PET imaging for a very early detection of rapid eye movement sleep behaviour disorder and Parkinson's disease - A model-based cost-effectiveness analysis.

Parkinson's disease (PD) is the second most prevalent neurodegenerative condition after Alzheimer's disease and it represents one of the fastest emerging neurological diseases worldwide. PD is usually diagnosed after the third decade of life with symptoms like tremors at rest and muscle stiffness. Rapid Eye Movement sleep behavioral disorder (RBD) is another disorder that is caused by a loss of typical muscle relaxation during sleep with a lot of motor activity. Usually, RBD is strongly associated with PD. Recent studies have demonstrated that PD reduces the life expectancy of patients to 10 and 20 years after being diagnosed. In addition, delayed diagnosis and treatment of these neurological disorders have significant socio-economic impacts on patients, their partners and on the general public. Often, it is not clear about PD associated financial burdens both in low and high-income countries. On the other hand, PD triggers neurological variations that affect differences in the dopamine transporter (DAT) and in glucose metabolism. Therefore, positron emission tomography (PET) using specific DAT radiotracers and fluorine-18 labeled desoxyglucose (FDG) has being considered a key imaging technique that could be applied clinically for the very early diagnosis of RBD and in PD. However, a few myths about PET is that it is very expensive. Here, we looked at the cost of treatment of PD and RBD in relation to early PET imaging. Our finding suggests that PET imaging might also be a cost sparing diagnostic option in the management of patients with PD and RBD, not only for first world countries as it is the case now but also for the third world countries. Therefore, PET is a cost-effective imaging technique for very early diagnostic of RBD and PD.

Montreal Cognitive Assessment and the Clock Drawing Test to Identify MCI and Predict Dementia in Isolated REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Patients with isolated/idiopathic REM sleep behavior disorder (iRBD) are at high risk for developing mild cognitive impairment (MCI) and dementia with Lewy bodies (DLB). However, there is a lack of scientific knowledge regarding the accuracy of cognitive screening tools to identify these conditions in iRBD. This study aimed to determine in iRBD the psychometrics of 2 screening tests to discriminate patients with MCI and those at risk of DLB. METHODS: We retrospectively selected and followed 64 patients with polysomnography-confirmed iRBD seen in sleep clinic between 2006 and 2021, 32 with MCI (mean age 68.44 years, 72% men), 32 without MCI (67.78 years, 66% men), and 32 controls (69.84 years, 47% men). Participants underwent a neurologic evaluation and neuropsychological assessment for MCI diagnosis. They also completed the Montreal Cognitive Assessment (MoCA) and Clock Drawing Test (CDT). Fifty-three patients were followed (mean of 5.10 ± 2.64 years); 6 developed DLB, and 16 developed Parkinson disease. An independent cohort of 10 patients with iRBD who later developed DLB was also recruited and followed. Receiver operating characteristic curves with area under the curve (AUC) were performed assessing the discriminant value of the MoCA and CDT. RESULTS: The cut-off values that best differentiated patients who developed DLB from controls were on the MoCA total score (≤25/30 with 100% [95% CI 61%-100%] sensitivity and 78% [61%-89%] specificity, AUC = 0.888) and delayed recall (≤3/5 with 83% [44%-97%] sensitivity and 78% [61%-89%] specificity, AUC = 0.875). Both values yielded a sensitivity of 90% (60%-98%) to detect patients at risk of DLB in the independent cohort. Cutoffs that best discriminated patients with MCI from controls were: ≤25/30 (MoCA total score) with 72% [55%-84%] sensitivity, 78% [61%-89%] specificity, AUC = 0.803 and ≤2/5 (MoCA delayed recall) with 63% [45%-77%] sensitivity, 94% [80%-98%] specificity, AUC = 0.843. No acceptable optimal values were found for the CDT. DISCUSSION: In iRBD, the MoCA demonstrates adequate psychometric properties to identify patients most at risk of developing DLB and to screen for MCI, whereas the CDT does not. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the MoCA, but not the CDT, is useful in screening patients with iRBD for the risk of developing DLB.

