Spoken Language Alterations can Predict Phenoconversion in Isolated Rapid Eye Movement Sleep Behavior Disorder: A Multicenter Study.

OBJECTIVE: This study assessed the relationship between speech and language impairment and outcome in a multicenter cohort of isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). METHODS: Patients with iRBD from 7 centers speaking Czech, English, German, French, and Italian languages underwent a detailed speech assessment at baseline. Story-tale narratives were transcribed and linguistically annotated using fully automated methods based on automatic speech recognition and natural language processing algorithms, leading to the 3 distinctive linguistic and 2 acoustic patterns of language deterioration and associated composite indexes of their overall severity. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The Cox proportional hazard was performed to evaluate the predictive value of language patterns for phenoconversion over a follow-up period of 5 years. RESULTS: Of 180 patients free of parkinsonism or dementia, 156 provided follow-up information. After a mean follow-up of 2.7 years, 42 (26.9%) patients developed neurodegenerative disease. Patients with higher severity of linguistic abnormalities (hazard ratio [HR = 2.35]) and acoustic abnormalities (HR = 1.92) were more likely to develop a defined neurodegenerative disease, with converters having lower content richness (HR = 1.74), slower articulation rate (HR = 1.58), and prolonged pauses (HR = 1.46). Dementia-first (n = 16) and parkinsonism-first with mild cognitive impairment (n = 9) converters had higher severity of linguistic abnormalities than parkinsonism-first with normal cognition converters (n = 17). INTERPRETATION: Automated language analysis might provide a predictor of phenoconversion from iRBD into synucleinopathy subtypes with cognitive impairment, and thus can be used to stratify patients for neuroprotective trials. ANN NEUROL 2024;95:530-543.

Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies.

Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49-87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41-88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks.

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.

Sleep electroencephalography biomarkers of cognition in obstructive sleep apnea.

Obstructive sleep apnea has been associated with cognitive impairment and may be linked to disorders of cognitive function. These associations may be a result of intermittent hypoxaemia, sleep fragmentation and changes in sleep microstructure in obstructive sleep apnea. Current clinical metrics of obstructive sleep apnea, such as the apnea-hypopnea index, are poor predictors of cognitive outcomes in obstructive sleep apnea. Sleep microstructure features, which can be identified on sleep electroencephalography of traditional overnight polysomnography, are increasingly being characterized in obstructive sleep apnea and may better predict cognitive outcomes. Here, we summarize the literature on several major sleep electroencephalography features (slow-wave activity, sleep spindles, K-complexes, cyclic alternating patterns, rapid eye movement sleep quantitative electroencephalography, odds ratio product) identified in obstructive sleep apnea. We will review the associations between these sleep electroencephalography features and cognition in obstructive sleep apnea, and examine how treatment of obstructive sleep apnea affects these associations. Lastly, evolving technologies in sleep electroencephalography analyses will also be discussed (e.g. high-density electroencephalography, machine learning) as potential predictors of cognitive function in obstructive sleep apnea.

Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression.

Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% male) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e. a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, P = 0.0007) and tissue deformation (r = 0.52, P = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function and can be recreated using the dynamics of agent-based modelling, structural connectivity and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology.

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.

Does identity disturbance contribute to inhibition in borderline personality? A preliminary report.

A research protocol was developed to test a theoretical model regarding impulsivity in borderline personality (BP) disorder. It was hypothesized that the impact of identity disturbance of individuals with BP features on their response-inhibition functions could be explained by the disposition of their self-concept to increase the intensity of negative emotions. Participants with different levels of BP features were assigned to a self-description condition (N=29) that had the potential to manipulate the identity coherence, or a control condition (N=27) prior to a response inhibition task with high and low arousal emotional stimuli. We also explored the relationship between participants' self-description and their performance on the inhibition task. The results showed a significant interaction between condition, level of BP features, valence, and stimulus intensity on commission errors. Post-hoc analysis did not reveal significant differences. In addition, a moderate correlation was found between a lesser differentiated description of the self and a higher mean of errors of commission. This preliminary study highlights the relevance of studying the relationship between the self-concept and inhibition regarding borderline impulsivity. The findings should be replicated with a larger sample and with individuals who meet the diagnostic criteria.

