Effectiveness of Yi-Zhi-An-Shen granules on cognition and sleep quality in older adults with amnestic mild cognitive impairment: protocol for a randomized, double-blind, placebo-controlled trial

Shengnan Yue, Ting He, Baiyang Li, Yanqin Qu, Hongmei Peng, Jinxin Chen, Ming Lei, Chongli Chen, Wenbin Wu, Shengnan Yue, Ting He, Baiyang Li, Yanqin Qu, Hongmei Peng, Jinxin Chen, Ming Lei, Chongli Chen, Wenbin Wu

Abstract

Background: Amnestic mild cognitive impairment (aMCI) is a syndrome characterized by significant forgetfulness that does not meet the criteria of dementia. Individuals with aMCI are at greater risk of progressing to dementia. Current studies suggest that good sleep quality is linked with preserved cognition in the elderly, and sleep complaints are common among the elderly with amnesia. Therefore, improving their sleep may be helpful for maintaining and improving their cognitive capacity. According to the theory of traditional Chinese medicine, Yi-Zhi-An-Shen is an herbal compound which may ameliorate forgetfulness and sleep disorders. As growing evidence indicates that the gut microbiome is associated with major mental symptoms, a hypothesis was proposed that Yi-Zhi-An-Shen granules (YZASG) might work by alternating microbial abundance and diversity. In this study, the investigators intend to assess the efficacy of YZASG on global cognition in the elderly suffering from aMCI and evaluate its safety as well as its potential mechanisms via sleep quality, fecal microbial 16S ribosomal DNA and metagenomics analyses, and serum markers.

Methods/design: This study is a randomized, double-blind, placebo-controlled clinical trial. A total of 80 patients (aged 60-85 years) will be recruited and allocated randomly to a treatment group and a placebo group in a 1:1 ratio and will then be administered YZASG or isodose placebo three times a day. The intervention course is 16 weeks, with an 18 months follow-up. The primary outcome is the Alzheimer's Disease Assessment Scale-Cognitive Subscale. Secondary outcome measures are the Mini-Mental State Examination, Montreal Cognitive Assessment, Pittsburgh Sleep Quality Index, serum concentrations of immunological factors and inflammatory cytokines, and fecal microbiota. Fecal microbiota will only be collected at the baseline and endpoint of the intervention.

Discussion: The results of this trial will be conducive to assessing the safety and effectiveness on cognition of YZASG in intervening aMCI among the elderly and determining if it takes effect via the improvement of sleep quality, regulation of gut microbiota, and concentration of certain serum markers.

Trial registration: ClinicalTrials.gov, NCT03601000 . Registered on 26 July 2018.

Keywords: Amnestic mild cognitive impairment; Gut microbiome; Older adults; Sleep.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schedule of interventions and assessments. Abbreviations: ADAS-cog Alzheimer’s Disease Assessment Scale-Cognitive Subscale, MMSE Mini-Mental State Examination, MoCA Montreal Cognitive Assessment, CDR Clinical Dementia Rating, PSQI Pittsburgh Sleep Quality Index, ADL activities of daily living, 16S rDNA 16S ribosomal deoxyribonucleic acid, ECG electrocardiography, CT computed tomography, MRI magnetic resonance imaging. Vital signs include an individual’s temperature, breaths and pulse per minute, and blood pressure
Fig. 2
Fig. 2
Flowchart of the trial

