Risk Of Phenoconversion Research Articles

Insular monoaminergic deficits in prodromal α-synucleinopathies.

This study assessed data from two cohorts of patients with alpha-synucleinopathies (University of Brescia and University of Rome Tor-Vergata cohorts). Consecutive participants with video-polysomnography-confirmed iRBD, Parkinson's disease (PD), dementia with Lewy bodies (DLB) and controls underwent neurological, clinical and 123I-FP-CIT SPECT imaging assessments. Individuals with iRBD were longitudinally monitored to collect clinical phenoconversion to PD or DLB. The main outcome was to identify whole brain 123 I-FP-CIT SPECT measures reflecting monoaminergic deficits in each clinical group as compared to controls. The cohort (n = 184) included 45 patients with iRBD, 47 PD, 42 DLB and 50 age-matched controls. Individuals with iRBD were categorized as RBD-DAT- (n = 32) and RBD-DAT+ (n = 13), according to nigrostriatal assessment used in clinical practice. Compared to controls, RBD-DAT- showed an early involvement of the left insula, which increased in RBD-DAT+, and was present in patients with Parkinson's disease and dementia with Lewy bodies. Longitudinal cox regression analyses revealed a higher risk of phenoconversion in individuals with iRBD and insular monoaminergic deficits [HR = 3.387; CI 95%: 1.18-10.27]. In this study, altered insular monoaminergic binding in iRBD was associated with phenoconversion to DLB or PD. These findings may provide a helpful stratification approach for future pharmacological or non-pharmacological interventions.

Blunted tachycardia and cardiac sympathetic denervation in isolated rapid eye movement sleep behavior disorder

BackgroundIsolated rapid eye movement sleep behavior disorder (iRBD) serves as a prodromal phase of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Blunted tachycardia (BT) during postural changes indicates neurogenic orthostatic hypotension, a marker of autonomic dysfunction. We aimed to investigate whether BT is associated with cardiac sympathetic neurogenic denervation. Additionally, we conducted a preliminary short-term follow-up to examine the potential prognostic significance of BT regarding phenoconversion and mortality.MethodsForty-three patients with iRBD at Shiga University of Medical Science Hospital underwent active standing tests to identify BT, defined by a specific ratio of decrease in systolic blood pressure to inadequate increase in heart rate after standing, and orthostatic hypotension. 123I-metaiodobenzylguanidine myocardial scintigraphy (123I-MIBG) and dopamine transporter single-photon emission computed tomography (DAT-SPECT) were performed. Participants were followed up for 3.4 ± 2.4 years for phenoconversion and 4.0 ± 2.3 years for mortality assessment, and the risk of events was analyzed using log-rank tests.ResultsAmong the 43 participants (mean age, 72.3 ± 7.9 years; 8 female), 17 met the BT criteria. We found no significant comorbidity-related differences in hypertension or diabetes between the BT(+) and BT(-) groups. Orthostatic hypotension was more prevalent in the BT(+) group than in the BT(-) group (47.1% vs 7.7%, p = 0.003). BT(+) patients were older with a lower early and delayed MIBG uptake; however, no significant differences were observed in DAT accumulation. Phenoconversion was observed in seven (41.2%) BT(+) and seven (26.9%) BT(-) patients. Three deaths were recorded in the BT(+) group (17.6%) and three in the BT(-) group (11.5%). No significant differences were observed in the risk of phenoconversion or mortality between the groups.ConclusionsWe have identified the possibility that BT reflects cardiac sympathetic neurogenic denervation in patients with iRBD. Future research is needed to elucidate the potential prognostic value of BT.

Rapid eye movement sleep behavior disorder: modern concept and Parkinson’s disease correlation

This review describes the association between rapid eye movement (REM) sleep behavior disorder (RBD) and synucleinopathies, primarily Parkinson's disease. This article reviews the diagnostic criteria, the epidemiology of RBDs, their pathogenesis, and their association with early non-motor symptoms. The data are presented to assess the risk of phenoconversion of RBDs to Parkinson's disease or other synucleinopathies such as Lewy body dementia and multiple system atrophy. A prodromal period of RBDs may precede synucleinopathies years or decades before potential manifestation of motor, cognitive, or autonomic disorders, and this may be important for initiating the neuroprotective therapy. Other causes of RBDs are also reviewed.

