1、论著494脑与神经疾病杂志2 0 2 3年第31卷第8 期89.10Zhang A Q,Wang L,Wang Y X,et al.Silencing miRNA-324-3p protects against cerebral ischemic injury via regulation of theGATA2/A1RaxisJ.中国神经再生研究:英文版,2 0 2 2,17(11):8.11 Li G,Zheng Y,Yao J,et al.Design and green synthesis ofpiperlongumine analogs and their antioxidant a
2、ctivity against cerebralischemia-reperfusion Injury.J.ACS Chem Neurosci,2019,10(11):4545-4557.12 Pisani C,Ramella M,Boldorini R,et al.Apoptotic and predictivefactors by Bax,Caspases 3/9,Bcl-2,p53 and Ki-67 in prostatecancer after 12?Gy single-doseJ.Sci Rep,2020,10(1):7050.13Zheng T,Shi Y,Zhang J,et
3、al.MiR-13Oa exerts neuroprotectiveeffects against ischemic stroke through PTEN/PI3K/AKT pathwayJ.Biome Pharmac,2019,117:109117.14 Zhu Z,Huang Y,Lv L,et al.Acute ethanol exposure-inducedautophagy-mediated cardiac injury via activation of the ROS-JNK-Bcl-2 pathwayJ.J Cell Physiol,2018,233(2):9 2 4-9 3
4、5.15Chen H,Kanai M,Inoue-Yamauchi A,et al.An interconnectedhierarchical model of cell death regulation by the BCL-2 familyJ.Nat Cell Biol,2015,17(10):1270-1281.(收稿日期:2 0 2 2-0 8-18)帕金森病患者认知障碍与神经内分泌的相关性研究刘向赵媛高雅李淑月杨国锋【摘要】目的技探讨帕金森病(PD)患者神经内分泌水平与认知障碍相关性,为PD中晚期患者的评估和治疗提供新靶标。方法以2 0 2 0 年12 月到2 0 2 1年10 月就
5、诊于河北省医科大学第二医院老年病科的PD患者32 例作为研究对象。根据是否并发认知障碍将其分为帕金森痴呆组(PDD组)15例和PD组17例;同期选取2 0 例健康志愿者作为健康对照组(N组)。收集所有受试者临床资料如性别、年龄及受教育程度等,PD患者同时记录其病程、Hoehn-Yahr分期(H-Y分期)和简易精神量表(MMSE)测评得分。检测各组游离三碘甲状腺素原氨酸(FT3)、游离甲状腺素(FT4)、促甲状腺素(TSH)、饥饿素(CHRL)及褪黑素(MT)水平并统计分析。采用多因素Logistic回归分析PD认知障碍发生和神经内分泌水平变化的相关性。结果PDD组FT4显著高于PD组和N组(P
6、0.05)。PD 组FT4水平显著高于N组(P0.05)。PDD组MMSE评分明显低于PD组(P0.01),且H-Y分期显著高于PD组(P0.05)。纳人性别_男、FT4、FT 3和CHRL构建多因素Logistic回归方程(=10.38 3,P=0.062),FT 4(x=14.6 15,P=0.0 0 1)、FT3(x=7.117,P=0.0 2 8)和GHRL(x=7.2 0 5,P=0.0 2 7)水平变化与PD认知障碍有相关性。结论PD患者FT4升高,并发认知障碍时水平进一步升高。FT4是PD认知障碍发生的危险因素。FT3、G H RL可能是PD认知障碍发生的保护因素。【关键词】帕金
7、森病;认知障碍;神经内分泌;甲状腺素;简易精神量表中图分类号:R742.5文献标识码:A文章编号:10 0 6-351X(2 0 2 3)0 8-0 49 4-0 5The analysis of relationship between cognitive impairment and neuroendocrinology in patients withParkinsons diseaseLiu Xiang,Zhao Yuan,Gao Ya,Li Shuyue,Yang GuofengDepartment of Geriatrics,the Second Hospital of Hebei
8、 Medical University,Shjiazhuang 050051,ChinaCorresponding author:Yang Guofeng,Email:yang-基金项目:河北省科学技术厅(2 137 7 7 45D)作者单位:0 50 0 0 0 石家庄,河北医科大学第二医院老年病科通信作者:杨国锋,Email:y a n g-g u o f e n g 16 3.c o m495脑与神经疾病杂志2 0 2 3年第31卷第8 期Abstract Objective To explore the correlation between neuroendocrine level
9、and cognitive impairmentin patients with Parkinsons disease(PD),and to provide a new target for the evaluation and treatment ofpatients with intermediate and advanced PD.Methods A total of 32 PD patients hospitalized in the Departmentof Geriatrics,the Second Hospital of Hebei Medical University from
