盐酸美金刚联合多奈哌齐治疗阿尔茨海默病女性患者的临床研究

Clinical study on treatment of female patients with Alzheimer's disease with memantine hydrochloride combined with donepezil

摘要

目的 探究盐酸美金刚联合多奈哌齐治疗阿尔茨海默病(AD)女性患者的疗效及其精神行为症状(BPSD)、血清相关因子的影响。方法 选择2020年7月至2023年6月于我院治疗的女性AD患者120例,依据随机数字表法分为联合组(n=60)、对照组(n=60)。对照组行多奈哌齐治疗,联合组行盐酸美金刚和多奈哌齐联合治疗。观察并分析治疗前后两组患者的BPSD、智力及认知功能[分别采用阿尔茨海默病病理行为评定量表(BEHAVE-AD)、简易智力状态检查量表(MMSE)、阿尔茨海默病评估量表认知量表(ADAS-Cog)评估]以及血清脑源性神经营养因子(BDNF)、胶原蛋白三螺旋重复蛋白1(CTHRC1)及组织金属蛋白酶抑制剂3(TIMP3)的水平。结果 治疗后,联合组BEHAVE-AD评分、ADAS-Cog评分及血清CTHRC1水平低于对照组,差异有统计学意义(t值介于5.541~27.989之间,P<0.001),MMSE评分及血清BDNF、TIMP3水平高于对照组,差异有统计学意义(t值介于4.201~6.579之间,P<0.001);联合组总有效率大于对照组,差异有统计学意义(96.67% vs. 85.00%,χ²=4.863,P<0.05)。两组不良反应发生率差异无统计学意义(10.00% vs. 6.67%,χ²=0.433,P>0.05)。结论 盐酸美金刚联合多奈哌齐治疗阿尔茨海默病女性患者可有效改善其精神行为症状、智力及认知功能,纠正异常血清CTHRC1、BDNF、TIMP3水平,疗效显著且安全可靠。

Abstract

Objective To explore therapeutic effect of memantine hydrochloride combined with donepezil on Alzheimer's disease (AD) in female patients and its influence on behavioral and psychological symptoms of dementia (BPSD) and serum-related factors of the female AD patients. Methods A total of 120 female patients with AD who were treated in our hospital from July 2020 to June 2023 were selected and divided into combination group (n=60) and control group (n=60) in random number table method. The female patients in the control group were treated with donepezil only, while the female patients in the combination group were treated with memantine hydrochloride combined with donepezil. Behavioral Pathology in Alzheimer's Disease Rating Scale (called BEHAVE-AD in simple) was used to evaluate BPSD. Mini-Mental State Examination (MMSE) was used to evaluate intelligence level and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) was used to evaluate cognitive function of the patients before and after treatment. In addition, the serum levels of brain-derived neurotrophic factor (BDNF), collagen triple helix repeat protein 1 (CTHRC1) and tissue metalloproteinase inhibitor 3 (TIMP3) of the patients in the two groups were detected before and after treatment. All results were analyzed and compared between the two groups. Results After treatment, the scores in BEHAVE-AD and ADAS-Cog and serum CTHRC1 level of the patients in the combination group were lower than those in the control group, and the differences were statistically significant (t=5.541-27.989, all P<0.001), while the score in MMSE and the serum BDNF and TIMP3 levels were higher than those in the control group, and the differences were statistically significant (t=4.201-6.579, all P<0.001). The total effective rate in the combination group was greater than that in the control group, and the difference was statistically significant (96.67% vs. 85.00%, χ²=4.863, P<0.05). There was no statistically significant difference in incidence of adverse reactions between the two groups (10.00% vs. 6.67%, χ²=0.433, P>0.05). Conclusion Memantine hydrochloride combined with donepezil can effectively improve BPSD, intelligence level and cognitive function of the female AD patients, correct their abnormal serum levels of CTHRC1, BDNF and TIMP3, with significant curative effect, high safety and high reliability.

关键词

女性 / 阿尔茨海默病 / 盐酸美金刚 / 多奈哌齐 / 精神行为症状 / 血清相关因子

Key words

female / Alzheimer's disease / memantine hydrochloride / donepezil / mental and behavioral symptoms of dementia / serum-related factor

参考文献

[1] Knopman D S, Amieva H, Petersen R C, et al. Alzheimer's disease[J]. Nat Rev Dis Primers, 2021, 7(1): 33.

[2] 董倩, 马青艳, 姜文慧, 等. 同伴关系与环境敏感性对青春期女性心理健康的影响及其相互作用的理论模型[J]. 中国妇幼健康研究, 2024, 35(2): 8-15.

[3] Rostagno A A. Pathogenesis of Alzheimer's disease[J]. Int J Mol Sci, 2022, 24(1): 107.

[4] 王爱花, 徐锐, 林荫. 重复经颅磁刺激联合盐酸多奈哌齐对阿尔茨海默病患者认知功能和血清炎症因子的影响[J]. 临床与病理杂志, 2023, 43(6): 1199-1205.

