Table 3. Summary of interventional clinical trials on cognitive function in populations with cognitive disorders.

First Author, Year, Study Design	Population	Age(y), N	Interventional Agent, Duration	Main Results (compared with control group)
Akbari, 2016 Randomized, Double-blind, Placebo-controlled	Patients with Alzheimer’s disease	60–95 n = 60	Probiotic milf containing Lactobacillus acidphlius, Lactobacillus casei, Lactobacillus fermentum, Bifidobacterium bifidum 12 weeks	Approximately 30% greater improvement in MMSE score
				Approximately 50% greater reduction of serum hs-CRP
				Approximately 25% greater reduction of serum MDA
				Improvement in insulin metabolism and lipid metabolism
Kobayashi, 2019 Randomized, Double-blind, Placebo-controlled	Elderly subjects withmemory complaints	50–80 n = 117	Bifidobacterium breve A1 12 weeks	Significant improvement in the subscale of ’immediate memory’ in RBANS and total score in MMSE in the subjects with low RBANS total score at baseline
				Significant difference in total MMSE score and in the subscale of ’recall’ in RBANS in the high-score group
				No significant differences in blood parameters
Hwang, 2019 Randomized, Double-blind, Placebo-controlled	Individuals with Mild Cognitive Impairment	55–85 n = 100	Lactobacillus plantarum C29-fermented soybean (DW2009) 12 weeks	Greter improvemet rate in the combined cognitive function (z = 2.36), especially
				in the attention domain (z = 2.34) in the computerized neurocognitive function tests
				Positive association between serum BDNF levels and the change of combined cognitive function
				No significant differences in vital signs, boday mass index, and laboratory profiles
Tamtaji, 2019 Randomized, Double-blind, Placebo-controlled	Patients with Alzheimer’s disease	55–100 n = 79	Lactobacillus acidphlius, Bifidobacterium bifidum, Bifidobacterium longum, elenium 12 weeks	Approximately 20% greater improvement rate in MMSE score
				Increased level of antioxdant molecules and decreased level of hs-CPR in blood
				No significant differences in the level of oxdative molecules
				Improvement in insulin metabolism and lipid profiles
Agashi, 2019 Randomized, Double-blind, Placebo-controlled	Patients with Alzheimer’s disease	65–90 n = 60	Lactobacillus fermentum, Lactobacillus plantarum, Lactobacillus acidophilus, Bifidobacterium longum, Bifidobacterium lactis, Bifidobacterium bifidum 12 weeks	Change rate between the scores in Test Your Memory test at the onset and the offset of the trial did not reach the statistical difference
				No statisticaly significant affects on the level of inflammatory cytokines,antidxdant, or oxdative molecules
Xiao, 2020 Randomized, Double-blind, Placebo-controlled	Patients with Mild Cognitive Impairment	50–79 n = 80	Bifidobacterium breve A1 16 weeks	Approximately 30% greater improvemet rate in RBANS total score
				Improvement in the domain of immediate memory, visuospatial/constructional, and delayed memory
				Approximately 5% greater change rate in JMCIS score
Sanborn, 2020 Randomized, double-blind, placebo- controlled	Community-dwelling adults including ones with cognitive impairment	52–75 n = 145	Lactobacillus rhamnosus GG 12 weeks	Significantly greater improvement in the NIH Toolbox Total Cognition Score compared with persons without cognitive impaiment
*Wang, 2021 Randomized, double-blind, placebo- controlled	Non-cardiac planned surgical patients	60–90 n = 120	Bifidobacterium longum, Lactobacillus acidophilus, Enterococcus faecalis From admission until discharge (more than 7 days)	Approximately 70% lower incidence of postoperative cognitive impairment
				Greater improvement in MMSE score
				Decreased plasma level of proinflammatory cytokine and cortisol
				No significant differences in postoperative pain, sleep quality, and gastrointesinal function recovery

Abbreviations used: MMSE, Mini-mental status examination; RBEANS, Repeatable Battery for Assessment of Neuropsycological Status, JMCIS; Japanese version of the MCI Screen test

hs-CRP, high-sensitivity C-reactive protein; MDA, malondialdehyde; BDNF, brain-derived neurotrophic factor

* perioperative study