抑郁症动物模型的研究进展(英文)

抑郁症是一种慢性的、具有高复发率的精神性疾病,往往会危及到病人的生命。尽管其全球发病率高达20%,但人们对其病理生理机制了解甚少,这主要归因于缺乏有效可靠的动物模型。此外,抑郁症的核心症状,例如抑郁心境、无价值感和反复出现自杀念头等,均无法在实验动物上得以模拟。目前,大部分动物模型的建立主要参照以下两个原则之一:对于已知抗抑郁药的作用或者是对应激的反应。本综述主要介绍目前最常用的几个抑郁症动物模型,包括获得性无助、慢性温和应激和社会失败应激,以及一些用于筛选有抗抑郁活性药物的行为学检测方法(如强迫游泳实验和悬尾实验),并对它们的优点与不足进行讨论。最后,对动物模型和行为学检测方法的发展方向进行展望。     

艾司西酞普兰对抑郁模型大鼠行为学及脑脊液、血清脑源性神经营养因子水平的影响

目的:探讨艾司西酞普兰对慢性应激致抑郁模型大鼠行为学及脑脊液、血清脑源性神经营养因子(BDNF)水平的影响。方法:将Sprague Dawley(SD)雄性大鼠随机分为应激组和非应激组,应激组给予慢性不可预知温和应激(CUMS)刺激8周;刺激4周后根据行为学评估[包括强迫游泳实验(FST)、蔗糖水偏爱实验(SPT)、旷场实验(OFT)]及体质量将抑郁行为大鼠随机分为抑郁模型组和抑郁给药组,非应激组随机分为正常对照组和正常给药组,各组6只。第5周起给予两给药组艾司西酞普兰(10 mg/kg·d)腹腔注射4周。刺激及给药结束后对各组大鼠再次行为学评估并检测脑脊液、血清BDNF水平。结果:CUMS 4周后,与非应激组相比,应激组FST中不动时间显著延长,SPT显著降低,OFT中路程及站立次数显著减少,体质量显著降低(P均0.01);药物干预4周后,与抑郁模型组相比,抑郁给药组FST中不动时间显著缩短,SPT及OFT中总路程显著增加(P均0.05);脑脊液、血清BDNF水平抑郁模型组显著低于正常对照组,抑郁给药显著高于抑郁模型组(P0.05或P0.01)。结论:艾司西酞普兰可改善抑郁大鼠的抑郁行为,提高脑脊液及血清BDNF水平。     

抑郁症大鼠海马神经元自噬与PTEN的表达

目的观察抑郁症大鼠海马神经元是否存在PTEN的异常表达,探讨其表达与自噬的相关性。方法成年健康雄性SD大鼠50只,随机分为对照组和模型组:每组25只。通过慢性不可预见温和性应激(CUMS)方法制备抑郁症大鼠模型。采取旷场、水迷宫、穿梭箱、悬尾实验及糖水偏好等行为学实验检测大鼠抑郁状态。分别于成模后0.5 d、1 d、3 d、7 d、14 d取海马组织,通过免疫组织荧光、Weston blot、实时荧光定量PCR等方法检测海马自噬相关蛋白LC3、Beclin1以及抑癌基因PTEN的表达变化。结果模型组大鼠好奇心缺失,空间学习记忆能力受损,行为绝望状态以及快感缺失(P<0.01);模型组LC3、Beclin1两种自噬相关蛋白有共定位表达,其中LC3也与PTEN蛋白呈共定位表达;抑郁症模型组大鼠海马LC3、Beclin1两种自噬相关蛋白与PTEN蛋白的表达均高于对照组(P<0.05),并呈随时间增加趋势;抑郁症模型组大鼠两种目的自噬相关基因和PTEN基因表达均高于对照组(P<0.01)。结论抑郁症大鼠海马神经元存在异常PTEN表达,其表达与自噬发生相关。     