Evaluation of a Structured Screening Assessment to Detect Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) cohorts have provided insights into the earliest neurodegenerative processes in α-synucleinopathies. Even though polysomnography (PSG) remains the gold standard for diagnosis, an accurate questionnaire-based algorithm to identify eligible subjects could facilitate efficient recruitment in research. OBJECTIVE: This study aimed to optimize the identification of subjects with iRBD from the general population. METHODS: Between June 2020 and July 2021, we placed newspaper advertisements, including the single-question screen for RBD (RBD1Q). Participants' evaluations included a structured telephone screening consisting of the RBD screening questionnaire (RBDSQ) and additional sleep-related questionnaires. We examined anamnestic information predicting PSG-proven iRBD using logistic regressions and receiver operating characteristic curves. RESULTS: Five hundred forty-three participants answered the advertisements, and 185 subjects fulfilling inclusion and exclusion criteria were screened. Of these, 124 received PSG after expert selection, and 78 (62.9%) were diagnosed with iRBD. Selected items of the RBDSQ, the Pittsburgh Sleep Quality Index, the STOP-Bang questionnaire, and age predicted iRBD with high accuracy in a multiple logistic regression model (area under the curve >80%). When comparing the algorithm to the sleep expert decision, 77 instead of 124 polysomnographies (62.1%) would have been carried out, and 63 (80.8%) iRBD patients would have been identified; 32 of 46 (69.6%) unnecessary PSG examinations could have been avoided. CONCLUSIONS: Our proposed algorithm displayed high diagnostic accuracy for PSG-proven iRBD cost-effectively and may be a convenient tool for research and clinical settings. External validation sets are warranted to prove reliability. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study.

BACKGROUND: Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson's disease from healthy controls. We used the well characterised, multicentre Parkinson's Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups. METHODS: This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson's disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) or hyposmia, and non-manifesting carriers of LRRK2 and GBA variants) from 33 participating academic neurology outpatient practices worldwide (in Austria, Canada, France, Germany, Greece, Israel, Italy, the Netherlands, Norway, Spain, the UK, and the USA). α-synuclein SAA analysis of CSF was performed using previously described methods. We assessed the sensitivity and specificity of the α-synuclein SAA in participants with Parkinson's disease and healthy controls, including subgroups based on genetic and clinical features. We established the frequency of positive α-synuclein SAA results in prodromal participants (RBD and hyposmia) and non-manifesting carriers of genetic variants associated with Parkinson's disease, and compared α-synuclein SAA to clinical measures and other biomarkers. We used odds ratio estimates with 95% CIs to measure the association between α-synuclein SAA status and categorical measures, and two-sample 95% CIs from the resampling method to assess differences in medians between α-synuclein SAA positive and negative participants for continuous measures. A linear regression model was used to control for potential confounders such as age and sex. FINDINGS: This analysis included 1123 participants who were enrolled between July 7, 2010, and July 4, 2019. Of these, 545 had Parkinson's disease, 163 were healthy controls, 54 were participants with scans without evidence of dopaminergic deficit, 51 were prodromal participants, and 310 were non-manifesting carriers. Sensitivity for Parkinson's disease was 87·7% (95% CI 84·9-90·5), and specificity for healthy controls was 96·3% (93·4-99·2). The sensitivity of the α-synuclein SAA in sporadic Parkinson's disease with the typical olfactory deficit was 98·6% (96·4-99·4). The proportion of positive α-synuclein SAA was lower than this figure in subgroups including LRRK2 Parkinson's disease (67·5% [59·2-75·8]) and participants with sporadic Parkinson's disease without olfactory deficit (78·3% [69·8-86·7]). Participants with LRRK2 variant and normal olfaction had an even lower α-synuclein SAA positivity rate (34·7% [21·4-48·0]). Among prodromal and at-risk groups, 44 (86%) of 51 of participants with RBD or hyposmia had positive α-synuclein SAA (16 of 18 with hyposmia, and 28 of 33 with RBD). 25 (8%) of 310 non-manifesting carriers (14 of 159 [9%] LRRK2 and 11 of 151 [7%] GBA) were positive. INTERPRETATION: This study represents the largest analysis so far of the α-synuclein SAA for the biochemical diagnosis of Parkinson's disease. Our results show that the assay classifies people with Parkinson's disease with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis. These findings suggest a crucial role for the α-synuclein SAA in therapeutic development, both to identify pathologically defined subgroups of people with Parkinson's disease and to establish biomarker-defined at-risk cohorts. FUNDING: PPMI is funded by the Michael J Fox Foundation for Parkinson's Research and funding partners, including: Abbvie, AcureX, Aligning Science Across Parkinson's, Amathus Therapeutics, Avid Radiopharmaceuticals, Bial Biotech, Biohaven, Biogen, BioLegend, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel, Coave, DaCapo Brainscience, 4D Pharma, Denali, Edmond J Safra Foundation, Eli Lilly, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, VanquaBio, Verily, Voyager Therapeutics, and Yumanity.

