帕金森病伴睡眠障碍的认知功能特征及与肿瘤坏死因子（TNF-α）关联性的研究
发布时间：2018-08-04 14:30
【摘要】：帕金森病(Parkinson disease, PD)是中老年人常见的神经系统变性疾病。主要临床表现包括运动迟缓,静止性震颤,肌强直和姿势步态障碍等。 随着临床研究的进展,人们逐渐认识到PD不仅仅以运动症状为主要临床表现,其非运动症状也很突出,包括睡眠障碍(Sleep disorders, SD)、认知功能损害、精神障碍、自主神经功能紊乱和感觉障碍等。近来一项对1072例PD患者进行的调查研究显示：几乎所有的患者均出现了至少一种非运动症状,其中睡眠障碍、认知功能损害和精神障碍是PD患者生活质量下降的三大主要非运动症状。同运动症状一样,这些非运动症状严重影响患者日常生活质量,增加家庭和社会的经济负担,加速疾病的进展,甚至是患者远期死亡的危险因素。 睡眠障碍可能在PD早期就会出现,但多数被认为与年老有关,在临床工作中常被患者、家属及临床医师忽视。PD伴发的睡眠障碍(Parkinson disease with sleep disorders, PD-SD)主要包括：失眠、快速动眼睡眠行为障碍(Rapid eye movement sleep behavior disorder, RBD)、日间过度思睡(Excessive daytime sleepiness, EDS)、睡眠发作、睡眠呼吸暂停综合征、不宁腿综合征、其他异态睡眠等。据报道,60%-98%的PD患者可能出现RBD。有研究观点认为,RBD和EDS是发展成PD的临床前期表现,或者可能是出现在PD运动症状之前的早期非运动症状。 帕金森病睡眠量表(Parkinson's Disease Sleep Scale,PDSS)是一个专门用于评估PD常见睡眠问题的量表,PDSS-2是在PDSS的基础上改良的新量表,能更简单有效的评估PD患者睡眠中出现的问题。多导睡眠监测(Polysomnography,PSG)是1957年Dement和Kleitmam创建的睡眠研究技术,广泛应用于临床。经过不断地发展,能同时记录脑电图、眼电图、心电图、肌电图、口鼻气流、血氧饱和度、鼾音、胸腹运动、腿动、体位等多项睡眠生理指标。PSG不仅能客观记录反映受试者的睡眠效率、睡眠结构以及睡眠中的异常行为等特点,还可以对一些通过病史无法准确诊断的情况,如RBD、周期性腿动、呼吸暂停综合征等进行确诊。PSG作为一种睡眠检查手段,日益受到国内外重视,成为睡眠障碍患者必不可少的检查手段,配合量表可以更好的评估各种睡眠障碍。 德国Braak认为PD的病理进程可先后分为6期,其中2期的病理改变以下位脑干为主,影响脊核、蓝斑、脑桥其他核团,继而产生睡眠障碍、运动减少和情感问题等；6期的病理改变主要与累及新皮质有关,临床表现为认知功能损害、视幻觉等精神症状。Braak分期使人们认识到PD早期可能出现一些如睡眠障碍、嗅觉障碍、情感障碍等非特异的临床特征,并且睡眠障碍可能出现在认知功能损害之前。 睡眠障碍预示着老年认知功能损害,睡眠障碍也可以作为认知功能损害的一个伴发症状表现出来,同时睡眠质量下降进一步加重认知功能损害。大多数PD的研究中,只是孤立的研究某种临床症状,很少将不同的临床症状联合起来研究,研究这些不同症状之间相互影响的关系,如在PD伴睡眠障碍的研究中仅注意睡眠问题而忽略了认知功能的改变,同样在认知功能的研究中也可能忽略了睡眠问题。为此我们对PD患者进行PSG监测,分析PD伴睡眠障碍患者的-般临床特征,主客观睡眠特点及认知功能特征,以期发现PD患者的睡眠障碍与认知功能之间可能存在的关系。 目前引起PD伴睡眠障碍的原因尚不完全清楚,可能有多种因素参与,如患者的年龄、疾病本身、夜间症状波动、疾病的并发症以及药物治疗等等。而目前关于PD伴睡眠障碍潜在病理发病机制更不清楚,且国内外在该方面的研究也甚少。国外有研究发现,PD伴睡眠障碍与体内铁代谢异常导致黑质过多的铁沉积有关。黑质中过量的铁沉积通过神经炎症机制诱导多巴胺能神经元变性。大量研究已证明,神经炎症机制在PD的发病中起着重要作用,但其在PD伴睡眠障碍发病机制中的作用尚不清楚。 肿瘤坏死因子(TNF)是巨噬细胞产生的促炎性细胞因子,是目前公认的对神经元有损伤作用的细胞因子之一。并有研究发现,PD黑质纹状体区发生明显改变的细胞因子主要有TNF-α、白细胞介素1(IL-1)等。Mogi等经过多次研究发现,PD患者尾状核、壳核处的TNF-α、转化生长因子(TGF-a)、上皮生长因子(EGF)等浓度明显高于患者大脑皮质区及正常对照组的相应部位,证实PD患者多巴胺能神经元的变性过程的确伴有细胞因子的改变。 有研究从遗传学角度分析PD发病过程中TNF-α及其浓度的改变,发现TNF-a基因多态性与散发性PD的易感性相关,如rs1799964、rs1800629、rs11931074、rs3857059等位点。