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.

NPC1 variants are not associated with Parkinson's disease, REM-sleep behavior disorder or dementia with Lewy bodies in European cohorts.

NPC1 encodes a lysosomal protein involved in cholesterol transport. Biallelic mutations in this gene may lead to Niemann-Pick disease type C (NPC), a lysosomal storage disorder. The role of NPC1 in alpha synucleinopathies is still unclear, as different genetic, clinical, and pathological studies have reported contradictory results. This study aimed to evaluate the association of NPC1 variants with the synucleinopathies Parkinson's disease (PD), dementia with Lewy bodies (DLB), and rapid eye movement-sleep behavior disorder (RBD). We analyzed common and rare variants from 3 cohorts of European descent: 1084 RBD cases and 2945 controls, 2852 PD cases and 1686 controls, and 2610 DLB cases and 1920 controls. Logistic regression models were used to assess common variants while optimal sequence Kernel association tests were used to assess rare variants, both adjusted for sex, age, and principal components. No variants were associated with any of the synucleinopathies, supporting that common and rare NPC1 variants do not play an important role in alpha synucleinopathies.

Symptoms assessment and decision to treat patients with advanced Parkinson's disease based on wearables data.

Body-worn sensors (BWS) could provide valuable information in the management of Parkinson's disease and support therapeutic decisions based on objective monitoring. To study this pivotal step and better understand how relevant information is extracted from BWS results and translated into treatment adaptation, eight neurologists examined eight virtual cases composed of basic patient profiles and their BWS monitoring results. Sixty-four interpretations of monitoring results and the subsequent therapeutic decisions were collected. Relationship between interrater agreements in the BWS reading and the severity of symptoms were analyzed via correlation studies. Logistic regression was used to identify associations between the BWS parameters and suggested treatment modifications. Interrater agreements were high and significantly associated with the BWS scores. Summarized BWS scores reflecting bradykinesia, dyskinesia, and tremor predicted the direction of treatment modifications. Our results suggest that monitoring information is robustly linked to treatment adaptation and pave the way to loop systems able to automatically propose treatment modifications from BWS recordings information.

HLA in isolated REM sleep behavior disorder and Lewy body dementia.

Background and Objectives: Isolated/idiopathic REM sleep behavior disorder (iRBD) and Lewy body dementia (LBD) are synucleinopathies that have partial genetic overlap with Parkinson's disease (PD). Previous studies have shown that neuroinflammation plays a substantial role in these disorders. In PD, specific residues of the human leukocyte antigen ( HLA ) were suggested to be associated with a protective effect. This study examined whether the HLA locus plays a similar role in iRBD, LBD and PD. Methods: We performed HLA imputation on iRBD genotyping data (1,072 patients and 9,505 controls) and LBD whole-genome sequencing (2,604 patients and 4,032 controls) using the multi-ethnic HLA reference panel v2 from the Michigan Imputation Server. Using logistic regression, we tested the association of HLA alleles, amino acids and haplotypes with disease susceptibility. We included age, sex and the top 10 principal components as covariates. We also performed an omnibus test to examine which HLA residue positions explain the most variance. Results: In iRBD, HLA-DRB1 *11:01 was the only allele passing FDR correction (OR=1.57, 95% CI=1.27-1.93, p =2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR=1.26, 95%CI=1.12-1.41, p =8.76e-05), 70Q (OR=0.81, 95% CI=0.72-0.91, p =3.65e-04) and 71R (OR=1.21, 95% CI=1.08-1.35, p =1.35e-03). In HLA-DRB1 , position 71 ( p omnibus =0.00102) and 70 ( p omnibus =0.00125) were associated with iRBD. We found no association in LBD. Discussion: This study identified an association between HLA-DRB1 11:01 and iRBD, distinct from the previously reported association in PD. Therefore, the HLA locus may play different roles across synucleinopathies. Additional studies are required better to understand HLA's role in iRBD and LBD.

At-Home Training With a Rhythmic Video Game for Improving Orofacial, Manual, and Gait Abilities in Parkinson's Disease: A Pilot Study.

