The Study In Non-motor Symptoms And Diffusion Tensor Imaging In Parkinson’s Disease With REM Sleep Behavior Disorder

Sleep disorders are common non-motor symptoms in PD patients, including insomnia, fractionated sleep, restless legs syndrome, rapid eye movement sleep behavioral disorder and so on. Sleep disorders have been reported to affected 65% to 98% of PD patients, and have a detrimental effect on health-related quality of life. Sleep disorders, especially rapid eye movement sleep behavioral disorder, could be early manifestations of Parkinson’s disease. Thus comprehensively assessing sleep disorders and explore their possible causes are imperative to make clinical decisions.Both rating scales and the polysomnography are commonly used methods to assess sleep disorders. The Pittsburgh Sleep Quality Index (PSQI) is a generic, classic questionnaire designed to evaluate mainly the quality of nocturnal sleep and to assess sleep habits and disturbances. The Parkinson’s disease sleep scale-2(PDSS-2) is a scale specific for sleep assessment in PD and help to define the nocturnal disturbance in PD patients. The Epworth Sleepiness Scale (ESS) is designed for evaluate the excessive daytime somnolence. The PSG is a newly developed method for objective sleep assessment, which could quantify specific sleep measures and be the golden standard for the diagnose of some sleep parasomnia, such as the obstructive sleep apnea and RBD. A combination of sleep scales and PSG would make a comprehensive and precise assessment of sleep disorders in Parkinson’s disease. While some polysomnographic studies of large sample PD patients have been reported abroad, in China, studies about PD sleep disorders were based on clinical scales only, or on polysomnography but within a relatively small sample. In the first part of the present study, we intended to combine three sleep scales and PSG, to evaluate both the subjective and objective sleep disorders and to explore the relationship between the sleep measures and the clinical characteristics.Rapid eye movement sleep behavioral disorder (RBD) is a rare sleep parasomnia characterized by abnormal vocalization and limb movements, as well as the absence of muscle atonia during the Rapid eye movement (REM) sleep stage in PSG recording.Lately, many studies have been focused on the relationship between RBD and Parkinson’s disease. RBD has once been classified as idiopathic and secondary. Now idiopathic RBD has been seen as a prodromal phase of neurodegenerative disease as evidences accumulate that most of the idiopathic RBD patients would develop into Parkinson’s disease, multiple system atrophy and lewy body dementia in years after the RBD onset. Thus the RBD patients could be the potential target of the future disease-modified medication development.On the other hand, the pathophysiology of RBD in PD and the relationship between them are still unveiled. About 15% to 58% PD patients develop RBD while others not. It has been reported that PD patients with and without RBD had different motor and non-motor symptoms, and that RBD in PD patients may be related to higher H-Y stages, non-tremor motor symptoms, more falls, hallucination, cognitive impairments and orthostatic hypotension. PD with and without RBD may result from different neurodegenerative patterns and belong to different clinical subtypes. More systemic investigations in the relationships between the PD with and without RBD and their motor and non-motor symptoms are in need.There have been only a small number of studies focusing on a comprehensive non-motor assessment in PD patients with and without RBD; and even fewer studies concerned about the subjective and objective sleep disorders between them. We hypothesized that PD patients with RBD would suffer more non-motor symptoms and more severe subjective and objective sleep disorders.The whole present study consists of three parts:1.The assessment of subjective and objective sleep disorders in PD patients based on sleep rating scales and polysomnography; 2.The investigation of non-motor symptom difference between PD patients with and without RBD, with a special focus on the subjective and objective sleep disorders.3.To compare the diffusion tensor imaging results between PD patients with and without RBD, and to clarify the microstructure damages in PD patients with RBD.Part I:The subjective and objective sleep disorders in patients with Parkinson’s diseaseObjective:Sleep disorders, the most commonly seen non-motor symptoms in Parkinson’s disease, consist of different types. This study aims to investigate the objective and subjective sleep disorders in patients with Parkinson’s disease.Method:A total of one hundred and forty two patients with Parkinson’s disease and thirty six age-and-sex matched healthy controls were enrolled in this study from March 2014 to January 2016. The demographic and clinical characteristics of PD patients and controls were collected, including the age, sex, disease duration, UPDRS-Ⅲ and MMSE scores.1. The assessment of subjective sleep disorders:the 22nd to the 26th item of the non-motor symptom questionnaire (NMSQuest) was used to screen for insomnia, excessive daytime