], P = 0.90; 0.5 points [95% CI, -3.3 to 4.3], P = 0.80; and 0.1 point [95% CI, -3.8 to 4.0], P = 0.97, respectively). The adjusted mean difference at 72 weeks between participants who received cinpanemab through 72 weeks and the pooled group of those who started cinpanemab at 52 weeks was -0.9 points (95% CI, -5.6 to 3.8) for the 250-mg dose, 0.6 points (95% CI, -3.3 to 4.4) for the 1250-mg dose, and -0.8 points (95% CI, -4.6 to 3.0) for the 3500-mg dose. Results for secondary end points were similar to those for the primary end points. DaT-SPECT imaging at week 52 showed no differences between the control group and any cinpanemab group. The most common adverse events with cinpanemab were headache, nasopharyngitis, and falls.Conclusions: In participants with early Parkinson's disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.). [ABSTRACT FROM AUTHOR]

Background and Objectives: Idiopathic/isolated REM sleep behavior disorder (iRBD) has been strongly linked to neurodegenerative synucleinopathies such as Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. However, there have been increasing reports of RBD as a presenting feature of serious and treatable autoimmune syndromes, particularly IGLON5. This study's objective was to investigate the frequency of autoantibodies in a large cohort of participants with iRBD., Methods: Participants were enrolled in the North American Prodromal Synucleinopathy cohort with polysomnography-confirmed iRBD, free of parkinsonism and dementia. Plasma samples were systematically screened for the autoantibodies IGLON5, DPPX, LGI1, and CASPR2 using plasma IgG cell-based assay. Positive or equivocal results were confirmed by repeat testing, plus tissue-based indirect immunofluorescence assay for IGLON5., Results: Of 339 samples analyzed, 3 participants (0.9%) had confirmed positive IGLON5 autoantibodies in the cell-based assay, which were confirmed by the tissue-based assay. An additional participant was positive for CASPR2 with low titer by cell-based assay only (of lower clinical certainty). These cases exhibited a variety of symptoms including dream enactment, cognitive decline, autonomic dysfunction, and motor symptoms. In 1 IGLON5 case and the CASPR2 case, evolution was suggestive of typical synucleinopathy, suggesting the possibility that findings were incidental. However, 2 participants with IGLON5 died before diagnosis was clinically suspected, with a final clinical picture highly suggestive of autoimmune disease., Discussion: Our finding that nearly 1% of a large iRBD cohort may have a serious but potentially treatable autoantibody syndrome has important clinical implications. In particular, it raises the question of whether autoantibody testing for IGLON-5-IgG should be widely implemented for participants with iRBD, considering the difficulty in diagnosis of autoimmune diseases, their response to treatment, and the potential for rapid disease progression. However, any routine testing protocol will also have to consider costs and potential adverse effects of false-positive findings., Trial Registration Information: NCT03623672.

Introduction: Evidence suggests an inverse correlation between smoking and Parkinson's disease (PD), yet the mechanisms remain unclear. This study examines the changing risk relationship between smoking and PD diagnosis using alcohol consumption, another reward-driven behavior, as a comparative measure., Methods: A nested case-control study was conducted using the UK Biobank (UKBB) database. Participants in the prediagnostic phase of PD were identified, and self-reported data on tobacco and alcohol use were analyzed employing conditional binary logistic regression. Polynomial and piece-wise regression models were employed to discern shifting associations with PD over time., Results: Of 502,304 participants (63 ± 5.3 years, 63 % male), 3049 prediagnostic PD cases were identified. Non-smokers had a heightened PD risk, and this association strengthened closer to diagnosis. The odds ratio (OR [95 % CI]) associated with PD in non-smokers was 2.02 [1.07-3.81] 1-4 years before diagnosis, compared to 1.36 [1.02-1.83] at >10-year intervals (linear trend, p = 0.012). The time trajectory of ORs was best depicted by a quadratic function, identifying a shift in risk 7.5 years before diagnosis documentation. Similar patterns emerged among alcohol non-consumers, with an 8.5-year interval inflection point., Conclusion: This study identified two disparate risk trajectories among non-smokers: an initial low-amplitude increased risk at prolonged prediagnostic intervals possibly related to genetic/personality factors, followed by a sharp escalation in risk association commencing 7-8 years before diagnosis, possibly propelled by reverse causality. Similar trends in alcohol consumption reinforce these conclusions. These findings could suggest that smoking cessation may serve as an early indicator of PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers., (© 2024. Springer Nature Limited.)

Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal syndrome for Parkinson's disease (PD) and related α -synucleinopathies. We conducted a longitudinal imaging study of network changes in iRBD and their relationship to phenoconversion. Expression levels for the PD-related motor and cognitive networks (PDRP and PDCP) were measured at baseline, 2 and 4 years, along with dopamine transporter (DAT) binding. PDRP and PDCP expression increased over time, with higher values in the former network. While abnormal functional connections were identified initially within the PDRP, others bridging the two networks appeared later. A model based on the rates of PDRP progression and putamen dopamine loss predicted phenoconversion within 1.2 years in individuals with iRBD. In aggregate, the data suggest that maladaptive reorganization of brain networks takes place in iRBD years before phenoconversion. Network expression and DAT binding measures can be used together to assess phenoconversion risk in these individuals., Competing Interests: Additional Declarations: There is NO Competing Interest.