研究发现,血浆TNF-a的含量与PD睡眠障碍、认知功能损害和抑郁障碍等多项非运动症状有关。TNF-α在正常脑组织中呈节律性表达,参与了睡眠生理调节作用,且睡眠最深时表达最高,但当TNF-α表达过量时则抑制正常睡眠。所以,TNF-α基因不仅与PD的易感性有关,也可能和PD睡眠障碍存在某些联系。 本研究以PD伴睡眠障碍患者为主要研究对象,全面评估患者睡眠质量,包括PDSS-2,匹兹堡睡眠质量指数量表(PSQI)、爱波沃斯嗜睡量表(ESS), PSG监测；认知功能评估,包括简易精神状态量表(MMSE)、蒙特利尔认知评估量表(MoCA);并应用ELISA法检测血浆TNF-α水平,采用连接酶检测反应(LDR)分型方法检测TNF-α基因位点多态性,为PD及PD睡眠障碍的早期诊断提供生化标记物,为临床干预提供指导。 本研究包括以下主要内容：1.帕金森病伴睡眠障碍的主客观睡眠及认知功能特征；2.帕金森病伴睡眠障碍与TNF-α血浆水平和基因多态性的关联性研究。 第一章帕金森病伴睡眠障碍的主客观睡眠及认知功能特征 目的：探索帕金森病伴睡眠障碍的临床特征、主客观睡眠特点；研究帕金森病伴睡眠障碍及睡眠障碍各亚组的认知功能特征。 方法：以66例PD患者、46例原发性睡眠障碍患者及24例正常对照作为研究对象。(1)收集所有受试者相关的临床资料,行运动功能、焦虑抑郁、日常生活能力(ADL)的评估。(2)主观睡眠调查：所有受试者均完成PDSS-2, PSQI, ESS的评估。(3)客观睡眠监测：对所有入组对象进行连续14小时的PSG监测。(4)认知功能评估：对受试者行MMSE、MoCA评估。对PD伴睡眠障碍患者的一般临床特征、主观客观睡眠特点及认知功能特征进行分析,再对PD伴睡眠障碍患者进行亚组分型,探讨各亚组的认知功能特点。 结果： ①66例PD患者中,睡眠障碍患者48例,占72.72%,其中失眠患者27例,占40.09%,RBD患者21例,占31.81%,睡眠正常(No sleep disorders, NSD)患者18例,占27.27%。与PD-NSD组相比,PD-SD在ADL方面更差。 ②PD-SD组在PDSS-2-T, PDSS-2-1,2,3,6,15和PSQI-T, F1, F2的评分较PD-NSD组显著增高。PD-SD组与原发性睡眠障碍组相比,在PDSS-2-T; PDSS-2-4,5,7,9,10,11,12,13,14,15, F5方面评分均增加,而在PSQI-T,F1,F3,F4方面评分则降低(P0.05)。 ③PD伴失眠与PD伴RBD的PSG监测相比,总睡眠时间,睡眠效率,睡眠潜伏期,N1、N2、REM各期所占百分比,REM时间方面均有差异(P0.05)。 ④PD-SD组、PD-NSD组、原发性睡眠障碍组及正常对照组四组的认知功能存在显著差异；MMSE、MoCA及MoCA各分项中,PD-SD组及原发性睡眠障碍组较PD-NSD及正常对照组得分低,且PD-SD患者的认知功能比原发性睡眠障碍患者的下降更明显(P0.05)。 ⑤PD-SD的亚组分型中,PD伴RBD组的MoCA评分及MoCA分项中的注意力评分均低于PD伴失眠组(P0.05)。 结论： (1) PDSS-2较PSQI更适合PD睡眠障碍的评估,能初步了解PD伴睡眠碍的潜在影响因素； (2)PD伴睡眠障碍可能加重认知功能障碍； (3)PD伴发不同类型的睡眠障碍对认知功能的影响不同,PD伴RBD的认知功能较PD伴失眠的更差。 第二章帕金森病伴睡眠障碍与TNF-a血浆水平和基因多态性关联性的研究 目的：对PD伴睡眠障碍患者的血浆TNF-a水平进行检测,探讨血浆TNF-α水平与PD伴睡眠障碍的关系；对中国汉族PD患者进行TNF-a基因的多态性分析,探讨TNF-α基因多态性与PD伴睡眠障碍的相关性。 方法：以96例PD患者和96例正常对照为研究对象,再将PD组分为PD-SD组和PD-NSD组；采用ELISA法检测血浆TNF-α水平,比较PD-SD组、PD-NSD组和对照组血浆TNF-a浓度；再以237例PD患者和259例正常对照为研究对象,对PD组进行睡眠评估,按照PSQI评估将PD患者分为PD-SD组与PD-NSD组,应用连接酶检测反应(LDR)分型方法测序,对PD与对照人群及PD-SD与PD-NSD的TNF-a基因的2个SNP位点(rsl799964、rs1800629)进行基因型分析。比较各组基因型和等位基因的总体分布频率。率的比较用X2检验,P0.05差异有统计学意义。 结果： ①PD-SD组、PD-NSD组与对照组三组间血浆TNF-α浓度存在显著差异,且PD-SD组较PD-NSD组血浆TNF-α水平明显增加(P0.05)。 ②经检验,PD组和对照组各位点基因型分布符合Hardy-Weinberg平衡。两组rs1799964位点基因型(C/C、C/T、T/T)和rs1800629位点基因型(A/A、A/G、G/G)的总体分布频率及等位基因(T、C)(A、G)总体分布频率差异无统计学意义(P0.05)。 ③将PD组分为PD-SD组和PD-NSD组,对两组行上述位点的基因型和等位基因总体分布频率的比较,结果显示两组间rs1799964和rs1800629位点基因型总体分布频率及等位基因频率分布差异无统计学意义(P0.05)。 结论： (1)血浆TNF-α水平在PD伴睡眠障碍中的含量增高,可能参与PD伴睡眠障碍的发病过程。 (2)TNF-a基因rs1799964, rs1800629位点的多态性与中国汉族人群PD伴睡眠障碍的发病可能无关。
