Treatment of isolated REM sleep behavior disorder using melatonin as a chronobiotic

Melatonin is recommended as a first-line treatment in isolated REM sleep behavior disorder (iRBD), although no large patient group has been reported. To assess effects, time course and confounding factors in the treatment of patients with iRBD using melatonin, 209 consecutive patients were included in this single-center, observational cohort study. A total of 171 patients had taken melatonin according to our chronobiotic protocol (2 mg, >= 6 months, always-at-the-same-clock time, 10-11pm, corrected for chronotype), 13 had applied melatonin for about 1-3 months, and 25 underwent mixed treatments. In total, 1529 clinical evaluations were performed, including Clinical Global Impression (CGI) and a newly developed RBD symptom severity scale (Ikelos-RS), analyzed using linear mixed models. Validation of Ikelos-RS showed excellent inter-rater reliability (rho = 0.9, P < .001), test-retest reliability (rho = 0.9, P < .001) and convergent validity (rho = 0.9, P < .001). With melatonin, RBD symptom severity gradually improved over the first 4 weeks of treatment (Ikelos-RS: 6.1 vs. 2.5; CGI Severity: 5.7 vs. 3.2) and remained stably improved (mean follow-up 4.2 +/- 3.1years; range: 0.6-21.7years). Initial response was slowed to up to 3 months with melatonin-suppressing (betablockers) or REM sleep spoiling co-medication (antidepressants) and failed with inadequately timed melatonin intake. When melatonin was discontinued after 6 months, symptoms remained stably improved (mean follow-up after discontinuation of 4.9 +/- 2.5years; range: 0.6-9.2). When administered only 1-3 months, RBD symptoms gradually returned. Without any melatonin, RBD symptoms persisted and did not wear off over time. Clock-timed, low-dose, long-term melatonin treatment in patients with iRBD appears to be associated with the improvement of symptoms. The outlasting improvement over years questions a pure symptomatic effect. Clock-time dependency challenges existing prescription guidelines for melatonin

Sleep stability in isolated rapid eye movement sleep behavior disorder, Parkinson's disease, and dementia with Lewy bodies

Publisher Copyright: © 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.Background: Non-REM sleep symptoms remain poorly understood in alpha-synucleinopathies. Aims: The aims of the study were to compare sleep stability and transitions, arousals, and sleep cycle structure between isolated rapid eye movement (REM) sleep behavior disorder (iRBD), Parkinson’s disease (PD), and dementia with Lewy Bodies (DLB). Materials and Methods: Sleep transition and stability measures were assessed in one-night video-polysomnography records. Transition measures were the number of shifts between Wake and REM, Wake and NREM, and REM and NREM. Stability measures were the number of passages within the same sleep stage. We assessed arousals, the number/duration of sleep cycles (defined as a sequence of any NREM stage to REM), and the duration of N3 and REM sleep in each cycle. These variables were compared between two sets of groups (PD vs. DLB vs. iRBD and RDB+ vs. RBD−). Results: We assessed 54 PD, 24 DLB, and 21 iRBD patients (54 RBD+, 22 RBD−). There were no significant differences regarding sleep stability measures. Arousal indices in N1 and N2 stages were significantly higher in PD compared with iRBD. 24% of the sample did not have any sleep cycle. PD had significantly fewer cycles than iRBD. Differences became non-significant when adjusting for medication. There was no effect of group or time of night in REM or N3 duration. There were no significant differences between RBD+ and RBD−. Discussion: There were no significant differences in stability/transition measures. Arousals and disturbance in sleep cycling were higher in PD, but the difference was no longer significant after adjusting for medication. Conclusion: Different alpha-synucleinopathies have a similar degree of non-REM sleep instability, but medication could worsen symptoms in PD.publishersversionpublishe

Comparing the accuracy and neuroanatomical correlates of the UPSIT-40 and the Sniffin' Sticks test in REM sleep behavior disorder