Misfolded α-Synuclein Assessment in the Skin and CSF by RT-QuIC in Isolated REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Real-time quaking-induced conversion (RT-QuIC) assay detects misfolded α-synuclein (AS) in the skin and CSF of patients with the synucleinopathies Parkinson disease and dementia with Lewy bodies. Isolated REM sleep behavior disorder (IRBD) constitutes the prodromal stage of these synucleinopathies. We aimed to compare the ability of RT-QuIC to identify AS in the skin and CSF of patients with IRBD. METHODS: This was a cross-sectional study where consecutive patients with polysomnographic-confirmed IRBD and age-matched controls without RBD underwent skin biopsy and lumbar puncture the same day. Three-millimeter skin punch biopsies were obtained bilaterally in the cervical region from dorsal C7 and C8 dermatomes and in distal legs. RT-QuIC assessed AS in these 6 skin sites and the CSF. RESULTS: We recruited 91 patients with IRBD and 41 controls. In the skin, sensitivity to detect AS was 76.9% (95% CI 66.9-85.1), specificity 97.6% (95% CI 87.1-99.9) positive predictive value 98.6% (95% CI 91.0-99.8), negative predictive value 65.6% (95% CI 56.6-73.6), and accuracy 83.3% (95% CI 75.9-89.3). In the CSF, the sensitivity was 75.0% (95% CI 64.6-83.6), the specificity was 97.5% (95% CI 86.8-99.9), the positive predictive value was 98.5% (95% CI 90.5-99.8), the negative predictive value was 63.9% (95% CI 55.2-71.9), and the accuracy was 82.0% (95% CI 74.3-88.3). Results in the skin and CSF samples showed 99.2% agreement. Compared with negative patients, RT-QuIC AS-positive patients had a higher likelihood ratio of prodromal Parkinson disease (p < 0.001) and showed more frequently hyposmia (p < 0.001), dopamine transporter imaging single-photon emission CT deficit (p = 0.002), and orthostatic hypotension (p = 0.014). No severe or moderate adverse effects were reported. There was no difference between the percentage of participants reporting mild adverse events secondary to skin biopsy or lumbar puncture (9.1% vs 17.2%; p = 0.053). One hundred and ten (83%) and 104 (80%) participants, respectively, stated they would accept to undergo skin biopsy and lumbar puncture again for research purposes. DISCUSSION: Our study in IRBD shows that (1) RT-QuIC detects AS in the skin and CSF with similar high sensitivity, specificity, and agreement, (2) AS RT-QuIC positivity is associated with supportive features and biomarkers of synucleinopathy, and (3) skin punch biopsy and lumbar puncture have comparable mild adverse effects, tolerance, and acceptance. RT-QuIC in the skin or CSF might represent a patient selection strategy for future neuroprotective trials targeting AS in IRBD. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that RT-QuIC-detected AS in the skin and CSF distinguishes patients with IRBD from controls.

Management of REM sleep behavior disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment.

This systematic review provides supporting evidence for a clinical practice guideline for the management of rapid eye movement (REM) sleep behavior disorder in adults and children. The American Academy of Sleep Medicine commissioned a task force of 7 experts in sleep medicine. A systematic review was conducted to identify randomized controlled trials and observational studies that addressed interventions for the management of REM sleep behavior disorder in adults and children. Statistical analyses were performed to determine the clinical significance of critical and important outcomes. Finally, the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence for making recommendations. The literature search identified 4,690 studies; 148 studies provided data suitable for statistical analyses; evidence for 45 interventions is presented. The task force provided a detailed summary of the evidence assessing the certainty of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations. CITATION: Howell M, Avidan AY, Foldvary-Schaefer N, et al. Management of REM sleep behavior disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2023;19(4):769-810.

Predictors of rapid eye movement sleep behavior disorder in patients with Parkinson's disease based on random forest and decision tree.

BACKGROUND AND OBJECTIVES: Sleep disorders related to Parkinson's disease (PD) have recently attracted increasing attention, but there are few clinical reports on the correlation of Parkinson's disease patients with rapid eye movement (REM) sleep behavior disorder (RBD). Therefore, this study conducted a cognitive function examination for Parkinson's disease patients and discussed the application effect of three algorithms in the screening of influencing factors and risk prediction effects. METHODS: Three algorithms (logistic regression, machine learning-based regression trees and random forest) were used to establish a prediction model for PD-RBD patients, and the application effects of the three algorithms in the screening of influencing factors and the risk prediction of PD-RBD were discussed. RESULTS: The subjects included 169 patients with Parkinson's disease (Parkinson's disease with RBD [PD-RBD] = 69 subjects; Parkinson's disease without RBD [PD-nRBD] = 100 subjects). This study compared the predictive performance of RF, decision tree and logistic regression, selected a final model with the best model performance and proposed the importance of variables in the final model. After the analysis, the accuracy of RF (83.05%) was better than that of the other models (decision tree = 75.10%, logistic regression = 71.62%). PQSI, Scopa-AUT score, MoCA score, MMSE score, AGE, LEDD, PD-course, UPDRS total score, ESS score, NMSQ, disease type, RLSRS, HAMD, UPDRS III and PDOnsetage are the main variables for predicting RBD, along with increased weight. Among them, PQSI is the most important factor. The prediction model of Parkinson's disease RBD that was established in this study will help in screening out predictive factors and in providing a reference for the prognosis and preventive treatment of PD-RBD patients. CONCLUSIONS: The random forest model had good performance in the prediction and evaluation of PD-RBD influencing factors and was superior to decision tree and traditional logistic regression models in many aspects, which can provide a reference for the prognosis and preventive treatment of PD-RBD patients.

