Effect of probiotics on cognitive function in adults with mild cognitive impairment or Alzheimer's disease: A meta-analysis of randomized controlled trials

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A fixed-effects model was applied to the meta-analysis of Language and Visuospatial/Constructional, while other domains used a random-effects model." ] ] ] "textoCompleto" => "IntroductionAlzheimer's disease (AD) is a degenerative disease of the central nervous system that mostly occurs in the elderly or presenile. With the global escalation of the aging process, the incidence of AD is increasing every year.<a class="elsevierStyleCrossRef" href="#bib0155">1</a> AD typically progresses in three stages: preclinical, mild cognitive impairment (MCI), and dementia. Regrettably, most existing treatment strategies cannot successfully prevent or cure AD.Although accumulated knowledge greatly expanded our understanding of AD, the underlying mechanism of AD pathogenesis remains elusive. In recent years, the gut–brain–microbiome axis, which consists of interactions between the gut, the brain, and the gut microbiota, has gained substantial attention. There were differences in gut microbiota composition among individuals with MCI, AD and healthy elderly.<a class="elsevierStyleCrossRef" href="#bib0160">2</a> Fecal microbiota transplantation of gut microbiota derived from the AD mice model impairs memory function and neurogenesis in normal mice.<a class="elsevierStyleCrossRef" href="#bib0165">3</a> Conversely, transplantation treatment could improve cognitive deficits and attenuate the pathological changes in AD mice also.<a class="elsevierStyleCrossRef" href="#bib0170">4</a> Thus, targeting the gut microbiota may be a useful therapeutic strategy for the development of novel candidates for the treatment of AD.Probiotics are defined as viable microorganisms that have beneficial effects on human health when consumed in adequate amounts, and they are widely available in the market currently. Preclinical studies have shown that probiotic products have neurotrophic and anti-inflammatory effects, these results indicated that probiotics might be an effective dietary intervention to improve cognitive function in patients with AD or MCI.<a class="elsevierStyleCrossRefs" href="#bib0175">5–7</a> However, findings from available clinical trials have yielded mixed results, with some showing ineffective outcomes.<a class="elsevierStyleCrossRef" href="#bib0190">8</a> Therefore, we performed a systematic meta-analysis to quantitatively examine the potential effect of probiotics on cognitive performance in AD and MCI subjects.MethodsThis study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (see <a class="elsevierStyleCrossRef" href="#sec0100">supplementary material</a> for the complete PRISMA checklist),<a class="elsevierStyleCrossRef" href="#bib0195">9</a> and was registered with the International Prospective Register of Systematic Reviews in advance (CRD42023462365).Search strategyElectronic databases include PubMed, Embase, and Cochrane Central Register of Controlled Trials were systematically searched for relevant literatures (see supplementary materials). The following search terms were used: “probiotic”, “synbiotic”, “symbiotic”, “Lactobacillus”, “Bifidobacterium”, “Lactococcus”, and “Alzheimer's disease”, “dementia”, “mild cognitive impairment”, “cognitive dysfunction”, “cognitive defect”. We also performed a manual search of references of the included articles and reviews for additional omitted studies. The literature search was performed by two independent investigators in Aug 2023, and any disagreements were resolved by consensus.Inclusion and exclusion criteriaThe inclusion criteria were as follows: (1) randomized controlled trials as the study design, (2) inclusion of adult human participants diagnosed with AD or MCI, (3) interventions of the studies were probiotics products, (4) changes and standard deviation (SD) in cognitive function measured by validated tools were available, and (5) publications were in English language. The exclusion criteria were the following: (1) reviews, case reports, editorials, meeting articles, or duplication of previous publications, (2) no change on scale scores of cognition was reported, and these data could not be calculated based on the information in the article, or (3) studies without a control group.Data extractionTwo independent investigators extracted and summarized the following information from each included study: the name of the first author, publication year, country, study design, characteristics of enrolled subjects (sample size, disease type and age), strain, dose, and form of probiotics, intervention duration, and cognitive outcomes. To perform the meta-analysis, the mean change score along with the associated variance were extracted. When change scores were not available, the cognitive assessment scores at baseline and post-intervention were extracted.Risk of bias and quality assessmentAll included studies were evaluated and classified according to the items set by Cochrane Collaboration's tool for assessing the risk of bias within and across randomized trials.<a class="elsevierStyleCrossRef" href="#bib0200">10</a> The following items were evaluated for each study: (1) random sequence generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) incomplete outcome data; (6) selective reporting and (7) other bias. The overall judgment of each item for each study was categorized as ‘low’, ‘high’ and ‘unclear’ according to the levels of bias.Statistical analysisThe effect of probiotics on cognitive function was defined as the mean difference between the intervention groups and control groups for pre–post changes in cognitive assessment scores. Changes within groups (mean values±standard deviation) from baseline were used to assess the intervention effect. Where modifications were not reported, SD changes were imputed assuming correlation coefficients as 0.5 calculated from other eligible studies that provided the SD baseline, SD final and SD change.The meta-analysis was performed by Review Manager 5.3 (Cochrane Collaboration, 2014). Heterogeneity among the eligible studies was evaluated by the Cochran's Q statistic and I2 test. The studies were considered homogeneous if the p-value of the Q-test was >0.1 or the I2 value was <50%, and then, a fixed-effects model was used. Otherwise, a random effects model was used. Subgroup analysis was performed to explore the influence of a variety of factors on the results, including the type of disease, cognitive rating scale and strains of probiotics. Publication bias was statistically assessed by Begg's test and Egger's regression test.<a class="elsevierStyleCrossRef" href="#bib0205">11</a> Whenever a publication bias was identified, we conducted a trim and fill adjusted analysis to recalculate the effect size at each iteration.<a class="elsevierStyleCrossRef" href="#bib0210">12</a> The Egger's test, Begg's test, and trim and fill test were performed using the metaphor package implemented in R software version 3.3.4 (R Foundation for Statistical Computing, Vienna, Austria).ResultsDescription of studiesA total of 903 articles were retrieved through literature searching in the PubMed, Embase and Cochrane databases, after duplicate articles were removed and preliminarily screened on the basis of their titles and abstracts, 22 articles remained for full-text reading. Finally, we identified 11 eligible articles in the present meta-analysis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0175">5–8,13–19</a> The characteristics of the included articles are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Of these selected articles, 10 were double-blinded design, 7 studies recruited subjects diagnosed with MCI, and other studies included AD patients. As Akhgarjand et al. applied two different single-strain probiotic intervention groups,<a class="elsevierStyleCrossRef" href="#bib0180">6</a> which we regard as two independent studies. Thus, a total of 12 studies were included in this meta-analysis.<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Risk of bias assessmentThe risks of bias assessment across the recruited studies are summarized in (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Based on the Cochrane Risk of Bias tool, one study was classified as high risk in the domain blinding of participants and personnel and blinding of outcome assessment, and the assessment of bias reported a low to moderate risk of bias across all domains in other included studies.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Effect of probiotics on global cognition and its domainsA total of twelve studies including 852 participants (429 in the probiotics groups and 429 in the placebo groups) contributed to global cognitive function analysis (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). A random effects model was selected for quantitative synthesis. The result revealed a notable difference between the probiotics and control group regarding improvement in global cognition (SMD=0.67; 95% CI: 0.32, 1.02; I2=83%). Meanwhile, random effects models were applied to meta analyses of orientation, registration/immediate memory, recall/delayed memory and attention domains due to heterogeneity among studies, while a fixed effects model was selected for analysis of language and visuospatial/constructional domains. The results showed an increase in recall/delayed memory (SMD=0.67; 95% CI: 0.32, 1.02; I2=83%), attention (SMD=0.31; 95% CI: 0.04, 0.58; I2=50%) and visuospatial/constructional (SMD=0.24; 95% CI: 0.06, 0.42; I2=36%). There were no substantial differences in orientation (SMD=0.35; 95% CI: −0.33, 1.03; I2=90%), registration/immediate memory (SMD=0.22; 95% CI: −0.06, 0.51; I2=66%) and language (SMD=0.14; 95% CI: −0.06, 0.35; I2=0%) between the probiotics and placebo group. The forest plots of these meta-analyses are shown in <a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>.<elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia>Subgroup analysisSubgroup analysis was performed to evaluate the effects of disease type (AD versus MCI), cognitive rating scale (MMSE versus non-MMSE) and strains of flora (multiple versus sole) on cognitive function. As shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>, the heterogeneity among the included studies failed to reduce after stratification. Additionally, the meta-analysis results from the subgroups were consistent with the overall pooled results.