Background: Olfactory impairment increases the risk of developing neurodegenerative diseases in patients with idiopathic REM sleep behavior disorder (IRBD). Knowing the test properties of distinct olfactory measures could contribute to their selection for clinical or research purposes. Objective: To compare the accuracy in distinguishing IRBD patients from controls with the University of Pennsylvania Smell Identification Test (UPSIT-40) and Sniffin' Sticks Extended test, and to assess the gray-matter volume correlates of these tests. Method: Twenty-one patients with IRBD and 27 healthy controls were assessed using both olfactory tests. Independent logistic regressions were computed with diagnosis as a dependent variable and olfactory measures as predictive variables. Receiver operating characteristic curves were computed for each olfactory subtest. Diagnostic accuracy for IRBD was calculated according to the resulting optimal cut-off score. Structural MRI data, acquired with a 3T scanner, were analyzed with voxel-based morphometry. Results: Patients differed from controls in all olfactory measures. The Sniffin-Identification correctly classified 89.1% of cases; the UPSIT-40, 85.4%; the Sniffin-Discrimination, 82.6%; the Sniffin-Total, 81.8%; and the Sniffin-Threshold, 77.3%. Respective AUROC, optimal cut-off, sensitivity, and specificity for each test were: 0.902, ≤26, 85.7%, and 85.2% for the UPSIT-40; 0.884, ≤29, 89.5%, and 76.0% for the Sniffin-Total; 0.922, ≤11, 90.5%, and 88.0% for the Sniffin-Identification; 0.739, ≤4, 73.7%, and 76.0% for the Sniffin-Threshold; and 0.838, ≤11, 85.7%, and 76.0% for the Sniffin-Discrimination. UPSIT-40 scores correlated with gray-matter volumes in orbitofrontal regions in anosmic patients. Conclusions: UPSIT-40 and Sniffin' Identification showed similar discrimination accuracy, but only the UPSIT-40 showed structural correlates (p ≤ .05 FDR-corrected)

Psychiatric symptoms in idiopathic rapid-eye-movement sleep behaviour disorder

Le trouble comportemental en sommeil paradoxal (TCSP) idiopathique est caractérisé par une activité motrice indésirable et souvent violente au cours du sommeil paradoxal. Le TCSP idiopathique est considéré comme un facteur de risque de certaines maladies neurodégénératives, particulièrement la maladie de Parkinson (MP) et la démence à corps de Lewy (DCL). La dépression et les troubles anxieux sont fréquents dans la MP et la DCL. L’objectif de cette étude est d’évaluer la sévérité des symptômes dépressifs et anxieux dans le TCSP idiopathique. Cinquante-cinq patients avec un TCSP idiopathique sans démence ni maladie neurologique et 63 sujets contrôles ont complété la seconde édition du Beck Depression Inventory (BDI-II) et le Beck Anxiety Inventory (BAI). Nous avons aussi utilisé le BDI for Primary Care (BDI-PC) afin de minimiser la contribution des facteurs confondant dans les symptômes dépressifs. Les patients avec un TCSP idiopathique ont obtenu des scores plus élevés que les sujets contrôles au BDI-II (9.63 ± 6.61 vs. 4.32 ± 4.58; P < 0.001), au BDI-PC (2.20 ± 2.29 vs. 0.98 ± 1.53; P = 0.001) et au BAI (8.37 ± 7.30 vs. 3.92 ± 5.26; P < 0.001). Nous avons également trouvé une proportion plus élevée des sujets ayant des symptômes dépressifs (4/63 ou 6% vs. 12/55 ou 22%; P = 0.03) ou anxieux (9/50 or 18% vs. 21/43 ou 49%; P = 0.003) cliniquement significatifs. La proportion des sujets ayant des symptômes dépressifs cliniquement significatifs ne change pas en utilisant le BDI-PC (11/55 or 20%) Les symptômes dépressifs et anxieux sont fréquents dans le TCSP idiopathique. L’examen de routine des patients avec un TCSP idiopathique devrait inclure un dépistage systématique des symptômes dépressifs et anxieux afin de les prévenir ou les traiter.Idiopathic rapid-eye-movement sleep behaviour (iRBD) disorder can be a premotor feature of Parkinson’s disease (PD) or dementia with Lewy bodies (DLB). Depressive and anxiety symptoms are frequent nonmotor features in PD or DLB. We assessed the frequency and severity of depressive and anxiety symptoms in patients with iRBD compared to healthy control subjects. Fifty-five iRBD patients and 63 age and sexmatched healthy subjects were studied. Participants completed the Beck Depression Inventory – Second Edition (BDI-II) and Beck Anxiety Inventory (BAI). We assessed the depressive and anxiety symptoms and compared the proportion of participants with clinically significant depressive or anxiety symptoms. We also used the BDI for Primary Care (BDI-PC) to minimize confounding factors that could overestimate depressive symptoms. iRBD patients scored higher than controls on the BDI-II (9.63 ± 6.61 vs. 4.32 ± 4.58; P < 0.001)), BDI-PC (2.20 ± 2.29 vs. 0.98 ± 1.53; P = 0.001) and BAI (8.37 ± 7.30 vs. 3.92 ± 5.26; P < 0.001). Compared to controls, we found a higher proportion of patients with iRBD with either clinically significant depressive (4/63 or 6% vs. 12/55 or 22% P = 0.03) or anxiety symptoms (9/50 or 18% vs. 21/43 or 49%; P = 0.003). The proportion of iRBD patients with clinically significant depressive symptoms remains unchanged using the BDI-PC (11/55 or 20%). Depressive and anxiety symptoms are frequent features in iRBD. Routine examination of patients with iRBD disorder should include an assessment of depressive and anxiety symptoms in order to prevent or treat them

