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Effect and Safety of Huannao Yicong Formula (还脑益聪方) in Patients with Mild-to-Moderate Alzheimer’s Disease: A Randomized, Double-Blinded, Donepezil-Controlled Trial

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Abstract

Objective

To assess the effect and safety of Huannao Yicong Formula (还脑益聪方, HYF) in the treatment of patients with mild-to-moderate Alzheimer’s disease (AD).

Methods

Sixty patients with mild-tomoderate AD were evenly randomized into HYF group and donepezil group with the random number method. Patients in the HYF group took 5 g of HYF granules twice daily and 5 mg placebo of donepezil once daily. Patients in the donepezil group took 5 mg donepezil once daily and 5 g placebo of HYF granules twice daily. The intervention lasted for 6 months. Clinical researchers, participants and statisticians were blinded to the treatment assignment throughout the study. The primary outcomes were scores of Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Chinese Medicine Symptom Scale (CM-SS). The secondary outcomes were scores of Montreal Cognitive Assessment (MoCA) test and Mini-Mental State Exam (MMSE). The serum levels of acetylcholinesterase (AchE) and amyloid-β protein 42 (Aβ42) were detected with enzymelinked immunosorbent assay kits. The scale assessments were conducted at baseline, the 3rd and 6th months of treatment, respectively. Biochemistry tests were conducted at baseline and the 6th month of treatment.

Results

A total of 52 patients completed the trial, 28 in HYF group and 24 in donepezil group. Compared with the baseline, HYF and donepezil signifificantly decreased the total scores of ADAS-Cog and CM-SS, and signifificantly increased the scores of MoCA and MMSE after 6-month treatment (all P<0.01). Both treatments remarkably reduced the serum levels of AchE and Aβ42 (both P<0.05). The CM-SS total effective rate of HYF was signifificantly higher than donepezil [75.00% (21/28) vs. 54.17% (13/24), P<0.05]. No severe adverse events were observed in both groups.

Conclusion

HYF is effective and safe for improving the cognitive function in mildto-moderate AD patients. [Trial registration: Chinese Clinical Trial Registry (Reg No. ChiCTR-IOR-17011746)]

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References

  1. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association Workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7:263–272.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Livingston G, Sommerlad A, Orgeta V, Costafreda S, Huntley J, Ames D, et al. Dementia prevention, intervention, and care. Lancet 2017;390:2673–2734.

    Article  PubMed  Google Scholar 

  3. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer’s disease. Lancet 2011;377:1019–1031.

    Article  PubMed  Google Scholar 

  4. Prince M, Comas–Herrera MA, Knapp M, Guerchet M, Karagiannidou MM. World Alzheimer Report 2016: improving healthcare for people living with dementia: coverage. Quality and costs now and in the future. Alzheimer’s Disease International (ADI), London, 2016. Available at http://eprints.lse.ac.uk/67858/

    Google Scholar 

  5. Blennow K, de Leon M, Zetterberg H. Alzheimer’s disease. Lancet 2006;368:387–403.

    Article  CAS  PubMed  Google Scholar 

  6. Egan M, Kost J, Tariot P, Aisen P, Cummings J, Vellas B, et al. Randomized trial of verubecestat for mild–to–moderate Alzheimer’s disease. N Engl J Med 2018;378:1691–1703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gauthier S, Feldman H, Schneider L, Wilcock G, Frisoni G, Hardlund J, et al. Efficacy and safety of tau–aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomized, controlled, double–blind, parallel–arm, phase 3 trial. Lancet 2016;388:2873–2884.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Steiner GZ, Yeung A, Liu JX, Camfield DA, De Blasio FM, Pipingas A, et al. The effect of Sailuotong (SLT) on neurocognitive and cardiovascular function in healthy adults: a randomized, double–blind, placebo controlled crossover pilot trial. BMC Complement Altern Med 2016;16:15–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang WT, Zheng XW, Chen S, Shan CS, Xu QQ, Zhu JZ, et al. Chinese herbal medicine for Alzheimer’s disease: clinical evidence and possible mechanism of neurogenesis. Biochem Pharmacol 2017;141:143–155.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang Y, Lin C, Zhang L, Cui Y, Gu Y, Guo J, et al. Cognitive improvement during treatment for mild Alzheimer’s disease with a Chinese herbal formula: a randomized controlled trial. PLoS One 2015;10:e0130353.

    Google Scholar 

  11. Shi J, Ni J, Lu T, Zhang X, Wei M, Li T, et al. Adding Chinese herbal medicine to conventional therapy brings cognitive benefits to patients with Alzheimer’s disease: a retrospective analysis. BMC Complement Altern Med 2017;17:533–539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cai LL, Li H, Liu JG, Liu LT, Guan J, Liu MF, et al. Effects of early intervention with Huannao Yicong Formula effective components on behavior and cholinergic system of betaamyloid precursor protein transgenic mice. J Chin Integr Med (Chin) 2011;9:292–298.