Rhythm disorders are consistently reported in Parkinson's disease (PD). They manifest across motor domains, such as in orofacial (oral diadochokinesis), manual (finger tapping), and gait tasks. It is still unclear, however, whether these disorders are domain- and task-specific, or result from impaired common mechanisms supporting rhythm processing (general dysrhythmia). We tested the possibility that an at-home intervention delivered via a rhythmic video game on tablet improves motor performance across motor domains in PD. Patients with PD (n = 12) played at home a rhythmic video game (Rhythm Workers) on tablet, in which they finger-tapped to the beat of music, for 6 weeks. A control group (n = 11) played an active non-rhythmic video game (Tetris). A third group (n = 10) did not receive any intervention. We measured rhythmic abilities in orofacial, manual and gait motor domains, as well as rhythm perception, before and after the intervention. Patients who performed the rhythmic training improved their orofacial and manual rhythmic performance. This beneficial effect was linked to improved rhythm perception only following the rhythmic training period. We did not observe any improvement in rhythmic abilities in the other two groups. In this pilot study, we demonstrated that at-home intervention with a rhythmic video game using finger tapping can have beneficial effects on motor performance across different motor domains (manual and orofacial). This finding provides evidence of a general dysrhythmia in PD and paves the way to technology-driven interventions aiming at alleviating rhythm-related motor deficits in PD.

Safety and efficacy of subcutaneous night-time only apomorphine infusion to treat insomnia in patients with Parkinson's disease (APOMORPHEE): a multicentre, randomised, controlled, double-blind crossover study.

BACKGROUND: Insomnia is a frequent complaint of patients with Parkinson's disease, and it negatively affects quality of life. Drugs that improve both sleep and parkinsonism would be of major benefit to patients with Parkinson's disease-related insomnia. We aimed to test the safety and efficacy of subcutaneous night-time only apomorphine infusion in patients with Parkinson's disease and insomnia. METHODS: We did a randomised, multicentre, double-blind, placebo-controlled, crossover trial in 11 expert centres in Parkinson's disease and sleep centres in France. Participants aged 35-90 years with fluctuating Parkinson's disease and moderate to severe insomnia (Insomnia Severity Index score ≥15) were randomly assigned to either first receive night-time subcutaneous apomorphine (up to 5 mg/h) or matching placebo. Randomisation was done using a computer-generated plan in blocks of four, stratified by centre. This first intervention was followed by a 14-night washout period, then crossover to the other intervention. The treatment periods consisted of a 10-night titration phase followed by a 7-night fixed-dose phase. The dose was adjusted during the titration phase on the basis of a daily telephone call assessing sleep quality and treatment tolerability. The primary efficacy endpoint was the difference in Parkinson's disease sleep scale (PDSS) scores from the beginning to the end of each treatment period. Analysis was done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT02940912. FINDINGS: Between Jan 31, 2017, and Jan 29, 2021, 46 participants were enrolled. 25 (54%) patients were randomly assigned to receive apomorphine first and 21 (46%) patients to receive placebo first. Mean change in PDSS score was significantly greater with night-time apomorphine infusion (15·18 [SD 24·34]) compared with placebo (5·23 [21·52]; treatment effect 9·95 [95% CI 0·88-19·03]; p=0·041). Adverse events were reported in 25 (54%) participants during the apomorphine period and in 17 (37%) participants during the placebo period (p=0·16). Apomorphine was associated with more frequent dizziness than was placebo (seven [15%] vs 0; p=0·041). INTERPRETATION: Subcutaneous night-time only apomorphine infusion improved sleep disturbances according to difference on PDSS score, with an overall safety profile consistent with previous studies in Parkinson's disease. This treatment might be useful to manage sleep disturbances in patients with advanced Parkinson's disease and moderate to severe insomnia. FUNDING: Orkyn and Aguettant Pharma. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Dopaminergic imaging and clinical predictors for phenoconversion of REM sleep behaviour disorder.

This is an international multicentre study aimed at evaluating the combined value of dopaminergic neuroimaging and clinical features in predicting future phenoconversion of idiopathic REM sleep behaviour (iRBD) subjects to overt synucleinopathy. Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD patients and 256 controls for centralized analysis. 123I-FP-CIT-SPECT images were semiquantified using DaTQUANTTM, obtaining putamen and caudate specific to non-displaceable binding ratios (SBRs). The following clinical variables were also analysed: (i) Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale, motor section score; (ii) Mini-Mental State Examination score; (iii) constipation; and (iv) hyposmia. Kaplan-Meier survival analysis was performed to estimate conversion risk. Hazard ratios for each variable were calculated with Cox regression. A generalized logistic regression model was applied to identify the best combination of risk factors. Bayesian classifier was used to identify the baseline features predicting phenoconversion to parkinsonism or dementia. After quality check of the data, 263 iRBD patients (67.6 ± 7.3 years, 229 males) and 243 control subjects (67.2 ± 10.1 years, 110 males) were analysed. Fifty-two (20%) patients developed a synucleinopathy after average follow-up of 2 years. The best combination of risk factors was putamen dopaminergic dysfunction of the most affected hemisphere on imaging, defined as the lower value between either putamina (P < 0.000001), constipation, (P < 0.000001) and age over 70 years (P = 0.0002). Combined features obtained from the generalized logistic regression achieved a hazard ratio of 5.71 (95% confidence interval 2.85-11.43). Bayesian classifier suggested that patients with higher Mini-Mental State Examination score and lower caudate SBR asymmetry were more likely to develop parkinsonism, while patients with the opposite pattern were more likely to develop dementia. This study shows that iRBD patients older than 70 with constipation and reduced nigro-putaminal dopaminergic function are at high risk of short-term phenoconversion to an overt synucleinopathy, providing an effective stratification approach for future neuroprotective trials. Moreover, we provide cut-off values for the significant predictors of phenoconversion to be used in single subjects.

