# paper.pdf ## Metadata - PDFFormatVersion=1.5 - Language=en-US - IsLinearized=true - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - pdf:producer=Adobe LiveCycle PDFG ES - xap:createdate=2026-04-29T11:38:06+05:30 - xap:creatortool=Arbortext Advanced Print Publisher - xap:modifydate=2026-04-29T11:38:06+05:30 - xap:metadatadate=2026-04-29T11:38:06+05:30 - xapmm:documentid=uuid:8addd02c-2a8d-4824-a074-0375b52bef83 - xapmm:instanceid=uuid:9735c38c-787b-4f5b-aca7-e8422204bc96 - prism:aggregationtype=Journal - prism:publicationname=Renal Failure - prism:copyright=© 2026 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. - prism:volume=48 - prism:number=1 - prism:pagerange=- - prism:doi=10.1080/0886022X.2026.2658981 - prism:url=https://doi.org/10.1080/0886022X.2026.2658981 - dc:format=application/pdf - dc:identifier=10.1080/0886022X.2026.2658981 - dc:language=en-US - dc:title=A prospective, randomized, double-blind, placebo-controlled, multicenter study of thiamin plus folic acid in the treatment of cognitive impairment in patients undergoing maintenance hemodialysis - dc:publisher=Taylor & Francis - dc:description=Renal Failure, 2026. doi: 10.1080/0886022X.2026.2658981 - dc:creator=Xie Kewei,Jiang Yan,Chen Tingfang,Liu Shang,Fang Yan,Chen Feihong,Shen Jianxiao,Zeng Xiaojun,Li Ping,Qiu Ting,Wang Jieying,Yu Ling,Zang Xiujuan,Wang Niansong,Yuan Jiangzi,Pang Huihua,Zhang Weiming,Ni Zhaohui,Gu Leyi,Guo Yongping,Lu Renhua - dc:subject=End-stage kidney disease,cognitive impairment,vitamin B,oxidative stress,cardiovascular outcomes - jav:journal_article_version=VoR ## Contents ### Page 1 A prospective, randomized, double-blind, placebo-controlled,multicenter study of thiamin plus folic acid in the treatment ofcognitive impairment in patients undergoing maintenancehemodialysis Kewei Xieabcaadaaaaefbca,daaaacaabcdef ,]. Ci is a common neurological complica-tion of MHd []. Our previous study demonstrated that Ci incidence in patients undergoing MHd is ashigh as 51.6%, and the 3-year survival rate is significantly lower in MHd cases with Ci compared with https://doi.org/10.1080/0886022X.2026.2658981 CONTACT Yongping Guo Department of nephrology, Sixth People’s Hospital, Shanghai Jiao Tonguniversity, Shanghai, China; Renhua lu Department of nephrology, Molecular Cell lab for Kidney Disease,Shanghai Peritoneal Dialysis Research Center, uremia Diagnosis and Treatment Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tonguniversity, Shanghai, China. Supplemental data for this article can be accessed online at. ARTICLE HISTORY Received 10 July 2025 Revised 22 October 2025 accepted 12 november2025 This is an Open access article distributed under the terms of the Creative Commons attribution license (), whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has beenpublished allow the posting of the accepted Manuscript in a repository by the author(s) or with their consent. KEYWORDS End-stage kidney disease;cognitive impairment;vitamin B; oxidativestress; cardiovascularoutcomes [](http://www.tandfonline.com/) [](http://crossmark.crossref.org/dialog/?doi=10.1080/0886022X.2026.2658981&domain=pdf&date_stamp=2026-4-29) CliniCal Study © 2026 The author(s). Published by informa uK limited, trading as Taylor & Francis Group. ### Page 2 counterparts with normal cognitive function []. this imposes a heavy burden on the country, society,and families, which requires widespread attention from the medical community. Our previous in vivo and in vitro studies demonstrated that in 5/6 of nephrectomized rats, the uremicenvironment results in thiamin and folic acid deficiency, increased homocysteine levels, and enhancedoxidative stress in the hippocampal region of the brain, leading to neuronal damage and Ci. in addition,the latter study found positive associations of serum thiamin and folic acid with cognitive function,which may be potential targets for the treatment in patients with Ci undergoing MHd []. Recent find-ings also reported that thiamin, as a cofactor of transketolase, plays an important role in reducing reac-tive oxygen species (ROS) production in the nervous system and alleviating oxidative stress []. Folic acidexerts a direct antioxidant effect and is an essential substance for the metabolism of homocysteine tomethionine, which reduces homocysteine levels []. Based on the above findings, a prospective, random-ized, controlled, open-label and single-center clinical study was performed, including 50 patients with Ciundergoing MHd. Of these patients,25 each were included in the treatment (thiamin tablets 90 mg/dayplus folic acid tablets 30 mg/day) and control (without intervention) groups, with a follow-up of 96 weeks. the results revealed a significant decrease of 25.2% in blood homocysteine levels and a significantimprovement of the MoCa score in the treatment group. However, the latter study had several limita-tions, including a small sample size, the absence of blinding and placebo control methods, and the useof only the MoCa score to assess cognitive function []. to further validate the above preliminary trial, a prospective, randomized, double-blind, placebo-controlledmulticenter clinical study [] was designed to examine the efficacy and safety of two B vitamin-intensivecombination therapies for improving cognitive function in patients with Ci undergoing MHd. 2. Patients and methods 2.1. Patients Patients undergoing maintenance hemodialysis at Renji Hospital affiliated to Shanghai Jiao tonguniversity School of Medicine, Songjiang Hospital affiliated to Shanghai Jiao tong university School ofMedicine, Shanghai Sixth People’s Hospital, and Baoshan Branch of Renji Hospital affiliated to ShanghaiJiao tong university School of Medicine were screened according to set inclusion and exclusion criteria(). 2.2. Methods 2.2.1. Study design this was a prospective, randomized, double-blind, placebo-controlled, multicenter clinical study. the cur-rent study was registered with the Chinese Clinical trial Registry (,date of Registration: 2020-01-22, Registration number: ChiCtR2000029297). this clinical trial was con-ducted from January 18, 2021, to april 30, 2023. 