| Parkinson’s disease (PD) is one common neurodegenerative movement disorder disease in the elderly. The most common symptoms include slowness of movement, tremor, muscle stiffness and postural instability and so on.With the progress of the clinical research, people gradually realize the Parkinson’s disease is not only a simple movement disorder, the non-motor symptoms are also very common. Such as sleep disorders (SD),cognitive impairment, autonomic dysfunction, sensory disturbances, mood disorders and so on. Recently, a multicenter survey in1,072consecutive patients with PD, found that98.6%of patients with PD reported the presence of non-motor symptoms. Sleep disorders,cognitive impairment and mood disorders are the most there non-moter symptoms affect quality of life. Like motor symptoms, these non-motor symptoms seriously affects patients’ quality of daily life, increase the burdens of the caregivers and the economic burden of the society, accelerate the progress of the disease, even be a risk factor of long-term death of the PD patients.Sleep disorders may be appeared in the early stage of PD. But most are associated with old age and often overlooked by patients, families and clinicians. Disturbances of sleep include insomnia, rapid eye movement (REM) sleep behavior disorder(RBD), excessive daytime sleepiness (EDS), sleep attacks, sleep apnea, restless legs syndrome, and parasomnias. Estimates of the prevalence of RBD in PD patients have ranged from60%to98%. RBD and EDS are preclinical performances developed into PD, or may be occur before motor symptoms of PD.Parkinson’s Disease Sleep Scale (PDSS) is a specific scale for the assessment of sleep disturbances in subjects with PD. PDSS-2is a new scale improved on the basis of PDSS, can be more simple and effective evaluate sleep problems of PD patients. Polysomnography (PSG) was created by Dement and Kleitmam in1957,which as a sleep research technology is widely used in clinical. It can also record electroencephalogram, electric eye chart, electromyography, electrocardiography, nose and mouth air, oxygen saturation, rhonchi and chest movement, leg movement, position and other physiological indexes of sleep. PSG not only reflects the objective records of patients’sleep efficiency, sleep structure and the characteristics of abnormal behavior, and some diseases cannot be accurate diagnosed through history, such as periodic leg, apnea syndrome diagnosis, RBD, etc. PSG, as a inspection tool of sleep, becoming indispensable inspection tool in sleep disorders, combining with sleep scales can better evaluate various sleep disorders.Braak and his colleagues thought that the pathological process of PD could be divided into6stages.The second stage of pathological changes mainly involved in the brain stem, affecting the ridge nucleus, locus coeruleus, pons and other areas, then patients exhibit sleep disorders, motor reduction, mood disorders. Through Braak stages, we recognize that some clinical features of non-moter symptoms may appear in the early stage of PD, such as sleep disorders, cognitive impairment, emotional disorders,and sleep disorders may occur before the cognitive impairment.Sleep disorders indicate that cognitive impairment, at the same time,sleep disorders can also be concomitant symptoms as cognitive impairment and aggravate the impairment of cognitive function.In most studies of PD,we may focus on only one non-motor symptom but pay less attention to their mutual relationship, such as in research of sleep disorders,we only pay attention to sleep problems while ignoring the cognitive function. At present, the causes of PD sleep disorder are not completely understood, there may be many factors involved, such as the age of the patients, the disease itself, night symptom fluctuation, complications of the disease and drug treatment. And the potential pathological pathogenesis of PD sleep disorders is also not clearly. Abnormal iron metabolism may cause excessive iron deposition in brain and be related to sleep disorders in PD patients through dual potential mechanisms, including neuroinflammation by activating microglia and neurotoxicity by targeting neurons. Neuroinflammatory factors may play an importent patterns of production in PD,which reasons remain unclear in PD sleep disorders.Tumor necrosis factor alpha (TNF-a) is a potent pro-inflammatory cytokine that plays an important role in immune-mediated inflammation in the brain. Previous studies have shown that the levels of TNFa, interleukin-1(IL-1) obviously changed in substantia nigra striatum of PD patients. Mogi and his coglleagues found that the concentration of TNF-a, transforming growth factor (TGF-a) and epidermal growth factor (EGF) were significantly higher in caudate nucleus, putamen than that cerebral cortex of patients with PD and corresponding location without neurological disease controls after repeated studies.It is confirmed that the degeneration of DA neurons in PD have cytokine changes.Many studies have found that the polymorphic variants of TNF-a gene may increase the risk of developing PD, for example rs1799964,rs1800629,rs11931074and rs3857059. Some studies found that plasma TNF-a content was related to a number of non-motor symptoms of PD,such as sleep disorders, cognitive impairment and depression. TNF-a is expressed rhythmicly involved in the regulation of sleep in normal brain tissue, and expressed of most in the deepest sleep. Moreover, TNF-a gene polymorphism is not only associated with PD, but also with PD sleep disorders.So, our work takes the PD patients with sleep disorders as the main research object.All the patients received comprehensive