BACKGROUND: Gut microbiota may influence brain functions. Therefore, we prepared a study protocol for a double-blind, crossover, randomized clinical trial to determine the complex effects of human probiotics on memory, psychological, and biological measures in the elderly. METHODS: We selected eligible participants using an effective electronic questionnaire containing the inclusion and exclusion criteria and a brief electronic cognitive test. One-third of the respondents with the worst cognitive scores on the electronic test are randomized to group A, starting with a 3-month probiotic intervention, and to group B, starting with a placebo. In a crossover design, both groups change their intervention/placebo status after 3 months for the next 3 months. Participants refusing longer personal assessments due to the COVID-19 pandemic were randomly allocated to one of two subgroups assessed online. Participants in both groups are matched in age, education, gender, and cognitive scores on electronic testing at baseline. At three time points, participants are assessed using a neuropsychological battery, self-report measures of mood, a physical fitness test, blood, urine, and stool samples, and actigraphy. A subset of participants also provided their biological samples and underwent the neuropsychological battery in an extended testing phase 3 months after study termination to find out the long-term effect of the intervention. DISCUSSION: This is the first trial to address the comprehensive effects of human probiotics on memory and many other measures in the elderly. We assume that the probiotic group will have better outcomes than the placebo group after the first and second trimesters. We expect that the probiotic effect will persist for the next 3 months. These study's findings will contribute to an interesting area of how to improve memory, psychological and biological and other factors naturally and will examine the importance of probiotics for overall health in the elderly. CLINICAL TRIAL REGISTRATION: [clinicaltrials.gov], identifier [NCT05051501].

3rd Faculty of Medicine Charles University Prague Czechia

Department of Neurology Faculty Hospital Královské Vinohrady Prague Czechia

National Institute of Mental Health Prague Czechia

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Akbari E., Asemi Z., Kakhaki R. D., Bahmani F., Kouchaki E., Tamtaji O. R., et al. (2016). Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer’s disease: A randomized, double-blind and controlled trial. Front. Aging Neurosci. 8:256. 10.3389/fnagi.2016.00256 PubMed DOI PMC

Bartos A. (2018). Remember PICNIR – a short test of picture naming and their recall aimed for early detection of cognitive impairment [article in Czech Pamatujte na POBAV – krátký test pojmenování obrázků a jejich vybavení sloužící ke včasnému záchytu kognitivních poruch]. Neurol. Praxi 19(Suppl.1), 5–10.

Bartos A. (2016). Do not test but PICNIR (ENTERTAIN) - Written intentional naming of pictures and their recall as a brief cognitive test [article in Czech Netestuj, ale POBAV - písemné záměrné pojmenování obrázků a jejich vybavení jako krátká kognitivní zkouška]. Cesk. Slov. Neurol. N 79/112, 671–679.

Bartos A. (2019). Two original Czech tests for memory evaluation in three minutes – Amnesia Light and Brief Assessment (ALBA) [article in Czech Dvě původní české zkoušky k vyšetření paměti za tři minuty – Amnesia Light and Brief Assessment (ALBA)]. Cesk. Slov. Neurol. N. 82 420–429. 10.14735/amcsnn2019420 DOI

Bartos A. (2021). ALBA and PICNIR tests used for simultaneous examination of two patients with dementia and their adult children. Cesk. Slov. Neurol. 84 583–586. 10.48095/cccsnn2021583 DOI

Bartos A., Diondet S. (2020). Amnesia Light and Brief Assessment (ALBA) test – the second version and repeated examinations [article in Czech Test Amnesia Light and Brief Assessment (ALBA) – druhá verze a opakovaná vyšetření]. Cesk. Slov. Neurol. N. 82 535–543. 10.14735/amcsnn2020535 DOI

Bartos A., Fayette D. (2018). Validation of the Czech Montreal cognitive assessment for mild cognitive impairment due to Alzheimer disease and Czech norms in 1,552 elderly persons. Dement. Geriatr. Cogn. Disord. 46 335–345. 10.1159/000494489 PubMed DOI

Bartos A., Hohinova M., Holla M. (2020). High electronic name agreement of 70 pictures in normative study of 5,290 Czechs for easy multicultural replication. Appl. Neuropsychol. Adult. 29 333–344. 10.1080/23279095.2020.1753744 PubMed DOI

Bartos A., Janoušek M., Petroušová R., Hohinová M. (2016). Three times of the clock drawing test rated with BaJa scoring in patients with early Alzheimer ‘s disease [article in Czech Tři časy Testu kreslení hodin hodnocené BaJa skórováním u časné Alzheimerovy nemoci]. Cesk. Slov. Neurol. 112 406–412.