10、 December 2020 to October 2021 were selectedas the research objects.The patients were divided into Parkinsons dementia group(PDD group)(15 cases)and PDgroup(17 cases)according to whether they were complicated with cognitive impairment.Twenty healthy volunteerswere selected as the healthy control gro
11、up(group N).Clinical data such as gender,age and education level of allsubjects were collected.The course of disease,Hoehn-Yahr staging(H-Y staging)and the score of the simpleMental Scale(MMSE)were recorded for PD patients.The levels of free triodothyronine(FT3),free thyroxine(FT4),thyrotropin(TSH),
12、GHRL and melatonin(MT)in each group were detected and statistically analyzed.Logisticregression was used to analyze the correlation between the occurrence of PD cognitive dysfunction and changes inneuroendocrine levels.Results Serum FT4 in the PDD group was significantly higher than in the PD group
13、andN group(P0.05).Serum FT4 levels in the PD group were significantly higher than in the N group(P0.05).TheMMSE score in the PDD group was significantly lower than that in the PD group(P0.01),and the H-Y staging wassignificantly higher than that in the PD group(P 17 分,小学 2 0分,初中及以上 2 4分。根据患者症状累及单、双侧
14、以及有无肢体平衡障碍进行H-Y分期。以上评估皆由两名神经内科主治医师完成。5.统计学方法利用SPSS26.0进行数据统计。分类资料表示为频率分布;定量资料且符合正态分布表示为(元s);偏态资料表示为中位数(四分位数间距)M(Q1,Q3);多组间比较采用单因素方差分析(One-WayANOVA)。采用多因素Logistic回归分析各因素与PD认知障碍发生的关系。以P0.05)。2.PDD组和PD组发病年龄、病程、MMSE得分及H-Y分级比较(表2)表2PDD组和PD组发病年龄、病程、MMSE得分及H-Y分级比较PDD 组(n=15)PD组(n=17)t/zP发病年龄(岁)66.6 8.2667.
15、1 4.780.1640.872病程(月)37.3 12.723.0 14.6-2.1300.045H-Y等级3.5(2.0)2.5(1.2 5)-2.5390.011MMSE得分9.5 4.8927.4 1.3717.4110.000PDD组与PD组相比,两组发病年龄相近(P 0.1),但PDD组比PD组病程更长(P=0.045),H-Y等级更高(P=0.011),M M SE得分显著降低(P0.001)。3.研究对象血清学水平比较(表3)表3研究对象各因素资料基本分析(s)PDD组PD组N组总计项目(n=15)(n=17)(n=20)(n=52)FT4(pmol Ll)16.83 4.03
16、ab 14.09 2.30 13.51 2.71b 14.23 2.92FT3(pmol L-)4.62 0.584.66 0.524.49 0.564.58 0.54TSH(mlU L-)2.96 2.334.23 10.882.37 1.733.21 6.70GHRL(ngmL-)1.18 0.942.12 2.701.81 1.571.84 2.03MT(pg mL-)1.34 0.981.20 0.521.25 0.911.24 0.77注:与N组比较,“P 0.0 5;与PD组比较,bP0.05FT4在PD患者中显著升高,当合并认知障碍时进一步显著升高(P0.05)。4.PD相关指标
17、的Logistic回归分析(表4、表5)表4PD相关性指标多因素Logistic回归分析结果纳人因素RP性别_男67.3060.6490.723FT481.27314.6150.001FT373.7747.1170.028GHRL73.8627.2050.027497脑与神经疾病杂志2 0 2 3年第31卷第8 期表5约纳人多元Logistic回归方程各参数的基本分析指标Waldx值P值OR值95%CIPDDa性别_男-1.0940.4890.484 0.3350.0167.186FT41.2356.1260.0133.4391.2939.146FT3-4.8264.0180.0450.008
18、7.160e0.898GHRL-2.5333.6590.056 0.0790.0061.065PDDb性别_男-1.2080.6000.4390.2990.0146.351FT41.2105.9700.0153.3531.2708.849FT3-3.9522.8290.0930.0190.0001.922GHRL-2.3713.2200.0730.0930.0071.245注:“对照组为PD组;对照组为N组采用多因素Logistic回归分析各因素之间与PD认知障碍发生的关系,最终纳入了性别_男、FT4、FT 3与GHRL建立多元回归方程(x=17.588,P=0.062)。结果显示:不同FT4