[5] 袁丹, 王海鹏, 王英鹏, 等. 美金刚联合盐酸多奈哌齐对阿尔茨海默病患者认知功能及神经递质的影响[J]. 脑与神经疾病杂志, 2022, 30(2): 71-75.

[6] Athar T, Al Balushi K, Khan S A. Recent advances on drug development and emerging therapeutic agents for Alzheimer's disease[J]. Mol Biol Rep, 2021, 48(7): 5629-5645.

[7] 李冬梅. 经颅磁刺激联合药物治疗阿尔茨海默病改善患者认知功能、精神行为症状及神经递质的效果[J]. 中国临床医生杂志, 2023, 51(10): 1183-1185.

[8] Graff-Radford J, Yong K X X, Apostolova L G, et al. New insights into atypical Alzheimer's disease in the era of biomarkers[J]. Lancet Neurol, 2021, 20(3): 222-234.

[9] 中国痴呆与认知障碍写作组, 中国医师协会神经内科医师分会认知障碍疾病专业委员会. 2018中国痴呆与认知障碍诊治指南(二):阿尔茨海默病诊治指南[J]. 中华医学杂志, 2018, 98(13): 971-977.

[10] Boada M, Tárraga L, Modinos G, et al. Behavioral pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD):Spanish validation. Neurologia[J]. 2006, 21(1): 19-25.

[11] Galea M, Woodward M. Mini-Mental State Examination (MMSE)[J]. Aust J Physiother, 2005, 51(3): 198.

[12] Kueper J K, Speechley M, Montero-Odasso M, et al. The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog):Modifications and Responsiveness in Pre-Dementia Populations.A Narrative Review[J]. J Alzheimers Dis, 2018, 63(2): 423-444.

[13] Balázs N, Bereczki D, Kovács T. Cholinesterase inhibitors and memantine for the treatment of Alzheimer and non-Alzheimer dementias[J]. Ideggyogy Sz, 2021, 74(11-12): 379-387.

[14] 王德端, 莫双铭, 邓利华. 盐酸美金刚联合尼莫地平治疗老年阿尔茨海默病患者的临床疗效观察[J]. 老年医学与保健, 2022, 28(3): 517-520.

[15] Kaur A, Nigam K, Srivastava S, et al. Memantine nanoemulsion:a new approach to treat Alzheimer's disease[J]. J Microencapsul, 2020, 37(5): 355-365.

[16] Ogbodo J O, Agbo C P, Njoku U O, et al. Alzheimer's Disease:Pathogenesis and Therapeutic Interventions[J]. Curr Aging Sci, 2022, 15(1): 2-25.

[17] Saeedi M, Mehranfar F. Challenges and Approaches of Drugs Such as Memantine,Donepezil,Rivastigmine,and Aducanumab in the Treatment,Control and Management of Alzheimer's Disease[J]. Recent Pat Biotechnol, 2022, 16(2): 102-121.

[18] Serrano-Pozo A, Das S, Hyman BT. APOE and Alzheimer's disease:advances in genetics,pathophysiology,and therapeutic approaches. Lancet Neurol, 2021, 20(1): 68-80.

[19] 程子昭, 张兰. 线粒体功能障碍在阿尔茨海默病中的研究进展[J]. 中国药理学与毒理学杂志, 2023, 37(7): 514.

[20] Wang H, Dey K K, Chen P C, et al. Integrated analysis of ultra-deep proteomes in cortex,cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer's disease[J]. Mol Neurodegener, 2020, 15(1): 43.

[21] 陈俊, 郑锦豪, 陈家良, 等. 阿尔茨海默病患者血清GGT、CTHRC1表达水平检测及临床意义[J]. 天津医药, 2023, 51(2): 216-220.

[22] Gao L, Zhang Y, Sterling K, et al. Brain-derived neurotrophic factor in Alzheimer's disease and its pharmaceutical potential[J]. Transl Neurodegener, 2022, 11(1): 4.

[23] 张海辉, 郭欣颖, 孙宁, 等. 剖宫产术后焦虑抑郁女性血清脑源性神经营养因子和酪氨酸激酶受体B表达水平及临床意义[J]. 中国妇幼保健, 2023, 38(19): 3669-3673.

[24] 史晓玲, 马小云, 拜翠莲. 手足口病合并脑炎患儿血清和脑脊液中MMP-9和TIMP-1水平的临床价值分析[J]. 中国妇幼健康研究, 2023, 34(5): 16-24.

[25] Park J H, Cho S J, Jo C, et al. Altered TIMP-3 Levels in the Cerebrospinal Fluid and Plasma of Patients with Alzheimer's Disease. J Pers Med, 2022, 12(5): 827.

[26] 周慧敏, 陈静, 王御林, 等. 阿尔茨海默病患者血清Ang、TIMP3水平与β-淀粉样蛋白沉积及认知功能的关系[J]. 国际检验医学杂志, 2023, 44(4): 416-420.

基金资助

浙江省基础公益研究计划(LGF22H090055)