sleepiness, rapid eye movement sleep behavior disorder(RBD) and restless leg syndrome (RLS) in PD patient. All of the patients and healthy controls completed the Pittsburgh sleep quality index (PSQI) and the Parkinson’s disease sleep scale-2 (PDSS-2) to evaluate the overall nocturnal sleep quality, and the Epworth sleepiness scale (ESS) to evaluate the severity of the excessive daytime sleepiness.2. The assessment of objective sleep disorders:a subgroup of PD patients, according to patients’own choices, as well as all the healthy controls, underwent the nocturnal in-hospital video-polysomnography recording, to evaluate objective sleep changes in PD patients.Results:1. The subjective sleep disorder assessment:(1) NMSQuest:of the total 142 PD patients,124(87.3%) patients had at least one sleep disorder, including insomnia (85 patients,59.5%), excessive daytime sleepiness, RLS, and RBD. (2)PSQI:the PSQI total scores were significantly higher in PD patients than healthy controls[7.00(7.00) vs 5.00(4.00), Z=-2.011,P=0.044].The component scores of sleep latency, sleep disturbances and use of sleeping medication was significantly higher in PD patients than in healthy controls. (3)PDSS-2:the PDSS-2 total scores were significantly higher in PD group than in healthy controls. Scores of each item of PDSS-2 were significantly higher in PD group than in healthy controls, except for the PDSS-2-8.(4)ESS:there was no significant difference in total scores of ESS between the PD group and healthy controls.(5) The total scores and some major component scores of PSQI and PDSS-2, were correlated with the age, disease duration, the HAMA and HAMD scores, and the severity of motor symptoms in PD patients.2. The objective sleep disorder assessment:a subgroup of 71(50.0%) PD patients and all the healthy controls underwent the nocturnal PSG recording. Compared to the control group, the PD patients showed significantly reduced total sleep time, reduced sleep efficiency, prolonged waking time, prolonged REM sleep latency and reduced REM sleep proportion. The sleep latency, the arousal times and the N1 to N3 sleep proportion showed no significant difference between the PD patients and the controls. In PD group, the sleep efficiency was significantly correlated with the UPDRS-Ⅲ scores and the HAMD scores. The proportion of REM sleep was correlated with the H-Y stage, the score of UPDRS-III, HAMA, and HAMD. There was significant difference in AHI between the PD patients and the healthy controls. The PD patients showed a trend of increased PLMS than the healthy controls, but the difference didn’t reach statistical significance.Conclusions:(1) Both subjective and objective sleep disorders are common in PD patients, including insomnia, RBD, RLS, and sleep architecture impairment. A combination of sleep scales and PSG would be of great importance in the comprehensive assessment of both subjective and objective sleep disorders in PD patients.(2) The objective sleep architecture impairment in PSG mainly consists of reduced total sleep time, reduced sleep efficiency and REM sleep proportion, while other PSG measures show no significant changes.(3) The subjective and objective sleep disorders are correlated with the severity of the depression, anxiety and motor symptoms.Part II:The non-motor symptoms and sleep disorders in Parkinson’s disease patients with rapid eye movement sleep behavioral disorderObjective:Rapid eye movement sleep behavioral disorder (RBD) has been gaining concerns in recent years due to its close relationship with Parkinson’s disease. Parkinson’s disease patients with and without RBD usually have different clinical manifestations and may belong to different subtypes of PD, but the non-motor symptoms, especially the sleep disorder difference between them have not been fully investigated. The present study aims to explore the difference of non-motor symptoms between PD patients with and without RBD, especially focusing on the subjective and objective sleep disorders.Methods:All PD patients participating in the first part of the whole study were enrolled.1. The non-motor symptoms assessment:The NMSQuest were used to screen for the thirty non-motor symptoms common in PD patients. All the participants were divided into two groups according to the 25th item answer of the NMSQuest:the PD patients with RBD if the answer was "yes"(the PDRBD+group), and the PD patients without RBD if the answer was "no" (the PDRBD-group). The HAMA and the HAMD were completed for the assessment of the depression and anxiety; the MMSE and MoCA were used for the assessment of cognition.2. The subjective and objective sleep disorder assessment:all the patients completed the PSQI and PDSS-2 for the assessment of overall subjective disorder, and also completed the ESS for the assessment of excessive daytime somnolence. According to patients’free choices, part of them underwent the nocturnal PSG recording to assess the objective sleep disorders. For patients who were divided into the PDRBD-group, if their PSG showed a definite diagnose of RBD, the patients were then re-divided into the PDRBD+group.Results:A total of 142 patients were enrolled in this study.60(42.3%) PD