19、、FT 3和GHRL水平对PD认知障碍发生的影响差异有统计学意义。其中,PDD组与PD组相比,FT4水平升高是PD认知障碍发生的独立危险因素(OR=3.439,9 5%CI 1.2 9 3-9.146,P=0.0 13);FT 3水平升高是PD认知障碍发生的独立保护因素(0 R=0.008,9 5%CI 7.16 0 e-5-0.8 9 8,P=0.045);G H RL水平升高有保护PD认知障碍发生的趋势,但不显著(0 R=0.079,9 5%CI 0.0 0 6-1.0 6 5,P=0.056)。讨论PD认知障碍定义为在运动征象出现1年后开始的临床或隐匿痴呆、认知波动和视幻觉,伴有进行性执
20、行功能障碍,视觉空间异常和记忆障碍8 。在临床中不易于与其他疾病如路易体痴呆(dementia withLewy bodies,D LB)等相鉴别,影响了早期的诊断及治疗9 。因此,寻找PD认知障碍的生物学标志物,为及时准确地评估患者病情提供依据。甲状腺疾病是与PD相关的最常见的内分泌功能障碍。氧化应激是多巴胺能神经元(dopaminergicneuron)丢失和 PD 进展的主要因素之一10 。甲状腺素能增强参与氧化应激的线粒体蛋白转换功能,而成为促进PD发生发展的潜在因素。Aziz 等12 发现PD患者FT4水平显著高于年龄、性别及体质量指数(BMI)相匹配的对照组。Choi等13 认为F
21、T4的升高与PD患者认知和执行功能测试的表现不佳呈负相关,而与FT3和TSH水平无直接相关性。另有学者研究发现PD伴亚临床甲状腺功能减退者的认知功能优于PD甲状腺功能正常者14。此实验结果显示FT4水平在PD患者中显著升高;当合并认知障碍时,其水平进一步显著升高。FT4是PD认知障碍发生的独立危险因素。FT3水平在PD患者中升高,但差异不显著,而在经过多因素Logistic回归后显示FT3是PD认知障碍发生的独立保护因素。甲状腺素有助于调节氧化剂和抗氧化剂的活性,通过不同机制在体内参与调节氧化应激过程。其中需要特殊注意的是,FT3除了有增强负责调节氧化应激的线粒体蛋白的转换功能外,还能通过上调
22、解耦联蛋白(uncouplingprotein,U CP)和超氧化物歧化酶(s u p e r o x i d e d i s mu t a s e,SO D)而发挥抗氧化作用,而FT4目前只被发现具有增强氧化应激的作用 15-16 。因此,FT3和FT4在体内综合作用对PD认知障碍发生的作用仍需进一步探究。作者发现,GHRL水平升高可能阻止PD认知障碍。酰基化的GHRL(a c l a t e d g h r e l i n,A G)通过其同源G蛋白偶联受体(GPCR)刺激细胞内下游信号传导,在海马、下丘脑、腹侧被盖区和中缝背核等结构有增强线粒体细胞内吞和阻止脑细胞凋亡等作用而具有神经保护作
23、用17-18 。研究发现高水平CHRL可以改善小鼠海马神经发生和可塑性,从而使小鼠的空间记忆障碍程度减轻。且GHRL水平在并发认知障碍的PD患者中明显降低 19 。DA作为神经递质与褪黑素(melatonin,M T)在视网膜间脑中脑松果体(RDMP)轴共同调节昼夜节律且作用相反。PD患者中枢神经系统DA失调引起昼夜节律改变,诱导神经炎症、受损的蛋白质稳态和氧化还原稳态2 0 。Breen等2 1 证实MT昼夜节律失调和显著的下丘脑灰质体积丢失与PD严重程度相关。综上,FT3、FT 4和GHRL的水平变化和PD认知障碍发生有关,FT4是PD认知障碍的独立危险因素,FT3和GHRL可能是PD认知
24、障碍的独立保护因素。然而,此研究所纳人样本量较小,仍需扩大样本量或更多的研究进一步验证。利益冲突所有作者均声明不存在利益冲突作者贡献声明月刘向:是本研究的实验设计者,完成数据分析及论文初稿的写作;赵媛:参与实验设计和结果分析;高雅和李淑月:完成本实验中实验数据检测部分;杨国锋:是项目的构思者及负责人,指导实验设计,论文指导与修改参考文献1 Cannon JR,Greenamyre JT.Gene-environment interactions inParkinsons disease:specific evidence in humans and mammalianmodelsJJ.Neur
25、obiol Dis,2013,57:38-46.2Dauer W,Przedborski S.Parkinsons disease:mechanisms andmodelsJ.Neuron,2003,39(6):8 8 9-9 0 9.论著498脑与神经疾病杂志2 0 2 3年第31卷第8 期3Armstrong MJ,Okun MS.Diagnosis and treatment of Parkinsondisease:a reviewJJ.JAMA,2020,323(6):548-56 0.4Fang C,Lv L,Mao S,et al.Cognition deficits in Par
26、kinsons disease:mechanisms and treatmentJJ.Parkinsons Dis,2020,2020:2076942.5 Shen Y,Guo X,Han C,et al.The implication ofneuronimmunoendocrine(NIE)mo d u l a t o r y n e t w o r k i n t h epathophysiologic process of Parkinsons diseaseJ.Cell Mol Life Sci,2017,74(2 0):37 41-37 6 8.6刘军.中国帕金森病的诊断标准(2 0
27、 16 版)J.中华神经科杂志,2 0 16,49(4):2 6 8-2 7 1.7中华医学会神经病学分会帕金森病及运动障碍学组,中国医师协会神经内科医师分会帕金森病及运动障碍学组,中华医学会神经病学分会神经心理与行为神经病学学组.帕金森病痴呆的诊断标准与治疗指南(第二版)J.中华神经科杂志,2 0 2 1,54(8):7 6 2-7 7 1.8Jellinger KA,Korczyn AD.Are dementia with Lewy bodies andParkinsons disease dementia the same disease?J.BMC Med,2018,16(1):34.