Isolated rapid eye movement sleep behaviour disorder (iRBD) in the Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study: protocol and baseline characteristics

Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is a sleep disorder that is characterised by dream enactment episodes during REM sleep. It is the strongest known predictor of α-synuclein-related neurodegenerative disease (αNDD), such that >80% of people with iRBD will eventually develop Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy in later life. More research is needed to understand the trajectory of phenoconversion to each αNDD. Only five 'gold standard' prevalence studies of iRBD in older adults have been undertaken previously, with estimates ranging from 0.74% to 2.01%. The diagnostic recommendations for video-polysomnography (vPSG) to confirm iRBD makes prevalence studies challenging, as vPSG is often unavailable to large cohorts. In Australia, there have been no iRBD prevalence studies, and little is known about the cognitive and motor profiles of Australian people with iRBD. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study will investigate the prevalence of iRBD in Tasmania, an island state of Australia, using validated questionnaires and home-based vPSG. It will also explore several cognitive, motor, olfactory, autonomic, visual, tactile, and sleep profiles in people with iRBD to better understand which characteristics influence the progression of iRBD to αNDD. This paper details the ISLAND Sleep Study protocol and presents preliminary baseline results

Making it count : novel behavioural tasks to quantify symptoms of dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is a neurodegenerative disease and a common cause of dementia in the elderly. The primary pathology of DLB is the mis-folding of the α-synuclein protein, classifying DLB as a synucleinopathy. However, concomitant pathologies are commonly found in post-mortem examination of DLB patients that may complicate diagnosis. Furthermore, DLB is a relatively new disease, first discovered in 1976, while the first official diagnostic criteria released in 1996. Consequently, the diagnostic criteria for DLB have evolved as more is learnt about the clinical and neuropathological profile. Synucleinopathies are also known to be heterogeneous, with no single symptom or biomarker present in all DLB cases. Instead, combinations of common symptoms lead to a diagnosis of probable DLB. Two of the most prominent and debilitating symptoms of DLB are visual hallucinations and cognitive fluctuations. Visual hallucinations (VH) in DLB patients are typically vivid, well-formed percepts and are a major cause of patient and caregiver stress as well as a risk factor for the patient being placed into professional care. Cognitive fluctuations (CF) involve a cycling change in attention and alertness and may occur on a daily or monthly basis, while drops in awareness may last seconds or hours. Currently, the only tools to measure cognitive fluctuations or visual hallucinations are scales or questionnaires that rely on responses from the patient or informant. Furthermore, severity of the symptom is then ranked on an arbitrary ranking system. While this method has advantages in a clinical setting, the subjective nature of the scales combined with the ranking of scores results in a loss of sensitivity. In a research setting, especially imaging or clinical trials, objective measures that are sensitive to changes in symptom severity are highly valued. This allows researchers to assess the relationship between behavioural and fMRI data and clinicians to observe subtle changes in severity. Furthermore, the measures need to be easy to conduct as patients are often severely impaired. The aim of this thesis is to test cognitive function using three paradigms that are novel to DLB patients: Sustained Attention Response Task (SART), the Mental Rotation (MR) task and the Bistable Percept Paradigm (BPP). Overall, this thesis provided the groundwork needed before these three tasks can be utilised in a clinical or research setting. Moreover, as each task was accessible to DLB patients and provided a measure associated with VH or CF, they may prove useful for future neuroimaging/neuropsychological studies