Longitudinal Network Changes and Phenoconversion Risk in Isolated REM Sleep Behavior Disorder.

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.

Assessing patterns of network degeneration in familial frontotemporal lobar degeneration using FDG‐PET and unsupervised machine learning

AbstractBackgroundGenetic mutations causative of familial fronto‐temporal lobar degeneration (f‐FTLD) are highly predictive of a specific proteinopathy, but there exists substantial inter‐individual variability in their system‐level pathophysiology, which can be assessed with 18Fluorodeoxyglucose‐positron emission tomography (FDG‐PET). Determining data‐driven patterns of network degeneration suggestive of underlying specific FTLD‐related genetic mutations is paramount to guide complex clinical decision making supported by the quantification of FDG‐PET.MethodWe collected clinical and FDG‐PET data from 39 patients with f‐FTLD, including 11 carrying the C9orf72 hexanucleotide expansion (1 asymptomatic, 9 with a predominant behavioral phenotype, 1 with a predominant language phenotype), 12 carrying a GRN mutation (1 asymptomatic, 7 behavioral, 4 language), and 16 carrying a MAPT mutation (6 asymptomatic, 10 behavioral). We performed a spectral covariance decomposition analysis between FDG‐PET images to yield latent patterns reflective of a distribution of metabolism opposing poles of relative hyper‐ and hypo‐metabolism across the entire brain (“eigenbrains” or EBs). We then conducted linear discriminant analyses (LDAs) to perform EB‐based multiclass predictions of genetic mutation and clinical phenotype.ResultThe spectral decomposition analysis yielded five eigenbrains, which explained 58.79% of the covariance between FDG‐PET images (Fig. 1). Gradients indicative of relative hypometabolism in left fronto‐temporo‐parietal areas distinguished GRN mutation carriers from other genetic mutations (EB1, EB2, EB4) and were associated with clinical phenotypes predominantly involving language (EB1, EB2, EB3). Conversely, those indicative of relative hypometabolism in prefrontal areas (EB3) and temporopolar areas (EB2) with a right hemispheric predominance were mostly associated with clinical phenotypes predominantly involving behavior/personality, and EB2 distinguished MAPT mutation carriers from other genetic mutations. The LDAs yielded accuracies of 80% and 75% in predicting genetic status and predominant clinical phenotype, respectively (Fig. 2).ConclusionFive EBs explained a high proportion of covariance in patterns of network degeneration across FTLD‐related genetic mutations. These EBs contained information relevant to the system‐level physiology associated with FTLD‐related pathogenic mechanisms and that allowed the prediction of clinical phenotype with relatively high accuracy. This supports the utility of FDG‐PET to guide the development of tools supporting clinical decision making and ongoing efforts to develop network‐based biomarkers to track disease progression and risk of phenoconversion in f‐FTLD.

Which factors affect phenoconversion in isolated rapid eye movement sleep behavior disorder?

AimIsolated REM sleep behavior disorder (IRBD) is characterized by loss of the normal atonia of REM sleep. Patients with IRBD are at substantial risk of developing the synuclein-related neurodegenerative diseases (NDD). Few predictors of phenoconversion (from IRBD to NDD) have been identified such as age >65 years, hyposmia, constipation, elevated Epworth sleepiness scale (ESS). We aimed to detect rate and risk factors of phenoconversion. MethodThe study designed as retrospectively. NDD was developed in 18 (27.27%) patients while NDD wasn’t developed in 48 (72.73%) patients after ten years. The data of the first visit (age, gender, hyposmia, constipation, ESS, comorbidities, physical/neurological examinations, laboratory, and polysomnography) were compared between NDD (n:18) and IRBD (46) groups. The statistical program IBM SPSS Statistics Version 20.0 was used for all analyzes. The threshold for statistical significance for each test was set at 0.05. ResultsAlthough, most first-visit data (age, gender, hyposmia, constipation, ESS, laboratory, polysomnography) were not different between NDD (n:18) and IRBD (n:48) groups, diabetes mellitus (DM) frequency (p:0.021), mean duration of DM (0.027), chest circumference (p:0.017), and hip circumference (p:0.045) were found higher in NDD than IRBD. If the risk of phenoconversion calculated by logistic regression analysis was different only in terms of DM frequency (p:0.030) [odds ratio: 4.909 (1.17–20.19)]. ConclusionThe present study showed that the phenoconversion rate for ten years is 27.27%, and IRBD patients with diabetes mellitus increase the phenoconversion risk nearly five times.