2.2.2. Randomization and double-blinding methods a total of 215 patients were consecutively enrolled between January and april 2021. Random sequenceswere generated with SaS (version 9.3) by an independent data manager, who printed the random num-bers and stored them in sealed opaque envelopes. a centralized 1:1 randomization was applied. Stratifiedrandomization was performed based on three key factors: study center, age (<60 vs. ≥60 years), anddialysis vintage (<36 vs. ≥36 months), to ensure balanced distribution of potential confounding variablesbetween groups. Each time a patient signed the informed consent form and met the inclusion criteria,the study doctor opened a random envelope to obtain a random number based on which the corre-sponding number of study drugs was assigned to the subject. 2.2.3. Patient grouping the treatment group was administered thiamin tablets (90 mg/day,30 mg tid po, specification 10 mg/tab-let,100 tablets/bottle) and folic acid tablets (30 mg/day,10 mg tid po, specification 5 mg/tablet, 100 ### Page 3 tablets/bottle). the placebo group was administered thiamin (90 mg/day, 30 mg tid po, Shanghai ChenponPharmaceutical Co., ltd., specification 10 mg/tablet, 100 tablets/bottle) and folic acid (30 mg/day,10 mgtid po, Changzhou Pharmaceutical Factory, specification 5 mg/tablet,100 tablets/bottle) placebos. 2.2.4. Drug management Each branch center managed the trial drugs using the same procedure, distributing 3 bottles of thiaminor placebo tablets and 2 bottles of folic acid or placebo tablets every 4 weeks. Before each distribution,the drug administrator collected the remaining drugs from the previous distribution and filled out thedrug distribution and Recovery Form. Meanwhile, all subjects filled out the Subject diary. 2.3. Efficacy evaluation indicators the primary efficacy endpoint was alzheimer’s disease assessment scale-cognitive section (adaS-Cog)score, which was assessed in the treatment and placebo groups at baseline and Week 96. Secondaryefficacy endpoints included changes in blood thiamin, folic acid, and homocysteine levels in the treat-ment and placebo groups at baseline and Week 96, as well as patient prognosis in both groups at96 weeks. Safety endpoints were changes in laboratory safety indicators and the incidence of aEs duringthe study period. 2.4. Main outcome measures 2.4.1. Cognitive function assessment at baseline, the MoCa score [,] was employed to diagnose Ci (<26 points [<25 points in case of <12educational years]). the version of the MoCa scoring system was the Beijing version (2006-8-26). at base-line, 48 weeks of follow-up, and 96 weeks of follow-up, the adaS-Cog score [,] was applied to assess ![Flowchart of patient screening, inclusion, and randomization for a cognitive impairment study among MHD patients. ** The flowchart details the screening and selection process for a study on cognitive impairment in 565 MHD patients. Initially, all patients completed the MoCA test, leading to 268 patients with scores <26 being considered. From this group, 215 met the inclusion criteria and were randomized into two groups: 107 patients received thiamine and folic acid, while 108 received placebos. The flowchart illustrates both inclusion and exclusion criteria, detailing reasons for ineligibility such as inability to complete the study and specific health conditions.]() Figure 1. Patient inclusion and exclusion criteria. according to the inclusion and exclusion criteria, a total of 215 main-tenance hemodialysis patients entered the randomized trial, Treatment Group (n = 107), Placebo Group (n = 108). ### Page 4 treatment efficacy. Both assessments were performed by trained neurologists before or within 1 h ofhemodialysis. the randomization data were kept confidential by neurologists performing cognitive func-tion assessments. 2.4.2. Blood thiamin, folic acid, and homocysteine detection Blood thiamin, folic acid, and homocysteine levels were measured at baseline and 48 and 96 weeks offollow-up. ultra-high performance liquid chromatography tandem quadrupole mass spectrometry (aPi4000 triple quadrupole liquid chromatography-mass spectrometer, aB Sciex analytical instrument tradingCo., ltd.) was performed, with analyst 1.61 for analysis. 2.5. Statistical analysis Efficacy and safety analyses will be performed according to the intention-to-treat (itt) principle on allrandomized subjects who received at least one dose of the study medication, using the last ObservationCarried Forward (lOCF) method to impute missing data for subjects who did not complete the full treat-ment course. normally distributed continuous data will be presented as Mean ± Standard deviation (Sd),non-normally distributed continuous data as Median and interquartile Range (iQR), and categorical dataas Proportions or Percentages (%). Quantitative data will be analyzed using the t-test or Wilcoxonrank-sum test, while qualitative data will be analyzed using the Chi-square test, Fisher’s exact test, orCochran-Mantel-Haenszel (CMH) chi-square test. Baseline comparisons between groups will utilize theMann-Whitney u test (non-parametric test). due to differences in sex composition between the twogroups at baseline, 2 × 3 × three factor repeated measures anOVa was used to analyze cognitive scores.among them, group (placebo group, treatment group) and biologic sex (male, female) were used asintergroup factors, and time (baseline, 48 weeks, 96 weeks) was used as intra group factors. this model isused to examine the interaction between groups and time (i.e. evaluate whether treatment responsepatterns vary by group), while controlling for the main effect of sex and all possible interactions. if thehigh-order interaction is not significant, it will be removed from the final model. Survival analysis willemploy Kaplan-Meier survival curves. all statistical analyses will be conducted using the SPSS version27.0 software package (SPSS inc., Chicago, il, uSa), with a p-value < 0.05 defined as statisticallysignificant. 