28、9Fang C,Lv L,Mao S,et al.Cognition deficits in Parkinsons disease:mechanisms and treatmentJJ.Parkinsons Dis,2020,2020:2076942.10Mancini A,Di Segni C,Raimondo S,et al.Thyroid hormones,oxidative stress,and inflammationJ.Mediators Inflamm,2016,2016:6757154.11Mohammadi S,Dolatshahi M,Rahmani F.Shedding
29、light on thyroidhormone disorders and Parkinson disease pathology:mechanisms andrisk factorsJJ.J Endocrinol Invest,2021,44(1):1-13.12Aziz NA,Pijl H,Frolich M,et al.Diurnal secretion profiles of growthhormone,thyrotrophin and prolactin in Parkinsons diseaseJ.Neuroendocrinol,2011,23(6):519-524.13Choi
30、SM,Kim BC,Choi KH,et al.Thyroid status and cognitivefunction in euthyroid patients with early Parkinsons diseaseJ.Dement Geriatr Cogn Disord,2014,38(3-4):178-185.14徐燕平,陈应柱,李晓波,等.亚临床甲减对帕金森病患者认知功能的影响.中国实用神经疾病杂志,2 0 15,18(9):56-57.15Petrovic N,Cvijic G,Davidovic V.Thyroxine and tri-iodothyroninediffere
31、ntly affect uncoupling protein-1 content and antioxidantenzyme activities in rat interscapular brown adipose tissueJ.JEndocrinol,2003,176(1):31-38.16 Mohammadi S,Dolatshahi M,Rahmani F.Shedding light on thyroidhormone disorders and Parkinson disease pathology:mechanisms andrisk factorsJ.J Endocrinol
32、 Invest,2021,44(1):1-13.17Mazon JN,de Mello AH,Ferreira GK,et al.The impact of obesity onneurodegenerative diseasesJJ.Life Sci,2017,182:22-28.18Reich N,Holscher C.Acylated ghrelin as a multi-targeted therapyfor Alzheimers and Parkinsons diseaseJ.Front Neurosci,2020,14:614828.19Hornsby AKE,Buntwal L,
33、Carisi MC,et al.Unacylated-ghrelinimpairs hippocampal neurogenesis and memory in mice and isaltered in Parkinsons dementia in humansJJ.Cell Rep Med,2020,1(7):100120.20Leng Y,Musiek ES,Hu K,et al.Association between circadianrhythms and neurodegenerative diseasesJ.Lancet Neurol,2019,18(3):307-318.21
34、Breen DP,Nombela C,Vuono R,et al.Hypothalamic volume loss isassociated with reduced melatonin output in Parkinsons diseaseJ.Mov Disord,2016,31(7):10 6 2-10 6 6.儿童神经副肿瘤综合征11例赵青高超王唯一刘崇王欣【摘要】目的分析儿童神经副肿瘤综合征(PNS)的临床特点。方法分析2 0 17 年1月至2022年6 月河北省儿童医院收治的11例儿童PNS患者的临床特点、影像及实验室检查结果、治疗及预后等。结果神经母细胞源性肿瘤的PNS患者8 例
35、,其中7 例接受手术及化疗治疗,4例术后同时免疫治疗,仅1例遗留神经系统后遗症,随访至2 0 2 2 年9 月肿瘤均无复发;畸胎瘤抗N-甲基-D-天冬氨酸(NMDA)受体脑炎患者3例,2 例成熟性畸胎瘤,1例囊实性未成熟性畸胎瘤,均接受手术联合免疫治疗,随访至2022年9 月均无复发。结论以共济失调、眼震起病的0-3岁小年龄组的PNS患者应首先考虑神经母细胞源性肿瘤,以抗NMDA受体脑炎起病的女性儿童,需警惕畸胎瘤。对于肿瘤筛查阴性的患者长期随访、定期筛查是必要的。早期发现及治疗原发肿瘤是决定预后的重要因素。基金项目:河北省医学科学研究课题计划项目(2 0 2 110 0 8)作者单位:0 50 0 31石家庄,河北省儿童医院神经内科通信作者:王欣,Email:x i n b e h e v e