Systematic quantitative assessment of motor function in clinically isolated REM sleep behaviour disorder: A diagnostic window into early alpha-synucleinopathies.

Mild motor abnormalities can herald the beginning of Parkinson´s disease but their diagnostic value is limited by multifactorial ageing-related influences on motor function. We characterized mild motor abnormalities in different motor domains by conducting a systematic motor assessment in 20 patients with clinically isolated REM sleep behaviour disorder (iRBD) without parkinsonian motor signs and 20 healthy controls. We addressed the influence of lifestyle factors and age on motor function, which needs to be distinguished from neurodegenerative motor features, and assessed the diagnostic value of innovative and established quantitative motor tests in iRBD. Patients with iRBD showed abnormalities in perceptual motor speed (falling stick test), trunk movement coordination (bend, twist and touch test) and dynamic balance (line walk test) without alterations in simple motor speed (alternate tap test), dexterity (grooved pegboard), static balance (force plate) and gait (timed up and go test). The falling stick test showed the highest diagnostic accuracy in identifying subjects with RBD (ROC-AUC 0.85, p ≤ 0.001). Multivariate analysis revealed physical activity and age as additional determinants of motor test performance. iRBD comprises a wide spectrum of mild motor abnormalities which cannot be verified by established tests for motor speed, gait and balance. The falling stick test, an innovative screening test for perceptual motor speed, provides high diagnostic potential in identifying subjects with subclinical neurodegenerative symptoms before parkinsonian motor signs become apparent. Normative data for physical activity and age need to be obtained to ensure correct interpretation of motor test results in prodromal Parkinson-related disease.

Health, social, and economic consequences of rapid eye movement sleep behavior disorder: a controlled national study evaluating societal effects.

STUDY OBJECTIVES: Parkinson's disease (PD) causes significant socioeconomic burdens. One of the strongest predictors of PD is rapid eye movement (REM) sleep behavior disorder (RBD; when there is no known other cause of RBD, referred to as idiopathic RBD [iRBD]), but there is no information about its factual welfare burden. We estimated the direct and indirect total costs of iRBD in a national sample of patients, based on a national register-based cohort study with matched controls. METHODS: Using records from the Danish National Patient Registry, patient's diagnosis with RBD from 2006 to 2016 were identified. We excluded patients with a prior diagnosis of narcolepsy, PD, and other neurodegenerative diseases. We identified and compared randomly chosen controls matched for age, gender, geographic area, and civil status. Direct costs included frequencies of primary and secondary sector contacts and procedures, and medication. Indirect costs included the effect on labor supply. Social-transfer payments were included to illustrate the effect on national accounts. RESULTS: A total of 246 iRBD patients and 982 matched controls were registered. iRBD patients had significantly higher rates of health-related contacts and of medication use, and higher socioeconomic costs than controls. The total additional direct net healthcare costs after the diagnosis (general practitioner services, hospital services, and medication) and indirect costs (loss of labor market income) was €13,088 for patients compared with controls. Patients already exhibited a negative social- and health-related status several years before the first diagnosis. CONCLUSIONS: Diagnoses of iRBD have major socioeconomic consequences for patients, their partners, and society.

Appropriate assessment method of 123I-MIBG myocardial scintigraphy for the diagnosis of Lewy body diseases and idiopathic REM sleep behavior disorder.

BACKGROUND: In 123I-metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy, the early heart-to-mediastinum (H/M) ratio is considered to reflect the density of the cardiac sympathetic nerve endings, washout rate (WR) is an indicator of the cardiac sympathetic tone, and the delayed H/M ratio reflects both. The Delayed H/M ratio is usually used to support the diagnosis of Lewy body diseases (LBDs) and idiopathic REM sleep behavior disorder (iRBD); however, which values should be used have not been specified. Here, we hypothesized that the combination of these values is appropriate for the diagnostic purpose. METHODS: In this single-center retrospective cohort study, we recruited 106 patients with LBDs or iRBD and 33 patients without those diseases, of whom we reviewed the 123I-MIBG myocardial scintigraphy results. RESULTS: Sensitivity/specificity to diagnose LBDs and iRBD were 0.77/0.94 for the early H/M ratio (≤ 2.0), 0.82/0.94 for the delayed H/M ratio (≤ 2.0), and 0.89/0.91 for WR (≥ 23.0). When patients were considered positive if at least either the early H/M ratio or WR was abnormal, the sensitivity significantly increased to 0.97, whereas the specificity remained similar at 0.91. Furthermore, our subgroup analyses revealed that WR enhancement preceded H/M ratio reduction, but, in patients with a severely reduced early H/M ratio, paradoxically normal WR could be observed. CONCLUSION: We propose the highly sensitive, combined early H/M ratio and WR assessments for 123I-MIBG myocardial scintigraphy. The temporal precedence of cardiac sympathetic dysfunction over denervation and the floor effect in 123I-MIBG uptake may underlie the sensitivity improvement.