A Prodromal Brain-Clinical Pattern of Cognition in Synucleinopathies.

OBJECTIVE: Isolated (or idiopathic) rapid eye movement sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Biomarkers are lacking to predict conversion to a dementia or a motor-first phenotype. Here, we aimed at identifying a brain-clinical signature that predicts dementia in iRBD. METHODS: A brain-clinical signature was identified in 48 patients with polysomnography-confirmed iRBD using partial least squares between brain deformation and 27 clinical variables. The resulting variable was applied to 78 patients with iRBD followed longitudinally to predict conversion to a synucleinopathy, specifically DLB. The deformation scores from patients with iRBD were compared with 207 patients with PD, DLB, or prodromal DLB to assess if scores were higher in DLB compared to PD. RESULTS: One latent variable explained 31% of the brain-clinical covariance in iRBD, combining cortical and subcortical deformation and subarachnoid/ventricular expansion to cognitive and motor variables. The deformation score of this signature predicted conversion to a synucleinopathy in iRBD (p = 0.036, odds ratio [OR] = 2.249; 95% confidence interval [CI] = 1.053-4.803), specifically to DLB (OR = 4.754; 95% CI = 1.283-17.618, p = 0.020) and not PD (p = 0.286). Patients with iRBD who developed dementia had scores similar to clinical and prodromal patients with DLB but higher scores compared with patients with PD. The deformation score also predicted cognitive performance over 1, 2, and 4 years in patients with PD. INTERPRETATION: We identified a brain-clinical signature that predicts conversion in iRBD to more severe/dementing forms of synucleinopathy. This pattern may serve as a new biomarker to optimize patient care, target risk reduction strategies, and administer neuroprotective trials. ANN NEUROL 2021;89:341-357.

Speech Biomarkers in Rapid Eye Movement Sleep Behavior Disorder and Parkinson Disease.

OBJECTIVE: This multilanguage study used simple speech recording and high-end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α-synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early-stage Parkinson disease (PD). METHODS: We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5-3.4 years), 149 with PD (mean duration of disease across language groups 1.7-2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12-month follow-up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria. RESULTS: No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12-month follow-up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups. INTERPRETATION: Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021;90:62-75.

Is Splitting Related to Resistance to Proactive Interference? A Process-Oriented Study of Kernberg's Conceptualization of Splitting.

INTRODUCTION: Splitting, as a defense mechanism in Kernberg's theory, plays a significant role in the development and maintenance of polarized and oscillating representations of self/other characteristics of borderline personality disorder (BPD). Although the notion of splitting can be considered from a structural and a functional point of view, almost all empirical studies to date have focused on the former elements to the detriment of related cognitive processes. METHODS: To further investigate the cognitive processes related to splitting, 60 participants were administered the Splitting Index and indexes of resistance to proactive interference (PI) using the interpersonal recent negative task with words that reflect negative or positive interactions compared to neutral words. RESULTS: The use of splitting was uniquely and significantly predicted by a higher capacity to resist PI and a lower capacity to consistently maintain this resistance when presented with negative words, above and beyond BPD traits, primitive defenses, and the presentation of neutral words. Results showed no evidence of a relationship between splitting and resistance to PI with positive words. CONCLUSION: Results appear compatible with Kernberg's conceptualization of splitting as an active defense process that relates to an unstable capacity to inhibit negative representations of the object from entering working memory.

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.

Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies.

OBJECTIVE: The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome-wide association studies of Parkinson disease (PD). We aimed to identify the specific disease-associated variants in this locus, and their potential implications. METHODS: Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta-analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function. RESULTS: Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants. INTERPRETATION: Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020;87:139-153.

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.

Sexual Attentional Bias in Young Adult Heterosexual Men: Attention Allocation Following Self-Regulation.