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Publication bias assessment and sensitivity analysisBegg's test and Egger's regression test were performed to quantitatively assess the publication bias of this meta-analysis. Evidence of publication bias on cognition was detected (Egger's test: 95% CI: −2.63, 0.01). Then we performed a trim and fill method to address the problem of publication bias. However, it became unchanged after we applied the trim and fill method. Besides, the sensitivity analysis was performed to test the reliability of the meta-analysis results by omitting studies one by one. Systematically removing each trial did not markedly influence the overall effects of probiotics on cognition (see supplementary materials). Thus, the findings between the probiotics and control groups regarding cognitive enhancement were considered reliable.DiscussionNumerous in vivo and clinical trials have been conducted to explore the specific mechanism of action of probiotics in preventing AD. Small chain fatty acids (SCFAs) are saturated fatty acids produced in the gut, which can influence brain function via three main functions: immune modulation, endocrine pathways and neuronal regulation.<a class="elsevierStyleCrossRef" href="#bib0250">20</a> Ma X et al. found that oral administration of Lactobacillus mucosae NK41 and Bifidobacterium longum NK46 can suppress gut dysbiosis and lipopolysaccharide (LPS) production, resulting in the attenuation of cognitive decline with the regulation of neuroinflammation via the microbiota–gut–brain axis in AD mice.<a class="elsevierStyleCrossRef" href="#bib0255">21</a> 12-Weeks of treatment with memantine plus Lactobacillus plantarum ameliorated cognitive deterioration, decreased Aβ levels in the hippocampus, protected neuronal integrity and plasticity, and reduced neuroinflammation.<a class="elsevierStyleCrossRef" href="#bib0260">22</a> Sun et al. demonstrated that Clostridium butyricum can prevent cognitive impairment, Aβ deposits, microglial activation, and production of tumor necrosis factor (TNF)-α and interleukin (IL)-1β by regulating the microbiota–gut–brain axis.<a class="elsevierStyleCrossRef" href="#bib0265">23</a> It is worthwhile to infer that inflammatory and oxidative stress pathways play an important role in various kinds of diseases, especially age-related diseases. Recent results from clinical studies showed that probiotic supplementation can regulate the abundance of intestinal flora and decrease some inflammatory and oxidative biomarkers in AD or MCI subjects.<a class="elsevierStyleCrossRef" href="#bib0270">24</a> More comprehensive metabolites need to be tested in future studies to further clarify the exact mechanism of the beneficial effect of probiotics on AD and MCI patients.According to a previous study which only include 3 RCTs,<a class="elsevierStyleCrossRef" href="#bib0275">25</a> there was no beneficial effect of probiotic supplementation on the cognitive function of individuals with AD. While another meta-analysis conducted by Deng et al. showed that probiotics consumption enhanced cognition in AD or MCI patients,<a class="elsevierStyleCrossRef" href="#bib0270">24</a> our analysis further confirmed the effect of probiotics. Although cognitive function gradually declines with dementia severity in AD as the disease progresses, the function of different cognitive domains may not decline equally at the same time.<a class="elsevierStyleCrossRef" href="#bib0280">26</a> To the best of our knowledge, this study is the first meta-analysis to elucidate the effects of probiotics on specific domains of cognitive functions besides the global cognitive function in individuals with AD or MCI. Probiotics may affect different cognitive domains and define cognitive improvement. Our results indicate that probiotic ingestion may improve recall/delayed memory, attention and visuospatial/constructional domains, with less apparent effect on orientation, registration/immediate memory or language domains. Future studies should examine the relationship between probiotics and specific (core) cognitive domain function in greater detail.In all of the included studies, only one study reported no measurable improvement of global cognitive function in AD patients.<a class="elsevierStyleCrossRef" href="#bib0190">8</a> Further subgroup analyses have proved the beneficial outcome of probiotics in both AD and MCI subjects. Apart from diverse interventions conditions, such as characteristics of participants, total intervention duration, dosage, probiotics themselves are also an important factor in the efficiency assessment. Based on the analysis, we can conclude more than 95% of the study is done based on the genera Bifidobacterium and Lactobacillus. The most widely used probiotics are Bifidobacteria breve, B. longum, Lactobacillus rhamnosus, L. plantarum, as single or multi-strain preparations. Our subgroup analyses revealed that neither single nor multi-strain probiotics are beneficial for improving cognitive function.At present, we failed to provide a dose-response of probiotics in ameliorating cognitive deficits. The dose of probiotics used in included studies are commonly ranging from 109 to 1010CFU, except for the study by Akhgarjand et al., in which participants received a capsule contained 1015CFU probiotic two times a day.<a class="elsevierStyleCrossRef" href="#bib0180">6</a> Several clinical studies demonstrated a positive protective effect in preventing antibiotic-associated diarrhea with high dose compared with low dose of the same probiotic.<a class="elsevierStyleCrossRef" href="#bib0285">27</a> However, it seems hard to epitomize one optimal dose of probiotics for improving cognitive outcomes. Additionally, the duration of probiotic administration should also be considered. Most commonly, probiotics were administered for 12 weeks in included RCTs. Given that duration of the intervention is a key factor to see changes in gut flora following probiotics consumption, longer interventions are desirable in order to ensure that a potential effect can be observed. While there was previous analysis examined efficacy according to the length of treatment, and claimed that taking probiotics for even a week is sufficient in preventing and treating gastrointestinal disease.<a class="elsevierStyleCrossRef" href="#bib0290">28</a> Thus, more reliable evidence from various dosages of probiotics and intervention duration trials is needed.Even though probiotic bacteria have the generally recognized as safe, there are several reports about side effects triggered by the presence of these organisms. Among the twelve studies included in our present study, four did not report on the incidence of side effects,<a class="elsevierStyleCrossRefs" href="#bib0175">5,13,18,19</a> seven reported no side effects,<a class="elsevierStyleCrossRefs" href="#bib0180">6,8,14–17</a> and only one reported mild to moderate adverse events,<a class="elsevierStyleCrossRef" href="#bib0185">7</a> including dizziness, stomach aches, headaches, gastritis, erectile dysfunction and seborrheic dermatitis. These results warrant the overall safety of probiotic supplementation, but unwanted side effects and bacteria–host interactions in rare cases could not be ignored.Among 12 included studies, Tamtaji OR et al. reported that AD patients who received both probiotics and selenium exhibited a notable improvement in cognitive function and metabolic status compared with those who were given only selenium or placebo.<a class="elsevierStyleCrossRef" href="#bib0215">13</a> This underscores the importance of multi-component interventions for AD or MCI patients. The multi-domain interventions include, but are not limited to, medicines, diet, exercise, cognitive training, and intensive risk management.<a class="elsevierStyleCrossRef" href="#bib0295">29</a> Such comprehensive therapeutic approaches have the potential to become mainstream treatments for AD and MCI.Several limitations of this meta-analysis are important to consider in interpreting the results. First, the publication bias was observed using the Begg's and Egger's test. Thus, a trim and fill method was used to correct for publication bias. A positive effect of probiotics was still observed. In addition, the analysis identified considerable heterogeneity among the included studies. Although we conducted subgroup analyses, the main source of the heterogeneity still remains unknown. Second, the recruited AD patients were all diagnosed based on the NINDS-ADRDA criteria.<a class="elsevierStyleCrossRefs" href="#bib0175">5,6,13,14</a> While the criteria for recruiting MCI subjects were inconsistent, two studies diagnosed MCI according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5),<a class="elsevierStyleCrossRefs" href="#bib0185">7,16</a> two studies selected subjects according to the MMSE score.<a class="elsevierStyleCrossRefs" href="#bib0190">8,15</a> Y. Fei et al. recruited subjects met the Peterson diagnostic criteria of MCI.<a class="elsevierStyleCrossRef" href="#bib0235">17</a> Sakurai K et al. discriminated MCI and normal individuals with an Memory Performance Index (MPI) score of less than 60.<a class="elsevierStyleCrossRef" href="#bib0245">19</a> Sanborn et al. selected patients met the Petersen/Winblad criteria (i.e., one or more NIH Toolbox t scores at or below 35).<a class="elsevierStyleCrossRef" href="#bib0240">18</a> This may have generated low comparability of these included RCTs. Third, as the cognitive function scales varied across the recruited studies, the unbalanced assessment methods may devaluate the meta-analysis outcome. The MMSE scale was used in seven studies,<a class="elsevierStyleCrossRefs" href="#bib0180">6,8,13,14,16,17</a> other cognitive rating scales including Cognitrax,<a class="elsevierStyleCrossRef" href="#bib0245">19</a> NIH toolbox,<a class="elsevierStyleCrossRef" href="#bib0240">18</a> Repeatable Battery for the Assessment of Neuropsychological Status (RBANS),<a class="elsevierStyleCrossRef" href="#bib0225">15</a> computerized neurocognitive function tests (CNT)<a class="elsevierStyleCrossRef" href="#bib0185">7</a> and Test Your Memory (TYM) test.<a class="elsevierStyleCrossRef" href="#bib0175">5</a> Last but not least, unrecognized and unpredictable bias may introduce additional uncertainties not captured by confidence intervals.<a class="elsevierStyleCrossRef" href="#bib0300">30</a> Therefore, caution should be applied when interpreting the analytical results and generalizing the study findings. Considering above limitations of this meta-analysis, future RCTs that control these confounding factors are needed to verify the effect of probiotics on cognitive function.ConclusionOur meta-analysis shows that in general, probiotics are beneficial in cognitive function improvement in AD and MCI patients. No differences in efficacy were observed for disease group or cognitive rating scales or for single vs. multiple species. Probiotic supplementation could be taken as a novel therapy for AD or MCI. With a view to the limitations of this meta-analysis, further high-quality studies involving larger samples are still required to explore the safety and efficacy of probiotics.Authors’ contributionsR.M. and R.Z.J. conceived the idea for the review. H.W.X. and M.J. performed the literature search, data extraction and analysis. R.M. drafted the article. All authors have read the manuscript and given their approval for publication.Ethical considerationsInformed consent was not required.FundingThis work was supported by the Youth Science Foundation of Shandong First Medical University (No. 202201-053).Conflict of interestsThe authors declare no conflict of interests." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres2168612" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1839088" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2168613" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1839089" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Search strategy" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Inclusion and exclusion criteria" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Data extraction" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Risk of bias and quality assessment" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Description of studies" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Risk of bias assessment" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Effect of probiotics on global cognition and its domains" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Subgroup analysis" ] 4 => array:2 [ "identificador" => "sec0065" "titulo" => "Publication bias assessment and sensitivity analysis" ] ] ] 7 => array:2 [ "identificador" => "sec0070" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0075" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0080" "titulo" => "Authors’ contributions" ] 10 => array:2 [ "identificador" => "sec0085" "titulo" => "Ethical considerations" ] 11 => array:2 [ "identificador" => "sec0090" "titulo" => "Funding" ] 12 => array:2 [ "identificador" => "sec0095" "titulo" => "Conflict of interests" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-11-05" "fechaAceptado" => "2024-01-09" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1839088" "palabras" => array:4 [ 0 => "Probiotic" 1 => "Mild cognitive impairment" 2 => "Alzheimer's disease" 3 => "Meta-analysis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1839089" "palabras" => array:4 [ 0 => "Probióticos" 1 => "Deterioro cognitivo leve" 2 => "Enfermedad de Alzheimer" 3 => "Metaanálisis" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundRecent clinical studies have yielded controversial results regarding the effect of probiotics on cognitive function in Alzheimer's disease (AD) or mild cognitive impairment (MCI) subjects. To clarify the efficacy of probiotics on cognition, we conducted a meta-analysis of randomized controlled trials (RCTs). MethodsInstructions of the PRISMA 2020 statement were followed. Literature from the PubMed, Embase and Cochrane databases were systematically searched and manually screened for relevant published RCTs. We performed statistical analysis using RevMan, and assessed the risk of bias using the R software. ResultsA total of 12 studies comprising 852 patients with MCI or AD were identified. The results of meta-analysis showed that probiotics improved global cognitive function (SMD=0.67; 95% CI, 0.32, 1.02), recall/delayed memory (SMD=0.67; 95% CI: 0.32, 1.02), attention (SMD=0.31; 95% CI: 0.04, 0.58) and visuospatial/constructional (SMD=0.24; 95% CI: 0.06, 0.42) cognitive domain. ConclusionThis meta-analysis found that probiotic supplementation is associated with an improvement in cognitive performance among patients with AD and MCI. However, current evidence is limited, and more reliable large-scale RCTs with higher methodological quality are needed." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "AntecedentesEstudios clínicos recientes han arrojado resultados controvertidos en cuanto al efecto de los probióticos en la función cognitiva de los pacientes con enfermedad de Alzheimer (EA) o deterioro cognitivo leve (DCL). Con el objetivo de aclarar la eficacia de los probióticos en la cognición, llevamos a cabo un metaanálisis de ensayos clínicos controlados aleatorizados (ECA). MétodosSe siguieron las instrucciones de la declaración PRISMA 2020. Realizamos una búsqueda sistemática y seleccionamos manualmente ensayos clínicos aleatorizados relevantes publicados en las bases de datos de PubMed, Embase y Cochrane. El análisis estadístico se realizó utilizando RevMan y el riesgo de sesgo fue evaluado utilizando el software R. ResultadosIdentificamos un total de 12 estudios que incluyeron a 852 pacientes con DCL o EA. Los resultados del metaanálisis mostraron que los probióticos mejoraron la función cognitiva global (DME=0,67; IC del 95%: 0,32-1,02), la memoria de recuerdo/demora (DME=0,67; IC del 95%: 0,32-1,02), la atención (DME=0,31; IC del 95%: 0,04-0,58) y el dominio cognitivo visoespacial/constructivo (DME=0,24; IC del 95%: 0,06-0,42). ConclusiónEste metaanálisis encontró que la suplementación con probióticos está asociada con una mejora en el rendimiento cognitivo entre los pacientes con EA y DCL. Sin embargo, la evidencia actual es limitada, y se necesitan ensayos clínicos aleatorizados a gran escala con mayor calidad metodológica para obtener resultados más confiables." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<elsevierMultimedia ident="upi0005"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0105" ] ] ] ] "multimedia" => array:7 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2571 "Ancho" => 1260 "Tamanyo" => 155494 ] ] "descripcion" => array:1 [ "en" => "Flow diagram of the literature search and abstraction process." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3933 "Ancho" => 2091 "Tamanyo" => 636078 ] ] "descripcion" => array:1 [ "en" => "Risk of bias summary: review authors’ judgements about each risk of bias item for each included study." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1006 "Ancho" => 3175 "Tamanyo" => 449796 ] ] "descripcion" => array:1 [ "en" => "Forest plot for studies examining the effect of probiotic vs placebo administration on cognitive function. A random-effects model was applied to the meta-analysis." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 4396 "Ancho" => 3341 "Tamanyo" => 1193769 ] ] "descripcion" => array:1 [ "en" => "Forest plots for studies examining the effect of probiotic vs placebo administration on cognitive domains: (a) Orientation, (b) Registration/Immediate memory, (c) Recall/Delayed memory, (d) Attention, (e) Language, and (f) Visuospatial/Constructional. A fixed-effects model was applied to the meta-analysis of Language and Visuospatial/Constructional, while other domains used a random-effects model." ] ] 4 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: PRO, probiotics group; CON, control group; CFU, colony-forming units; AD, Alzheimer's disease; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment Scale; ADAS-Jcog, Japanese version of Alzheimer's Disease Assessment Scale; JMCIS, Japanese version of the MCI Screen; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; CNT, computerized neurocognitive function tests; TYM, Test Your Memory; CFT, categorical verbal fluency test." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Country \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Design \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Participants \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mean age (year) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Probiotics \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Delivery method \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dosage (CFU daily) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Duration \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cognitive assessment \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Main findings \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sakurai K et al. (2022) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Japan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">78 MCI patients (39 in probiotic group) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PRO 76.8±4.6 CON 76.9±4.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lactiplantibacillus plantarum OLL2712 (OLL2712) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1g/package \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>5×10^9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cognitrax \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OLL2712 ingestion has protective effects against memory function decline in older adults. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Y Fei et al. (2023) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">China \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42 MCI patients (21 in probiotic group) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PRO 76.40±9.61 CON 75.30±9.75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lactobacillus, Lactococcus and Bifidobacterium genera \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Capsule \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>4×10^10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMSE, MoCA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">The probiotic group had a much higher MMSE score and MoCA score compared to the placebo group after 12 weeks of intervention. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sanborn et al. (2020) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42 MCI patients (19 in probiotic group) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PRO 65.6±5.27 CON 62.7±5.27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lactobacillus rhamnosus GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Capsule \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2×10^10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NIH toolbox \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lactobacillus rhamnosus GG probiotic supplementation was associated with improved cognitive performance in MCI adults. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">D Asaoka et al. (2022) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Japan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">115 MCI patients (55 in probiotic group) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PRO 77.2±5.8 CON 78.9±4.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bifidobacterium breve MCC1274 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sachets \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>2×10^10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMSE, ADAS-Jcog \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMSE subscales “orientation in time” and “writing” were significantly improved compared to placebo in the lower baseline MMSE (<25) subgroup. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">J Xiao et al. (2020) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Japan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">79 MCI patients (39 in probiotic group) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PRO 61.3±7.7 CON 60.9±6.