assessment,such as the assessment of sleep quality, including polysomnography, PDSS-2, Pittsburgh sleep quality index, Epworth sleepiness scale, the assessment of cognitive function, including MMSE, MoCA. Detection of the plasma levels of TNF-a of all the patients with Elisa method and TNF-α gene polymorphism with the ligase detection reaction (LDR) genotyping method. To provide biomarkers for early diagnosis and guidance for clinical intervention of PD and PD sleep disorders.This paper includes two parts:Ⅰ. Study of the objective and subjective sleep characteristics and cognitive function features of sleep disorders in PD. II.The plasma levels and polymorphisms gene analysis of TNF-a with sleep disorders in PD.Part Ⅰ:The objective and subjective sleep characteristics and cognitive function analysis of sleep disorders in Parkinson diseaseObjective:To explore the clinical,subjective and objective sleep features of sleep disorders in Parkinson disease.To study the characteristics of cognitive function in patients with sleep disorders and subtype in Parkinson disease.Methods:66PD cases and46primary sleep disorders cases and24normal controls were included for research.(1)The related clinical data,motor function, anxiety, depression and ability of daily life (ADL) assessments were collected in all subjects.(2)The subjective sleep survey:all subjects completed the PDSS-2, Pittsburgh sleep quality index (PSQI), the Epworth sleepiness scale (ESS) assessments.(3) The objective sleep monitoring:14hours of continuous PSG were monitored for all the groups of objects.(4) The assessment of cognitive function:all the subjects completed Mini Mental State Examination (MMSE), the Montreal cognitive assessment scale (MoCA) assessments. Analysis of the general clinical features, subjective and objective sleep characteristics and cognitive function of PD patients with sleep disorders.And then classify PD patients with sleep disorders, to explore the cognitive characteristics of each subtype.Results:1. A total of72.72%of subjects(48) were classified as sleep disorders in66patients with PD. The most common were as follows:insomnia(40.09%), RBD(31.81%) and no sleep disorders(NSD)(27.27%). PD-SD group had more severe ADL than the PD-NSD group.2. PD-SD group in PDSS-2-T, PDSS,2,3,6,15and PSQI-T, F1, F2score increased significantly than the PD-NSD group.3. PD insomnia group compared with PD patients with concomitant RBD, the total sleep time, sleep efficiency, sleep latency, N1, REM periods percentage, REM time have differences.4. There were significant differences in cognitive function in PD-SD group, PD-NSD group, the primary sleep disorders group and normal control group. PD-SD and primary sleep disorders group were lower than those of PD-NSD and normal control group in MMSE, MoCA and each component of MoCA. Cognitive function in PD-SD decreased more obviously than primary sleep disorders.5. In the subtype of PD-SD, RBD group was lower than that of insomnia group in MoCA, especially in the area of attention.Conclusions:1. PDSS-2is more suitable for PD sleep disorders than the PSQI. It can be preliminary understanding of the potential impact factors of sleep disorders;2. Sleep disorders may accelerate PD cognitive function;3. Different types of PD sleep disorders have different effect on cognitive function, PD with RBD have more effects on cognitive function than PD with insomnia. Parts II:The plasma levels and polymorphisms gene analysis of TNF-a with sleep disorders in Parkinson’s diseaseObjective:We aimed to determine plasma TNF-a levels of PD patients with sleep disorders and then analyze the relationship between plasma TNF-a levels and PD sleep disorders. To analyze the TNF-a gene polymorphisms and investigate the relationship between the TNF-a gene polymorphisms and PD and PD sleep disorders.Method:First,96PD patients and96normal controls were included and then the PD patients were divied into PD-SD group and PD-NSD group. Assessment of TNF-a was run in duplicate with an Elisa assay detection and comparison of plasma TNF-a levels in PD-SD group, PD-NSD and the control group, and also between PD-SD group and the PD-NSD group. Second,237PD patients and259normal controls were included. According to PSQI test, some PD patients were divided into PD-SD group and PD-NSD group. The genotype of the two SNPs (rs1799964and rs18006290) using Ligase detection reaction (LDR) sequencing classification, and a statistical analysis of the data was made. Genotype and allele frequencies were tested for significance using a95%two-sided χ2test between the groups.Results:1. There were significant differences in plasma TNF-a in PD-SD group, PD-NSD group and control group, and PD-SD are higher than PD-NSD group.2. The genotype frequencies were consistent with Hardy-Weinberg equilibrium distribution in PD and control groups.There were no significant differences in the genotypes (C/C,C/T,T/T) and alleles (C,T) frequencies of rs1799964and in the genotypes (A/A,A/G,G/G) and alleles (A,G) frequencies of rs1800629between PD and control group (P>0.05).3. PD-SD compared with PD-NSD group:Make comparisons of genotypes and alleles frequencies among the PD-SD and PD-NSD group, the results show that there was no significant difference in rs1799964and rs1800629.Conclusions: 1. The levels of plasma TNF-a was increased in PD patients and PD sleep disorders, TNF-a may play a role in the pathogenesis of PD and PD sleep disorders.2. The development of PD and PD sleep disorders are lack of associated with rs1799964and rs1800629polymorphisms of TNF-a in Chinese Han population. |
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