    Article  Google Scholar 

  13. Li H, Cai L, Liu J, Liu L, Guan J, Liu M, et al. Effect of early intervention with extract of Huannao Yicong Decoction on the pathologic picture of hippocampus and neurocyte apoptosis in APP transgenic mice model of dementia. Chin J Integr Med 2011;17:430–435.

    Article  PubMed  Google Scholar 

  14. Wang ZY, Liu JG, Wei Y, Liu MX, Wang Q, Liang L, et al. Huannao Yicong Formula regulates γ–secretase activity through APH–1 and PEN–2 gene regulation pathways in hippocampus of APP/PS1 double transgenic mice. Chin J Integr Med 2017;23:270–278.

    Article  CAS  PubMed  Google Scholar 

  15. Wang Q, Li H, Wang Fx, Gao L, Qin JC, Liu JG, et al. Huannao Yicong Decoction extract reduces inflammation and cell apoptosis in Aβ–induced Alzheimer’s disease model of rats. Chin J Integr Med 2017;23:672–680.

    Article  PubMed  Google Scholar 

  16. Li H, Liu M, Liu J, Liu L, Guan J, Cai L, et al. Effect of Huannao Yicong Prescription extract on β–amyloid precursor protein metabolic signal transduction–related protein in brain tissue of dementia model transgenic mouse. Chin J Integr Med 2012;18:683–689.

    Article  PubMed  Google Scholar 

  17. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fourth edition. Washington: American Psychiatric Association;1994:139–143.

    Google Scholar 

  18. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, et al. The diagnosisof dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association Workgroups on diagnostic guidelines for Alzheimer’sdisease. Alzheimers Dement 2011;7:263–269.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Fullerton T, Binneman B, David W, Delnomdedieu M, Kupiec J, Lockwood P, et al. A phase 2 clinical trial of PF–05212377 (SAM–760) in subjects with mild to moderate Alzheimer’s disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil. Alzheimers Res Ther 2018;10:38–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. O’Bryant SE, Waring SC, Cullum CM, Hall J, Lacritz L, Massman PJ, et al. Staging dementia using Clinical Dementia Rating Scale Sum of Boxes scores: a Texas Alzheimer’s research consortium study. Arch Neurol 2008;65:1091–1095.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53:695–699.

    Article  PubMed  Google Scholar 

  22. Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. BMJ 2010;340:c332.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža–Jeriž K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med 2013;158:200–207.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Li H, Yao MJ, Zhao WM, Guan J, Cai LL, Cui L. A randomized, controlled, double–blind trial of Huannao Yicong Capsule in senile patients with mild cognitive impairment. J Chin Integr Med (Chin) 2008;6:25–31.

    Article  Google Scholar 

  25. Wessels AM, Dowsett SA, Sims JR. Detecting treatment group differences in Alzheimer’s disease clinical trials: a comparison of Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS–Cog) and the Clinical Dementia Rating–Sum of Boxes (CDR–SB). J Prev Alzheimers Dis 2018;5:15–20.

    CAS  PubMed  Google Scholar 

  26. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–1364.

    Article  CAS  PubMed  Google Scholar 

  27. Verma N, Beretvas SN, Pascual B, Masdeu J, Markey MK. New scoring methodology improves the sensitivity of the Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS–Cog) in clinical trials. Alzheimers Res Ther 2015;7:64–80.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zheng XY, ed. Guiding principles of clinical research on new drugs of traditional Chinese medicine. Beijing: China Medical Science Press;2002:105–109.

    Google Scholar 

  29. Folstein MF, Folstein S, McHugh P. Mini–mental State. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.

    CAS  PubMed  Google Scholar 

  30. Kueper JK, Speechley M, Montero–Odasso M. The Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS–Cog): modifications and responsiveness in pre–dementia populations. A narrative review. J Alzheimers Dis 2018;63:423–444.

    Article  PubMed  Google Scholar 

  31. Trzepacz PT, Hochstetler H, Wang S, Walker B, Saykin A. Relationship between the Montreal Cognitive Assessment and Mini–mental State Examination for assessment of mild cognitive impairment in older adults. BMC Geriatr 2015;15:107–115.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Liu M, Wei Y, Yang Y, Liu L, Liang LG, Liu J, et al. Effects and mechanism of Huannao Yicong Decoction Extract on the ethology of transgenic APP/PS1 Mice. Evid Based Complement Alternat Med 2017;e9502067.

    Google Scholar 

  33. Mori T, Koyama N, Guillot–Sestier MV, Tan J, Town T. Ferulic acid is a nutraceutical β–secretase modulator that improves behavioral impairment and alzheimer–like pathology in transgenic mice. PLoS One 2013;8:e55774.

    Article  CAS  Google Scholar 

  34. Kim MJ, Choi SJ, Lim ST, Kim HK, Heo HJ, Kim EK, et al. Ferulic acid supplementation prevents trimethyltin–induced cognitive deficits in mice. Biosci Biotechnol Biochem 2007;71:1063–1068.

    Article  CAS  PubMed  Google Scholar 

  35. Jung HA, Min BS, Yokozawa T, Lee JH, Kim YS, Choi JS. Anti–Alzheimer and antioxidant activities of Coptidis Rhizoma alkaloids. Biol Pharm Bull 2009;32:1433–1438.