Low Cost Screening for Features of Prodromal Parkinson's Disease in General Medical Practice in Italy.

The aim of the study was to determine the feasibility of screening older adults attending general medical practice for features suggesting prodromal Parkinson's disease (PD). Four general practitioners recruited 392 subjects aged ≥60 years, attending their primary clinics. A self-administered questionnaire collected information on history of probable rapid eye movements sleep behavior disorder (pRBD), constipation, risk markers for PD, and on subjective cognitive function. Olfactory function was tested. Constipation (27.8%), and hyposmia (19.9%), but not pRBD (4.3%), were more prevalent with age. Further supporting the feasibility of a longitudinal study, 299 subjects agreed to be followed.

Assessment of cognitive profile as a prodromal marker of the evolution of rapid eye movement sleep behavior disorder.

STUDY OBJECTIVES: To search for a specific neuropsychological profile in idiopathic REM sleep behavior disorder (iRBD), able to predict the onset of neurodegenerative disorders. METHODS: In a longitudinal follow-up study of 63 consecutive iRBD patients (follow-up duration 6.7 ± 3.8 years), the baseline cognitive profile of converters to neurodegenerative disease was compared with that of the nonconverters. Five cognitive domains were assessed: memory, attention-working memory, executive functions, visuospatial abilities, language. Mild cognitive impairment (MCI) was diagnosed according to the Movement Disorder Society's diagnostic criteria for Parkinson's disease. RESULTS: 30 subjects (47.6%) developed a neurodegenerative disease (latency to conversion 60.33 ± 44.81 months). MCI was found in 50% of the converters and 12% of the nonconverters (p = .001), and its presence conferred a neurodegenerative disease risk of 10% at 3 years, 36% at 5 years, and 73% at 10 years (p = .002). Pathological equivalent scores on at least one neuropsychological test were detected in 46.7% of the converters versus 21.2% of the nonconverters in the memory domain (p = .032), in 40.0% versus 6.1% in that of executive functions (p = .002), and in 20.0% versus 3% in the visuospatial abilities domain (p = .047). On multivariate analysis, impaired executive functions significantly correlated with phenoconversion (p = .018). Lower Mini Mental State Examination (MMSE) scores (p = .004) and memory deficits (p = .031) were found in patients who developed dementia first. CONCLUSIONS: Cognitive profile is useful for stratifying risk of phenoconversion in patients with iRBD. The presence of MCI and impaired executive functions, memory, and visuospatial abilities discriminated the converters. Lower MMSE scores and memory deficits may characterize those subjects who first develop dementia.

Characteristics, correlates, and assessment of psychosis in Parkinson disease without dementia.

INTRODUCTION: Considering that psychosis in Parkinson disease (PD) is associated with worse outcomes, including dementia, we aimed to study the characteristics, correlates, and assessment of PD psychosis in those without dementia. METHODS: 101 PD subjects without dementia (Montreal Cognitive Assessment ≥21/30) were recruited to participate in a study of neuropsychiatric symptoms in PD. This study included a baseline standard neurological exam and common PD symptom assessments. Using the Scale for the Assessment of Positive Symptoms (SAPS) and separate assessment of visual illusions and sense of presence, NINDS-NIMH criteria for PD psychosis were applied. RESULTS: Of the 33 (32.7%) PD subjects who met diagnostic criteria for psychosis in PD, visual illusions were most common (72.7%), followed by visual hallucinations (39.4%). Adjusted for presence of REM sleep behavior disorder (RBD) (p = 0.097), use of dopamine agonists (OR = 3.7, p = 0.012) and greater autonomic symptom burden (OR = 1.1 (per 1-unit change in score on SCOPA-AUT), p = 0.012) were associated with greater risk of psychosis. Use of dopamine agonists (OR = 5.0, p = 0.007), higher MDS-UPDRS Part II score (OR = 1.1, p = 0.010), and presence of RBD (OR = 4.8, p = 0.012) were independent predictors of visual hallucinations and visual illusions. MDS-UPDRS item 1.2 score ≥1 had highly correlated with the SAPS score (r = 0.65, p < 0.0001), but was 42% sensitive and 96% specific for identifying psychosis. CONCLUSION: This study confirms the association between dopamine agonists and psychosis in PD patients without dementia. The association of RBD, autonomic symptoms, and MDS-UPDRS Part II scores with psychosis underscore its link to brainstem dysfunction and greater PD motor symptom severity.

Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study.

BACKGROUND: Findings from longitudinal follow-up studies in patients with idiopathic rapid-eye-movement sleep behaviour disorder (IRBD) have shown that most patients will eventually develop the synucleinopathies Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Neuroinflammation in the form of microglial activation is present in synucleinopathies and is a potential therapeutic target to halt or delay the neurodegenerative process. We aimed to investigate whether neuroinflammation is present in patients with IRBD and its possible relation to nigrostriatal dopamine function. METHODS: In this prospective, case-control, PET study, patients with IRBD and no clinical evidence of parkinsonism and cognitive impairment were recruited from tertiary sleep centres in Spain (Barcelona) and Denmark (Aarhus). We included patients with polysomnography-confirmed IRBD according to established criteria. Healthy controls were recruited through newspaper advertisements. Controls had no motor or cognitive complaints, a normal neurological examination, and a mean group age similar to the IRBD group. In patients with IRBD, we assessed microglial activation in the substantia nigra, putamen, and caudate with 11C-PK11195 PET, and dopaminergic axon terminal function in the putamen and caudate with 18F-DOPA PET. Controls underwent either 11C-PK11195 PET or 18F-DOPA PET. We compared 18F-DOPA uptake and 11C-PK11195 binding potential between groups with an unpaired, two-tailed Student's t test. FINDINGS: Between March 23, 2015, and Oct 19, 2016, we recruited 20 consecutive patients with IRBD and 19 healthy controls. 11C-PK11195 binding was increased on the left side of the substantia nigra in patients with IRBD compared with controls (Student's t test, mean difference 0·153 [95% CI 0·055 to 0·250], p=0·003), but not on the right side (0·121 [-0·007 to 0·250], p=0·064). 11C-PK11195 binding was not significantly increased in the putamen and caudate of patients with IRBD. 18F-DOPA uptake was reduced in IRBD in the left putamen (-0·0032 [-0·0044 to -0·0021], p<0·0001) and right putamen (-0·0032 [-0·0044 to -0·0020], p<0·0001), but not in the caudate. INTERPRETATION: In patients with IRBD, increased microglial activation was detected by PET in the substantia nigra along with reduced dopaminergic function in the putamen. Further studies, including more participants than were in this study and longitudinal follow-up, are needed to support our findings and evaluate whether the presence of activated microglia in patients with IRBD represents a marker of short-term conversion to a clinically defined synucleinopathy in the near future. FUNDING: Danish Council for Independent Research, Instituto de Salud Carlos III (Spain).

Uso da actigrafia na avaliação do ritmo atividade-repouso em pacientes com doença de Parkinson / Use of actigraphy on assessment of activity-rest rhythm in patients with Parkinson's disease

Distúrbios do sono são os mais comuns sintomas não-motores encontrados na doença de Parkinson (DP). OBJETIVOS: Avaliar a relação entre actigrafia e distúrbios do sono mais incidentes na DP. MÉTODOS: Pacientes com e sem DP foram avaliados quanto aos sintomas motores, qualidade do sono, cronotipo e objetivamente através do uso do actímetro. RESULTADOS: Encontrou-se uma significante redução da qualidade do sono entre os pacientes com DP (p = 0.0023), uma pior qualidade subjetiva do sono, maior uso de medicamentos para insônia, mais distúrbios do sono e uma maior fragmentação do ritmo atividade-repouso (IV) (p=0.0271). CONCLUSÃO: Pacientes com DP possuem uma pior qualidade de sono e um ritmo atividade-repouso mais fragmentado. A actigrafia pode ser útil na avaliação da qualidade do sono e do ciclo atividade repouso em pacientes com DP, contribuindo para o rastreio e acompanhamento de eventuais distúrbios do ritmo circadiano a esta doença associados. (AU)

Sleep disorders are the most common non-motor symptom found in Parkinson's Disease (PD). OBJECTIVES: To evaluate the relationship between actigraphy and more incidents sleep disorders in PD. METHODS: Patients with and without PD were assessed regarding motor symptoms, sleep quality, chronotype and objectively through the use of an actimeter. RESULTS: It was found a significant reduction of sleep quality among the patients with PD (p = 0.0023), a worse subjective sleep quality, they used more medications to sleep, they had more sleep disorders and a significantly higher fragmentation of pace (IV) (p = 0.0271). CONCLUSION: Patients with PD have a worse sleep quality and a rest-activity rythm fragmented. Actigraphy can be useful for assessing the quality of sleep and activity/rest cycle in patients with PD, contributing to the screening and follow-up of any circadian rhythm disorders associated to this disease. (AU)

Validation of the MDS research criteria for prodromal Parkinson's disease: Longitudinal assessment in a REM sleep behavior disorder (RBD) cohort.