3. Results 3.1. Basic information of patients undergoing MHD a total of 215 patients undergoing MHd met the inclusion and exclusion criteria. according to the studyprotocol, the patients were randomly divided into the treatment (n = 107) and placebo (n = 108) groupsat a ratio of 1:1, with a follow-up period of 96 weeks (). there were no statistically significant differences in baseline demographic data, past history, and cog-nitive function scores (MoCa and adaS-Cog scores) between the treatment and placebo groups, exceptfor a significantly lower proportion of male patients in the treatment group versus the placebo group.the proportion of male patients was significantly lower in the treatment group (54.2%) than in the pla-cebo group (68.5%, p = 0.036). there were also no significant differences in baseline hemodialysis-relateddata and laboratory indicators between the treatment and placebo groups (). 3.2. ADAS-cog scores at baseline and Week 96 after 96 weeks of follow-up, adaS-Cog scores were significantly lower in the treatment group than in thecontrol group. Meanwhile, adaS-Cog scores in the treatment group (n = 85) were significantly lower thanbaseline values. at Week 96, adaS-Cog scores in the placebo group (n = 86) showed an upward trendcompared with baseline values, but without statistical significance (). the interaction betweengroup and time was significant (F = 41.25, p < 0.001), indicating a significant difference in the pattern ofcognitive score changes over time between the two groups of patients, supporting the therapeutic effect ### Page 5 of the drug. the third-order interaction between group, sex, and time was not significant (F = 0.007,p = 0.993), and the interaction between time and sex was also not significant (F = 0.097, p = 0.908). thisindicates that sex differences did not significantly alter the pattern of cognitive score changes over time,nor did they modulate the efficacy pattern of drugs. therefore, subsequent analysis will focus on signif-icant group time interactions (). Based on significant between-group differences in overall cognitive function (adaS-Cog total score)(between-group effect F = 20.306, p < 0.001; interaction effect F = 29.239, p < 0.001), the scores werecategorized into five cognitive domains for analysis: memory function, language ability, executivefunction, visuospatial ability, and orientation. Results showed that the treatment group demonstratedcontinuous and significant improvements in all cognitive domains (all p < 0.001). at week 96, signifi-cant decreases from baseline were observed in memory function (26.0% reduction), language ability(36.5% reduction), executive function (36.2% reduction), visuospatial ability (36.3% reduction), andorientation (36.5% reduction), with particularly prominent improvements in memory function(within-group F = 80.87) and orientation (within-group F = 20.54). in contrast, the control group exhib-ited only marginally significant deterioration trends in language ability (p = 0.056) and executive func-tion (p = 0.059), while the remaining domains remained stable (all p > 0.05). Significant interactioneffects were observed across all domains (all p < 0.001, strongest in the memory domain F = 40.25),confirming that the therapeutic intervention comprehensively slowed cognitive decline in mainte-nance hemodialysis patients, with particularly significant effects on memory improvement, as detailedin and. ![Flowchart detailing early discontinuation reasons and study completion rates for Treatment \(n=107\) and Placebo \(n=108\) groups. ** The flowchart presents two panels for Treatment \(n=107\) and Placebo \(n=108\) groups, showing a total of 22 early discontinuations per group. Reasons are categorized by timing: 0-48 weeks and 48-96 weeks. In the Treatment group, there are 7 deaths and 3 kidney transplantations in the first period, totaling 11 discontinuations. For the second period, 6 deaths and 3 transplantations yield another 11. In the Placebo group, 8 deaths and 0 transplantations occur in the first period \(total 8\), while 5 deaths and 3 transplantations in the second lead to 14 discontinuations. Completion rates by Week 48 are 96 \(Treatment\) and 100 \(Placebo\); by Week 96, 85 \(Treatment\) and 86 \(Placebo\).]() Figure 2. Patient disposition from randomiztion to end of study. This study was followed up for 96 weeks, with 96(Treatment Group) and 100 patients (Placebo Group) completing 48 weeks of follow-up, while 85 (Treatment Group) and86 (Placebo Group)patients completed 96 weeks of follow-up, respectively. Both groups had 22 patients who did notcomplete 96 weeks of follow-up. ### Page 6 3.3. Blood thiamin, folic acid, and homocysteine levels at baseline and Week 96 there were no significant differences in blood thiamin, folic acid, and homocysteine levels between thetwo groups at baseline. after 96 weeks of follow-up, blood homocysteine levels were significantly lowerin the treatment group compared with the placebo group. Meanwhile, blood thiamin and folic acid lev-els were significantly higher in the treatment group compared with the placebo group (). in addition, at 48 and 96 weeks of follow-up, blood thiamin and folic acid levels were significantlyhigher in the treatment group versus baseline values, while blood homocysteine levels were significantlylower than baseline values, with decrease rates of 19.79% and 37.09%, respectively. Blood thiamin andfolic acid levels were significantly lower in the placebo group at 96 weeks of follow-up versus baselinevalues, while no significant differences were found in blood homocysteine levels between 48 and96 weeks (). Table 1. Characteristics of the patients at baseline. | Total (n = 215) | Treatment group (n = 107) | Placebo group (n = 108) | P Value | | - | - | - | - | | age, years | 59.12 ± 11.82 | 