抑郁症大鼠海马BDNF及其受体TrkB和p75NTR的表达及米氮平的调节作用

目的观察抑郁症模型大鼠学习记忆力改变情况,研究海马脑源性神经营养因子(BDNF)、酪氨酸激酶受体B(TrkB)和神经营养因子低亲和力受体(p75NTR)蛋白的表达变化,以及米氮平的调节作用。方法制备抑郁症大鼠模型;采用Morris水迷宫实验方法记录大鼠游动距离变化;免疫组化染色方法测定海马BDNF、TrkB和p75NTR表达阳性区吸光度值。结果抑郁症模型大鼠在目标象限游动距离减少,海马BDNF及TrkB蛋白表达减少,p75NTR蛋白表达增加;米氮平逆转上述行为学异常及蛋白表达异常(p﹤0.01)。结论抑郁症模型大鼠可能存在BDNF-p75NTR通路信息传递增强,而抗抑郁治疗用药可能通过BDNFTrkB信号通路的改变引起相应行为学改善。     

下丘脑NK2受体在应激介导抑郁症发生中的作用

目的 阐明神经激肽A的受体NK2在慢性不可预见性温和刺激(CUMS)所致的抑郁样行为发生、发展中的可能作用和机制.方法 SD大鼠随机分为对照组、氟西汀组和抑郁模型组3组,行为学检测后,氟西汀组和抑郁模型组均给予孤养+CUMS造成大鼠抑郁症模型,再次行为学检测后,氟西汀组大鼠给予氟西汀腹腔注射21d,抑郁模型组给予同体积生理盐水腹腔注射21d,再次进行行为学检测,麻醉后取大鼠下丘脑,提取组织mRNA和蛋白后,采用荧光定量PCR技术和Western Blot技术检测NK2的表达.结果 应激前3组大鼠的糖水偏好率和强迫游泳的不动时间均无统计学意义.应激后,氟西汀组和抑郁模型组大鼠的糖水摄入明显减少、强迫游泳不动时间明显增长,差异均有统计学意义(P＜0.05).而给予氟西汀后,氟西汀组大鼠的糖水偏好率有所增加,强迫游泳的不动时间有所减少,与对照组比较差异无统计学意义(P＞0.05),但与抑郁组大鼠相比,差异均有统计学意义(P＜0.05).与对照组和氟西汀组比较,抑郁组下丘脑NK2受体的mRNA和蛋白的表达量明显升高,差异有统计学意义(P＜0.05),而氟西汀组与对照组相比差异无统计学意义(P＞0.05).结论 CUMS可引起大鼠行为学改变,造成大鼠抑郁模型;NK2受体的mRNA和蛋白的表达量在应激后大鼠的下丘脑中明显升高,经氟西汀干预后可恢复到正常水平,说明NK2受体与抑郁症的发生、发展过程具有相关性,在抑郁症的发病机制中可能发挥重要作用.     

抑郁症的社会认知理论研究

一般来说 ,对抑郁症的病因学研究有两种途径 ,一是从生物学角度 ,探索抑郁症病人脑形态结构及生理功能的改变 ;另一是从社会心理学的角度来研究环境及个体心理因素对抑郁症的发生所起的作用。 2 0世纪 80年代 ,Abramson、Beck[1]等提出了抑郁症的社会 -认知心理因素模型 ,他们认为 ,抑郁症是由于素质性因素和应激的交互作用而产生的。但这里的素质性因素主要是认知心理因素 ,应激性因素是各种社会刺激 ,如灾难性生活事件、日常生活事件等。自他们的理论提出后 ,人们开始对抑郁症的社会认知因素进行了许多研究。抑郁症的社会认知理论以 Bec…     

慢性应激对大鼠行为学及脑神经颗粒素水平的影响及药物防治

目的探讨慢性应激对大鼠外显行为学变化的影响,检测体内儿茶酚胺类物质及神经颗粒素(Neurogranin,Ng)表达的变化及三七皂苷Rg1的防治效果。方法成年雄性SD大鼠36只,随机分为对照组(CON)、模型组(CUS)、和治疗组(CUS-G),采用慢性不可预见性应激方法建立慢性应激动物模型;采用旷场试验检测行为学变化,运用Morris水迷宫实验进行学习记忆力测试,使用放射免疫法检测血浆、脑组织儿茶酚胺类含量,Western blot法检测皮质、海马、下丘脑Ng含量。结果 6 w慢性应激后,实验组大鼠在水平运动和垂直运动方面得分均明显低于对照组与药物组,均P0.05;水迷宫实验显示慢性应激后动物逃避潜伏期明显延长,而治疗组大鼠逃避潜伏期呈下降趋势(P0.05);血浆、脑组织去甲肾上腺素与多巴胺在对照组、实验组与药物组间无明显变化;慢性应激大鼠皮质、海马、下丘脑Ng含量水平皆与模型大鼠有差异(P0.05、P0.01、P0.05),治疗大鼠皮质、海马、下丘脑Ng含量亦皆与模型大鼠有差异(P0.01、P0.05、P0.05)。结论慢性应激研究领域,神经颗粒素的敏感性优于单胺类神经递质,可作为敏感指标加以观察;100 mg/kg剂量的三七皂苷Rg1能够抑制应激所致学习记忆功能紊乱,对应激所致外显行为有积极的调节作用,对脑内神经颗粒素表达水平降低趋势有较好抑制作用。     