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bifidobacterium breve MCC1274 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Capsule \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2×10^10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RBANS, JMCIS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RBANS total score was significantly improved in probiotic group compared to palcebo. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Akbari et al. (2016) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Iran \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60 AD patients (30 in probiotic group) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PRO 77.67±2.62 CON 82.00±1.69 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">200ml probiotic milk \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8×10^9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMSE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Probiotics intervention resulted in an improvement in MMSE score in the probiotic group compared to their control counterparts. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Y Kobayashi et al. (2019) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Japan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">117 MCI patients (59 in probiotic group) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PRO 61.5±6.83 CON 61.6±6.37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bifidobacterium breve A1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Capsule \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2×10^10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMSE, RBANS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No significant difference was noted between the groups in total scores of MMSE and in terms of the changes of RBANS scores against baseline. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR Tamtaji et al. (2018) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Iran \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">79 AD patients (27 in probiotic group) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PRO 76.2±8.1 CON 78.8±10.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lactobacillus acidophilus, Bifdobacterium bifdum, Bifdobacterium longum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Not clear \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2×10^9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMSE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Probiotic and selenium combination resulted in a signifcant increase in MMSE scores compared to selenium only and placebo. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hwang et al. (2019) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Korea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">100 MCI patients (50 in probiotic group) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PRO 68.0±5.12 CON 69.2±7.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lactobacillus Plantarum C29-fermented soybean (DW2009) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Capsule \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>1×10^10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CNT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">There were greater improvements in the combined cognitive functions, especially in attention domain. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Agahi et al. (2018) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Iran \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">48 AD patients (25 in probiotic group) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PRO 79.70±1.72 CON 80.57±1.79 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, and Bifidobacterium bifidum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Capsule \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3×10^9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TYM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cognitive and biochemical indications in the patients with severe AD were insensitive to the probiotic supplementation. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Akhgarjand et al. (2022)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Iran</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">90 AD patients (30 in each probiotic group)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">a PRO 67.93±7.8 CON 67.77±7.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">a PRO: Lactobacillus rhamnosus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Capsule</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2×10^15</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 weeks</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMSE, CFT</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12-Week probiotic supplementation compared with placebo had beneficial effects on the cognition status of patients with AD.</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">b PRO 67.90±7.9 CON 67.77±7.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">b PRO:Bifidobacterium longum \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3572232.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Main characteristics of the included studies." ] ] 5 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Note: I2for heterogeneity: I2>50% was considered to indicate heterogeneity across studies." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Subgroup \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No. studies \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Participants \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Effect estimated \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">I2 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type of disease</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">281 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.99 [0.36, 1.63] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">84% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.002 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MCI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">571 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.43 [0.09, 0.77] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">74% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cognitive rating scale</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMSE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">505 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.87 [0.30, 1.44] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">89% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.003 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-MMSE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">347 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.42 [0.08, 0.76] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.0002 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Probiotic strains</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Single strain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">651 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.56 [0.18, 0.93] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">81% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.004 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multi strain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">201 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.90 [0.10, 1.71] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">86% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.03 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3572231.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Subgroup analyses of effect of probiotics on cognition." ] ] 6 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.doc" "ficheroTamanyo" => 197929 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0155" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Global, regional, and national burden of Alzheimer's disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. 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Effect of probiotics on cognitive function in adults with mild cognitive impairment or Alzheimer's disease: A meta-analysis of randomized controlled trials

Efecto de los probióticos en la función cognitiva en los adultos con deterioro cognitivo leve o enfermedad de Alzheimer: un metaanálisis de ensayos aleatorios controlados

Rui Moa, Man Jiangb, Hongwei Xua, Ruzhen Jiaa,

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jrz032303092@163.com

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a Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China

b Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China

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    "titulo" => "Effect of probiotics on cognitive function in adults with mild cognitive impairment or Alzheimer&#39;s disease&#58; A meta-analysis of randomized controlled trials"
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        "titulo" => "Efecto de los probi&#243;ticos en la funci&#243;n cognitiva en los adultos con deterioro cognitivo leve o enfermedad de Alzheimer&#58; un metaan&#225;lisis de ensayos aleatorios controlados"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Forest plots for studies examining the effect of probiotic vs placebo administration on cognitive domains&#58; &#40;a&#41; Orientation&#44; &#40;b&#41; Registration&#47;Immediate memory&#44; &#40;c&#41; Recall&#47;Delayed memory&#44; &#40;d&#41; Attention&#44; &#40;e&#41; Language&#44; and &#40;f&#41; Visuospatial&#47;Constructional&#46; A fixed-effects model was applied to the meta-analysis of Language and Visuospatial&#47;Constructional&#44; while other domains used a random-effects model&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Alzheimer&#39;s disease &#40;AD&#41; is a degenerative disease of the central nervous system that mostly occurs in the elderly or presenile&#46; With the global escalation of the aging process&#44; the incidence of AD is increasing every year&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> AD typically progresses in three stages&#58; preclinical&#44; mild cognitive impairment &#40;MCI&#41;&#44; and dementia&#46; Regrettably&#44; most existing treatment strategies cannot successfully prevent or cure AD&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Although accumulated knowledge greatly expanded our understanding of AD&#44; the underlying mechanism of AD pathogenesis remains elusive&#46; In recent years&#44; the gut&#8211;brain&#8211;microbiome axis&#44; which consists of interactions between the gut&#44; the brain&#44; and the gut microbiota&#44; has gained substantial attention&#46; There were differences in gut microbiota composition among individuals with MCI&#44; AD and healthy elderly&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> Fecal microbiota transplantation of gut microbiota derived from the AD mice model impairs memory function and neurogenesis in normal mice&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> Conversely&#44; transplantation treatment could improve cognitive deficits