[Abstract]:Parkinson's disease (Parkinson disease, PD) is a common neurodegenerative disease of middle and old people. The main clinical manifestations include dystagmus, static tremor, myotonic and postural gait disorders.
With the progress of clinical research, people gradually realize that PD is not only the main clinical manifestation of motor symptoms, but also its non motor symptoms are also prominent, including sleep disorder (Sleep disorders, SD), cognitive impairment, mental disorder, autonomic nervous dysfunction and sensory obstacle. A recent study of 1072 patients with PD has been investigated and studied. Almost all patients had at least one non motor symptom, in which sleep disorders, cognitive impairment, and mental disorders were the three major non motor symptoms of the decline in the quality of life of PD patients. As with exercise symptoms, these non motor symptoms seriously affected the daily living quality of the patients and increased the economic burden of family and society. Rapid disease progression is even a risk factor for long-term mortality.
Sleep disorders may appear early in the PD, but most are thought to be associated with age. In clinical work, patients, families and clinicians neglect the.PD associated sleep disorders (Parkinson disease with sleep disorders, PD-SD), including insomnia, and rapid eye movement sleep behavior disorder (Rapid eye movement sleep) R, RBD), excessive daytime sleep (Excessive daytime sleepiness, EDS), sleep seizures, sleep apnea syndrome, restless leg syndrome, and other heteromorphic sleep. It is reported that 60%-98% PD patients may appear RBD. in the view that RBD and EDS are the pre clinical manifestations of PD, or may be before the symptoms of movement symptoms. Early non motor symptoms.