58.39 ± 13.12 | 59.84 ± 10.37 | 0.370 | | Male, n (%) | 132 (61.4) | 58 (54.2) | 74 (68.5) | 0.036 | | Height (cm) | 166.63 ± 7.24 | 166.53 ± 7.0 | 166.73 ± 7.50 | 0.842 | | Body Mass index (BMi) | 21.97 ± 3.15 | 22.17 ± 3.33 | 21.77 ± 2.97 | 0.390 | | education status (≥12 years, n [%]) | 89 (41.4) | 42 (39.3) | 47 (43.5) | 0.793 | | Primary cause of MHD, n (%) | | Primary glomerulonephritis | 73 (34) | 32 (29.9) | 41 (38) | 0.250 | | Diabetic nephropathy | 33 (15.3) | 12 (11.2) | 21 (19.4) | 0.129 | | Hypertensive nephrosclerosis | 8 (3.7) | 3 (2.8) | 5 (4.6) | 0.721 | | aDPKD | 17 (7.9) | 11 (10.3) | 6 (5.6) | 0.218 | | unknown cause | 84 (39) | 45 (42) | 39 (36.2) | 0.851 | | Complication, n (%) | | Hypertension | 141 (65.6) | 68 (63.6) | 73 (67.6) | 0.568 | | Diabetes | 61 (28.40 | 27 (25.2) | 34 (31.5) | 0.365 | | Cardiovascular disease | 25 (11.6) | 13 (12.1) | 12 (11.1) | 0.835 | | Cerebrovascular disease | 11 (5.1) | 4 (3.7) | 7 (6.5) | 0.538 | | urine, ml/day | 0 (0, 100) | 0 (0, 100) | 0 (0, 100) | 0.803 | | Dialysis vintage, months | 40.5 (17, 97.75) | 40 (19, 99) | 41 (16.5, 94.5) | 0.711 | | MoCa Score | 19.65 ± 5.06 | 19.40 ± 5.40 | 19.94 ± 4.65 | 0.454 | | aDaS-Cog Score | 22.93 ± 10.98 | 22.19 ± 10.31 | 23.65 ± 11.61 | 0.327 | | autogenous arteriovenous fistula(patients, %) | 211 (98.1) | 105 (98.1) | 106 (98.1) | 1.000 | | intradialytic hypotension(patients, %) | 17 (7.9) | 9 (8.4) | 8 (7.4) | 0.594 | | Pre-dialysis weight (Kg) | 62.88 ± 10.22 | 63.62 ± 11.23 | 62.16 ± 10.62 | 0.336 | | Post-dialysis weight (Kg) | 60.86 ± 10.83 | 61.68 ± 11.11 | 60.06 ± 10.54 | 0.283 | | ultrafiltration (ml) | 2407.63 ± 817.18 | 2438.5 ± 754.5 | 2377.3 ± 876.9 | 0.587 | | Pre-dialysis systolic pressure(mmHg) | 143.94 ± 24.86 | 144.26 ± 23.17 | 143.63 ± 26.56 | 0.854 | | Post-dialysis systolic pressure(mmHg) | 136.27 ± 24.44 | 136.87 ± 25.1 | 135.68 ± 23.86 | 0.725 | | Pre-dialysis diastolic pressure(mmHg) | 76.79 ± 17.12 | 77.24 ± 14.9 | 76.33 ± 19.15 | 0.703 | | Post-dialysis diastolic pressure(mmHg) | 77.4 ± 14.81 | 78.91 ± 15.71 | 75.9 ± 13.76 | 0.139 | | Hb (g/l) | 112.01 ± 12.34 | 113.18 ± 12.05 | 110.94 ± 12.56 | 0.201 | | alb (g/l) | 40.06 ± 2.97 | 40.27 ± 3.23 | 39.86 ± 2.70 | 0.318 | | Glu (mmol/l) | 7.29 ± 3.72 | 6.98 ± 3.70 | 7.6 ± 3.73 | 0.230 | | Glycated hemoglobin (%) | 5.77 ± 1.07 | 5.61 ± 0.94 | 5.96 ± 1.19 | 0.058 | | TC (mmol/l) | 4.14 ± 1.06 | 4.23 ± 1.12 | 4.05 ± 0.99 | 0.217 | | TG (mmol/l) | 2.01 ± 1.39 | 2.1 ± 1.64 | 1.92 ± 1.09 | 0.350 | | lDl (mmol/l) | 2.48 ± 0.85 | 2.53 ± 0.91 | 2.42 ± 0.78 | 0.373 | | HCO3− (mmol/l) | 22.18 ± 3.2 | 21.75 ± 3.43 | 22.62 ± 2.87 | 0.113 | | K+ (mmol/l) | 4.56 ± 1.09 | 4.57 ± 0.98 | 4.58 ± 1.11 | 0.954 | | Ca (mmol/l) | 2.22 ± 0.42 | 2.27 ± 0.45 | 2.17 ± 0.38 | 0.082 | | P (mmol/l) | 1.99 ± 0.67 | 1.97 ± 0.66 | 2.0 ± 0.68 | 0.755 | | TSaT (%) | 27.89 ± 12.41 | 28.32 ± 11.63 | 27.45 ± 13.22 | 0.636 | | Ferritin (ng/ml) | 117(42.75, 357) | 154(42, 373) | 104(43, 340.5) | 0.452 | | iPTH (pg/ml) | 337.82 ± 286.26 | 315.52 ± 277.92 | 359.06 ± 293.74 | 0.277 | | 25-(OH)-D3 (miu/l) | 12.52 ± 5.92 | 12.71 ± 5.36 | 12.32 ± 6.52 | 0.754 | | CRP (mg/dl) | 2(0, 5) | 2(0, 4) | 4.26(1.77, 7.77) | 0.425 | | β2-MG (mg/l) | 26.99 ± 13.85 | 27.67 ± 14.49 | 26.29 ± 13.21 | 0.481 | | BnP (pg/ml) | 598(183, 2676.25) | 448.5(183, 2540) | 686(185.75, 2890.75) | 0.377 | | spKt/V | 1.43 ± 0.32 | 1.47 ± 0.31 | 1.39 ± 0.33 | 0.110 | ### Page 7 3.4. Patient prognosis at 96weeks of follow-up during the follow-up period, a total of 26 patients died, including 13 each in the treatment (12.1%) andplacebo (12%) groups, indicating no significant difference between the two groups (p = 0.978).Kaplan-Meier survival analysis also revealed no significant difference in survival rate between the treat-ment and placebo groups (p = 0.854), as shown in. in addition, 9 patients in each group did notcomplete the 96 weeks of follow-up. Of these, 6 patients in the treatment group had kidney transplan-tation surgery (5.6%), 2 were transferred to another center (1.9%), and 1 (0.9%) requested to withdrawfrom the study. in the placebo group, 3 patients had kidney transplantation (2.8%), 5 were transferred toanother center (4.6%), and 1 requested to withdraw from the study (0.9%). there was no significant dif-ference between the two groups (p = 0.683), as shown in. the major causes of death were cardiovascular and cerebrovascular diseases (16 cases, 61.5%), infec-tions (8 cases, 23.1%), malignant tumors (1 case, 3.8%), and gastrointestinal bleeding (1 case, 3.8%) (). there was no significant difference (p = 0.688) between the treatment and placebo groups in the 16patients who died from cardiovascular and cerebrovascular diseases. 3.5. Changes in laboratory safety indicators and incidence of AEs during the study period Compared with the placebo group, there were no significant differences in hemodialysis-related data andlaboratory indicators between the treatment and placebo groups at 48 and 96 weeks of follow-up, exceptfor significantly lower blood phosphorus levels in the treatment group compared with the placebo groupat Week 96 (see). during the study period, a total of 101 aEs occurred, including 34 (33.7%) and 67 (66.3%) in thetreatment and placebo groups, respectively. the incidence of aEs was significantly higher in the placebogroup compared with the treatment group (p = 0.0017). during the follow-up period, a total of 42 cardio-vascular and cerebrovascular aEs occurred, including 14 and 28 in the treatment and placebo groups,respectively, indicating a significant difference between the two groups (p = 0.001). Seven patients hadnovel coronavirus pneumonia during the study period, including 3 and 4 in the treatment and placebogroups, respectively, indicating no statistically significant difference between the two groups (p = 1.000)(). ![Multi-panel figure with line graphs displaying cognitive scores over 96 weeks for placebo \(blue\) and treatment \(red\) groups across various measures. ** The figure presents six line graphs \(Panels A-F\) comparing cognitive scores of placebo and treatment groups over 96 weeks. Key findings include: ADAS-Cog scores slightly decline for treatment and stabilize for placebo; Memory scores show a decrease in treatment scores, while placebo remains stable; Language scores fluctuate minimally; Executive Function scores decline in treatment but rise slightly in placebo; Visuospatial scores remain steady; Orientation scores increase for placebo but decline for treatment. Error bars represent variability.]