To know or not to know? Opinions of patients with Parkinson's Disease on disclosing risk of phenoconversion in RBD.

The aim of our study was to find out the opinion of patients with Parkinson's Disease (PD) whose disease was preceded by REM sleep behaviour disorder (RBD) regarding early information about the high risk of phenoconversion in RBD. RBD is an early clinical manifestation of α-synucleinopathies with a more than 90% risk of phenoconversion to PD, dementia with Lewy bodies (DLB) or multiple system atrophy (MSA). It remains a subject for debate as to whether and how RBD patients should be informed about the high risk of phenoconversion. The patient's right to full knowledge regarding his or her health conflicts with the potentially destructive impact of this information on his or her mental state and quality of life of them and their relatives. Thirty-nine patients with PD whose disease was preceded by RBD were surveyed. Data on the course of RBD and PD was collected. Questions were asked about early information about the high risk of phenoconversion to patients with RBD and factors determining the opinion of the surveyed persons. The majority ( > 60%) of respondents gave a positive answer when asked whether patients should be informed about their high risk of developing PD once diagnosed with RBD. Only a few (7.7%) respondents believed that disclosing such information to the patient should be possible only after obtaining his or her consent. Respondents associated consent to information about the high risk of developing PD in people with RBD with high expectations of the healthcare system. We were unable to determine whether factors such as the gender of the subject, the clinical course of the PD, and the RBD duration had an impact on patients' opinions regarding disclosing knowledge about phenoconversion. Our study provides important information that should influence physicians' communication with patients with RBD, especially regarding how they communicate about the high risk of phenoconversion.

Cognitive and motor profiles as prodromal markers in predicting phenoconversion and phenotype in isolated REM sleep behavior disorder

ObjectiveTo determine the clinical markers based on cognitive and motor profiles in predicting phenoconverion and phenotype in isolated rapid eye movement sleep behavior disorder (iRBD). Methods45 iRBD patients and 25 healthy controls were included in the follow-up study. All participates received comprehensive evaluations of cognitive, motor and autonomic function at baseline. Positive phenoconversion were identified according to standard diagnostic criteria during follow-up. Results21 iRBD patients displayed phenoconversion in a mean follow-up of 2.9 ± 1.6 years, with 14 presenting motor phenotype and 7 cognitive phenotype. In iRBD, visuospatial, memory, attention-executive function, information processing speed, and motor function predicted phenoconversion, with the combination of Trail Making Test (TMT) and Alternate-tap Test (ATT) performing best (sensitivity = 95.0 %, specificity = 75.0 %); attention-executive function, information processing speed, and motor function predicted motor phenotype conversion, with the combination of TMT and ATT performing best (sensitivity = 100 %, specificity = 66.7 %); visuospatial, memory, and attention-executive function predicted cognitive phenotype conversion, with TMT performing best (sensitivity = 83.3 %, specificity = 91.7 %). Furthermore, individuals with lower z-scores of TMT, Symbol Digit Modalities Test, and ATT than the established cutoff values in iRBD exhibited a significantly higher risk for phenoconversion at follow-up (HR = 2.98, 9.53, 11.68; respectively). ConclusionsIn iRBD, the attention-executive and motor function served as optimum combined markers in predicting phenoconversion and motor phenotype, whereas the attention-executive function performed best in predicting cognitive phenotype. Poor attention-executive function, information processing speed and motor function in iRBD independently increased the risk of phenoconversion.