Bartos A., Krejcova M. (2022). Development of the electronic memory test for the elderly (ALBAV) [article in Czech Vývoj elektronického testu paměti pro starší osoby (ALBAV)]. Cesk. Slov. Neurol. N 85 in press.

Bartos A., Raisova M. (2016). The Mini-Mental State Examination: Czech norms and cutoffs for mild dementia and mild cognitive impairment due to Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 42 50–57. 10.1159/000446426 PubMed DOI

Bean J. (2011). “Rey auditory verbal learning test, rey AVLT,” in Encyclopedia of clinical neuropsychology, eds Kreutzer J. S., DeLuca J., Caplan B. (New York, NY: Springer; ), 2174–2175.

Beck A. T., Epstein N., Brown G., Steer R. A. (1988). An inventory for measuring clinical anxiety: Psychometric properties. J. Consult. Clin. Psychol. 56 893–897. 10.1037//0022-006x.56.6.893 PubMed DOI

Beck A. T., Steer R. A., Brown G. K. (1996). Beck depression inventory (BDI-II), Vol. 10. London: Pearson.

Bercik P., Verdu E. F., Foster J. A., MacRi J., Potter M., Huang X., et al. (2010). Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology 139 2102–2112. 10.1053/j.gastro.2010.06.063 PubMed DOI

Boehme M., Guzzetta K. E., Bastiaanssen T. F. S., van de Wouw M., Moloney G. M., Gual-Grau A., et al. (2021). Microbiota from young mice counteracts selective age-associated behavioral deficits. Nat. Aging 1 666–676. 10.1038/s43587-021-00093-9 PubMed DOI

Bravo J. A., Forsythe P., Chew M. V., Escaravage E., Savignac H. M., Dinan T. G., et al. (2011). Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl. Acad. Sci. U.S.A. 108 16050–16055. 10.1073/pnas.1102999108 PubMed DOI PMC

Collins S. M., Surette M., Bercik P. (2012). The interplay between the intestinal microbiota and the brain. Nat. Rev. Microbiol. 10 735–742. 10.1038/nrmicro2876 PubMed DOI

Desbonnet L., Garrett L., Clarke G., Bienenstock J., Dinan T. G. (2008). The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat. J. Psychiatr. Res. 43 164–174. 10.1016/j.jpsychires.2008.03.009 PubMed DOI

Desbonnet L., Garrett L., Clarke G., Kiely B., Cryan J. F., Dinan T. G. (2010). Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 170 1179–1188. 10.1016/j.neuroscience.2010.08.005 PubMed DOI

Eastwood J., Walton G., Van Hemert S., Williams C., Lamport D. (2021). The effect of probiotics on cognitive function across the human lifespan: A systematic review. Neurosci. Biobehav. Rev. 128 311–327. 10.1016/j.neubiorev.2021.06.032 PubMed DOI

Faul F., Erdfelder E., Lang A.-G., Buchner A. (2007). G * Power 3 : A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav. Res. Methods 39 175–191. 10.3758/bf03193146 PubMed DOI

Handajani Y. S., Turana Y., Yogiara Y., Sugiyono S. P., Lamadong V., Widjaja N. T., et al. (2022). Effects of tempeh probiotics on elderly with cognitive impairment. Front. Aging Neurosci. 14:891773. 10.3389/fnagi.2022.891773 PubMed DOI PMC

Huang S. Y., Chen L. H., Wang M. F., Hsu C. C., Chan C. H., Li J. X., et al. (2018). Lactobacillus paracasei PS23 delays progression of age-related cognitive decline in senescence accelerated mouse prone 8 (SAMP8) mice. Nutrients 10 1–13. 10.3390/nu10070894 PubMed DOI PMC

Kaufman A. S., Lichtenberger E. O. (2005). Assessing adolescent and adult intelligence. Hoboken, NJ: John Wiley & Sons.

Klann E. M., Dissanayake U., Gurrala A., Farrer M., Shukla A. W., Ramirez-Zamora A., et al. (2022). The gut–brain axis and its relation to Parkinson’s disease: A review. Front. Aging Neurosci. 13:782082. 10.3389/fnagi.2021.782082 PubMed DOI PMC

Lach H. W., Chang Y.-P., Edwards D. (2010). Can older adults with dementia accurately report depression using brief forms? Reliability and validity of the Geriatric Depression Scale. J. Gerontol. Nurs. 36 30–37. 10.3928/00989134-20100303-01 PubMed DOI

Lesher E. L., Berryhill J. S. (1994). Validation of the geriatric depression scale - short form among inpatients. J. Clin. Psychol. 50 256–260. PubMed

Lezak M. D., Howieson D. B., Bigler E. D., Tranel D. (2012). Neuropsychological assessment. New York, NY: Oxford University Press.