() Figure 3. Comparison of aDaS-Cog Scores Between Treatment and Placebo Groups: Based on aDaS-Cog scores, thetreatment group demonstrated improved cognitive impairment compared to the placebo group, with a statistically sig-nificant difference in aDaS-Cog scores between the two groups at 96 weeks. Panels a–F represent the aDaS-Cog totalscore and domain scores for memory function, language ability, executive function, visuospatial ability, and orientation,respectively. ### Page 8 4. Discussion this study employed a prospective, randomized, double-blind, placebo-controlled design. the resultsshowed that after 96 weeks of follow-up, patients in the treatment group exhibited a significant reduc-tion in adaS-Cog scores, indicating that supplementation with thiamin and folic acid can improve Table 2. Comparison of aDaS-cog scores between two groups of maintenance hemodialysis patients at differentfollow-up time points. | indicator (aDaS-Cog Scores) | Control group (n = 86) | Treatment group (n = 85) | Z-value | p-value | | - | - | - | - | - | | 0 week | 24.53 ± 11.01 | 21.25 ± 9.20 | 1.071 | 0.301 | | 48 weeks | 24.68 ± 12.12 | 18.07 ± 8.57 | 18.467 | <0.001 | | 96 weeks | 26.53 ± 14.43 | 15.07 ± 8.38 | 48.329 | <0.001 | | F-value | 2.638 | 98.87 | | p-value | 0.077 | <0.001 | | Between-group effect | | Group | F = 20.183, p < 0.001 | | Sex | F = 0.040, p = 0.842 | | Group × Sex | F = 0.408, p = 0.524 | | Within-group effect | | Time | F = 11.463, p < 0.001 | | Time × Group | F = 41.250, p < 0.001 | | Time × Sex | F = 0.097, p = 0.908 | | Time × Group × Sex | F = 0.007, p = 0.993 | | indicator (memory scores) | Control group (n = 86) | Treatment group (n = 85) | Z-value | p-value | | 0 week | 16.07 ± 4.18 | 14.91 ± 4.18 | 0.578 | 0.447 | | 48 weeks | 16.01 ± 4.59 | 13.09 ± 4.54 | 16.421 | <0.001 | | 96 weeks | 16.43 ± 4.97 | 11.04 ± 4.49 | 44.254 | <0.001 | | F-value | 1.148 | 80.87 | | p-value | 0.322 | <0.001 | | Between-group effect | F = 24.073, p < 0.001 | | Within-group effect | F = 26.229, p < 0.001 | | Group × Time interaction | F = 40.25, p < 0.001 | | indicator (language scores) | Control group (n = 86) | Treatment group (n = 85) | Z-value | p-value | | 0 week | 2.88 ± 3.5 | 2.03 ± 2.55 | 2.329 | 0.127 | | 48 weeks | 3.02 ± 3.93 | 1.53 ± 2.22 | 12.339 | <0.001 | | 96 weeks | 3.67 ± 4.77 | 1.29 ± 2.15 | 35.722 | <0.001 | | F-value | 2.979 | 12.558 | | p-value | 0.056 | <0.001 | | Between-group effect | F = 10.65, p = 0.001 | | Within-group effect | F = 3.413, p = 0.035 | | Group × Time interaction | F = 11.037, p < 0.001 | | indicator (executive Function Scores) | Control group (n = 86) | Treatment group (n = 85) | Z-value | p-value | | 0 week | 2.31 ± 2.01 | 1.74 ± 1.73 | 3.008 | 0.083 | | 48 weeks | 2.42 ± 2.18 | 1.32 ± 1.26 | 13.799 | <0.001 | | 96 weeks | 2.71 ± 2.48 | 1.11 ± 1.18 | 38.624 | <0.001 | | F-value | 2.932 | 12.331 | | p-value | 0.059 | <0.001 | | Between-group effect | F = 1.448, p < 0.001 | | Within-group effect | F = 2.45, p = 0.089 | | Group × Time interaction | F = 12.081, p < 0.001 | | indicator (Visuospatial abilitiesScores) | Control group (n = 86) | Treatment group (n = 85) | Z-value | p-value | | 0 week | 1.97 ± 1.37 | 1.6 ± 1.15 | 1.871 | 0.171 | | 48 weeks | 1.99 ± 1.38 | 1.22 ± 0.68 | 17.221 | <0.001 | | 96 weeks | 2.12 ± 1.47 | 1.02 ± 0.64 | 40.291 | <0.001 | | F-value | 1.798 | 17.208 | | p-value | 0.172 | <0.001 | | Between-group effect | F = 19.67, p < 0.001 | | Within-group effect | F = 6.697, p = 0.002 | | Group × Time interaction | F = 15.133, p < 0.001 | | indicator (Orientation Scores) | Control group (n = 86) | Treatment group (n = 85) | Z-value | p-value | | 0 week | 1.23 ± 1.1 | 0.96 ± 1.03 | 2.225 | 0.136 | | 48 weeks | 1.24 ± 1.30 | 0.89 ± 0.96 | 3.044 | 0.081 | | 96 weeks | 1.59 ± 1.78 | 0.61 ± 1.01 | 30.609 | <0.001 | | F-value | 2.699 | 20.539 | | p-value | 0.073 | <0.001 | | Between-group effect | F = 10.469, p = 0.001 | | Within-group effect | F = 0.12, p = 0.851 | | Group × Time interaction | F = 8.507, p < 0.001 | ### Page 9 cognitive function in MHd patients with Ci. Simultaneously, serum homocysteine levels were significantlylower in the treatment group than in the placebo group, while serum thiamin and folic acid levels weresignificantly higher. Furthermore, the incidence of adverse events, particularly cardiovascular and cerebro-vascular events, was significantly higher in the placebo group than in the treatment group. However,there was no significant difference in survival rates between the two groups. Table 3. Secondary outcomes. | Treatment group | Placebo group | P Value | | - | - | - | | Secondary outcomes | | Thiamin (ng/ml) | | Baseline (n) | 5.59 ± 0.95(107) | 5.03 ± 0.72(108) | 0.637 | | 48 Weeks (n) | 18.84 ± 2.68(96) | 5.08 ± 0.95(100) | <0.001 | | 96 Weeks (n) | 18.21 ± 3.91(85) | 3.31 ± 0.28(86) | <0.001 | | Comparison between 96 weeks andbaseline, p value | 0.003 | 0.037 | | Folic acid (ng/ml) | | Baseline (n) | 12.37 ± 4.62(107) | 8.44 ± 3.07(108) | 0.478 | | 48 weeks (n) | 62.15 ± 10.2(96) | 7.74 ± 0.52(100) | <0.001 | | 96 weeks (n) | 63.33 ± 16.02(85) | 7.63 ± 0.08(86) | <0.001 | | Comparison between 96 weeks andbaseline, p value | <0.001 | 0.008 | | Homocysteine (ng/ml) | | Baseline (n) | 4709.06 ± 353.15(107) | 5440.45 ± 336.33(108) | 0.135 | | 48 weeks (n) | 3777.02 ± 1230.8(96) | 5484.09 ± 513.91(100) | 0.003 | | 96 weeks (n) | 2962.68 ± 158.87(85) | 5158.17 ± 361.87(86) | <0.001 | | Comparison between 96 weeks andbaseline, p value | <0.001 | 0.648 | | Death (n, %) | 13(12.1%) | 13(12.0%) | 0.978 | | Cardiovascular and cerebrovascular events,n (%) | 9(8.4%) | 7(6.5%) | | infection, n (%) | 3(2.8%) | 5(4.6%) | | Malignant tumor, n (%) | 0(0) | 1(0.9%) | | Gastrointestinal bleeding, n (%) | 1(0.9%) | 0(0%) | ![Kaplan-Meier survival curves for Treatment and Placebo groups over 96 weeks show similar survival rates, both declining from 100% to above 85%. ** The Kaplan-Meier survival curve compares the Treatment and Placebo groups over 96 weeks. The Y-axis represents survival percentage \(0% to 100%\), and the X-axis denotes time in weeks \(0, 48, 96\). Both groups start at 100% survival, declining to around 86% for Treatment and 85% for Placebo by week 96. A table below lists the sample sizes: Treatment Group \(n=107\) and Placebo Group \(n=108\), with a P-value of 0.854 indicating no significant difference between groups.]() Figure 4. Survival curve analysis. Kaplan–Meier survival analysis also revealed no significant difference in survival ratebetween the treatment and placebo groups (p = 0.854). Table 4. adverse events. | Treatment group (n = 107) | Placebo group (n = 108) | p-value | | - | - | - | | Cardiovascular and cerebrovascularevents, n (%) | 14 (13.1%) | 28 (25.9%) | 0.001 | | Vascular access events, n (%) | 4 (3.7%) | 10 (9.3%) | 0.089 | | infection, n (%) | 5 (4.7%) | 9 (8.3%) | 0.125 | | Covid-19, n (%) | 3 (2.8%) | 4 (3.7%) | 1.000 | | Gastrointestinal events, n (%) | 5 (4.7%) | 7 (6.5%) | 0.357 | | Malignant tumor, n (%) | 0 (0) | 2 (1.9%) | 0.845 | | Other events, n (%) | 6 (5.6%) | 11 (10.2%) | 0.108 | | Total, n (%) | 34 (31.8%) | 67 (62%) | 0.0017 | ### Page 10 the primary finding of this study is that after 96 weeks of treatment with thiamin (90 mg/day) com-bined with folic acid (30 mg/day), patients in the treatment group had significantly lower adaS-Cogscores than those in the placebo group, suggesting improved cognitive function. thiamin and folic aciddeficiency have been confirmed to induce increased oxidative stress in the cerebral cortex and hippo-campus, leading to neuronal damage and cognitive impairment, a conclusion supported by in vivo andin vitro studies [,]. Recent studies indicate that B vitamin supplementation (including thiamin andfolic acid) can effectively slow cognitive decline and neurodegeneration in the elderly Chinese popula-tion [] and improve cognitive function in alzheimer’s disease patients []. the underlying mechanismsinclude: thiamin acts as an oxygen free radical scavenger, reducing the production of reactive oxygenspecies (ROS) in the nervous system and alleviating hypermethylation of redox-related genes nudt15and tXnRd1, thereby mitigating oxidative stress [] and oxidative damage [], and improving cogni-tive function; Folic acid has direct antioxidant effects, inhibiting inflammatory cytokine expression andalleviating oxidative stress [,] by reducing S-adenosylhomocysteine (SaH) levels and increasingS-adenosylmethionine (SaM) levels, consequently enhancing cognitive ability. animal experiments furtherfound that folic acid supplementation improves cognitive function by increasing thymidylate synthase(tS) expression in SaMP8 (Senescence-accelerated Mouse Prone 8), thereby reducing dna damage andneuronal apoptosis []. Cognitive domain-specific analysis further revealed that this combined interven-tion particularly significantly improved memory and executive function in MHd patients: the hippocam-pus (the memory center) is highly sensitive to uremic toxins and hyperhomocysteinemia [], and thefolic acid pathway specifically protects memory function by promoting homocysteine remethylation,reducing oxidative stress and abnormal tau protein phosphorylation []; the prefrontal cortex (executivefunction) is impaired due to thiamin-dependent glycolytic dysfunction, which thiamin corrects by restor-ing neuronal mitochondrial atP synthesis and enhancing dopaminergic signaling [,]. together, theyform a synergistic ‘metabolic-synaptic protection’ effect, while brain regions related to visuospatial ability/orientation are relatively less sensitive to this vitamin intervention. in the chronic kidney disease (CKd) population, our previous small-sample pilot study also found that96 weeks of combined thiamin and folic acid treatment improved Montreal Cognitive assessment (MoCa)scores in MHd patients with Ci []. However, a limitation of that study was that it only used MoCa scoresto assess cognitive function before and after treatment. Previous literature points out that in cognitivefunction research, MoCa scores are primarily used for diagnosing cognitive impairment, while adaS-Cogscores are the standard metric for assessing cognitive improvement following pharmacotherapy []. thisstudy employed adaS-Cog scores as the efficacy evaluation criterion, addressing the limitations of theprevious study and further validating that thiamin combined with folic acid improves cognitive functionin MHd patients with Ci. it is noteworthy that cognitive impairment is now considered a hard endpointindicator for the prognosis of MHd patients [], meaning that improving cognitive function may improveprognosis; the results of this study provide an important basis for future in-depth research. this study found that patients in both groups had serum thiamin and folic acid deficiency at baseline,with levels lower than those in the normal population. this result is consistent with our previous animalstudy [] and small-sample pilot experiment []. the reasons may be related to the fact that thiamin andfolic acid, as water-soluble vitamins, have their absorption affected by uremic toxins []; additionally, theyare cleared during MHd, especially when receiving high-flux dialysis. Some studies have reported thathigh-dose thiamin (100 mg tid × 7 days, then 100 mg qd) and folic acid (40 mg qd) supplementation canimprove cognitive function and reduce