大鼠抑郁症模型脑磁共振成像和波谱研究

采用长期不可预见性中等强度应激造成分养大鼠抑郁症模型。运用敞箱实验等方法测定动物行为;磁共振成像和波谱学方法研究抑郁大鼠脑内整体形态学及前脑和下丘脑变化。结果显示抑郁大鼠大脑纵裂加深、扩大;前脑和下丘脑区域磁共振１Ｈ谱ＮＡＡ峰降低。提示本抑郁症模型大鼠有脑萎缩,前脑和下丘脑区域神经元数目减少。     

抑郁大鼠海马的双向凝胶电泳图谱分析

目的　建立抑郁症的动物模型，利用双向电泳技术分析海马组织差异蛋白质表达谱，为探索抑郁症的发病机制提供线索。方法　雄性成年Spraguedawley大鼠10只，选择旷场实验法行为评分相近的大鼠随机分为模型组和正常组，每组各5只。对模型组大鼠采用慢性不可预见的轻度应激制作抑郁症大鼠模型，以行为学测试评估模型。三氯乙酸／丙酮沉淀法提取海马组织蛋白质，固相pH梯度双向凝胶电泳分离蛋白质，考马斯亮蓝染色，Image　Master2D软件进行图像分析，MALDI—TOF—MS质谱仪鉴定蛋白质。结果 蔗糖水实验：模型组大鼠饮用蔗糖水量在应激第15，22天[（68．3±2．9）ml，（65．6±3．9）ml]与正常组[（76．3±4．2）ml，（76．5±1．4）ml]的差异均有统计学意义（P均〈0．01）。旷场实验：模型组大鼠水平得分[（21．27±5．89）分]及垂直得分[（7．58±2．65）分]均低于正常组[（35．70±7．87）分，（11．56±2．45）分]，差异均有统计学意义（P均〈0．01）。模型组平均蛋白质点数为（1609±15）点。正常组平均蛋白点数为（1616±30）点，匹配率为72％；其中27个蛋白点在两组间有显著的量的改变，集中在pH4．0～9．7和相对分子质量为25000—70000。质谱鉴定了4类共15个蛋白质，其中模型组4个与神经发生有关的蛋白质表达量明显下降。结论 差异蛋白点的检测为抑郁症的发病机制及治疗靶点的选择提供了参考依据。     

电针对慢性抑郁模型大鼠行为学及血清雌二醇、皮质醇水平的影响

目的观察电针百会、内关、三阴交穴对慢性抑郁模型大鼠行为学及血清雌二醇、皮质醇水平的影响,探讨其治疗抑郁症的可能机制。方法将30只雌性Wistar大鼠随机分为模型组、电针组和对照组各10只,前2组均采用慢性中等程度不可预见性应激结合孤养方法造模21d,电针组再接受百会、内关、三阴交穴的电针治疗14d。测定大鼠行为学改变,采用放射免疫法测定大鼠血清雌二醇及皮质醇水平。结果与对照组比较,造模后模型组和电针组大鼠的旷场实验得分减少(P<0.01),糖水偏爱率下降(P<0.01),而强迫游泳不动时间增加(P<0.01)。治疗后,与模型组比较,电针组的旷场实验得分增加(P<0.01),糖水偏爱率提高(P<0.01),而强迫游泳不动时间减少(P<0.01);与对照组比较,模型组大鼠血清雌二醇水平下降(P<0.01)而皮质醇水平升高(P<0.01);与模型组比较,电针组血清皮质醇水平降低(P<0.05),雌二醇水平升高但差异无统计学意义(P>0.05)。结论血清皮质醇升高和雌二醇降低可能与抑郁症相关;电针具有抗抑郁作用,这可能与其对皮质醇水平的调节有关。     