Li B., Deng A., Li K., Hu Y., Li Z., Xiong Q., et al. (2022). Viral infection and transmission in a large, well-traced outbreak caused by the SARS-CoV-2 Delta variant. Nat. Commun. 13:460. 10.1038/s41467-022-28089-y PubMed DOI PMC

Li H., Ni J., Qing H. (2021). Gut microbiota: Critical controller and intervention target in brain aging and cognitive impairment. Front. Aging Neurosci. 13:671142. 10.3389/fnagi.2021.671142 PubMed DOI PMC

Marotta A., Sarno E., Del Casale A., Pane M., Mogna L., Amoruso A., et al. (2019). Effects of probiotics on cognitive reactivity, mood, and sleep quality. Front. Psychiatry 10:164. 10.3389/fpsyt.2019.00164 PubMed DOI PMC

Mukilan M. (2022). Effects of probiotics, prebiotics and synbiotic supplementation on cognitive impairment: A review. J. Exp. Biol. 10 1–11. 10.18006/2022.10(1).1.11 PubMed DOI

Oosterman J. M., Vogels R. L. C., Van Harten B., Gouw A. A., Poggesi A., Scheltens P., et al. (2010). Assessing mental flexibility: Neuroanatomical and neuropsychological correlates of the trail making test in elderly people. Clin.Neuropsychol. 24 203–219. 10.1080/13854040903482848 PubMed DOI

Pfeffer R. I., Kurosaki T. T., Harrah C. H., Jr., Chance J. M., Filos S. (1982). Measurement of functional activities in older adults in the community1. J. Gerontol. 37 323–329. 10.1093/geronj/37.3.323 PubMed DOI

Polanska H., Bartos A. (2022). Telemedicine assessments with remote versions of ALBA, POBAV and ACE-III tests [article in Czech Telemedicínské vyšetření kognitivní testy ALBA, POBAV a ACE-III]. Cesk. Slov. Neurol. N 85, 296–305. 10.48095/cccsnn2022296 DOI

Preiss M., Bartos A., Čermáková R., Nondek M., Benešová M., Rodriguez M., et al. (2012). Neuropsychologická baterie psychiatrického centra Praha : Klinické vyšetření základních kognitivních funkcí (3.). Praha: Psychiatrické Centrum.

Rodrigues D. M., Sousa A. J., Johnson-Henry K. C., Sherman P. M., Gareau M. G. (2012). Probiotics are effective for the prevention and treatment of citrobacter rodentium-induced colitis in mice. J. Infect. Dis. 206 99–109. 10.1093/infdis/jis177 PubMed DOI

Salami M. (2021). Interplay of good bacteria and central nervous system: Cognitive aspects and mechanistic considerations. Front. Neurosci. 15:613120. 10.3389/fnins.2021.613120 PubMed DOI PMC

Wilmanski T., Diener C., Rappaport N., Patwardhan S., Wiedrick J., Lapidus J., et al. (2021). Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nat. Metab. 3 274–286. 10.1038/s42255-021-00348-0 PubMed DOI PMC

Wu J. C. Y. (2012). Psychological co-morbidity in functional gastrointestinal disorders: Epidemiology, mechanisms and management. J. Neurogastroenterol. Motil. 18 13–18. 10.5056/jnm.2012.18.1.13 PubMed DOI PMC

Wu S., Liu X., Jiang R., Yan X., Ling Z. (2021). Roles and mechanisms of gut microbiota in patients with Alzheimer’s disease. Front. Aging Neurosci. 13:650047. 10.3389/fnagi.2021.650047 PubMed DOI PMC

Xiang S., Ji J.-L., Li S., Cao X.-P., Xu W., Tan L. (2022). Efficacy and safety of probiotics for the treatment of Alzheimer’s disease, mild cognitive impairment, and Parkinson’s disease: A systematic review and meta-analysis. Front. Aging Neurosci. 14:730036. 10.3389/fnagi.2022.730036 PubMed DOI PMC

Serum neurofilament light chain in response to probiotics in bi-center, double-blind, randomized, placebo-controlled clinical trial (CleverAge Biota)

Effects of human probiotics on memory and psychological and physical measures in community-dwelling older adults with normal and mildly impaired cognition: results of a bi-center, double-blind, randomized, and placebo-controlled clinical trial (CleverAge biota)

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NCT05051501