GBA variants in REM sleep behavior disorder: A multicenter study.

OBJECTIVE: To study the role of GBA variants in the risk for isolated REM sleep behavior disorder (iRBD) and conversion to overt neurodegeneration. METHODS: A total of 4,147 individuals were included: 1,061 patients with iRBD and 3,086 controls. GBA was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of GBA variants on the risk of iRBD, age at onset (AAO), and conversion rates. RESULTS: GBA variants were found in 9.5% of patients with iRBD compared to 4.1% of controls (odds ratio, 2.45; 95% confidence interval [CI], 1.87-3.22; p = 1 × 10-10). The estimated OR for mild p.N370S variant carriers was 3.69 (95% CI, 1.90-7.14; p = 3.5 × 10-5), while for severe variant carriers it was 17.55 (95% CI, 2.11-145.9; p = 0.0015). Carriers of severe GBA variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or noncarriers (p = 0.029). Of the GBA variant carriers with available data, 52.5% had converted, compared to 35.6% of noncarriers (p = 0.011), with a trend for faster conversion among severe GBA variant carriers. However, the results on AAO and conversion were based on small numbers and should be interpreted with caution. CONCLUSIONS: GBA variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe GBA variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of GBA variants should be studied as a potential way to identify GBA variant carriers who will develop a synucleinopathy in the future.

SMPD1 variants do not have a major role in rapid eye movement sleep behavior disorder.

Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene were reported to be associated with Parkinson's disease and dementia with Lewy bodies. In the current study, we aimed to evaluate the role of SMPD1 variants in isolated rapid eye movement sleep behavior disorder (iRBD). SMPD1 and its untranslated regions were sequenced using targeted next-generation sequencing in 959 iRBD patients and 1287 controls from European descent. Our study reports no statistically significant association of SMPD1 variants and iRBD. It is hence unlikely that SMPD1 plays a major role in iRBD.

Why do we move to the beat? A multi-scale approach, from physical principles to brain dynamics.

Humans' ability to synchronize movement with auditory rhythms relies on motor networks, such as cortical areas, basal ganglia and the cerebellum, which also participate in rhythm perception and movement production. Current research has provided insights into the dependence of this action-perception coupling upon the entrainment of neuronal activity by external rhythms. At a physical level, advances on wearable robotics have enriched our understanding of the dynamical properties of the locomotor system showing evidence of mechanical entrainment. Here we defend the view that modelling brain and locomotor oscillatory activities as dynamical systems, at both neural and physical levels, provides a unified theoretical framework for the understanding of externally driven rhythmic entrainment of biological systems. To better understand the underlying mechanisms of this multi-level entrainment during locomotion, we review in a common framework the core questions related to the dynamic properties of biological oscillators and the neural bases of auditory-motor synchronization. Illustrations of our approach, using personalized auditory stimulation, to gait rehabilitation in Parkinson disease and to manipulation of runners' kinematics are presented.

Individualization of music-based rhythmic auditory cueing in Parkinson's disease.

Gait dysfunctions in Parkinson's disease can be partly relieved by rhythmic auditory cueing. This consists in asking patients to walk with a rhythmic auditory stimulus such as a metronome or music. The effect on gait is visible immediately in terms of increased speed and stride length. Moreover, training programs based on rhythmic cueing can have long-term benefits. The effect of rhythmic cueing, however, varies from one patient to the other. Patients' response to the stimulation may depend on rhythmic abilities, often deteriorating with the disease. Relatively spared abilities to track the beat favor a positive response to rhythmic cueing. On the other hand, most patients with poor rhythmic abilities either do not respond to the cues or experience gait worsening when walking with cues. An individualized approach to rhythmic auditory cueing with music is proposed to cope with this variability in patients' response. This approach calls for using assistive mobile technologies capable of delivering cues that adapt in real time to patients' gait kinematics, thus affording step synchronization to the beat. Individualized rhythmic cueing can provide a safe and cost-effective alternative to standard cueing that patients may want to use in their everyday lives.