Environmental factors in the development and progression of late-onset Alzheimer＇s disease

Late-onset Alzheimer＇s disease （LOAD） is an age-related neurodegenerative disorder characterized by gradual loss of synapses and neurons, but its pathogenesis remains to be clarified. Neurons live in an environment constituted by neurons themselves and glial cells. In this review, we propose that the neuronal degeneration in the AD brain is partially caused by diverse environmental factors. We first discuss various environmental stresses and the corresponding responses at different levels. Then we propose some mechanisms underlying the specific pathological changes, in particular, hypothalamic-pituitary adrenal axis dysfunction at the systemic level; cerebrovascular dysfunction, metal toxicity, glial activation, and Aβ toxicity at the intercellular level; and kinase-phosphatase imbalance and epigenetic modification at the intracellular level. Finally, we discuss the possibility of developing new strategies for the prevention and treatment of LOAD from the perspective of environmental stress. We conclude that environmental factors play a significant role in the development of LOAD through multiple pathological mechanisms.     

Edema and neuronal apoptosis in the hippocampus and cortex of elderly rats following transient cerebral ischemia/reperfusion injury

BACKGROUND： Previous studies of cerebral ischemia have used young animals, with an ischemic time greater than 5 minutes （safe time limit）. Despite an increased understanding of neuronal apoptosis, it remains uncertain whether brief cerebral ischemic events of 5 minutes or less damage brain tissue in elderly rodents. OBJECTIVE： To investigate the effects of transient cerebral ischemia （5 minutes）/reperfusion injury on brain cortical and hippocampal edema, aquaporin-4 （AQP-4） expression, and neuronal apoptosis in aged rats, and to compare ischemic sensitivity between cortex and hippocampus. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Institute of Cerebrovascular Disease, Qingdao University Medical School from April 2008 to March 2009. MATERIALS： Rabbit anti-AQP-4 polyclonal antibody, TUNEL kit, and SABC immunohistochemistry kit were purchased from Wuhan Boster Bioengineering, China. METHODS： A total of 160 healthy, male, aged 19-21 months, Wistar rats were randomly assigned to 4 groups： sham-surgery, and ischemia 1-, 3-, and 5-minute groups, with 40 rats in each group. The global cerebral ischemia model was established using the Pusinelli four-vessel occlusion, and the three cerebral ischemia groups were subdivided into reperfusion 12-hour, 1-, 2-, 3-, and 7-day subgroups, with 8 rats in each subgroup. The sham-surgery group was subjected to exposure of the first cervical bilateral alar foramina and bilateral common carotid arteries. MAIN OUTCOME MEASURES： The dry-wet weight assay was used to measure brain water content and histopathology of the cortex and hippocampus was observed following hematoxylin-eosin staining. In addition, cortical and hippocampal AQP-4 expression was detected by streptavidin-biotin complex immunohistochemistry, and neuronal apoptosis was detected by the TUNEL method. RESULTS： There was no significant difference in brain water content or AQP-4 expression in the cortex and hippocampus between ischemia 1- and 3-minute groups and the sham-surgery group or brain water content or AQP-4 expression in the cortex between ischemia 5-minute group and sham-surgery group （P 〉 0.05）. However, brain water content and AQP-4 expression in the hippocampus after 5 minutes of cerebral ischemia were significantly increased compared with the sham-surgery group （P 〈 0.05 or P 〈 0.01）. Several TUNEL-positive cells were observed in the cortex and hippocampus of the sham-surgery group and ischemia 1-minute group, as well as in the cortex of the ischemia 3-minute group. In addition, the number of apoptotic neurons in the hippocampus of ischemia 3-minute group and in the cortex and hippocampus of ischemia 5-minute group was significantly increased （P 〈 0.05 or P 〈 0.01 ）. Neuronal apoptosis was increased after 12 hours of ischemia/reperfusion, and it reached a peak by 2 days （P 〈 0.01）. CONCLUSION： Transient cerebral ischemia （5 minutes） resulted in increased hippocampal edema, AQP-4 expression, and neuronal apoptosis. Moreover, cerebral ischemia had a greater effect on neuronal apoptosis than brain edema or AQP-4 expression, and the hippocampus was more sensitive than the cortex.     