The Parkinson Disease Sleep Scale (PDSS) is a scale specially designed to assess the common sleep problems of PD. PDSS-2 is a modified new scale on the basis of PDSS, which can be used to assess the problems in the sleep of PD patients more easily and effectively. Polysomnography (Polysomnography, PSG) was created in 1957. Sleep research technology, widely used in clinical. After continuous development, the ability to record electroencephalogram, electrocardiogram, electrocardiogram, electromyography, EMG, nose and mouth airflow, oxygen saturation, snoring, thoracic and abdominal movement, leg movement, body position, etc.,.PSG can not only objectively record the sleep efficiency, sleep structure, and sleep differences of the subjects. The diagnosis of.PSG, such as RBD, cyclical leg movement, and apnea syndrome, can be used as a means of sleep examination, which is becoming a necessary measure for patients with sleep disorders. Hindering.
German Braak believes that the pathological process of PD can be divided into 6 stages, of which 2 stages of pathology change the following brain stem mainly, affecting the spinal nucleus, blue spots, and the other nuclei of the pontine, resulting in sleep disorders, movement reduction and emotional problems, and the 6 stage of pathological changes are mainly related to the involvement of the neocortex, the clinical manifestation is cognitive impairment, visual hallucination and other semen The.Braak staging of the symptoms of God has made people realize that early PD may have some nonspecific clinical features such as sleep disorders, olfactory disorders, and emotional disorders, and sleep disorders may occur before cognitive impairment.
Sleep disorders indicate impairment of cognitive function in the elderly, and sleep disorders can also be seen as a symptom of cognitive impairment, while sleep quality decreases further exacerbating cognitive impairment. Most of the PD studies are only isolated to study some clinical symptoms, and rarely combine different clinical symptoms to study, The relationship between these different symptoms, such as the neglect of cognitive function changes in the study of PD with sleep disorders, may also overlook the sleep problems in the study of cognitive function. For this reason, we do PSG monitoring for the patients with PD and analyze the clinical features of the patients with PD with sleep disorders, the subject and the guest. Objective To observe the characteristics of sleep and cognitive function in order to find out the possible relationship between sleep disorders and cognitive function in PD patients.
The causes of PD with sleep disorders are not yet fully understood. There may be a variety of factors involved, such as the age of the patient, the disease itself, the fluctuation of nocturnal symptoms, the complications of the disease, and the drug treatment. The current mechanism of the underlying pathological pathogenesis of PD with sleep disorders is less clear, and there are few studies at home and abroad. A number of studies have shown that the mechanism of neuroinflammation plays an important role in the pathogenesis of PD, but it is in the pathogenesis of PD with sleep disorders. The effect is not yet clear.
Tumor necrosis factor (TNF) is a proinflammatory cytokine produced by macrophages. It is recognized as one of the cytokines that have damage to neurons. Some studies have found that the major changes in the striatum of the PD substantia nigra are TNF- alpha, interleukin 1 (IL-1) and other.Mogi, and the caudate nucleus of PD patients The concentrations of TNF- alpha, transforming growth factor (TGF-a) and epithelial growth factor (EGF) at the putamen were significantly higher than those of the cerebral cortex and the normal control group. It was confirmed that the degeneration process of dopaminergic neurons in PD patients was indeed associated with the change of cytokines.
A genetic analysis of the changes in TNF- alpha and its concentration in the pathogenesis of PD was studied. It was found that the polymorphism of the TNF-a gene was associated with the susceptibility to sporadic PD, such as rs1799964, rs1800629, rs11931074, rs3857059 and other loci. The study found that the content of TNF-a in plasma was associated with many non motor symptoms such as PD sleep disorder, cognitive impairment and depressive disorder. .TNF- alpha is rhythmical in normal brain tissue, participates in the physiological regulation of sleep, and expresses the highest sleep at the deepest level. But when the expression of TNF- alpha is excessive, it inhibits normal sleep. Therefore, the TNF- alpha gene is not only related to the susceptibility of PD, but also may be associated with PD sleep disorder.