Marqueurs électroencéphalographiques du développement d’une maladie neurodégénérative dans le trouble comportemental en sommeil paradoxal

Le trouble comportemental en sommeil paradoxal (TCSP) est une parasomnie se caractérisant par la perte de l’atonie musculaire, la paralysie qui accompagne généralement le sommeil paradoxal, suivie de l’apparition de comportements indésirables et souvent violents. Des études suggèrent que le TCSP idiopathique (TCSPi) est fortement lié au développement ultérieur de la maladie de Parkinson, de la démence à corps de Lewy et de l’atrophie multisystémique. En effet, des signes subtils de neurodégénérescence sont observés chez ces patients, notamment un ralentissement de l’activité électrique cérébrale (EEG) à l’éveil et la présence de troubles cognitifs. Le but de cette thèse est 1) d’évaluer sur le plan transversal la contribution du trouble cognitif léger (TCL) dans le ralentissement de l’EEG à l’éveil observé chez ces patients et 2) d’évaluer la valeur prédictive des mesures de l’EEG à l’éveil mesurées au temps de base par rapport au développement d’une maladie neurodégénérative (MND) lors du suivi longitudinal. Dans le cadre de la première étude, l’EEG à l’éveil d’un groupe de patients avec un TCSPi présentant des atteintes cognitives a été comparé à celui d’un groupe de patients sans troubles cognitifs et à des sujets témoins sains. Seuls les patients avec un TCL affichaient un ralentissement de l’EEG d’éveil plus prononcé au niveau postérieur, c’est-à-dire une puissance relative thêta plus élevée dans les régions pariétale, temporale et occipitale, une puissance relative alpha plus faible dans les régions occipitale et temporale, en plus d’un ratio spectral (ondes lentes sur ondes rapides) plus élevé dans ces régions en comparaison avec les deux autres groupes. De plus, le ratio spectral corrélait négativement avec les fonctions attentionnelles/exécutives, visuospatiales et la mémoire épisodique verbale. La deuxième étude a quant à elle évalué l’EEG à l’éveil au temps initial de patients qui ont développé une MND sur une période de 3,5 ans en comparaison à celui de patients qui sont demeurés idiopathiques et à un groupe de témoins sains. Les patients avec un TCSPi qui ont évolué vers une MND présentaient une augmentation de la puissance de l’activité absolue delta et thêta, en plus d’un ratio spectral plus élevé dans les cinq régions corticales en comparaison avec les deux autres groupes. Cette thèse suggère ainsi que le ralentissement de l’EEG à l’éveil dans le TCSPi est relié à la présence d’un TCL concomitant. De plus, ces anomalies sont associées à un plus grand risque de développer une maladie de Parkinson, une démence à corps de Lewy ou une atrophie multisystémique à court terme chez ces patients. Le ralentissement de l’EEG à l’éveil semble donc être un marqueur prometteur d’une neurodégénérescence cérébrale plus sévère chez les patients souffrant d’un TCSPi.Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the loss of normal muscle atonia during REM sleep leading to undesirable and often violent behaviors associated with dream mentation. Idiopathic RBD (iRBD) patients are particularly at risk of developing a synucleinopathy such as dementia with Lewy bodies, Parkinson’s disease or multiple system atrophy. Indeed, subtle signs of neurodegeneration are seen in these patients including a slowing of brain electrical activity (EEG) during wakefulness and the presence of cognitive impairment. The purpose of this thesis is 1) to investigate waking EEG abnormalities specific to RBD patients with mild cognitive impairment (MCI) and 2) to assess the usefulness of baseline EEG spectral analysis performed during wakefulness for predicting the development of a neurodegenerative disease. The first study compared a group of iRBD patients with MCI to cognitively intact patients and a group of healthy control. Only those with concomitant MCI showed waking EEG slowing in the posterior cortical regions, namely higher relative theta power in the parietal, temporal, and occipital regions, lower relative alpha power in the occipital region, and higher slow-to-fast frequency ratio compared to patients without MCI and controls. Moreover, the spectral ratio negatively correlated with attentional/executive function, visuospatial abilities and verbal episodic memory. The second study compared baseline waking EEG of iRBD patients who developed disease on a mean longitudinal follow-up of 3,5 years with patients who remained disease-free and controls. iRBD patients who developed disease showed higher absolute delta and theta power and higher slow-to-fast power ratio in all five cortical regions compared to disease-free patients and controls. This thesis identified specific EEG abnormalities during wakefulness in iRBD patients with MCI. Moreover, these anomalies are associated with greater short-term risk of developing parkinson’s disease, dementia with Lewy bodies or multiple system atrophy. Therefore, EEG slowing seems to be a promising marker of neurodegeneration in iRBD patients