Total saponins of Panax ginseng effects on proliferation and differentiation of human embryonic neural stem cells and in a Parkinson’s disease mouse model

BACKGROUND： Total saponins of Panax ginseng （TSPG） exhibits neuroprotection against Parkinson＇s disease in the substantia nigra. OBJECTIVE： To investigate the effects of TSPG on human embryonic neural stem cells （NSCs） proliferation and differentiation into dopaminergic neurons using in vitro studies, and to observe NSC differentiation in a mouse model of Parkinson＇s disease, as well as behavioral changes before and after transplantation. DESIGN, TIME AND SETTING： In vitro neural cell biology trial and in vivo randomized, controlled animal trial were performed at the Institute of Basic Medical Sciences, Chongqing Medical University between September 2004 and December 2007. MATERIALS： TSPG （purity 〉 95%） was isolated, extracted, and identified by Chongqing Academy of Chinese Materia Medica. Recombinant human basic fibroblast growth factor （bFGF） and recombinant human epidermal growth factor （EGF） were purchased from PeproTech, USA. A total of 25 C57/BL6J mice, aged 18-20 weeks were included. Twenty were used to establish a Parkinson＇s disease model with i.p. injection of MPTP （1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine） and TSPG alone or combined with interleukin-1 （IL-1）-treated NSCs prior to transplantation into the corpus striatum. The remaining five mice were pretreated for 3 days with TSPG prior to MPTP injection, serving as the TSPG prevention group. METHODS： Primary NSCs were isolated, cultured and purified from embryonic cerebral cortex. Immunocytochemistry was employed to detect specific antigen expression in the NSCs. In vitro experiment： （1） to induce proliferation, NSCs were treated with TSPG, EGF＋bFGF, or TSPG＋EGF＋bFGF, respectively; （2） to induce dopaminergic neuronal differentiation, NSCs were treated with TSPG, IL-1, or TSPG＋IL-1, respectively. MAIN OUTCOME MEASURES： In vitro experiment： the effects of TSPG on NSCs proliferation were evaluated with flow cytometry and MTT assay. Tyrosine hydroxylase expression was determined by immunocytochemistry assay to observe effects of TSPG on dopaminergic neuronal differentiation. In vivo experiment： differentiation of grafted NSCs in the mouse brain was determined by immunohistochemical staining. Behavioral changes were evaluated by spontaneous activity frequency, memory function, and score of paralysis agitans. RESULTS： （1） NSCs were cultured and passaged for more than three passages. Immunocytochemistry revealed positive nestin staining, as well as neurofilament protein and glial fibrillary acidic protein. （2） TSPG significantly increased NSC proliferation, in particular when combined with EGF and bFGF, which was twice as effective as FGF or bFGF alone. TSPG also induced dopaminergic differentiation in NSCs, in particular when TSPG was added together with IL-1, resulting in an effect five times greater than that of IL-1 alone. （3） At day 30 following transplantation, most NSCs in the TSPG prevention group differentiated into dopaminergic neurons, and the scores of paralysis agitans, spontaneous activity, and memory function were significantly increased compared with TSPG alone or TSPG＋IL-1 groups （P 〈 0.05）. CONCLUSION： TSPG stimulated NSC proliferation, in particular when combined with FGF and bFGF. TSPG significantly induced dopaminergic neuronal differentiation of NSCs, and the effect was greater when combined with IL-1. In addition, TSPG greatly improved behavior in the Parkinson＇s disease mouse model following NSC transplantation. Following NSC transplantation, TSPG pretreatment exhibited superior efficacy over either TSPG alone or TSPG in combination with IL-1, in terms of behavioral improvements in the Parkinson＇s disease mouse model.     