patients were classified into the PDRBD+group, and 82(57.7%) into the PDRBD-group. The patients in PDRBD+group were significantly older than patients in the PDRBD-group(63.55±9.21 vs 59.29+11.27, t=-2.385,P=0.018).There was no significant difference in the sex distribution, the age of disease onset and the disease duration between the two groups. After adjusting for age, there was no significant difference in the H-Y stage and UPDRS-III scores between the two groups.1. Non-motor symptoms:the NMSQuest indicated that apart from sleep disorders, the incidences of a variety of non-motor symptoms were increased in PD patients with RBD compared with PD patients without RBD, including hyposmia, constipation, nocturia, pain, weight loss, memory impairment, loss of interest, hallucinations, concentrating problems, depression, orthostatic dizzy and falls. The PDRBD+group showed significantly higher scores of HAMA and HAMD than the PDRBD-group. There were no statistical difference in the MMSE and MoCA total scores between the two groups, but as for the components of MoCA, patients in the PDRBD+group performed worse in the part of visuospatial function and executive function than the PDRBD-group.2. Subjective sleep disorder assessment:the NMSQuest indicated significantly increased incidence of insomnia, nightmare and RLS in the PDRBD+group. As for the PSQI, the PDRBD+group attained higher PSQI total score than the PDRBD-group(9.53±4.89 vs 7.00±4.64, P=0.002); The component scores of sleep time, sleep efficiency and sleep disturbance were also higher in the PDRBD+group than in the PDRBD-group(P<0.05). The PDRBD+group showed higher PDSS-2 total scores than the PD RBD-group (19.67±11.70 vs 14.99±11.44, P=0.018).The scores of the item 1,6,7,8,9,15 of the PDSS-2 were higher in the PDRBD+group than in the PDRBD-group (P<0.05). There was no significant difference in the ESS total scores between the two groups(5.00±4.41 vs 4.57±4.28, P=0.563).3. Objective sleep disorder assessment:a total of 71 PD patients completed the nocturnal PSG recording, including 36 PD patients with RBD (the PDRBD+group) and 35 PD patients without RBD (the PDRBD-group). We found no statistical difference in the total sleep time, sleep efficiency, the proportion of REM and NREM sleep stages, or other sleep architecture measures between the PD patients with and without RBD. There was no statistical difference in the AHI and PLMS index between the two groups.Conclusions:RBD in PD patients is related to an increasing incidence of a variety of non-motor symptoms. The subjective sleep disorders were worse in PD patients with RBD than PD patients without RBD. The RBD symptom in PD patients may not have an impact on the excessive daytime somnolence, the objective sleep architecture, the sleep apnea and PLMS.PartⅢ:The diffusion tensor imaging study of Parkinson’s disease with rapid eye movement sleep behavioral disorderObjective:Parkinson’s disease patients with and without RBD usually have different clinical manifestations and may belong to different subtypes of PD. PD patients with RBD tend to suffer from more severe motor and non-motor symptoms than those without RBD, which indicates more extensive and profound brain pathological changes in this kind of patients. The present study aims to compare diffusion tensor imaging results between PD patients with and without RBD, and try to explore the microstructure damages in PD patients with RBD.Methods:A total of 64 PD patients were enrolled. They underwent a set of assessments as follow:1. The demographic and clinical characteristics:the age, sex, education degree and the UPDRS-III score, modified H-Y stage, MMSE and MoCA scores;2. The polysomnography:according to patients’free choices, part of them underwent the nocturnal PSG recording.3. Diffusion tensor imaging:all the patients underwent a DTI scan, and global FA and ADC values were compared between the PDRBD+group and PDRBD-group by voxel based analysis (VBA).Results:Of all the PD patients,27(42.2%) were classified into the PDRBD+ group, and 37 (57.8%) into the PDRBD-group. There was no significant difference in age, sex distribution, the disease duration between the two groups, neither in the UPDRS-Ⅲ score, modified H-Y scale, MMSE score or MoCA score. Without the FDR correction, the PDRBD+group showed significantly decreased FA value in some brain clusters compared with the PDRBD-group, including the right Middle Temporal Gyrus, the right Inferior Temporal Gyrus, the left Middle Temporal Gyrus, the right Middle Frontal Gyrus, the right orbitalfrotal cortex and the left orbitalfrotal cortex(P<0.0005,uncorrected). The PDRBD+group also showed significantly increased ADC value in some brain clusters compared with the PDRBD-group, including the left Middle and inferior Temporal Gyrus, the right Middle and inferior Temporal Gyrus, and the left midbrain and Substania Nigra. No brain cluster showed significantly increased FA value or decreased ADC value in PDRBD+group compared with PDRBD-group.Conclusions:PD patients with RBD showed a widespread brain areas with abnormal diffusity, indicating more severe and extensive microstructure damages compared with PD patients without RBD.