Mild behavioral impairment linked to phenoconversion to Alzheimer’s disease and cortical thinning in mild cognitive impairment

AbstractBackgroundMild Behavioral Impairment (MBI) is a neurobehavioral syndrome characterized by later life emergence of sustained neuropsychiatric symptoms, as an at‐risk state for dementia (Ismail Z, Alzheimers Dement, 2016). However, the associations between MBI and a risk of phenocoversion to dementia and its neuroanatomical correlates in MCI are still unclear.MethodA total 1326 older adults with MCI was followed for a mean of 3.0 ± 2.0 years. MBI was approximated using a transformation algorithm for the neuropsychiatric inventory at baseline. Two‐step cluster analysis was used to explore classes of 5 MBI domains (decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, abnormal perception/thought content). A Cox regression analysis was applied to investigate the association between the clusters and phenoconversion to AD. A subset of participants (n = 225) underwent 3D T1‐weighted MRI scans and cortical thickness was compared among the clusters of MBI domains.ResultThe cluster analysis identified 3 groups of participants: (1) people without MBI (47.8%, asymptomatic); (2) people with only affective dysregulation (29.3%, affective dysregulation); (3) people with relatively high probability of affective dysregulation, followed by impulse dyscontrol and affective dysregulation (22.9%, multiple domains). Compared to the asymptomatic, multiple domains was associated with a higher risk of phenoconversion to AD (hazard ratio = 2.589 [1.981 – 3.385], p = < 0.001), but affective dysregulation did not predict phenoconversion (1.204 [0.896 – 1.620], p = 0.219) (Fig 1). MCI individuals with symptoms in multiple domains revealed thinning in the bilateral superior and inferior parietal, superior temporal, and prefrontal cortex, and the right precuneus compared to those with only affective dysregulation (Fig 2). We did not find differences in cortical thickness between phenocoverter and non‐phenoconverter, and interaction of clusters of MBI domains and phenoconversion.ConclusionThe multiple co‐occuring MBI domains in individuals with MCI are associated with a higher risk of phenoconversion to AD. Moreover, MCI individuals with symptoms in multiple domains revealed cortical thinning in the superior parietal and precuneus, which have suggested as AD signatures (Dickerson BC, Cereb Cortex, 2009). These results suggest that evaluation of MBI and neuroimaging characteristics could be useful for risk stratification in MCI individuals.

Altered Brain Glymphatic Flow at Diffusion-Tensor MRI in Rapid Eye Movement Sleep Behavior Disorder.

Background Brain glymphatic dysfunction may contribute to the development of α-synucleinopathies. Yet, noninvasive imaging and quantification remain lacking. Purpose To examine glymphatic function of the brain in isolated rapid eye movement sleep behavior disorder (RBD) and its relevance to phenoconversion with use of diffusion-tensor imaging (DTI) analysis along the perivascular space (ALPS). Materials and Methods This prospective study included consecutive participants diagnosed with RBD, age- and sex-matched control participants, and participants with Parkinson disease (PD) who were enrolled and examined between May 2017 and April 2020. All study participants underwent 3.0-T brain MRI including DTI, susceptibility-weighted and susceptibility map-weighted imaging, and/or dopamine transporter imaging using iodine 123-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane SPECT at the time of participation. Phenoconversion status to α-synucleinopathies was unknown at the time of MRI. Participants were regularly followed up and monitored for any signs of α-synucleinopathies. The ALPS index reflecting glymphatic activity was calculated by a ratio of the diffusivities along the x-axis in the projection and association neural fibers to the diffusivities perpendicular to them and compared according to the groups with use of the Kruskal-Wallis and Mann-Whitney U tests. The phenoconversion risk in participants with RBD was evaluated according to the ALPS index with use of a Cox proportional hazards model. Results Twenty participants diagnosed with RBD (12 men; median age, 73 years [IQR, 66-76 years]), 20 control participants, and 20 participants with PD were included. The median ALPS index was lower in the group with RBD versus controls (1.53 vs 1.72; P = .001) but showed no evidence of a difference compared with the group with PD (1.49; P = .68). The conversion risk decreased with an increasing ALPS index (hazard ratio, 0.57 per 0.1 increase in the ALPS index [95% CI: 0.35, 0.93]; P = .03). Conclusion DTI-ALPS in RBD demonstrated a more severe reduction of glymphatic activity in individuals with phenoconversion to α-synucleinopathies. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Filippi and Balestrino in this issue.

Neuropsychological evaluation of phenoconversion risk in REM sleep behaviour disorder: A scoping review.