墨蝶呤还原酶基因与精神分裂症相关性的研究进展

墨蝶呤还原酶（SPR）催化四氢生物蝶呤（BH4）从头合成途径的最后一步反应。SPR基因遗传缺陷或突变可导致BH。的合成紊乱,影响单胺类神经递质（如多巴胺、5-羟色胺及谷氨酸等）的合成或释放,进而参与包括精神分裂症在内的多种神经精神系统疾病的发生发展过程。此外,SPR基因敲除小鼠表现出持续增强的自主活动等类精神分裂症症状,说明该基因在精神分裂症的发病中扮演重要的角色。进一步研究SPR基因及其单核苷酸多态性的功能,可为阐明精神分裂症的发病机制提供重要的线索,也为新一代抗精神病药物的研制及开发开拓新的视野。现对SPR基因与精神分裂症的相关研究做一综述。     

Disrupted structural and functional brain connectomes in mild cognitive impairment and Alzheimer＇s disease

Alzheimer＇s disease （AD） is the most common type of dementia, comprising an estimated 60-80% of all dementia cases. It is clinically characterized by impairments of memory and other cognitive functions. Previous studies have demonstrated that these impairments are associated with abnormal structural and functional connections among brain regions, leading to a disconnection concept of AD. With the advent of a combination of non-invasive neuroimaging （structural magnetic resonance imaging （MRI）, diffusion MRI, and functional MRI） and neurophysiological techniques （electroencephalography and magnetoencephaJography） with graph theoretical analysis, recent studies have shown that patients with AD and mild cognitive impairment （MCI）, the prodromal stage of AD, exhibit disrupted topological organization in large-scale brain networks （i.e., connectomics） and that this disruption is significantly correlated with the decline of cognitive functions. In this review, we summarize the recent progress of brain connectomics in AD and MCI, focusing on the changes in the topological organization of large-scale structural and functional brain networks using graph theoretical approaches. Based on the two different perspectives of information segregation and integration, the literature reviewed here suggests that AD and MCI are associated with disrupted segregation and integration in brain networks. Thus, these connectomics studies open up a new window for understanding the pathophysiological mechanisms of AD and demonstrate the potential to uncover imaging biomarkers for clinical diagnosis and treatment evaluation for this disease.     

Wnt信号通路与骨髓间充质干细胞增殖及分化的关系

骨髓间充质干细胞（bonemarrow—derived mesenchymal stem cells,BMSCs）是骨髓中不同于造血干细胞的一类细胞,其来源丰富,取材简便,易分离、纯化、培养,在一定的条件下可以迅速体外扩增,具有多向分化潜能,可以通过不同的方法被诱导分化成骨细胞、软骨细胞、肌细胞、神经胶质细胞、神经元细胞等,而且它具有低免疫源性,向病变部位迁移的能力,     

癫痫与自杀

自杀而导致死亡被为是增加癫痫患者死亡率的最重要原因之一。国外许多研究报道都表明癫痫患者的自杀率比普通人群的自杀率高几倍到二十几倍。可能导致癫痫患者自杀的危险性因素是有多方面的,本文将从5-HT、抗癫痫药及癫痫手术治疗、精神病理等方面对癫痫患者可能存在自杀危险因素进行综述,并希望在癫痫的综合治疗中对这些危险因素能加以考虑。     

Neuronal failure in Alzheimer＇s disease： a view through the oxidative stress looking-glass

Considerable debate and controversy surround the cause（s） of AIzheimer＇s disease （AD）. To date, several theories have gained notoriety, however none is universally accepted. In this review, we provide evidence for the oxidative stress-induced AD cascade that posits aged mitochondria as the critical origin of neurodegeneration in AD.     

高血压脑出血的显微外科治疗进展

高血压脑出血（Hypertensive intrac-rebral hemorrhage,HICH）是具有高发病率、高病死率、高致残率的急性脑血管疾病,占所有脑卒中患者的10%-20%,早期病死率可高达49.4%。随着人口老龄化,其发病率逐年提高;而外科手术的干预,使其病死率有所下降,但致残率居高不下。如何提高手术疗效和患者生存质量,一直是神经外科医师努力的方向。微侵袭血肿清除术因其手术创伤小,恢复快,是目前国内治疗高血压脑出血的重要手段。     

阿尔茨海默病治疗的研究进展

阿尔茨海默病（AD）是一种隐匿性起病,进行性恶化的神经退行性疾病,临床最初表现为认知功能障碍,并有可能在5～10年内完全衰退。患者往往伴随严重的记忆力丧失、精神行为异常、人格改变、言语功能障碍,无法独立生活,最终近乎于植物状态。Ferri等采用DISMOD软件在全球60岁以上人群中估计,全球的痴呆患者人数到2040年将达到8llO万左右。