The purpose of this study was to assess the quality of sleep in patients with PD with sleep disorders, including PDSS-2, the Pittsburgh sleep quality index (PSQI), the EPO sleepy sleepiness scale (ESS), PSG monitoring, and the cognitive function assessment, including the simple mental state scale (MMSE), and the Montreal cognitive Assessment Scale (MoCA); and the ELISA method test. The plasma TNF- alpha level was measured and the ligase detection reaction (LDR) typing was used to detect the polymorphism of TNF- alpha gene loci, which provided biochemical markers for the early diagnosis of PD and PD sleep disorders, providing guidance for clinical intervention.
This study includes the following main contents: 1. the subjective and objective sleep and cognitive functions of Parkinson's disease with sleep disorders; 2. the association of sleep disorders with sleep disorders and TNF- alpha plasma level and gene polymorphism in Parkinson's disease.
Chapter 1 subjective and objective sleep and cognitive function in Parkinson's disease with sleep disorders
Objective: To explore the clinical features of Parkinson's disease with sleep disorders, the characteristics of subjective and objective sleep, and to study the cognitive functions of the subgroups of Parkinson's disease with sleep disorders and sleep disorders.
Methods: 66 patients with PD, 46 patients with primary sleep disorders and 24 normal controls were used as subjects. (1) all subjects were collected and related clinical data were collected, exercise function, anxiety and depression, and daily living ability (ADL) assessment. (2) subjective sleep survey: all subjects completed the evaluation of PDSS-2, PSQI, ESS. (3) objective sleep supervision. Test: PSG monitoring of all the subjects for 14 hours. (4) evaluation of cognitive function: MMSE, MoCA assessment of subjects. The general clinical features, subjective objective sleep characteristics and cognitive function of patients with PD with sleep disorders were analyzed, and then the subtypes of PD with sleep disorders were subdivided, and the cognitive functions of each subgroup were discussed. Characteristic.
Result:
(1) of 66 patients with PD, 48 cases of sleep disorders, accounting for 72.72%, 27 cases of insomnia, 40.09%, 21 of RBD patients, 31.81%, and 18 cases of normal sleep (No sleep disorders, NSD), accounting for 27.27%. worse in ADL than in PD-NSD group.
In group PD-SD, the scores of PDSS-2-T, PDSS-2-1,2,3,6,15 and PSQI-T, F1, F2 were significantly higher than those in the PD-NSD group. Compared with the primary sleep disorder group, the score of.PD-SD group was increased in PDSS-2-T, PDSS-2-4,5,7,9,10,11,12,13,14,15, F5.
(3) the percentage of total sleep time, sleep efficiency, sleep latency, N1, N2, REM and REM time were different (P0.05) compared with the PSG monitoring of PD and PD with RBD.
(4) there were significant differences in cognitive function between group PD-SD, group PD-NSD, primary sleep disorder group and normal control group. Among the sub items of MMSE, MoCA and MoCA, group PD-SD and primary sleep disorder group had lower scores than those in PD-NSD and normal control group, and the cognitive function of PD-SD patients was more obvious than those of primary sleep disorder (P0.05).
Among the subtypes of PD-SD, the MoCA scores and the attention scores in MoCA scores of PD and RBD groups were lower than those of PD with insomnia group (P0.05).
Conclusion:
(1) PDSS-2 is more suitable for evaluation of PD sleep disorders than PSQI, and can preliminarily understand the potential influence factors of PD with sleep disturbance.
(2) PD with sleep disorders may aggravate cognitive dysfunction.
(3) PD with different types of sleep disorders had different effects on cognitive function. The cognitive function of PD with RBD was worse than that of PD with insomnia.
The second chapter is about the association between Parkinson's disease and sleep disturbance and TNF-a plasma level and gene polymorphism.
Objective: to detect the plasma TNF-a level in patients with PD with sleep disorder, to explore the relationship between the level of plasma TNF- alpha and PD with sleep disorders, and to analyze the polymorphism of TNF-a gene in Chinese Han people with PD, and to explore the correlation between the polymorphism of TNF- a gene and PD with sleep disorder.
Methods: 96 PD patients and 96 normal controls were studied. The PD group was divided into PD-SD group and PD-NSD group. The level of plasma TNF- alpha was detected by ELISA, and the concentration of TNF-a in PD-SD group, PD-NSD group and control group was compared. 237 cases of PD patients and 259 normal controls were studied, and the PD group was sleep evaluated, and the PSQI assessment would be evaluated. PD patients were divided into group PD-SD and group PD-NSD, and sequenced by ligase detection reaction (LDR) typing method, the 2 SNP loci (rsl799964, rs1800629) of TNF-a gene of PD and PD-SD and PD-NSD were analyzed by genotyping. The overall frequency of genotype and allele of each group was compared. Learning meaning.