LRRK2 protective haplotype and full sequencing study in REM sleep behavior disorder.

BACKGROUND: Individuals with rapid eye movement (REM)-sleep behavior disorder (RBD) are likely to progress to synucleinopathies, mainly Parkinson's disease (PD), dementia with Lewy-bodies (DLB) and multiple system atrophy (MSA). The genetics of RBD only partially overlaps with PD and DLB, and the role of LRRK2 variants in risk for RBD is still not clear. METHODS: The full coding sequence, exon-intron boundaries and 5' and 3' untranslated regions of LRRK2 were sequenced using targeted next-generation sequencing. A total of 350 RBD patients and 869 controls were sequenced, and regression and burden models were used to examine the association between LRRK2 variants and RBD. RESULTS: No pathogenic mutations that are known to cause PD were identified in RBD patients. The p.N551K-p.R1398H-p.K1423K haplotype was associated with a reduced risk for RBD (OR = 0.66, 95% CI 0.44-0.98, p = 0.0055 for the tagging p.N551K substitution). A common variant, p.S1647T, was nominally associated with risk for RBD (OR = 1.28, 95% CI 1.05-1.56, p = 0.029). Burden analysis identified associations with domains and exons that were derived by the variants of the protective haplotype, and no burden of other rare variants was identified. CONCLUSIONS: Carriers of the LRRK2 p.N551K-p.R1398H-p.K1423K haplotype have a reduced risk for developing RBD, yet PD-causing mutations probably have minor or no role in RBD. Additional work is needed to confirm these results and to identify the mechanism associated with reduced risk for RBD.

The dementia-associated APOE ε4 allele is not associated with rapid eye movement sleep behavior disorder.

The present study aimed to examine whether the APOE ε4 allele, associated with dementia with Lewy bodies (DLB), and possibly with dementia in Parkinson's disease (PD), is also associated with idiopathic rapid eye movement sleep behavior disorder (RBD). Two single nucleotide polymorphisms, rs429358 and rs7412, were genotyped in RBD patients (n = 480) and in controls (n = 823). APOE ε4 allele frequency was 0.14 among RBD patients and 0.13 among controls (OR = 1.11, 95% CI: 0.88-1.40, p = 0.41). APOE ε4 allele frequencies were similar in those who converted to DLB (0.14) and those who converted to Parkinson's disease (0.12) or multiple system atrophy (0.14, p = 1.0). The APOE ε4 allele is neither a risk factor for RBD nor it is associated with conversion from RBD to DLB or other synucleinopathies.

Left temporopolar impairment in a case of posttraumatic hypersomnia.

OBJECTIVE: We report a focal morphofunctional brain impairment within the left temporopolar cortex in a patient with a posttraumatic hypersomnia. This case may contribute to better understanding the possible pathophysiological mechanism for posttraumatic hypersomnia.

Assessment of quality of life with the multiple system atrophy health-related quality of life scale.

BACKGROUND: Multiple system atrophy (MSA) has considerable effect on health-related quality of life (Hr-QoL). The aim of this study was to prospectively evaluate Hr-QoL by using the MSA health-related Quality of Life (MSA-QoL) scale. METHODS: Evaluation of 100 patients at baseline and after a mean follow-up of 11.5 months was performed. Assessment was made of potential associations with established markers of disease progression. Calculation was performed of sample-size estimates for various effect sizes. RESULTS: MSA-QoL scale scores were less responsive to change than Unified MSA Rating Scale (UMSARS) scores. Responsiveness was largely improved and reasonable sample-size estimates were obtained when limiting the analysis to items with significant change over time. CONCLUSIONS: The UMSARS remains the "gold standard" for disease-modifying/neuroprotection trials. An MSA-QoL Change Scale, based on the most responsive items, may become a valuable tool.

Suggested immobilization test for diagnosis of restless legs syndrome in Parkinson's disease.

Diagnosis of restless leg syndrome (RLS) in Parkinson's disease (PD) is difficult because of clinical confounds. The suggested immobilization test (SIT) is validated for diagnosis of primary RLS. This study evaluated the usefulness of the SIT for diagnosis of RLS in PD. We compared SIT scores, as well as polysomnography measures in 50 patients with PD (25 with RLS, 25 without), 25 patients with primary RLS, and 25 age/sex matched controls. Mean leg discomfort score was increased in patients with PD and RLS compared to PD without RLS, and also in patients with primary RLS compared to controls. Leg discomfort was significantly higher at the end of the test in patients with RLS compared to patients without RLS. Intensity of leg discomfort was similar between patients with RLS, with or without PD. Using a mean leg discomfort cutoff of 11, we showed sensitivity of 91% and specificity of 72% for RLS diagnosis in PD during symptomatic time intervals. Periodic leg movements index during the SIT did not differ between groups. Periodic leg movements index during sleep and wakefulness was increased in patients with primary RLS compared to controls, but did not differ between patients with PD, with and without RLS. The sensory SIT is a simple test that may help diagnose RLS in patients with PD.