The objective of this study was to assess the role of cognitive evaluation in the prediction of phenoconversion in polysomnography-confirmed idiopathic or isolated rapid eye movement sleep behaviour disorder, through a scoping review focussing on a longitudinal comprehensive neuropsychological assessment of patients with idiopathic REM sleep behaviour disorder. A literature search (2006-2022) yielded 1034 records, and 20 were selected for analysis. The sample included 899 patients from eight different cohorts and five countries. We extracted data on clinical evolution, mild cognitive impairment diagnosis, neuropsychological tests used, and classification of cognitive domains. Tests, cognitive domains, and mild cognitive impairment definitions were heterogeneous across the studies, precluding a meta-analysis. Ten studies (50%) evaluated the presence of mild cognitive impairment; 14 studies (70%) grouped neuropsychological tests into between three (6 studies, 21.4%) and seven (1 study, 7.1%) cognitive domains. The most frequently used tests were semantic fluency, Stroop colour word test, trail making test A and B, digit span, Rey auditory verbal learning test, and Rey-Osterrieth figure. All except digit span showed a role in predicting phenoconversion. The authors did not consistently assign tests to specific cognitive domains. In conclusion, we discuss methodological differences between the studies and highlight the need for a standardised framework for neuropsychological data acquisition and presentation, based on a multilevel approach covering test selection, domain assignment, and mild cognitive impairment diagnostic criteria.

Early- and late-onset of isolated rapid eye movement sleep behavior disorder: A retrospective cohort study

ObjectiveAge at onset of neurodegenerative disease has significant implications in differentiating disease profiles. We aimed to determine whether age at onset could identify clinical and neurodegenerative profiles in patients with isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) - a prodromal stage of α-synucleinopathies. MethodsIn this retrospective cohort study, the time of the first episode of dream-enactment behaviors that the patient/bed-partners recalled at the time of the patient's first visit to sleep clinic was collected. The distribution of age at onset was examined and patients were dichotomized into early- and late-onset groups based on the intersection point of underlying two Gaussian distributions of onset age. ResultsA total of 241 patients were included. The intersection of underlying two Gaussian models of onset age was 64.6 years, yielding 168 early- (median onset age: 58.0 years, range: 38.0–64.0) and 73 late-onset patients (median onset age: 70.0 years, range: 65.0–82.0). Among them, 154 of early- and 68 late-onset patients were followed-up. Late-onset patients had milder RBD symptoms, but worse sleep, cognition, olfactory and motor functions, and a higher risk of phenoconversion (adjusted hazard ratio (aHR) = 2.2, 95% confidence interval (CI) = 1.2–3.9), especially to probable dementia with Lewy bodies (DLB) (aHR = 8.9, 95% CI = 3.0–26.2), than early-onset patients. ConclusionsLate-onset iRBD was associated with a higher level of neurodegenerative markers and a quicker phenoconversion, especially to probable DLB. Age at onset of iRBD could help identify clinical features and predict prognosis of iRBD.

Neurologic and psychiatric features of impending neurodegeneration in iRBD

IntroductionIdiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is linked to Parkinson’s disease and other alpha-synucleinopathies, but various subsets of iRBD may not carry equal risk (i.e., those with depression are at higher risk than those without). Here, we prospectively focus on neurologic and psychiatric aspects of subjects with iRBD, in an attempt to determine what factors are prominent in those who undergo phenoconversion as opposed to those who do not. MethodsWe analyzed data from the “REM Sleep Behavior Disorder Associations with Parkinson’s Disease Study (RAPiDS)” cohort both at baseline and then at follow-up evaluations (1 to 3 years later) utilizing several neurologic batteries, including the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), the Montreal Cognitive Assessment (MoCA), the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP), the 10-M Walk Test (10MWT), and the Epworth Sleepiness Scale. Determination of phenoconversion was ascertained from physical examination and medical chart review from the initial evaluation onward. ResultsOf those who completed both evaluations, there were 33 subjects with iRBD, with an average age of 63.1 ± 12.8 years, with 9 women and 24 men. Of these, 8 (24%) iRBD subjects developed neurodegenerative illness, and demonstrated multiple areas of neurologic and psychiatric signs and symptoms, such as speech and movement problems as well as anxiety and depression. ConclusionsOur data adds to the literature regarding risk of phenoconversion in those with iRBD. Further study will be needed, but it is clear that not all subjects with iRBD present the same risk for neurodegeneration.