Result:
(1) There were significant differences in plasma TNF-a levels between PD-SD group, PD-NSD group and control group, and plasma TNF-a levels in PD-SD group were significantly higher than those in PD-NSD group (P 0.05).
(2) the distribution of genotypes in group PD and control group was consistent with Hardy-Weinberg balance. The overall distribution frequency of two groups of rs1799964 loci genotypes (C/C, C/T, T/T) and rs1800629 loci genotypes (A/A, A/G, G/G) and the overall frequency difference of alleles (T, C) were not statistically significant.
(3) the PD group was divided into PD-SD group and PD-NSD group. The comparison of the genotype and allele distribution frequency of the two groups showed that there was no significant difference in the general distribution frequency and allele frequency distribution of the rs1799964 and rs1800629 loci between the two groups (P0.05).
Conclusion:
(1) increased plasma TNF- alpha levels in PD with sleep disorders may be involved in the pathogenesis of PD accompanied by sleep disorders.
(2) the polymorphism of the rs1799964 and rs1800629 loci of TNF-a gene may not be related to the incidence of PD sleep disorders in Chinese Han population.
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R742.5
本文编号：2164174
[Abstract]:Parkinson's disease (Parkinson disease, PD) is a common neurodegenerative disease of middle and old people. The main clinical manifestations include dystagmus, static tremor, myotonic and postural gait disorders.
With the progress of clinical research, people gradually realize that PD is not only the main clinical manifestation of motor symptoms, but also its non motor symptoms are also prominent, including sleep disorder (Sleep disorders, SD), cognitive impairment, mental disorder, autonomic nervous dysfunction and sensory obstacle. A recent study of 1072 patients with PD has been investigated and studied. Almost all patients had at least one non motor symptom, in which sleep disorders, cognitive impairment, and mental disorders were the three major non motor symptoms of the decline in the quality of life of PD patients. As with exercise symptoms, these non motor symptoms seriously affected the daily living quality of the patients and increased the economic burden of family and society. Rapid disease progression is even a risk factor for long-term mortality.
Sleep disorders may appear early in the PD, but most are thought to be associated with age. In clinical work, patients, families and clinicians neglect the.PD associated sleep disorders (Parkinson disease with sleep disorders, PD-SD), including insomnia, and rapid eye movement sleep behavior disorder (Rapid eye movement sleep) R, RBD), excessive daytime sleep (Excessive daytime sleepiness, EDS), sleep seizures, sleep apnea syndrome, restless leg syndrome, and other heteromorphic sleep. It is reported that 60%-98% PD patients may appear RBD. in the view that RBD and EDS are the pre clinical manifestations of PD, or may be before the symptoms of movement symptoms. Early non motor symptoms.
The Parkinson Disease Sleep Scale (PDSS) is a scale specially designed to assess the common sleep problems of PD. PDSS-2 is a modified new scale on the basis of PDSS, which can be used to assess the problems in the sleep of PD patients more easily and effectively. Polysomnography (Polysomnography, PSG) was created in 1957. Sleep research technology, widely used in clinical. After continuous development, the ability to record electroencephalogram, electrocardiogram, electrocardiogram, electromyography, EMG, nose and mouth airflow, oxygen saturation, snoring, thoracic and abdominal movement, leg movement, body position, etc.,.PSG can not only objectively record the sleep efficiency, sleep structure, and sleep differences of the subjects. The diagnosis of.PSG, such as RBD, cyclical leg movement, and apnea syndrome, can be used as a means of sleep examination, which is becoming a necessary measure for patients with sleep disorders. Hindering.
German Braak believes that the pathological process of PD can be divided into 6 stages, of which 2 stages of pathology change the following brain stem mainly, affecting the spinal nucleus, blue spots, and the other nuclei of the pontine, resulting in sleep disorders, movement reduction and emotional problems, and the 6 stage of pathological changes are mainly related to the involvement of the neocortex, the clinical manifestation is cognitive impairment, visual hallucination and other semen The.Braak staging of the symptoms of God has made people realize that early PD may have some nonspecific clinical features such as sleep disorders, olfactory disorders, and emotional disorders, and sleep disorders may occur before cognitive impairment.