References

    1. Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med. 2010;362:329–344. doi: 10.1056/NEJMra0909142.
    1. Alzheimer’s Disease International . World Alzheimer’s Report 2016. London: Alzheimer’s Disease International; 2017.
    1. Jia J, Wang F, Wei C, et al. The prevalence of dementia in urban and rural areas of China. Alzheimers Dement. 2014;10:1–9. doi: 10.1016/j.jalz.2013.01.012.
    1. Silverberg N, Elliott C, Ryan L, Masliah E, Hodes R. NIA commentary on the NIA-AA Research Framework: towards a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14:576–578. doi: 10.1016/j.jalz.2018.03.004.
    1. Magaki S, Mueller C, Dickson C, Kirsch W. Increased production of inflammatory cytokines in mild cognitive impairment. Exp Gerontol. 2007;42:233–240. doi: 10.1016/j.exger.2006.09.015.
    1. Petersen RC. Mild cognitive impairment: transition from aging to Alzheimer's disease. In: Iqbal K, Sisodia SS, Winblad B, editors. Alzheimer's disease: advances in etiology, pathogenesis and therapeutics. Hoboken: Wiley; 2001. pp. 141–151.
    1. Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352:2379–2388. doi: 10.1056/NEJMoa050151.
    1. Petersen RC, Lopez O, Armstrong MJ, et al. Practice guideline update summary: mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90:126–135. doi: 10.1212/WNL.0000000000004826.
    1. Zhong G, Naismith SL, Rogers NL, Lewis SJ. Sleep-wake disturbances in common neurodegenerative diseases: a closer look at selected aspects of the neural circuitry. J Neurol Sci. 2011;307:9–14. doi: 10.1016/j.jns.2011.04.020.
    1. Lim J, Dinges DF. A meta-analysis of the impact of short-term sleep deprivation on cognitive variables. Psychol Bull. 2010;136:375–389. doi: 10.1037/a0018883.
    1. Diekelmann S, Born J. The memory function of sleep. Nat Rev Neurosci. 2010;11:114–126. doi: 10.1038/nrn2762.
    1. Beaulieu-Bonneau S, Hudon C. Sleep disturbances in older adults with mild cognitive impairment. Int Psychogeriatr. 2009;21:654–666. doi: 10.1017/S1041610209009120.
    1. Bliwise DL, Mercaldo ND, Avidan AY, Boeve BF, Greer SA, Kukull WA. Sleep disturbance in dementia with Lewy bodies and Alzheimer's disease: a multicenter analysis. Dement Geriatr Cogn Disord. 2011;31:239–246. doi: 10.1159/000326238.
    1. Moran M, Lynch CA, Walsh C, Coen R, Coakley D, Lawlor BA. Sleep disturbance in mild to moderate Alzheimer's disease. Sleep Med. 2005;6:347–352. doi: 10.1016/j.sleep.2004.12.005.
    1. Potvin O, Lorrain D, Forget H, et al. Sleep quality and 1-year incident cognitive impairment in community-dwelling older adults. Sleep. 2012;35:491–499. doi: 10.5665/sleep.1732.
    1. Saint MM, Sforza E, Barthelemy JC, Thomas-Anterion C, Roche F. Does subjective sleep affect cognitive function in healthy elderly subjects? The Proof cohort. Sleep Med. 2012;13:1146–1152. doi: 10.1016/j.sleep.2012.06.021.
    1. Malkki H. Alzheimer disease: sleep alleviates AD-related neuropathological processes. Nat Rev Neurol. 2013;9:657. doi: 10.1038/nrneurol.2013.230.
    1. Neylan TC, Mueller SG, Wang Z, et al. Insomnia severity is associated with a decreased volume of the CA3/dentate gyrus hippocampal subfield. Biol Psychiatry. 2010;68:494–496. doi: 10.1016/j.biopsych.2010.04.035.
    1. Schliebs R, Arendt T. The significance of the cholinergic system in the brain during aging and in Alzheimer's disease. J Neural Transm. 2006;113:1625–1644. doi: 10.1007/s00702-006-0579-2.
    1. Moraes WS, Poyares DR, Guilleminault C, Ramos LR, Bertolucci PH, Tufik S. The effect of donepezil on sleep and REM sleep EEG in patients with Alzheimer disease: a double-blind placebo-controlled study. Sleep. 2006;29:199–205. doi: 10.1093/sleep/29.2.199.
    1. Cooke JR, Loredo JS, Liu L, et al. Acetylcholinesterase inhibitors and sleep architecture in patients with Alzheimer's disease. Drugs Aging. 2006;23:503–511. doi: 10.2165/00002512-200623060-00005.
    1. Cardinali DP, Furio AM, Brusco LI. Clinical aspects of melatonin intervention in Alzheimer’s disease progression. Curr Neuropharmacol. 2010;8:218. doi: 10.2174/157015910792246209.
    1. Cardinali DP, Vigo DE, Olivar N, Vidal MF, Furio AM, Brusco L. Therapeutic application of melatonin in mild cognitive impairment. Am J Neurodegenerative Dis. 2012;1:280.
    1. Winblad B, Gauthier S, Scinto L, et al. Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology. 2008;70:2024–2035. doi: 10.1212/01.wnl.0000303815.69777.26.