Comparative Analysis of Pupillometry in Idiopathic Rapid Eye Movement Sleep Behavior Disorder and Parkinson’s Disease

Background and Objective Pupillary light reflex (PLR) abnormalities have been reported in patients with Parkinson’s disease (PD). However, few studies have been conducted on the abnormality of PLR in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD), which is a prodromal stage of α-synucleinopathy. We herein quantitatively analyzed the PLR of iRBD using an automated pupillometer, and compared the results with those of PD.Methods In this cross-sectional study, we prospectively enrolled 27 patients with polysomnography-confirmed iRBD, and 23 patients with PD. Pupillometry was performed three times in each eye, alternating left and right. We compared seven pupillometric parameters between the iRBD and PD patients.Results Maximum and minimum pupil diameters were significantly larger in PD patients than in iRBD patients. However, the other pupillometric parameters, such as mean constriction velocity, maximum constriction velocity, reflex amplitude, latency, and mean dilation velocity, did not differ between the two groups. Among iRBD patients, the pupillometric parameters were not correlated with any clinical characteristics related to autonomic dysfunction or neurodegeneration.Conclusions We found that the pupillary constriction and dilation in response to light of iRBD were not different from those of PD. These findings suggest that autonomic pupillary dysfunction already existed in the prodromal stage of α-synucleinopathy to a degree comparable to that in PD. Larger pupil diameters in PD than in iRBD may reflect the pharmacological effect of dopaminergic medications. Future studies are needed to elucidate the association between the PLR abnormalities and the risk of phenoconversion in iRBD.

Development and Validation of a clinical scale for defining RBD severity in participants of the North American Prodromal Synucleinopathy (NAPS) consortium

AbstractBackgroundREM Sleep Behavior Disorder (RBD) is a prodromal marker of α‐synucleinopathies with no standardized tool for assessing severity in clinical or research practice. RBD severity may have implications in measuring risk of phenoconversion, monitoring response to treatment and clinical trial design. This study assessed the validity of the RBD symptom severity scale (RBDSSS) and its correlation to the clinical global impression of severity (CGI‐S) in a cohort of participants enrolled in the North American Prodromal Synucleinopathy (NAPS) Consortium.MethodParticipants and their bedpartners enrolled in the NAPS cohort filled out an 8‐item questionnaire, developed by the International RBD Study Group, assessing frequency and severity of dreams, vocalizations, movements, and injuries associated with RBD, with higher scores indicating more severe symptoms. The CGI‐S is a 7‐point scale ranging from normal (1) to most severely ill (7) and was completed by a clinician based on an independent interview with the participant ± their bedpartners. Total scores for participant (RBDSSS‐PT) and bed partner (RBDSSS‐BP) questionnaires were derived by multiplying frequency and severity scores for each feature, then summing the products for possible maximum scores of 54 and 38 respectively.ResultThis cohort (n = 212) was predominantly male (82.5%) with a mean ± SE age of 65.16 ± 1.46 years. The median (interquartile range) for RBDSSS‐PT, RBDSSS‐BP and CGI‐S was 11 (4‐17), 8 (4‐14.3) and 3 (3‐4), respectively. Spearman’s rank correlation coefficients (rs) were as follows: RBDSSS‐PT vs. RBDSSS‐BP, rs = 0.579; RBDSSS‐PT vs. CGI‐S, rs = 0.642; RBDSSS‐BP vs. CGI‐S, rs = 0.487 (all P<0.0001). RBDSSS‐BP scores were significantly lower in women (6 vs. 9, Chi‐Square p = 0.009) while there were no differences in RBDSSS‐PT scores by sex. (9 vs. 11, p = 0.473).ConclusionA moderate correlation was observed between RBDSSS‐PT and RBDSSS‐BP suggesting good construct validity for the scale. CGI‐S correlated most with RBDSSS‐PT and had a weaker association with RBDSSS‐BP. Women had lower severity scores as reported by bed partners unlike their self‐reported scores, indicating possible sex differences in perceived RBD severity.

Tonic REM sleep muscle activity is the strongest predictor of phenoconversion risk to neurodegenerative disease in isolated REM sleep behaviour disorder.