Sleep disorders indicate impairment of cognitive function in the elderly, and sleep disorders can also be seen as a symptom of cognitive impairment, while sleep quality decreases further exacerbating cognitive impairment. Most of the PD studies are only isolated to study some clinical symptoms, and rarely combine different clinical symptoms to study, The relationship between these different symptoms, such as the neglect of cognitive function changes in the study of PD with sleep disorders, may also overlook the sleep problems in the study of cognitive function. For this reason, we do PSG monitoring for the patients with PD and analyze the clinical features of the patients with PD with sleep disorders, the subject and the guest. Objective To observe the characteristics of sleep and cognitive function in order to find out the possible relationship between sleep disorders and cognitive function in PD patients.
The causes of PD with sleep disorders are not yet fully understood. There may be a variety of factors involved, such as the age of the patient, the disease itself, the fluctuation of nocturnal symptoms, the complications of the disease, and the drug treatment. The current mechanism of the underlying pathological pathogenesis of PD with sleep disorders is less clear, and there are few studies at home and abroad. A number of studies have shown that the mechanism of neuroinflammation plays an important role in the pathogenesis of PD, but it is in the pathogenesis of PD with sleep disorders. The effect is not yet clear.
Tumor necrosis factor (TNF) is a proinflammatory cytokine produced by macrophages. It is recognized as one of the cytokines that have damage to neurons. Some studies have found that the major changes in the striatum of the PD substantia nigra are TNF- alpha, interleukin 1 (IL-1) and other.Mogi, and the caudate nucleus of PD patients The concentrations of TNF- alpha, transforming growth factor (TGF-a) and epithelial growth factor (EGF) at the putamen were significantly higher than those of the cerebral cortex and the normal control group. It was confirmed that the degeneration process of dopaminergic neurons in PD patients was indeed associated with the change of cytokines.
A genetic analysis of the changes in TNF- alpha and its concentration in the pathogenesis of PD was studied. It was found that the polymorphism of the TNF-a gene was associated with the susceptibility to sporadic PD, such as rs1799964, rs1800629, rs11931074, rs3857059 and other loci. The study found that the content of TNF-a in plasma was associated with many non motor symptoms such as PD sleep disorder, cognitive impairment and depressive disorder. .TNF- alpha is rhythmical in normal brain tissue, participates in the physiological regulation of sleep, and expresses the highest sleep at the deepest level. But when the expression of TNF- alpha is excessive, it inhibits normal sleep. Therefore, the TNF- alpha gene is not only related to the susceptibility of PD, but also may be associated with PD sleep disorder.
The purpose of this study was to assess the quality of sleep in patients with PD with sleep disorders, including PDSS-2, the Pittsburgh sleep quality index (PSQI), the EPO sleepy sleepiness scale (ESS), PSG monitoring, and the cognitive function assessment, including the simple mental state scale (MMSE), and the Montreal cognitive Assessment Scale (MoCA); and the ELISA method test. The plasma TNF- alpha level was measured and the ligase detection reaction (LDR) typing was used to detect the polymorphism of TNF- alpha gene loci, which provided biochemical markers for the early diagnosis of PD and PD sleep disorders, providing guidance for clinical intervention.
This study includes the following main contents: 1. the subjective and objective sleep and cognitive functions of Parkinson's disease with sleep disorders; 2. the association of sleep disorders with sleep disorders and TNF- alpha plasma level and gene polymorphism in Parkinson's disease.
Chapter 1 subjective and objective sleep and cognitive function in Parkinson's disease with sleep disorders
Objective: To explore the clinical features of Parkinson's disease with sleep disorders, the characteristics of subjective and objective sleep, and to study the cognitive functions of the subgroups of Parkinson's disease with sleep disorders and sleep disorders.
Methods: 66 patients with PD, 46 patients with primary sleep disorders and 24 normal controls were used as subjects. (1) all subjects were collected and related clinical data were collected, exercise function, anxiety and depression, and daily living ability (ADL) assessment. (2) subjective sleep survey: all subjects completed the evaluation of PDSS-2, PSQI, ESS. (3) objective sleep supervision. Test: PSG monitoring of all the subjects for 14 hours. (4) evaluation of cognitive function: MMSE, MoCA assessment of subjects. The general clinical features, subjective objective sleep characteristics and cognitive function of patients with PD with sleep disorders were analyzed, and then the subtypes of PD with sleep disorders were subdivided, and the cognitive functions of each subgroup were discussed. Characteristic.