BACKGROUND: Recently, the International Parkinson and Movement Disorder Society introduced the prodromal criteria for PD. Objectives Our study aimed to examine diagnostic accuracy of the criteria as well as the independence of prodromal markers to predict conversion to PD or dementia with Lewy bodies. METHODS: This prospective cohort study was performed on 121 individuals with rapid eye movement sleep behavior disorder who were followed annually for 1 to 12 years. Using data from a comprehensive panel of prodromal markers, likelihood ratio and post-test probability of the criteria were calculated at baseline and during each follow-up visit. RESULTS: Forty-eight (39.7%) individuals with rapid eye movement sleep behavior disorder converted to PD/dementia with Lewy bodies. The prodromal criteria had 81.3% sensitivity and 67.9% specificity for conversion to PD/dementia with Lewy bodies at 4-year follow-up. One year before conversion, sensitivity was 100%. The criteria predicted dementia with Lewy bodies with even higher accuracy than PD without dementia at onset. Those who met the threshold of prodromal criteria at baseline had significantly more rapid conversion into a neurodegenerative state (4.8 vs. 9.1 years; P < 0.001). Pair-wise combinations of different prodromal markers showed that markers were independent of one another. CONCLUSION: The prodromal criteria are a promising tool for predicting incidence of PD/dementia with Lewy bodies and conversion time in a rapid eye movement sleep behavior disorder cohort, with high sensitivity and high specificity with long follow-up. Prodromal markers influence the overall likelihood ratio independently, allowing them to be reliably multiplied. Defining additional markers with high likelihood ratio, further studies with longitudinal assessment and testing thresholds in different target populations will improve the criteria. © 2017 International Parkinson and Movement Disorder Society.

Normal 'heart' in Parkinson's disease: is this a distinct clinical phenotype?

BACKGROUND AND PURPOSE: Reduction of metaiodobenzylguanidine (MIBG) uptake has been observed in almost all patients with Parkinson's disease (PD), associated with hyposmia, orthostatic hypotension and rapid eye movement sleep behavioral disorder (RBD). In contrast, a subgroup of patients with PD with normal MIBG uptake have been reported to have milder disease and preserved cognition compared with those with lower MIBG. The aim of this study was to investigate whether non-motor manifestations of PD differ between patients with normal and abnormal myocardial MIBG uptake. METHODS: Among 160 de-novo cases of PD, 44 had normal MIBG uptake. Twelve candidate non-motor features were evaluated using questionnaires and laboratory tests. RESULTS: Patients with decreased MIBG uptake had more constipation, RBD, cognitive impairment, hyposmia and orthostatic hypotension than did those with normal MIBG uptake. On linear regression analysis, orthostatic hypotension, olfactory function and probable RBD were significantly associated with MIBG uptake in PD. The principal component analysis showed that the group with normal MIBG was not associated with non-motor impairments. CONCLUSIONS: These results suggest that patients with PD with normal MIBG scans have a relatively low disease burden compared with those with abnormal MIBG. Fewer synuclein pathologies in the myocardia and sympathetic ganglia in PD with preserved MIBG uptake might be associated with lower threshold patterns of Braak synuclein pathology for non-motor manifestations compared with PD with decreased MIBG.

Assessment of α-synuclein in submandibular glands of patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study.