and attenuate the pathological changes in AD mice also&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> Thus&#44; targeting the gut microbiota may be a useful therapeutic strategy for the development of novel candidates for the treatment of AD&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Probiotics are defined as viable microorganisms that have beneficial effects on human health when consumed in adequate amounts&#44; and they are widely available in the market currently&#46; Preclinical studies have shown that probiotic products have neurotrophic and anti-inflammatory effects&#44; these results indicated that probiotics might be an effective dietary intervention to improve cognitive function in patients with AD or MCI&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">5&#8211;7</span></a> However&#44; findings from available clinical trials have yielded mixed results&#44; with some showing ineffective outcomes&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> Therefore&#44; we performed a systematic meta-analysis to quantitatively examine the potential effect of probiotics on cognitive performance in AD and MCI subjects&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses &#40;PRISMA&#41; guidelines &#40;see <a class="elsevierStyleCrossRef" href="#sec0100">supplementary material</a> for the complete PRISMA checklist&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> and was registered with the International Prospective Register of Systematic Reviews in advance &#40;CRD42023462365&#41;&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Search strategy</span><p id="par0025" class="elsevierStylePara elsevierViewall">Electronic databases include PubMed&#44; Embase&#44; and Cochrane Central Register of Controlled Trials were systematically searched for relevant literatures &#40;see supplementary materials&#41;&#46; The following search terms were used&#58; &#8220;probiotic&#8221;&#44; &#8220;synbiotic&#8221;&#44; &#8220;symbiotic&#8221;&#44; &#8220;Lactobacillus&#8221;&#44; &#8220;Bifidobacterium&#8221;&#44; &#8220;Lactococcus&#8221;&#44; and &#8220;Alzheimer&#39;s disease&#8221;&#44; &#8220;dementia&#8221;&#44; &#8220;mild cognitive impairment&#8221;&#44; &#8220;cognitive dysfunction&#8221;&#44; &#8220;cognitive defect&#8221;&#46; We also performed a manual search of references of the included articles and reviews for additional omitted studies&#46; The literature search was performed by two independent investigators in Aug 2023&#44; and any disagreements were resolved by consensus&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Inclusion and exclusion criteria</span><p id="par0030" class="elsevierStylePara elsevierViewall">The inclusion criteria were as follows&#58; &#40;1&#41; randomized controlled trials as the study design&#44; &#40;2&#41; inclusion of adult human participants diagnosed with AD or MCI&#44; &#40;3&#41; interventions of the studies were probiotics products&#44; &#40;4&#41; changes and standard deviation &#40;SD&#41; in cognitive function measured by validated tools were available&#44; and &#40;5&#41; publications were in English language&#46; The exclusion criteria were the following&#58; &#40;1&#41; reviews&#44; case reports&#44; editorials&#44; meeting articles&#44; or duplication of previous publications&#44; &#40;2&#41; no change on scale scores of cognition was reported&#44; and these data could not be calculated based on the information in the article&#44; or &#40;3&#41; studies without a control group&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Data extraction</span><p id="par0035" class="elsevierStylePara elsevierViewall">Two independent investigators extracted and summarized the following information from each included study&#58; the name of the first author&#44; publication year&#44; country&#44; study design&#44; characteristics of enrolled subjects &#40;sample size&#44; disease type and age&#41;&#44; strain&#44; dose&#44; and form of probiotics&#44; intervention duration&#44; and cognitive outcomes&#46; To perform the meta-analysis&#44; the mean change score along with the associated variance were extracted&#46; When change scores were not available&#44; the cognitive assessment scores at baseline and post-intervention were extracted&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Risk of bias and quality assessment</span><p id="par0040" class="elsevierStylePara elsevierViewall">All included studies were evaluated and classified according to the items set by Cochrane Collaboration&#39;s tool for assessing the risk of bias within and across randomized trials&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> The following items were evaluated for each study&#58; &#40;1&#41; random sequence generation&#59; &#40;2&#41; allocation concealment&#59; &#40;3&#41; blinding of participants and personnel&#59; &#40;4&#41; blinding of outcome assessment&#59; &#40;5&#41; incomplete outcome data&#59; &#40;6&#41; selective reporting and &#40;7&#41; other bias&#46; The overall judgment of each item for each study was categorized as &#8216;low&#8217;&#44; &#8216;high&#8217; and &#8216;unclear&#8217; according to the levels of bias&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">The effect of probiotics on cognitive function was defined as the mean difference between the intervention groups and control groups for pre&#8211;post changes in cognitive assessment scores&#46; Changes within groups &#40;mean values<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation&#41; from baseline were used to assess the intervention effect&#46; Where modifications were not reported&#44; SD changes were imputed assuming correlation coefficients as 0&#46;5 calculated from other eligible studies that provided the SD baseline&#44; SD final and SD change&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The meta-analysis was performed by Review Manager 5&#46;3 &#40;Cochrane Collaboration&#44; 2014&#41;&#46; Heterogeneity among the eligible studies was evaluated by the Cochran&#39;s <span class="elsevierStyleItalic">Q</span> statistic and <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> test&#46; The studies were considered homogeneous if the <span class="elsevierStyleItalic">p</span>-value of the <span class="elsevierStyleItalic">Q</span>-test was &#62;0&#46;1 or the <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> value was &#60;50&#37;&#44; and then&#44; a fixed-effects model was used&#46; Otherwise&#44; a random effects model was used&#46; Subgroup analysis was performed to explore the influence of a variety of factors on the results&#44; including the type of disease&#44; cognitive rating scale and strains of probiotics&#46; Publication bias was statistically assessed by Begg&#39;s test and Egger&#39;s regression test&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> Whenever a publication bias was identified&#44; we conducted a trim and fill adjusted analysis to recalculate the effect size at each iteration&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> The Egger&#39;s test&#44; Begg&#39;s test&#44; and trim and fill test were performed using the metaphor package implemented in R software version 3&#46;3&#46;4 &#40;R Foundation for Statistical Computing&#44; Vienna&#44; Austria&#41;&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Description of studies</span><p id="par0055" class="elsevierStylePara elsevierViewall">A total of 903 articles were retrieved through literature searching in the PubMed&#44; Embase and Cochrane databases&#44; after duplicate articles were removed and preliminarily screened on the basis of their titles and abstracts&#44; 22 articles remained for full-text reading&#46; Finally&#44; we identified 11 eligible articles in the present meta-analysis &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">5&#8211;8&#44;13&#8211;19</span></a> The characteristics of the included articles are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Of these selected articles&#44; 10 were double-blinded design&#44; 7 studies recruited subjects diagnosed with MCI&#44; and other studies included AD patients&#46; As Akhgarjand et al&#46; applied two different single-strain probiotic intervention groups&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a> which we regard as two independent studies&#46; Thus&#44; a total of 12 studies were included in this meta-analysis&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Risk of bias assessment</span><p id="par0060" class="elsevierStylePara elsevierViewall">The risks of bias assessment across the recruited studies are summarized in &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Based on the Cochrane Risk of Bias tool&#44; one study was classified as high risk in the domain blinding of participants and personnel and blinding of outcome assessment&#44; and the assessment of bias reported a low to moderate risk of bias across all domains in other included studies&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Effect of probiotics on global cognition and its domains</span><p id="par0065" class="elsevierStylePara elsevierViewall">A total of twelve studies including 852 participants &#40;429 in the probiotics groups and 429 in the placebo groups&#41; contributed to global cognitive function analysis &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; A random effects model was selected for quantitative synthesis&#46; The result revealed a notable difference between the probiotics and control group regarding improvement in global cognition &#40;SMD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;67&#59; 95&#37; CI&#58; 0&#46;32&#44; 1&#46;02&#59; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>83&#37;&#41;&#46; Meanwhile&#44; random effects models were applied to meta analyses of orientation&#44; registration&#47;immediate memory&#44; recall&#47;delayed memory and attention domains due to heterogeneity among studies&#44; while a fixed effects model was selected for analysis of language and visuospatial&#47;constructional domains&#46; The results showed an increase in recall&#47;delayed memory &#40;SMD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;67&#59; 95&#37; CI&#58; 0&#46;32&#44; 1&#46;02&#59; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>83&#37;&#41;&#44; attention &#40;SMD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;31&#59; 95&#37; CI&#58; 0&#46;04&#44; 0&#46;58&#59; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50&#37;&#41; and visuospatial&#47;constructional &#40;SMD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;24&#59; 95&#37; CI&#58; 0&#46;06&#44; 0&#46;42&#59; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>36&#37;&#41;&#46; There were no substantial differences in orientation &#40;SMD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;35&#59; 95&#37; CI&#58; &#8722;0&#46;33&#44; 1&#46;03&#59; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>90&#37;&#41;&#44; registration&#47;immediate memory &#40;SMD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;22&#59; 95&#37; CI&#58; &#8722;0&#46;06&#44; 0&#46;51&#59; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>66&#37;&#41; and language &#40;SMD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;14&#59; 95&#37; CI&#58; &#8722;0&#46;06&#44; 0&#46;35&#59; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#37;&#41; between the probiotics and placebo group&#46; The forest plots of these meta-analyses are shown in <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Subgroup analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">Subgroup analysis was performed to evaluate the effects of disease type &#40;AD versus MCI&#41;&#44; cognitive rating scale &#40;MMSE versus non-MMSE&#41; and strains of flora &#40;multiple versus sole&#41; on cognitive function&#46; As shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#44; the heterogeneity among the included studies failed to reduce after stratification&#46; Additionally&#44; the meta-analysis results from the subgroups were consistent with the overall pooled results&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Publication bias assessment and sensitivity analysis</span><p id="par0075" class="elsevierStylePara elsevierViewall">Begg&#39;s test and Egger&#39;s regression test were performed to quantitatively assess the publication bias of this meta-analysis&#46; Evidence of publication bias on cognition was detected &#40;Egger&#39;s test&#58; 95&#37; CI&#58; &#8722;2&#46;63&#44; 0&#46;01&#41;&#46; Then we performed a trim and fill method to address the problem of publication bias&#46; However&#44; it became unchanged after we applied the trim and fill method&#46; Besides&#44; the sensitivity analysis was performed to test the reliability of the meta-analysis results by omitting studies one by one&#46; Systematically removing each trial did not markedly influence the overall effects of probiotics on cognition &#40;see supplementary materials&#41;&#46; Thus&#44; the findings between the probiotics and control groups regarding cognitive enhancement were considered reliable&#46;</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">Numerous in vivo and clinical trials have been conducted to explore the specific mechanism of action of probiotics in preventing AD&#46; Small chain fatty acids &#40;SCFAs&#41; are saturated fatty acids produced in the gut&#44; which can influence brain function via three main functions&#58; immune modulation&#44; endocrine pathways and neuronal regulation&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> Ma X et al&#46; found that oral administration of <span class="elsevierStyleItalic">Lactobacillus mucosae</span> NK41 and <span class="elsevierStyleItalic">Bifidobacterium longum</span> NK46 can suppress gut dysbiosis and lipopolysaccharide &#40;LPS&#41; production&#44; resulting in the attenuation of cognitive decline with the regulation of neuroinflammation via the microbiota&#8211;gut&#8211;brain axis in AD mice&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> 12-Weeks of treatment with memantine plus <span class="elsevierStyleItalic">Lactobacillus plantarum</span> ameliorated cognitive deterioration&#44; decreased A&#946; levels in the hippocampus&#44; protected neuronal integrity and plasticity&#44; and reduced neuroinflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> Sun et al&#46; demonstrated that <span class="elsevierStyleItalic">Clostridium butyricum</span> can prevent cognitive impairment&#44; A&#946; deposits&#44; microglial activation&#44; and production of tumor necrosis factor &#40;TNF&#41;-&#945; and interleukin &#40;IL&#41;-1&#946; by regulating the microbiota&#8211;gut&#8211;brain axis&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> It is worthwhile to infer that inflammatory and oxidative stress pathways play an important role in various kinds of diseases&#44; especially age-related diseases&#46; Recent results from clinical studies showed that probiotic supplementation can regulate the abundance of intestinal flora and decrease some inflammatory and oxidative biomarkers in AD or MCI subjects&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a> More comprehensive metabolites need to be tested in future studies to further clarify the exact mechanism of the beneficial effect of probiotics on AD and MCI patients&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">According to a previous study which only include 3 RCTs&#44;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> there was no beneficial effect of probiotic supplementation on the cognitive function of individuals with AD&#46; While another meta-analysis conducted by Deng et al&#46; showed that probiotics consumption enhanced cognition in AD or MCI patients&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a> our analysis further confirmed the effect of probiotics&#46; Although cognitive function gradually declines with dementia severity in AD as the disease progresses&#44; the function of different cognitive domains may not decline equally at the same time&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a> To the best of our knowledge&#44; this study is the first meta-analysis to elucidate the effects of probiotics on specific domains of cognitive functions besides the global cognitive function in individuals with AD or MCI&#46; Probiotics may affect different cognitive domains and define cognitive improvement&#46; Our results indicate that probiotic ingestion may improve recall&#47;delayed memory&#44; attention and visuospatial&#47;constructional domains&#44; with less apparent effect on orientation&#44; registration&#47;immediate memory or language domains&#46; Future studies should examine the relationship between probiotics and specific &#40;core&#41; cognitive domain function in greater detail&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In all of the included studies&#44; only one study reported no measurable improvement of global cognitive function in AD patients&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> Further subgroup analyses have proved the beneficial outcome of probiotics in both AD and MCI subjects&#46; Apart from diverse interventions conditions&#44; such as characteristics of participants&#44; total intervention duration&#44; dosage&#44; probiotics themselves are also an important factor in the efficiency assessment&#46; Based on the analysis&#44; we can conclude more than 95&#37; of the study is done based on the genera <span class="elsevierStyleItalic">Bifidobacterium</span> and <span class="elsevierStyleItalic">Lactobacillus</span>&#46; The most widely used probiotics are <span class="elsevierStyleItalic">Bifidobacteria breve</span>&#44; <span class="elsevierStyleItalic">B&#46; longum</span>&#44; <span class="elsevierStyleItalic">Lactobacillus rhamnosus</span>&#44; <span class="elsevierStyleItalic">L&#46; plantarum</span>&#44; as single or multi-strain preparations&#46; Our subgroup analyses revealed that neither single nor multi-strain probiotics are beneficial for improving cognitive function&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">At present&#44; we failed to provide a dose-response of probiotics in ameliorating cognitive deficits&#46; The dose of probiotics used in included studies are commonly ranging from 10<span class="elsevierStyleSup">9</span> to 10<span class="elsevierStyleSup">10</span><span class="elsevierStyleHsp" style=""></span>CFU&#44; except for the study by Akhgarjand et al&#46;&#44; in which participants received a capsule contained 10<span class="elsevierStyleSup">15</span><span class="elsevierStyleHsp" style=""></span>CFU probiotic two times a day&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a> Several clinical studies demonstrated a positive protective effect in preventing antibiotic-associated diarrhea with high dose compared with low dose of the same probiotic&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a> However&#44; it seems hard to epitomize one optimal dose of probiotics for improving cognitive outcomes&#46; Additionally&#44; the duration of probiotic administration should also be considered&#46; Most commonly&#44; probiotics were administered for 12 weeks in included RCTs&#46; Given that duration of the intervention is a key factor to see changes in gut flora following probiotics consumption&#44; longer interventions are desirable in order to ensure that a potential effect can be observed&#46; While there was previous analysis examined efficacy according to the length of treatment&#44; and claimed that taking probiotics for even a week is sufficient in preventing and treating gastrointestinal disease&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> Thus&#44; more reliable evidence from various dosages of probiotics and intervention duration trials is needed&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Even though probiotic bacteria have the generally recognized as safe&#44; there are several reports about side effects triggered by the presence of these organisms&#46; Among the twelve studies included in our present study&#44; four did not report on the incidence of side effects&#44;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">5&#44;13&#44;18&#44;19</span></a> seven reported no side effects&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">6&#44;8&#44;14&#8211;17</span></a> and only one reported mild to moderate adverse events&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> including dizziness&#44; stomach aches&#44; headaches&#44; gastritis&#44; erectile dysfunction and seborrheic dermatitis&#46; These results warrant the overall safety of probiotic supplementation&#44; but unwanted side effects and bacteria&#8211;host interactions in rare cases could not be ignored&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Among 12 included studies&#44; Tamtaji OR et al&#46; reported that AD patients who received both probiotics and selenium exhibited a notable improvement in cognitive function and metabolic status compared with those who were given only selenium or placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> This underscores the importance of multi-component interventions for AD or MCI patients&#46; The multi-domain interventions include&#44; but are not limited to&#44; medicines&#44; diet&#44; exercise&#44; cognitive training&#44; and intensive risk management&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> Such comprehensive therapeutic approaches have the potential to become mainstream treatments for AD and MCI&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Several limitations of this meta-analysis are important to consider in interpreting the results&#46; First&#44; the publication bias was observed using the Begg&#39;s and Egger&#39;s test&#46; Thus&#44; a trim and fill method was used to correct for publication bias&#46; A positive effect of probiotics was still observed&#46; In addition&#44; the analysis identified considerable heterogeneity among the