the risk of cardiovascular and cerebrovascular events []. theresults of this study show that after 96 weeks of supplementation with thiamin (90 mg/day) combinedwith folic acid (30 mg/day), serum thiamin and folic acid levels in the treatment group were significantlyhigher than baseline. However, serum thiamin levels remained below the normal range (22.4–57.6 ng/ml)[], which may be related to the relatively low therapeutic dose and the downregulation of thiamintransporter 1 (tHtR1) and thiamin transporter 2 (tHtR2) expression caused by the uremic environment[]. this suggests that the current dose, while effective for cognitive improvement, may be suboptimalfor fully correcting thiamin deficiency in MHd patients. Future prospective dose-finding studies are neededto establish the optimal therapeutic dose that normalizes thiamin levels while maximizing clinical benefits.whereas serum folic acid levels were higher than the range for the general population (2.7–17 ng/ml), a ### Page 11 phenomenon consistent with the pilot results []. notably, serum homocysteine levels decreased signifi-cantly in the treatment group, with the increase in serum folic acid levels presumed to play a major role.However, the significant increase in serum thiamin levels and its contribution to alleviating oxidativestress, reducing homocysteine levels, and improving cognitive function should not be overlooked.although the dose used in this study improved cognitive function, future prospective studies are neededto explore the optimal therapeutic dose for MHd patients with Ci to achieve better survival outcomes. Recent studies indicate that elevated serum homocysteine levels are closely associated with cognitiveimpairment [,]. in MHd patients, the mechanism for its elevation includes B vitamin deficiency (espe-cially thiamin and folic acid) []. in this study, baseline serum homocysteine levels in both groups weresignificantly higher than the normal range, indicating the presence of oxidative stress []. after 96 weeksof intervention, serum homocysteine levels in the treatment group decreased significantly (a reductionof 37.09%). literature reports that oxidative stress is one of the common pathogenic mechanisms forcognitive impairment and cardiovascular/cerebrovascular diseases in MHd patients [], and a reductionin homocysteine levels >20%, as an indicator of oxidative stress, can significantly reduce the risk ofadverse cardiovascular events []. this is consistent with the observation in this study that the incidenceof adverse cardiovascular/cerebrovascular events was significantly lower in the treatment group than inthe placebo group. although cardiovascular/cerebrovascular disease is the leading cause of death inMHd patients, this study found no statistically significant difference in overall survival rates between thetwo groups, which may be related to the relatively small sample size, limited number of mortality events,and short follow-up period, which constrained the statistical power to detect a survival difference. Futurerandomized controlled trials (RCts) with larger sample sizes, longer follow-up, and patient prognosis asthe primary endpoint are needed for verification. this study has the following limitations: 1. it primarily relied on adaS-Cog scores to assess cognitivefunction, which is subjective; future studies need to incorporate more objective assessment indicators(such as functional magnetic resonance imaging [fMRi] []); 2. the combination therapy design makesit difficult to distinguish the independent effects of thiamin and folic acid. Future studies with a factorialdesign are warranted to elucidate their individual contributions; 3. the optimal therapeutic dose for thetwo drugs was not explored. in conclusion, supplementation with thiamin (90 mg/day) combined with folic acid (30 mg/day) cansafely and effectively improve cognitive function and reduce the risk of adverse cardiovascular/cerebro-vascular events in MHd patients with Ci. Ethics approval and consent to participate all procedures performed in the present study were in accordance with the principles outlined in the 1964 Helsinkideclaration and its later amendments. this study was approved by the Ethics Committee of Renji Hospital affiliatedto Shanghai Jiao tong university School of Medicine (approval no. Ky2019-199),and all patients provided signedinformed consent before enrollment. Author contributions CRedit: Kewei Xie: data curation, Writing – original draft; Yan Jiang: Writing – original draft; Tingfang Chen: datacuration; Shang Liu: data curation, Software; Yan Fang: data curation, Software; Feihong Chen: data curation, Software;Jianxiao Shen: data curation, Software; Xiaojun Zeng: data curation, Software; Ping Li: data curation, investigation;Ting Qiu: data curation, investigation, Project administration; Jieying Wang: Methodology; Ling Yu: Methodology;Xiujuan Zang: data curation, investigation; Niansong Wang: Project administration; Jiangzi Yuan: investigation,Supervision; Huihua Pang: data curation, investigation, Supervision; Weiming Zhang: Formal analysis, Methodology,Supervision; Zhaohui Ni: Project administration; Leyi Gu: Conceptualization; Yongping Guo: Conceptualization, Writing– review & editing; Renhua Lu: Conceptualization, Funding acquisition, Project administration, Writing – review & editing. Disclosure interest no potential conflict of interest was reported by the author(s). ### Page 12 Funding the study was supported by the following foundation projects: Crosswise projects of Renji Hospital, School ofMedicine, Shanghai Jiao tong university (no. iit-2023-0070, iit-2024-0084), Shanghai Hospital development Center,Clinical three-year action Plan (no. SHdC2020CR 4004); 2019 Scientific Research Seed Fund training Program of RenjiHospital affiliated to Shanghai Jiao tong university School of Medicine (no. RJZZ19-04); 2019 Special ScientificResearch Fund of Chinese Medical association (no. 18020030782). Data availability statement all data generated and described in this article are available from the corresponding author on reasonablerequest. References [] uSRdS annual data Report; 2023.. [] CnRdS annual data Report; 2023.. [] lu R, Kiernan MC, Murray a, et al. Kidney-brain crosstalk in the acute and chronic setting. nat Rev nephrol.2015;11(12):707–719. doi:. [] lu R, Xu C, li y, et al. the incidence prognosis and risk factors of cognitive impairment in maintenance hae-modialysis patients. Blood Purif. 