    1. Peters O, Lorenz D, Fesche A, et al. A combination of galantamine and memantine modifies cognitive function in subjects with amnestic MCI. J Nutr Health Aging. 2012;16:544–548. doi: 10.1007/s12603-012-0062-8.
    1. Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to Alzheimer's disease. N Engl J Med. 2018;378:321–330. doi: 10.1056/NEJMoa1705971.
    1. He B, Xu F, Xiao F, et al. Neuroprotective effects of nootkatone from Alpiniae oxyphyllae Fructus against amyloid-beta-induced cognitive impairment. Metab Brain Dis. 2018;33:251–259. doi: 10.1007/s11011-017-0154-6.
    1. Liu ZK, Ng CF, Shiu HT, et al. Neuroprotective effect of Da Chuanxiong Formula against cognitive and motor deficits in a rat controlled cortical impact model of traumatic brain injury. J Ethnopharmacol. 2018;217:11–22. doi: 10.1016/j.jep.2018.02.004.
    1. Guan D, Su Y, Li Y, et al. Tetramethylpyrazine inhibits CoCl2-induced neurotoxicity through enhancement of Nrf2/GCLc/GSH and suppression of HIF1alpha/NOX2/ROS pathways. J Neurochem. 2015;134:551–565. doi: 10.1111/jnc.13161.
    1. Michel HE, Tadros MG, Esmat A, Khalifa AE, Abdel-Tawab AM. Tetramethylpyrazine ameliorates rotenone-induced Parkinson’s disease in rats: involvement of its anti-inflammatory and anti-apoptotic actions. Mol Neurobiol. 2017;54:4866–4878. doi: 10.1007/s12035-016-0028-7.
    1. Ringman JM, Frautschy SA, Teng E, et al. Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimers Res Ther. 2012;4:43. doi: 10.1186/alzrt146.
    1. Vidal B, Vazquez-Roque RA, Gnecco D, et al. Curcuma treatment prevents cognitive deficit and alteration of neuronal morphology in the limbic system of aging rats. Synapse. 2017;71:e21952. doi: 10.1002/syn.21952.
    1. Zhao C, Zhang H, Li H, et al. Geniposide ameliorates cognitive deficits by attenuating the cholinergic defect and amyloidosis in middle-aged Alzheimer model mice. Neuropharmacology. 2017;116:18–29. doi: 10.1016/j.neuropharm.2016.12.002.
    1. Zang CX, Bao XQ, Li L, et al. The protective effects of Gardenia jasminoides (Fructus Gardenia) on amyloid-beta-induced mouse cognitive impairment and neurotoxicity. Am J Chin Med. 2018;46:389–405. doi: 10.1142/S0192415X18500192.
    1. Zheng M, Qu L, Lou Y. Effects of icariin combined with Panax notoginseng saponins on ischemia reperfusion-induced cognitive impairments related with oxidative stress and CA1 of hippocampal neurons in rat. Phytother Res. 2008;22:597–604. doi: 10.1002/ptr.2276.
    1. Huang JL, Feng YQ, Bai LR, et al. Fraction n-butanol of Radix Notoginseng protects PC12 cells from Abeta25-35-induced cytotoxicity and alleviates cognitive deficits in SAMP8 mice by attenuating oxidative stress and Abeta accumulation. Evid Based Complement Alternat Med. 2017;2017:8469754.
    1. Wu WB, Xie SL, Lei M, Zhang TM, Zhang WW. Research on extraction process of Yizhi Anshen oral liquid. Pharm Clin Chinese Materia Medica. 2016;7:27–30.
    1. Yang K, Xie SL, Zhang X, Lei M, Wu WB. Effects of Xiangshao capsules on hormone and 5-HT receptors in older female rats. Pharmacol Clin Chinese Materia Medica. 2015;31:207–210.
    1. Frohlich EE, Farzi A, Mayerhofer R, et al. Cognitive impairment by antibiotic-induced gut dysbiosis: analysis of gut microbiota-brain communication. Brain Behav Immun. 2016;56:140–155. doi: 10.1016/j.bbi.2016.02.020.
    1. Cattaneo A, Cattane N, Galluzzi S, et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging. 2017;49:60–68. doi: 10.1016/j.neurobiolaging.2016.08.019.
    1. Mahmoudian Dehkordi S, Arnold M, Nho K, et al. Altered bile acid profile associates with cognitive impairment in Alzheimer's disease—an emerging role for gut microbiome. Alzheimers Dement. 2019;15:76–92. doi: 10.1016/j.jalz.2018.07.217.
    1. Molnar FJ, Man-Son-Hing M, Fergusson D. Systematic review of measures of clinical significance employed in randomized controlled trials of drugs for dementia. J Am Geriatr Soc. 2009;57:536–546. doi: 10.1111/j.1532-5415.2008.02122.x.
    1. Miao YC, Tian JZ, Shi J, Mao M. Effects of Chinese medicine for tonifying the kidney and resolving phlegm and blood stasis in treating patients with amnestic mild cognitive impairment: a randomized, double-blind and parallel-controlled trial. Zhong Xi Yi Jie He Xue Bao. 2012;10:390–397. doi: 10.3736/jcim20120407.

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