Being sexually aroused can lead to a stronger propensity to engage in sexual risk-taking and sexually coercive behaviors possibly by narrowing attentional focus toward immediate gratification rather than long-term consequences. The goal of this paper was to investigate the attentional processes implicated in sexual self-regulation failure and its moderating factors, namely having a stronger sensitivity to sexual cues (dual control model) or being less able to implement behavioral intentions (action control theory) following a first effortful task. A total of 82 young adult heterosexual men completed a Dot Probe task to assess their attentional bias toward sexual stimuli. Effortful control was manipulated using a Stroop task. Regardless of conditions, higher sexual excitability was predictive of a stronger attentional bias toward sexual cues, while higher inhibition due to threat of performance failure was predictive of a lower bias for such cues. In the experimental condition, action-oriented individuals were able to negate this attentional bias by staying more focused on the task, while state-oriented participants showed higher orientation toward the sexual cues and thus a higher bias. These results suggest that both higher-order processes, like intention implementation, and lower-order processes, like sexual inhibition and excitation systems, are the key to regulation failure.

Behavioral and Psychological Symptoms that Predict Cognitive Decline or Impairment in Cognitively Normal Middle-Aged or Older Adults: a Meta-Analysis.

Epidemiological studies have revealed that behavioral and psychological (or non-cognitive) symptoms are risk factors for cognitive decline in older adults. This study aimed to systematically review the literature and determine which behavioral and psychological symptoms are most predictive of future cognitive decline among individuals with no pre-existing cognitive impairments. The selected studies included middle-aged or older adults without cognitive impairments. The predictors were assessed using behavioral and psychological questionnaires, or diagnostic interviews, to identify non-cognitive symptoms or psychiatric clinical conditions. The follow-up period was at least one year, and the design of the selected studies was either retrospective or prospective. This study compared individuals with and without non-cognitive manifestations and resulted in one of three outcomes: (a) a score change on a cognitive measure, (b) a diagnosis of mild cognitive impairment, or (c) a diagnosis of Alzheimer's disease or dementia. Four online databases were searched for eligible studies from the database inception to January 17, 2017: MEDLINE (PubMed), Embase (OVID), PsycINFO, and Web of Science. Pooled effect sizes were estimated using a random-effect model. Higgins I2, the Q statistic, and tau-squared were used to quantify the observed heterogeneity between the studies. Results indicate that depression and sleep duration (long and short) were the most consistent associations between behavioral or psychological symptoms and cognitive decline. This meta-analysis supports the need to assess behavioral and psychological symptoms in cognitively intact older adults to identify those who are at risk for cognitive decline.

Changes in Regional Cerebral Perfusion Over Time in Idiopathic REM Sleep Behavior Disorder.

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder is associated with increased risk of neurodegeneration, but the temporal evolution of regional perfusion, a marker of cerebral activity, has not been characterized. The objective of the current study was to study longitudinal regional perfusion in patients with idiopathic rapid eye movement sleep behavior disorder. METHODS: Thirty-seven patients and 23 controls underwent high-resolution single-photon emission computed tomography. After 17 months on average, scans were repeated for idiopathic rapid eye movement sleep behavior disorder patients. We compared regional cerebral blood flow between groups and over time. RESULTS: At baseline, patients showed lower relative regional perfusion in the anterior frontal and lateral parietotemporal cortex compared with controls. However, over time, patients showed an increase in relative regional perfusion in the anterior frontal, lateral parietal, and occipitotemporal cortex, reverting toward normal control levels. CONCLUSIONS: Patients with idiopathic rapid eye movement sleep behavior disorder showed significant areas of relative regional hypoperfusion, which disappeared over time to finally return to average levels, suggesting possible developing compensation in areas affected by neurodegeneration. © 2020 International Parkinson and Movement Disorder Society.

Chronic Neuroleptic-Induced Parkinsonism Examined With Positron Emission Tomography.