2019;47(1–3):101–108. doi:. [] lu y, Xu C, Xie K, et al. Renal failure. the relationship between thiamin, folic acid and cognitive function in arat model of uremia. Ren Fail. 2024;46(1):2329257. doi:. [] Calingasan ny, Chun WJ, Park lC, et al. Oxidative stress is associated with region-specific neuronal deathduring thiamine deficiency. J neuropathol Exp neurol. 1999;58(9):946–958. doi:. [] Stanger O. Physiology of folic acid in health and disease. Curr drug Metab. 2002;3(2):211–223. doi:. [] lu R, Fang y, Zhou y, et al. a pilot study of thiamine and folic acid in hemodialysis patients with cognitiveimpairment. Ren Fail. 2021;43(1):766–773. doi:.[33913373] [] lu R, Gu l-y, Zhang W, et al. Protocol for thiamine and folic acid in the treatment of cognitive impairment inmaintenance haemodialysis patients: a prospective, randomised, placebo-controlled, double-blind, multicentrestudy. BMJ Open. 2021;11(12):e050605. doi:.[34907051] [] drew da, tighiouart H, Scott tM, et al. Cognitive performance before and during haemodialysis: a randomizedcross-over trial. nephron Clin Pract. 2013;124(3–4):151–158. doi:. [] nasreddine ZS, Phillips na, Bédirian V, et al. the Montreal Cognitive assessment, MoCa: a brief screening toolfor mild cognitive impairment. J am Geriatr Soc. 2005;53(4):695–699. doi:. [. [] Mohs RC, Rosen WG, davis Kl. the alzheimer’s disease assessment scale: an instrument for assessing treatmentefficacy. Psychopharmacol Bull. 1983;19(3):448–450. [] Gong yS, Hu K, yang lQ, et al. Comparative effects of EtOH consumption and thiamine deficiency on cognitiveimpairment, oxidative damage, and β-amyloid peptide overproduction in the brain. Free Radic Biol Med.2017;108:163–173. doi:. [] Elens i, dekeyster E, Moons l, et al. Methotrexate affects cerebrospinal fluid folate and tau levels and induceslate cognitive deficits in mice. neuroscience. 2019;404:62–70. doi:. [] iimura y, andoh S, Kawamata t, et al. thiamine deficiency and neurological symptoms in patients with hema-tological cancer receiving chemotherapy: a retrospective analysis. J neurosci Rural Pract. 2021;12(4):726–732.doi:. [] Jiang X, Guo y, Cui l, et al. Study of diet habits and cognitive function in the chinese middle-aged and elder-ly population: the association between folic acid, B vitamins, vitamin d, coenzyme Q10 supplementation andcognitive ability. nutrients. 2023;15(5):1243. doi:. [] Chen H, liu S, Ge B, et al. Effects of folic acid and vitamin B12 supplementation on cognitive impairment andinflammation in patients with alzheimer’s disease: a randomized, single-blinded, placebo-controlled trial. J Prevalzheimers dis. 2021;8(3):249–256. doi:.[34101780] [] Wang Z, Zhu W, Xing y, et al. B vitamins and prevention of cognitive decline and incident dementia: a system-atic review and meta-analysis. nutr Rev. 2022;80(4):931–949. doi:.[34432056] [] Zhou d, lv X, Wang y, et al. Folic acid alleviates age-related cognitive decline and inhibits apoptosis of neuro-cytes in senescence-accelerated mouse prone 8: deoxythymidine triphosphate biosynthesis as a potentialmechanism. J nutr Biochem. 2021;97:108796. doi:.[34102282] ### Page 13 [] Watanabe K, Sato E, Mishima E, et al. Effect of uremic toxins on hippocampal cell damage: analysis in vitro andin rat model of chronic kidney disease. Heliyon. 2021;7(2):e06221. doi:. [] Chen l, liu R, He X, et al. Synergistically effects of n-3 PuFa and B vitamins prevent diabetic cognitive dysfunc-tion through promoting tEt2-mediated active dna demethylation. Clin nutr. 2025;45:111–123. doi:. [] Park EJ, Seong E, Kim y, et al. ammonium lauryl sulfate-induced apoptotic cell death may be due to mitochon-drial dysfunction triggered by caveolin-1. toxicol in Vitro. 2019;57:132–142. doi:. [] Kenney PM, Bennett JP.Jr. alzheimer’s disease frontal cortex mitochondria show a loss of individual respiratoryproteins but preservation of respiratory supercomplexes. int J alzheimers dis. 2019;2019:4814783. doi:. [. [] Pépin M, Ferreira aC, arici M, et al. Cognitive disorders in patients with chronic kidney disease: specificities ofclinical assessment. nephrol dial transplant. 2021;37(Suppl 2):ii23–ii32. doi:. [] Rosati R, Ma H, Cabelof dC. Folate and colorectal cancer in rodents: a model of dna repair deficiency. J Oncol.2012;2012:105949–105917. doi:. [] listabarth S, Vyssoki B, Marculescu R, et al. Can thiamine substitution restore cognitive function in alcohol usedisorder? alcohol alcohol. 2023;58(3):315–323. doi:. [] Weber W, Kewitz H. determination of thiamine in human plasma and its pharmacokinetics. Eur J Clin Pharmacol.1985;28(2):213–219. doi:. [] Ji y, lyu P, Jin W, et al. Homocysteine: a modifiable culprit of cognitive impairment for us to conquer? J neurolSci. 2019;404:128–136. doi:. [] Zhou F, Chen S. Hyperhomocysteinemia and risk of incident cognitive outcomes: an updated dose-responsemeta-analysis of prospective cohort studies. ageing Res Rev. 2019;51:55–66. doi:. [] Friedman an, Bostom aG, Selhub J, et al. the kidney and homocysteine metabolism. J am Soc nephrol.2001;12(10):2181–2189. doi:. [] Himmelfarb J, McMonagle E. Manifestations of oxidant stress in uremia. Blood Purif. 2001;19(2):200–205. doi:. [] Qin X, Huo y, langman CB, et al. Folic acid therapy and cardiovascular disease in ESRd or advanced chronickidney disease: a meta-analysis. Clin J am Soc nephrol. 2011;6(3):482–488. doi:. [] Zhang Hy, Wang SJ, liu B, et al. Resting brain connectivity: changes during the progress of alzheimer disease.Radiology. 2010;256(2):598–606. doi:.