Previous studies have shown that rapid eye movement sleep without atonia during polysomnography can predict the risk of phenoconversion to neurodegenerative disease in patients with isolated rapid eye movement sleep behaviour disorder. Discrepancy remains with regards to the morphology of rapid eye movement sleep without atonia that best predicts phenoconversion risk. This study aimed to ascertain the predictive value of tonic, phasic and mixed rapid eye movement sleep without atonia in patients with isolated rapid eye movement sleep behaviour disorder, at time of diagnosis. Sixty-four patients with polysomnography-confirmed isolated rapid eye movement sleep behaviour disorder, including 19 who phenoconverted during follow-up, were identified from an existing database. Tonic, phasic, mixed and "any" rapid eye movement sleep without atonia activity from the mentalis, tibialis anterior and flexor digitorum superficialis muscles was analysed blind to status using the diagnostic polysomnography. Rapid eye movement sleep without atonia variables were compared between converters and non-converters. Rapid eye movement sleep without atonia cut-offs predicting phenoconversion were established using receiver-operating characteristic analysis. The mean follow-up duration was 5.50 ± 4.73 years. Phenoconverters (n= 19) had significantly higher amounts of tonic (22.2± 19.1%, p= 0.0014), mixed (18.1± 14.1%, p= 0.0074) and "any" (mentalis muscle; 58.7± 28.0%, p= 0.0009) and all muscles (68.0± 20.8%, p= 0.0049) rapid eye movement sleep without atonia at diagnosis than non-converters. Optimal rapid eye movement sleep without atonia cut-off values predicting phenoconversion were 5.8% for tonic (73.7% sensitivity; 75.6% specificity), 7.3% for mixed (68.4% sensitivity; 73.3% specificity) and 43.6% for "any" (mentalis muscle; 68.4% sensitivity; 80.0% specificity) activity. "Any" (mentalis muscle) rapid eye movement sleep without atonia had the highest area under the curve (0.809) followed by tonic (0.799). The percentage of tonic rapid eye movement sleep without atonia was the strongest biomarker of phenoconversion in this cohort of patients with isolated rapid eye movement sleep behaviour disorder.

A Machine Learning Approach for Detecting Idiopathic REM Sleep Behavior Disorder.

Background and purpose: Growing evidence suggests that Machine Learning (ML) models can assist the diagnosis of neurological disorders. However, little is known about the potential application of ML in diagnosing idiopathic REM sleep behavior disorder (iRBD), a parasomnia characterized by a high risk of phenoconversion to synucleinopathies. This study aimed to develop a model using ML algorithms to identify iRBD patients and test its accuracy. Methods: Data were acquired from 32 participants (20 iRBD patients and 12 controls). All subjects underwent a video-polysomnography. In all subjects, we measured the components of heart rate variability (HRV) during 24 h recordings and calculated night-to-day ratios (cardiac autonomic indices). Discriminating performances of single HRV features were assessed. ML models based on Logistic Regression (LR), Random Forest (RF) and eXtreme Gradient Boosting (XGBoost) were trained on HRV data. The utility of HRV features and ML models for detecting iRBD was evaluated by area under the ROC curve (AUC), sensitivity, specificity and accuracy corresponding to optimal models. Results: Cardiac autonomic indices had low performances (accuracy 63-69%) in distinguishing iRBD from control subjects. By contrast, the RF model performed the best, with excellent accuracy (94%), sensitivity (95%) and specificity (92%), while XGBoost showed accuracy (91%), specificity (83%) and sensitivity (95%). The mean triangular index during wake (TIw) was the best discriminating feature between iRBD and HC, with 81% accuracy, reaching 84% accuracy when combined with VLF power during sleep using an LR model. Conclusions: Our findings demonstrated that ML algorithms can accurately identify iRBD patients. Our model could be used in clinical practice to facilitate the early detection of this form of RBD.

Predictive risk factors of phenoconversion in idiopathic REM sleep behavior disorder: the Italian study “FARPRESTO”