Result:
(1) of 66 patients with PD, 48 cases of sleep disorders, accounting for 72.72%, 27 cases of insomnia, 40.09%, 21 of RBD patients, 31.81%, and 18 cases of normal sleep (No sleep disorders, NSD), accounting for 27.27%. worse in ADL than in PD-NSD group.
In group PD-SD, the scores of PDSS-2-T, PDSS-2-1,2,3,6,15 and PSQI-T, F1, F2 were significantly higher than those in the PD-NSD group. Compared with the primary sleep disorder group, the score of.PD-SD group was increased in PDSS-2-T, PDSS-2-4,5,7,9,10,11,12,13,14,15, F5.
(3) the percentage of total sleep time, sleep efficiency, sleep latency, N1, N2, REM and REM time were different (P0.05) compared with the PSG monitoring of PD and PD with RBD.
(4) there were significant differences in cognitive function between group PD-SD, group PD-NSD, primary sleep disorder group and normal control group. Among the sub items of MMSE, MoCA and MoCA, group PD-SD and primary sleep disorder group had lower scores than those in PD-NSD and normal control group, and the cognitive function of PD-SD patients was more obvious than those of primary sleep disorder (P0.05).
Among the subtypes of PD-SD, the MoCA scores and the attention scores in MoCA scores of PD and RBD groups were lower than those of PD with insomnia group (P0.05).
Conclusion:
(1) PDSS-2 is more suitable for evaluation of PD sleep disorders than PSQI, and can preliminarily understand the potential influence factors of PD with sleep disturbance.
(2) PD with sleep disorders may aggravate cognitive dysfunction.
(3) PD with different types of sleep disorders had different effects on cognitive function. The cognitive function of PD with RBD was worse than that of PD with insomnia.
The second chapter is about the association between Parkinson's disease and sleep disturbance and TNF-a plasma level and gene polymorphism.
Objective: to detect the plasma TNF-a level in patients with PD with sleep disorder, to explore the relationship between the level of plasma TNF- alpha and PD with sleep disorders, and to analyze the polymorphism of TNF-a gene in Chinese Han people with PD, and to explore the correlation between the polymorphism of TNF- a gene and PD with sleep disorder.
Methods: 96 PD patients and 96 normal controls were studied. The PD group was divided into PD-SD group and PD-NSD group. The level of plasma TNF- alpha was detected by ELISA, and the concentration of TNF-a in PD-SD group, PD-NSD group and control group was compared. 237 cases of PD patients and 259 normal controls were studied, and the PD group was sleep evaluated, and the PSQI assessment would be evaluated. PD patients were divided into group PD-SD and group PD-NSD, and sequenced by ligase detection reaction (LDR) typing method, the 2 SNP loci (rsl799964, rs1800629) of TNF-a gene of PD and PD-SD and PD-NSD were analyzed by genotyping. The overall frequency of genotype and allele of each group was compared. Learning meaning.
Result:
(1) There were significant differences in plasma TNF-a levels between PD-SD group, PD-NSD group and control group, and plasma TNF-a levels in PD-SD group were significantly higher than those in PD-NSD group (P 0.05).
(2) the distribution of genotypes in group PD and control group was consistent with Hardy-Weinberg balance. The overall distribution frequency of two groups of rs1799964 loci genotypes (C/C, C/T, T/T) and rs1800629 loci genotypes (A/A, A/G, G/G) and the overall frequency difference of alleles (T, C) were not statistically significant.
(3) the PD group was divided into PD-SD group and PD-NSD group. The comparison of the genotype and allele distribution frequency of the two groups showed that there was no significant difference in the general distribution frequency and allele frequency distribution of the rs1799964 and rs1800629 loci between the two groups (P0.05).
Conclusion:
(1) increased plasma TNF- alpha levels in PD with sleep disorders may be involved in the pathogenesis of PD accompanied by sleep disorders.
(2) the polymorphism of the rs1799964 and rs1800629 loci of TNF-a gene may not be related to the incidence of PD sleep disorders in Chinese Han population.
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R742.5
【参考文献】
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1 刘贤臣;唐茂芹;胡蕾;王爱祯;吴宏新;赵贵芳;高春霓;李万顺;;匹兹堡睡眠质量指数的信度和效度研究[J];中华精神科杂志;1996年02期
，本文编号：2164174
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