included studies&#46; Although we conducted subgroup analyses&#44; the main source of the heterogeneity still remains unknown&#46; Second&#44; the recruited AD patients were all diagnosed based on the NINDS-ADRDA criteria&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">5&#44;6&#44;13&#44;14</span></a> While the criteria for recruiting MCI subjects were inconsistent&#44; two studies diagnosed MCI according to the Diagnostic and Statistical Manual of Mental Disorders&#44; 5th edition &#40;DSM-5&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">7&#44;16</span></a> two studies selected subjects according to the MMSE score&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8&#44;15</span></a> Y&#46; Fei et al&#46; recruited subjects met the Peterson diagnostic criteria of MCI&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> Sakurai K et al&#46; discriminated MCI and normal individuals with an Memory Performance Index &#40;MPI&#41; score of less than 60&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a> Sanborn et al&#46; selected patients met the Petersen&#47;Winblad criteria &#40;i&#46;e&#46;&#44; one or more NIH Toolbox t scores at or below 35&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a> This may have generated low comparability of these included RCTs&#46; Third&#44; as the cognitive function scales varied across the recruited studies&#44; the unbalanced assessment methods may devaluate the meta-analysis outcome&#46; The MMSE scale was used in seven studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">6&#44;8&#44;13&#44;14&#44;16&#44;17</span></a> other cognitive rating scales including Cognitrax&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a> NIH toolbox&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a> Repeatable Battery for the Assessment of Neuropsychological Status &#40;RBANS&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> computerized neurocognitive function tests &#40;CNT&#41;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> and Test Your Memory &#40;TYM&#41; test&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> Last but not least&#44; unrecognized and unpredictable bias may introduce additional uncertainties not captured by confidence intervals&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> Therefore&#44; caution should be applied when interpreting the analytical results and generalizing the study findings&#46; Considering above limitations of this meta-analysis&#44; future RCTs that control these confounding factors are needed to verify the effect of probiotics on cognitive function&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conclusion</span><p id="par0115" class="elsevierStylePara elsevierViewall">Our meta-analysis shows that in general&#44; probiotics are beneficial in cognitive function improvement in AD and MCI patients&#46; No differences in efficacy were observed for disease group or cognitive rating scales or for single vs&#46; multiple species&#46; Probiotic supplementation could be taken as a novel therapy for AD or MCI&#46; With a view to the limitations of this meta-analysis&#44; further high-quality studies involving larger samples are still required to explore the safety and efficacy of probiotics&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Authors&#8217; contributions</span><p id="par0120" class="elsevierStylePara elsevierViewall">R&#46;M&#46; and R&#46;Z&#46;J&#46; conceived the idea for the review&#46; H&#46;W&#46;X&#46; and M&#46;J&#46; performed the literature search&#44; data extraction and analysis&#46; R&#46;M&#46; drafted the article&#46; All authors have read the manuscript and given their approval for publication&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Ethical considerations</span><p id="par0125" class="elsevierStylePara elsevierViewall">Informed consent was not required&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Funding</span><p id="par0130" class="elsevierStylePara elsevierViewall">This work was supported by the <span class="elsevierStyleGrantSponsor" id="gs1">Youth Science Foundation of Shandong First Medical University</span> &#40;No&#46; <span class="elsevierStyleGrantNumber" refid="gs1">202201-053</span>&#41;&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflict of interests</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interests&#46;</p></span></span>"
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              "titulo" => "Inclusion and exclusion criteria"
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              "titulo" => "Effect of probiotics on global cognition and its domains"
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              "titulo" => "Subgroup analysis"
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            0 => "Probiotic"
            1 => "Mild cognitive impairment"
            2 => "Alzheimer&#39;s disease"
            3 => "Meta-analysis"
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            0 => "Probi&#243;ticos"
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            2 => "Enfermedad de Alzheimer"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Recent clinical studies have yielded controversial results regarding the effect of probiotics on cognitive function in Alzheimer&#39;s disease &#40;AD&#41; or mild cognitive impairment &#40;MCI&#41; subjects&#46; To clarify the efficacy of probiotics on cognition&#44; we conducted a meta-analysis of randomized controlled trials &#40;RCTs&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Instructions of the PRISMA 2020 statement were followed&#46; Literature from the PubMed&#44; Embase and Cochrane databases were systematically searched and manually screened for relevant published RCTs&#46; We performed statistical analysis using RevMan&#44; and assessed the risk of bias using the R software&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of 12 studies comprising 852 patients with MCI or AD were identified&#46; The results of meta-analysis showed that probiotics improved global cognitive function &#40;SMD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;67&#59; 95&#37; CI&#44; 0&#46;32&#44; 1&#46;02&#41;&#44; recall&#47;delayed memory &#40;SMD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;67&#59; 95&#37; CI&#58; 0&#46;32&#44; 1&#46;02&#41;&#44; attention &#40;SMD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;31&#59; 95&#37; CI&#58; 0&#46;04&#44; 0&#46;58&#41; and visuospatial&#47;constructional &#40;SMD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;24&#59; 95&#37; CI&#58; 0&#46;06&#44; 0&#46;42&#41; cognitive domain&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This meta-analysis found that probiotic supplementation is associated with an improvement in cognitive performance among patients with AD and MCI&#46; However&#44; current evidence is limited&#44; and more reliable large-scale RCTs with higher methodological quality are needed&#46;</p></span>"
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            "titulo" => "Background"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Estudios cl&#237;nicos recientes han arrojado resultados controvertidos en cuanto al efecto de los probi&#243;ticos en la funci&#243;n cognitiva de los pacientes con enfermedad de Alzheimer &#40;EA&#41; o deterioro cognitivo leve &#40;DCL&#41;&#46; Con el objetivo de aclarar la eficacia de los probi&#243;ticos en la cognici&#243;n&#44; llevamos a cabo un metaan&#225;lisis de ensayos cl&#237;nicos controlados aleatorizados &#40;ECA&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se siguieron las instrucciones de la declaraci&#243;n PRISMA 2020&#46; Realizamos una b&#250;squeda sistem&#225;tica y seleccionamos manualmente ensayos cl&#237;nicos aleatorizados relevantes publicados en las bases de datos de PubMed&#44; Embase y Cochrane&#46; El an&#225;lisis estad&#237;stico se realiz&#243; utilizando RevMan y el riesgo de sesgo fue evaluado utilizando el <span class="elsevierStyleItalic">software</span> R&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Identificamos un total de 12 estudios que incluyeron a 852 pacientes con DCL o EA&#46; Los resultados del metaan&#225;lisis mostraron que los probi&#243;ticos mejoraron la funci&#243;n cognitiva global &#40;DME<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;67&#59; IC del 95&#37;&#58; 0&#44;32-1&#44;02&#41;&#44; la memoria de recuerdo&#47;demora &#40;DME<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;67&#59; IC del 95&#37;&#58; 0&#44;32-1&#44;02&#41;&#44; la atenci&#243;n &#40;DME<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;31&#59; IC del 95&#37;&#58; 0&#44;04-0&#44;58&#41; y el dominio cognitivo visoespacial&#47;constructivo &#40;DME<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;24&#59; IC del 95&#37;&#58; 0&#44;06-0&#44;42&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Este metaan&#225;lisis encontr&#243; que la suplementaci&#243;n con probi&#243;ticos est&#225; asociada con una mejora en el rendimiento cognitivo entre los pacientes con EA y DCL&#46; Sin embargo&#44; la evidencia actual es limitada&#44; y se necesitan ensayos cl&#237;nicos aleatorizados a gran escala con mayor calidad metodol&#243;gica para obtener resultados m&#225;s confiables&#46;</p></span>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Forest plots for studies examining the effect of probiotic vs placebo administration on cognitive domains&#58; &#40;a&#41; Orientation&#44; &#40;b&#41; Registration&#47;Immediate memory&#44; &#40;c&#41; Recall&#47;Delayed memory&#44; &#40;d&#41; Attention&#44; &#40;e&#41; Language&#44; and &#40;f&#41; Visuospatial&#47;Constructional&#46; A fixed-effects model was applied to the meta-analysis of Language and Visuospatial&#47;Constructional&#44; while other domains used a random-effects model&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; PRO&#44; probiotics group&#59; CON&#44; control group&#59; CFU&#44; colony-forming units&#59; AD&#44; Alzheimer&#39;s disease&#59; MCI&#44; mild cognitive impairment&#59; MMSE&#44; Mini-Mental State Examination&#59; MoCA&#44; Montreal Cognitive Assessment Scale&#59; ADAS-Jcog&#44; Japanese version of Alzheimer&#39;s Disease Assessment Scale&#59; JMCIS&#44; Japanese version of the MCI Screen&#59; RBANS&#44; Repeatable Battery for the Assessment of Neuropsychological Status&#59; CNT&#44; computerized neurocognitive function tests&#59; TYM&#44; Test Your Memory&#59; CFT&#44; categorical verbal fluency test&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Country&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Design&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Participants&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mean age &#40;year&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Probiotics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Delivery method&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dosage &#40;CFU