BACKGROUND: Neuroleptic drug-induced parkinsonism (NIP) is a leading cause of parkinsonism, particularly in aging. Based on abnormal dopamine transporter scan results, individuals displaying chronic NIP are often diagnosed with Lewy-body Parkinson's disease (PD), but this assumption needs further substantiation. OBJECTIVE: To quantitate the profile of striatal dopaminergic nerve terminal density in NIP relative to PD. METHODS: We used the positron emission tomography ligand [11 C](+)-dihydrotetrabenazine targeting vesicular monoamine transporter type 2 (VMAT2) binding sites and collected various clinical parameters (motor ratings, olfaction, polysomnography to document rapid eye movement sleep muscle activity, quantitative sensory testing for pain thresholds) possibly predicting binding results in patients older than age 50 living with schizophrenia spectrum disorders under long-term stable antipsychotic drug treatment, with (N = 11) or without (N = 11) chart documention of chronic NIP, and compared them to healthy volunteers (N = 11) and others medicated for PD (N = 12). RESULTS: Striatal VMAT2 binding was dichotomous in the NIP group between those with spared (N = 5) or low (N = 6) PD-like values. Striatal binding reduction in the low VMAT2-NIP group was asymmetric without the gradient of maximal involvement in the posterior putamen typical of PD. Anosmia was the only nonmotor parameter measured matching the abnormal striatal VMAT2 binding status. CONCLUSION: These preliminary observations suggest that striatal VMAT2 binding is abnormal in a fraction of chronic NIP cases and differs in spatial distribution from PD. The possibility of a drug-induced axonopathy and resultant synaptopathy, as well as the evolution of the binding deficit, warrant further longitudinal studies in a large cohort. © 2020 International Parkinson and Movement Disorder Society.

Evolution of prodromal Parkinson's disease and dementia with Lewy bodies: a prospective study.

Parkinson's disease has a long prodromal stage with various subclinical motor and non-motor manifestations; however, their evolution in the years before Parkinson's disease is diagnosed is unclear. We traced the evolution of early motor and non-motor manifestations of synucleinopathy from the stage of idiopathic rapid eye movement (REM) sleep behaviour disorder until defined neurodegenerative disease. During 2004-16, we recruited and then annually followed 154 polysomnography-proven patients with idiopathic REM sleep behaviour disorder, of whom 55 phenoconverted to defined parkinsonism or dementia. Longitudinal data on multiple prodromal features, including the Unified Parkinson's Disease Rating Scale parts I-III, quantitative motor tests, olfaction, colour vision, cognition, and autonomic functions were gathered annually (average = five follow-up visits, range: 2-12 years). The same measures were also assessed in 102 age- and sex-matched healthy control subjects. By looking backward from the time of dementia or parkinsonism diagnosis, we examined trajectories of each prodromal feature using mixed effect models. Based on analysis, olfactory loss was first to develop, with predicted onset >20 years before phenoconversion. This was followed by impaired colour vision, constipation, and erectile dysfunction, starting 10-16 years prior to phenoconversion. At 7-9 years before phenoconversion, slight urinary dysfunction and subtle cognitive decline could be detected. Among motor symptoms altered handwriting, turning in bed, walking, salivation, speech, and facial expression began to be disrupted starting 7-11 years prior to parkinsonism diagnosis, but remained mild until soon before phenoconversion. Motor examination abnormalities began 5-7 years before phenoconversion, with the alternate tap test having the longest interval (8 years before phenoconversion). Among cardinal motor phenotypes, bradykinesia appeared first, ∼5-6 years prior to phenoconversion, followed by rigidity (Year -3) and tremor (Year -2). With direct prospective evaluation of an idiopathic REM sleep behaviour disorder cohort during phenoconversion, we documented an evolution of prodromal manifestations similar to that predicted by pathological staging models, with predicted prodromal intervals as long as 20 years.

Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study.

Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.

Inhibitory Control in Sexually Coercive Men: Behavioral Insights Using a Stop-Signal Task With Neutral, Emotional, and Erotic Stimuli.

Response inhibition is defined as one's ability to voluntarily override an automatic or already initiated action when that action is inappropriate. Although a core mechanism of self-control, its association with sexual coercion perpetration and the impact of erotic cues on its exertion remain unknown. According to a domain-specific perspective on impulsivity, response inhibition performances should be disproportionately hindered by sexual cues in sexual coercion perpetrators. In total, 94 male college students completed a stop-signal task that included neutral, emotional, and erotic distracters. Results showed that men who reported past use of sexual coercion obtained overall poorer stop-signal task (SST) performances. Highly arousing sexual stimuli equally hindered the performances of perpetrators and non-perpetrators, whereas moderately arousing sexual and nonsexual positive stimuli did not significantly affect performances. Results do not support a domain-specific perspective on the link between response inhibition and sexual coercion, but rather suggest generally poorer inhibitory control among sexual coercion perpetrators.