Diagnosis and Treatment of Parkinson's Disease

Parkinson's disease is diagnosed by history and physical examination and there are no laboratory investigations available to aid the diagnosis of Parkinson's disease. Confirmation of diagnosis of Parkinson's disease thus remains a difficulty. This book brings forth an update of most recent developments made in terms of biomarkers and various imaging techniques with potential use for diagnosing Parkinson's disease. A detailed discussion about the differential diagnosis of Parkinson's disease also follows as Parkinson's disease may be difficult to differentiate from other mimicking conditions at times. As Parkinson's disease affects many systems of human body, a multimodality treatment of this condition is necessary to improve the quality of life of patients. This book provides detailed information on the currently available variety of treatments for Parkinson's disease including pharmacotherapy, physical therapy and surgical treatments of Parkinson's disease. Postoperative care of patients of Parkinson's disease has also been discussed in an organized manner in this text. Clinicians dealing with day to day problems caused by Parkinson's disease as well as other healthcare workers can use beneficial treatment outlines provided in this book

Autonomic Nervous System and Rem Behavior Sleep Disorder: a new tool to identify Idiopathic or Parkinsonians patients through Heart Rate Variability Polysomnography Analysis

Objective: RBD is a sleep disorder known to be associated in a very high percentage of cases with alfa-synucleopathies. During rapid eye movement (REM) sleep, the cardiovascular system is unstable and greatly influenced by sympathetic activity. Heart Rate Variability (HRV) indirectly tests functions and activities of the ANS during sleep. We evaluate whether HRV and Hypnogram Indices are polysomnographic valid biomarkers to distinguish subjects with idiopathic RBD from those with Parkinson's Disease. METHODS: Our study examines HRV linear and non-linear indices of 37 patients aged 53 years and older (median 72.7; mean 72.3 ± 7.4; range 53-84), 7 women (18.9%) and 30 men (81.1%). 22 pts were idiopathic REM sleep behavior disorder (59.5%; age: median 72.5; mean 74.5 ± 5.2; range 68 83), of which 3 women (13.6%) and 19 men (86.4%); 15 pts had REM Sleep Behavior Disorder secondary to Parkinson's disease (40.5%; a ge: median 73; mean 69.5 ± 9 ; range 53 84), including 4 women (26.7%) and 11 men (73.3%). A parallel Analysis was made on Hypnogram Parameters. RESULTS: The REM sleep phase allowed to record the greatest number of significant differences in HRV Index between the two groups of patients. Among the Frequency HRV Linear Indices, VLF signal band recorded the highest number of significant results suggesting that the sympathetic component may be the one most compromised in the autonomic neurodegeneration process of RBD. HRV Complexity Non-Linear Indices (LZC and KC) have the highest number of statistically significant results so that could be the right parameter to use to distinguish our two RBD populations. Hypnogram Indices Analysis showed no significant value for not even a parameter. CONCLUSIONS: HRV can be a valid biomarker to distinguish the two populations of patients affected by RBD, both idiopathic and affected by Parkinson's disease. It could represent a new and easy tool to identify, among the REM Behavior Sleep Disorder, patients affected or not by Parkinson’s desease or could be even useful when an early diagnosis is needed or it is necessary monitoring a probable conversion from idiopathic form to PD or evaluate the effectiveness of RBD therapies