Assessment of the Scopa-Aut questionnaire in multiple system atrophy: relation to UMSARS scores and progression over time.

Autonomic failure is a key feature of multiple system atrophy (MSA). Moreover, early autonomic failure is an independent predictive factor for rapid disease progression and shorter survival. The assessment of autonomic failure is therefore important for both, the diagnosis and prognosis of MSA. Here, we evaluate autonomic dysfunction in MSA patients by the Scopa-Aut questionnaire. Potential associations between the Scopa-Aut questionnaire and established markers of disease progression - that is the Unified MSA Rating Scale (UMSARS) - were further assessed. The results confirm early and prominent autonomic failure in MSA patients. Relative scores were highest for the sexual and urinary subdomains. Surprisingly, relative scores in the cardiovascular subdomain were lowest suggesting that the Scopa-Aut questionnaire is suboptimal for the screening and evaluation of cardiovascular symptoms in MSA. A multivariate regression showed an association between total Scopa-Aut and UMSARS I scores. No significant changes in Scopa-Aut scores were observed during follow-up except for the urinary subdomain, while UMSARS I, II and IV scores significantly increased over time. In conclusion, Scopa-Aut can be used as a simple auto-questionnaire for the screening of autonomic symptoms in multiple system atrophy. It seems not useful as endpoint for disease-modification or neuroprotection trials.

A motor signature of REM sleep behavior disorder.

BACKGROUND: The purpose of this study was to determine if there was a common pattern in movements during REM sleep behavior disorder (RBD). METHODS: We blindly compared video-monitored movements during RBD (n = 136 clips) and wakefulness/arousal (n = 53 clips) in patients with Parkinson's disease (n = 29) and without parkinsonism (idiopathic RBD, n = 31; narcolepsy, n = 5). RESULTS: The scorers accurately guessed the sleep/wake stage of 94% of video clips. Compared with wake movements, RBD movements were faster and more often repeated, jerky, and pseudohallucinatory, not self-centered, never associated with tremor, and rarely involved the environment in an appropriate manner. A specific posture of the hand (limp wrist with flexed digits) during grasping movements was evidenced during RBD in 48% of patients, reminiscent of hand-babbling in babies. CONCLUSIONS: These characteristics of movements were found in the 3 conditions (Parkinson's disease, idiopathic RBD, and primary narcolepsy), delineating a common motor signature of RBD.

Hallucinations in narcolepsy with and without cataplexy: contrasts with Parkinson's disease.

BACKGROUND: Narcolepsy and Parkinson's disease (PD) are associated with hallucinations, excessive daytime sleepiness, REM sleep behavior disorder (RBD), as well as complete (narcolepsy with cataplexy) vs. partial (PD, narcolepsy without cataplexy) hypocretin-1 deficiency. OBJECTIVE: To compare the hallucinations associated with narcolepsy to those of PD. METHODS: One hundred patients with narcolepsy (with and without cataplexy) and 100 patients with PD were consecutively interviewed about their hallucinations (frequency, phenomenology, insight into unreality and association with sleep) as well as their risk factors. RESULTS: Hallucinations occurred more frequently and with more motor and multimodal aspects in narcolepsy with cataplexy (59%) than in narcolepsy without cataplexy (28%) and PD (26%). Compared to PD, the hallucinations in narcolepsy were less frequently of the passage/presence type (passage: brief visions of a person or animal passing sideways; presence: perception that a living character or an animal is behind or near the subject, without the subject actually seeing, hearing or touching it), more frequently auditory and more often associated with sleep. However, in 40% of the patients with narcolepsy and 54% of the patients with PD, the hallucinations occurred while the patients were wide awake. Patients with cataplexy had reduced immediate insight into the unreality of their hallucinations compared to patients with PD, but the delusions were exceptional (2%), transient and based on hallucinations in both groups. The risk factors for hallucinations were sleep paralysis and RBD in narcolepsy and motor disability and sleepiness in PD. CONCLUSIONS: The multimodal, dreamlike aspect of hallucinations in narcolepsy with cataplexy could transiently impair the patients' insight. The high frequency of these hallucinations (compared to those in narcolepsy without cataplexy or PD) suggests that complete (more than partial) hypocretin-1 deficiency promotes hallucinations.