BACKGROUND: The histological feature of Parkinson's disease is the presence of intraneuronal aggregates of phosphorylated α-synuclein (αSyn). In patients with Parkinson's disease, deposits of αSyn are found in the autonomic nerve fibres of the submandibular gland. Since patients with idiopathic rapid-eye-movement sleep behaviour disorder (IRBD) can develop Parkinson's disease and other synucleinopathies, we investigated whether αSyn deposits could also be detected in their submandibular gland nerve fibres. METHODS: We did a case-control study at the Hospital Clinic de Barcelona (Barcelona, Spain) in patients with polysomnographic-confirmed IRBD, patients with clinically diagnosed Parkinson's disease, and controls matched by age with the IRBD group. The controls were either healthy, had had elective neck surgery in the clinic, or were patients who had died in the clinic and had an autopsy. We did a transcutaneous core needle biopsy of the submandibular gland with ultrasound guidance in patients with IRBD or Parkinson's disease, and healthy controls, and without ultrasound guidance in the other controls. We assessed the presence of αSyn with immunohistochemistry using 129-phosphorylated antiserine monoclonal antibody, and analysed quantitative variables with Kruskall-Wallis tests and qualitative variables with Fisher's exact tests. FINDINGS: We did our study between July 16, 2014, and May 16, 2015, and recruited 21 patients with IRBD, 24 patients with Parkinson's disease, and 26 controls (seven healthy, 11 patients undergoing neck surgery, and eight autopsies). We obtained submandibular biopsy material containing glandular parenchyma in nine (43%) of 21 patients with IRBD, 12 (50%) of 24 patients with Parkinson's disease, and all (100%) of the 26 controls. αSyn aggregates were detected in nerve fibres of the glandular parenchyma in eight (89%) of nine patients with IRBD and eight (67%) of 12 with Parkinson's disease, but none of the controls. Of the individuals whose biopsy samples did not contain glandular parenchyma, deposits of αSyn were found in extraglandular tissues in an additional three (25%) of 12 patients with IRBD and five (42%) of 12 patients with Parkinson's disease. None of the controls showed αSyn immunoreactivity in extraglandular tissues. Of the 52 participants who had ultrasonography-guided biopsy, 11 (21%) reported mild-to-moderate local pain, and nine (17%) developed a subcutaneous haematoma; however, these adverse events were transient and did not need treatment. INTERPRETATION: Our findings suggest that, in patients with IRBD, submandibular gland biopsy is a safe procedure for the detection of αSyn aggregates. αSyn detection could be useful for histological confirmation in individuals clinically diagnosed with Parkinson's disease. FUNDING: Centre for Networked Biomedical Research in Neurodegenerative Disorders (CIBERNED), Barcelona, Spain.

Quantitative assessment of motor speech abnormalities in idiopathic rapid eye movement sleep behaviour disorder.

OBJECTIVE: Patients with idiopathic rapid eye movement sleep behaviour disorder (RBD) are at substantial risk for developing Parkinson's disease (PD) or related neurodegenerative disorders. Speech is an important indicator of motor function and movement coordination, and therefore may be an extremely sensitive early marker of changes due to prodromal neurodegeneration. METHODS: Speech data were acquired from 16 RBD subjects and 16 age- and sex-matched healthy control subjects. Objective acoustic assessment of 15 speech dimensions representing various phonatory, articulatory, and prosodic deviations was performed. Statistical models were applied to characterise speech disorders in RBD and to estimate sensitivity and specificity in differentiating between RBD and control subjects. RESULTS: Some form of speech impairment was revealed in 88% of RBD subjects. Articulatory deficits were the most prominent findings in RBD. In comparison to controls, the RBD group showed significant alterations in irregular alternating motion rates (p = 0.009) and articulatory decay (p = 0.01). The combination of four distinctive speech dimensions, including aperiodicity, irregular alternating motion rates, articulatory decay, and dysfluency, led to 96% sensitivity and 79% specificity in discriminating between RBD and control subjects. Speech impairment was significantly more pronounced in RBD subjects with the motor score of the Unified Parkinson's Disease Rating Scale greater than 4 points when compared to other RBD individuals. CONCLUSION: Simple quantitative speech motor measures may be suitable for the reliable detection of prodromal neurodegeneration in subjects with RBD, and therefore may provide important outcomes for future therapy trials.

Polysomnographic Assessment of Sleep Comorbidities in Drug-Naïve Narcolepsy-Spectrum Disorders--A Japanese Cross-Sectional Study.

This is a large cross-sectional study which aimed to investigate comorbidity rate, degree of sleep-related breathing disorder, polysomnigraphically diagnosible rapid eye movement sleep behavior disorder/rapid eye movement sleep without atonia and periodic limb movements during sleep in Japanese drug-naïve patients with narcolepsy-spectrum disorders. A total of 158 consecutive drug naïve patients with narcolepsy with cataplexy, 295 patients with narcolepsy without cataplexy and 395 patients with idiopathic hypersomnia without long sleep time were enrolled. From retrospectively analyzed data of nocturnal polysomnography and multiple sleep latency test, higher rates of periodic limb movements during sleep (> = 15 h(-1)) (10.2%) and polysomnographically diagnosable rapid eye movement sleep behavior disorder (1.9%) were found in patients with narcolepsy with cataplexy. They had more severe periodic limb movements during sleep especially during rapid eye movement sleep and higher percentages of rapid eye movement sleep without atonia than the other two patient groups. In the present large sample study, Japanese drug naïve patients with narcolepsy with cataplexy showed the highest comorbidity rates of periodic limb movements during sleep, polysomnographically diagnosable rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia among those with the other narcolepsy-spectrum disorders; the rates were lower than those for Western patients.