    Article  CAS  PubMed  Google Scholar 

  36. MAsai Iwata N, Yoshikawa A, Aizaki Y, Ishiura S, Saido TC, et al. Berberine alters the processing of Alzheimer’s amyloid precursor protein to decrease Aβ secretion. Biochem Biophys Res Commun 2007;352:498–502.

    Article  CAS  Google Scholar 

  37. Song XY, Hu JF, Chu SF, Zhang Z, Xu S, Yuan YH, et al. Ginsenoside Rg1 attenuates okadaic acid induced spatial memory impairment by the GSK3β/tau signaling pathway and the Aβ formation prevention in rats. Eur J Pharmacol 2013;710:29–38.

    Article  CAS  PubMed  Google Scholar 

  38. Wang Q, Sun LH, Jia W, Liu XM, Dang HX, Mai WL, et al. Comparison of ginsenosides Rg1 and Rb1 for their effects on improving scopolamine–induced learning and memory impairment in mice. Phytother Res 2010;24:1748–1754.

    Article  CAS  PubMed  Google Scholar 

  39. Tao L, Xie J, Wang Y, Wang S, Wu S, Wang Q, et al. Protective effects of aloe–emodin on scopolamine–induced memory impairment in mice and H2O2–induced cytotoxicity in PC12 cells. Bioorg Med Chem Lett 2014;24:5385–5389.

    Article  CAS  PubMed  Google Scholar 

  40. Liu T, Jin H, Sun QR, Xu JH, Hu HT. Neuroprotective effects of emodin in rat cortical neurons against β–amyloidinduced neurotoxicity. Brain Res 2010;1347:149–160.

    Article  CAS  PubMed  Google Scholar 

  41. Cho IH. Effects of Panax ginseng in neurodegenerative diseases. J Ginseng Res 2012;36:342–353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kim HJ, Kim P, Shin CY. A comprehensive review of the therapeutic and pharmacological effects of ginseng and ginsenosides in central nervous system. J Ginseng Res 2013;37:8–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 2016;8:595–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992;256:184–185.

    Article  CAS  PubMed  Google Scholar 

  45. Upadhaya AR, Lungrin I, Yamaguchi H, Fandrich M, Thal DR. High–molecular weight Abeta oligomers and protofibrils are the predominant Abeta species in the native soluble protein fraction of the AD brain. J Cell Mol Med 2012;16:287–295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, et al. Alzheimer’s disease–affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A 2003;100:10417–10422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. De Ferrari GV, Canales MA, Shin I, Weiner LM, Silman I, Inestrosa NC. A structural motif of acetylcholinesterase that promotes amyloid beta–peptide fibril formation. Biochemistry 2001;40:10447–10457.

    Article  CAS  PubMed  Google Scholar 

  48. Hou LN, Xu JR, Zhao QN, Gao XL, Cui YY, Xu J, et al. A new motif in the N–terminal of acetylcholinesterase triggers amyloid–beta aggregation and deposition. CNS Neurosci Ther 2014;20:59–66.

    Article  CAS  PubMed  Google Scholar 

  49. Li H, Liu MF, Liu JG, Liu LT, Guan J, Cai L, et al. Effects of Huannao Yicong Recipe extract on the learning and memory and related factors of Abeta generation in the brain of APP transgenic mice. Chin J Integr Tradit West Med (Chin) 2013;33:90–94.

    Google Scholar 

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Acknowledgement

We are grateful to Community Healthcare Centers of Jingzhuang Town, Yanqing District, Beijing and Xiaoshi Town, Sanhe, Hebei Province for participating and collecting data in this trial. We are also thankful to all those who provided excellent professional support and assistance during the study.

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Authors and Affiliations

  1. Graduate School, Beijing University of Chinese Medicine, Beijing, 100029, China

    Yang Yang, Jun-yan Fang & Hui-chan Wang

  2. Department of Geratology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China

    Yang Yang, Hui-chan Wang, Yun Wei, Yu Cao & Hao Li

  3. Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China

    Jian-ping Liu

  4. Department of Traditional Chinese Medicine, Tongling Hospital of Integrated Traditional Chinese and Western Medicine, Tongling, Anhui Province, 244099, China

    Jun-yan Fang

  5. Department of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China

    Jian-gang Liu & Long-tao Liu

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  1. Yang Yang
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Correspondence to Hao Li.

Additional information

Supported by the National Science and Technology Projects for Significant Major New Drug Creation (No. 2009ZX09103391), the National Natural Science Foundation of China (No. 81573819), and the Self-determined Project of China Academy of Chinese Medical Sciences (No. ZZ0808003)

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Yang, Y., Liu, Jp., Fang, Jy. et al. Effect and Safety of Huannao Yicong Formula (还脑益聪方) in Patients with Mild-to-Moderate Alzheimer’s Disease: A Randomized, Double-Blinded, Donepezil-Controlled Trial. Chin. J. Integr. Med. 25, 574–581 (2019). https://doi.org/10.1007/s11655-018-3054-7

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