Most patients with idiopathic REM sleep behavior disorder (iRBD) will develop an overt α-synucleinopathy over time, with a rate of phenoconversion of 73.5% after 12 years from diagnosis. Several markers of phenoconversion were identified; however, most studies investigated biomarkers separately, with retrospective study designs, in small cohorts or without standardized data collection methods. The risk FActoRs PREdictive of phenoconversion in idiopathic REM sleep behavior disorder: the Italian STudy (FARPRESTO) is a multicentric longitudinal retrospective and prospective study with a cohort of incident (prospective recruitment) and prevalent (retrospective recruitment) iRBD patients, whose primary aim is to stratify the risk of phenoconversion, through the systematic collection by means of electronic case report forms of different biomarkers. Secondary aims are to (1) describe the sociodemographic and clinical characteristics of patients with iRBD; (2) collect longitudinal data about the development of α-synucleinopathies; (3) monitor the impact of iRBD on quality of life and sleep quality; (4) assess the correlation between phenoconversion, cognitive performance, and loss of normal muscle atony during REM sleep; (5) identify RBD phenotypes through evaluating clinical, biological, neurophysiological, neuropsychological, and imaging biomarkers; and (6) validate vPSG criteria for RBD diagnosis. The FARPRESTO study will collect a large and harmonized dataset, assessing the role of different biomarkers providing a unique opportunity for a holistic, multidimensional, and personalized approach to iRBD, with several possible application and impact at different levels, from basic to clinical research, and from prevention to management. The FARPRESTO has been registered at clinicaltrials.gov (NCT05262543).

Selected autonomic signs and symptoms as risk markers for phenoconversion and functional dependence in prodromal Parkinson's disease.

To determine whether dysautonomia can stratify individuals with other prodromal markers of Parkinson's disease (PD) for risk of phenoconversion and functional decline, which may help identify subpopulations appropriate for experimental studies. Data were obtained from Parkinson's Progression Markers Initiative. Cohorts without PD but with at-risk features were included (hyposmia and/or rapid-eye-movement-sleep behavior disorder, LRRK2 gene mutation, GBA gene mutation). Dysautonomia measures included Scales-for-Outcomes-in-Parkinson's-Disease Autonomic (SCOPA-AUT), seven SCOPA-AUT subscales, and cardiovascular dysfunction (supine hypertension, low pulse pressure, neurogenic orthostatic hypotension). Outcome measures were phenoconversion and Schwab-and-England Activities-of-Daily-Living (SE-ADL) ≤ 70, which indicates functional dependence. Cox proportional-hazards regression was used to evaluate survival to phenoconversion/SE-ADL ≤ 70 for each dysautonomia measure. If a significant association was identified, a likelihood-ratio test was employed to evaluate whether a significant interaction existed between the measure and cohort. If so, regression analysis was repeated stratified by cohort. Median follow-up was 30months. On multivariable analysis, gastrointestinal and female sexual dysfunction subscales were associated with increased risk of phenoconversion, while the cardiovascular subscale and neurogenic orthostatic hypotension were associated with increased risk of SE-ADL ≤ 70; respective hazard ratios (95% confidence intervals) were 1.13 (1.01-1.27), 3.26 (1.39-7.61), 1.87 (1.16-2.99), 5.45 (1.40-21.25). Only the association between the cardiovascular subscale and SE-ADL ≤ 70 was modified by cohort. Symptoms of gastrointestinal and female sexual dysfunction predict phenoconversion in individuals with other risk markers for PD, while signs and symptoms of cardiovascular dysfunction may be associated with functional decline.

Personality profile and its association with conversion to neurodegenerative disorders in idiopathic REM sleep behavior disorder

Patients with Parkinson’s disease (PD) were described less extraverted and more neurotic. It remained unclear whether similar personality traits could be found in idiopathic rapid eye movement sleep behavior disorder (iRBD), a prodromal stage of PD, and could predict phenoconversion to neurodegenerative disorders. We aimed to investigate the personality profile and its association with future neurodegenerative phenoconversion in iRBD patients. One hundred and eighty-five video-polysomnography confirmed iRBD patients and 91 age- and sex-matched controls underwent personality assessment using the NEO five-factor inventory, and 171 iRBD patients were followed up. Our results showed that iRBD was marginally negatively associated with extraverted personality trait (B = −0.28, 95% confidence interval (CI) = −0.55, −0.001). During a median follow-up of 5.9 years, 47 iRBD patients (27.5%) had phenoconversion. More neurotic (adjusted hazard ratio (HR) = 2.0, 95% CI = 1.3, 3.1) and less extraverted personality traits (adjusted HR = 0.53, 95% CI = 0.36, 0.77) were associated with an increased risk of phenoconversion in iRBD patients. Our findings suggest that personality profile may be a potential prodromal marker of iRBD.