daily&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Duration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cognitive assessment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Main findings&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sakurai K et al&#46; &#40;2022&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Japan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">78 MCI patients &#40;39 in probiotic group&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PRO 76&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;6 CON 76&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Lactiplantibacillus plantarum</span> OLL2712 &#40;OLL2712&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1<span class="elsevierStyleHsp" style=""></span>g&#47;package&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10&#94;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cognitrax&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">OLL2712 ingestion has protective effects against memory function decline in older adults&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Y Fei et al&#46; &#40;2023&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">China&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42 MCI patients &#40;21 in probiotic group&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PRO 76&#46;40<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;61 CON 75&#46;30<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;75&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Lactobacillus</span>&#44; <span class="elsevierStyleItalic">Lactococcus</span> and <span class="elsevierStyleItalic">Bifidobacterium</span> genera&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Capsule&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;4<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10&#94;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MMSE&#44; MoCA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The probiotic group had a much higher MMSE score and MoCA score compared to the placebo group after 12 weeks of intervention&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sanborn et al&#46; &#40;2020&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42 MCI patients &#40;19 in probiotic group&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PRO 65&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;27 CON 62&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Lactobacillus rhamnosus</span> GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Capsule&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10&#94;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NIH toolbox&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Lactobacillus rhamnosus</span> GG probiotic supplementation was associated with improved cognitive performance in MCI adults&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">D Asaoka et al&#46; &#40;2022&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Japan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">115 MCI patients &#40;55 in probiotic group&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PRO 77&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;8 CON 78&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Bifidobacterium breve</span> MCC1274&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sachets&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10&#94;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MMSE&#44; ADAS-Jcog&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MMSE subscales &#8220;orientation in time&#8221; and &#8220;writing&#8221; were significantly improved compared to placebo in the lower baseline MMSE &#40;&#60;25&#41; subgroup&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">J Xiao et al&#46; &#40;2020&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Japan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">79 MCI patients &#40;39 in probiotic group&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PRO 61&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;7 CON 60&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Bifidobacterium breve</span> MCC1274&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Capsule&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10&#94;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RBANS&#44; JMCIS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RBANS total score was significantly improved in probiotic group compared to palcebo&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Akbari et al&#46; &#40;2016&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Iran&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60 AD patients &#40;30 in probiotic group&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PRO 77&#46;67<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;62 CON 82&#46;00<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;69&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Lactobacillus acidophilus</span>&#44; <span class="elsevierStyleItalic">Lactobacillus casei</span>&#44; <span class="elsevierStyleItalic">Bifidobacterium bifidum</span>&#44; and <span class="elsevierStyleItalic">Lactobacillus fermentum</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">200<span class="elsevierStyleHsp" style=""></span>ml probiotic milk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10&#94;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MMSE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Probiotics intervention resulted in an improvement in MMSE score in the probiotic group compared to their control counterparts&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Y Kobayashi et al&#46; &#40;2019&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Japan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">117 MCI patients &#40;59 in probiotic group&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PRO 61&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;83 CON 61&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Bifidobacterium breve</span> A1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Capsule&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10&#94;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MMSE&#44; RBANS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No significant difference was noted between the groups in total scores of MMSE and in terms of the changes of RBANS scores against baseline&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">OR Tamtaji et al&#46; &#40;2018&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Iran&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">79 AD patients &#40;27 in probiotic group&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PRO 76&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;1 CON 78&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Lactobacillus acidophilus</span>&#44; <span class="elsevierStyleItalic">Bifdobacterium bifdum</span>&#44; <span class="elsevierStyleItalic">Bifdobacterium longum</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Not clear&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10&#94;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MMSE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Probiotic and selenium combination resulted in a signifcant increase in MMSE scores compared to selenium only and placebo&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hwang et al&#46; &#40;2019&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Korea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100 MCI patients &#40;50 in probiotic group&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PRO 68&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;12 CON 69&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Lactobacillus Plantarum</span> C29-fermented soybean &#40;DW2009&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Capsule&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;1<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10&#94;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CNT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">There were greater improvements in the combined cognitive functions&#44; especially in attention domain&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Agahi et al&#46; &#40;2018&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Iran&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48 AD patients &#40;25 in probiotic group&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PRO 79&#46;70<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;72 CON 80&#46;57<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Lactobacillus acidophilus</span>&#44; <span class="elsevierStyleItalic">Lactobacillus casei&#44; Lactobacillus fermentum</span>&#44; and <span class="elsevierStyleItalic">Bifidobacterium bifidum</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Capsule&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10&#94;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TYM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cognitive and biochemical indications in the patients with severe AD were insensitive to the probiotic supplementation&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Akhgarjand et al&#46; &#40;2022&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Iran</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t">RCT</td><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t">90 AD patients &#40;30 in each probiotic group&#41;</td><td class="td" title="\n
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                  \t\t\t\t">a PRO 67&#46;93<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;8 CON 67&#46;77<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">a PRO&#58; <span class="elsevierStyleItalic">Lactobacillus rhamnosus</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">12-Week probiotic supplementation compared with placebo had beneficial effects on the cognition status of patients with AD&#46;</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">0&#46;43 &#91;0&#46;09&#44; 0&#46;77&#93;&nbsp;\t\t\t\t\t\t\n
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                      "titulo" => "Altered microbiomes distinguish Alzheimer&#39;s disease from amnestic mild cognitive impairment and health in a Chinese cohort"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Liu"
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                            4 => "R&#46; Tang"
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                      "doi" => "10.1016/j.bbi.2019.05.008"
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                        "tituloSerie" => "Brain Behav Immun"
                        "fecha" => "2019"
                        "volumen" => "80"
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Article information

ISSN: 23870206
Original language: English

DOI:10.1016/j.medcle.2024.01.011

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