Introduction 1 2 3 4 5 6 7 8 9 n 10 11 13 14 Methods Study design  14 Participants  15 1 1 Table 1 Inclusion and exclusion criteria for participation in the trial  Operationalization of Petersen criteria for MCI (1–5) and additional inclusion criteria for the RCT (6–12) 16 17 18 19 20 5. Absence of dementia; TICS ≥ 19 + MMSE ≥ 24 6. Being able to perform moderate intensity physical activity, without making use of walking devices, e.g., a rollator or a walking frame  7. Not using vitamin supplements/vitamin injections/drinks with dose of vitamin B6, B11 or B12 comparable to vitamin supplement given in intervention 8. Not suffering from epilepsy, multiple sclerosis, Parkinson’s disease, kidney disorder requiring haemodialysis, psychiatric impairment 21 10. Not using medication for rheumatoid arthritis or psoriasis interfering with vitamin supplement 11. No alcohol abuse (men < 21 consumptions a week, women < 15 consumptions a week) 12. Not currently living in a nursing home or on a waiting list for a nursing home MCI = Mild Cognitive Impairment, RCT = Randomized Controlled Trial, 10 WLT = 10 Word Learning Test, TICS = Telephone Interview for Cognitive Status, MMSE = Mini Mental State Examination, GARS = Groningen Activity Restriction Scale, GDS = Geriatric Depression Scale  Randomization  22 1 Fig. 1 Flow chart. TI = Telephone Interview, WP = Walking Program, PAP = Placebo Activity Program, FA/B12/B6 = Folic Acid, Vitamin B12, Vitamin B6 supplementation, SO = significant other, T6 = follow-up after 6 months, T12= follow-up after 12 months, *reason for exclusion: only baseline data available  Exercise intervention 23 Vitamin supplementation (FA/B12/B6) Subjects in the vitamin supplementation group took one pill containing 5 mg vitamin B11 (Folic Acid), 0.4 mg vitamin B12 (Cyanocobalamin) and 50 mg vitamin B6 (Pyridoxine-hydrochloride) daily during 1 year. This vitamin supplement is available on prescription in The Netherlands. Subjects randomized to the control group took an identically looking placebo pill. The pills were packed in blister packs for 1 week, which were labeled for each day of the week. Compliance with the vitamin supplementation was verified by pill counts in returned blister packs during the intervention. Outcome measures 2 14 24 25 24 25 Table 2 n  Exercise intervention Vitamin intervention n n n n Age (Mean (SD)) 75 (2.9) 75 (2.8) 75 (2.8) 75 (2.9) Gender (% male) 48* 64 56 55 MMSE (Median (10th–90th ‰)) 29 (26–30) 29 (27–30) 29 (25–30) 29 (27–30) Education (% low/middle/high)  61/22/17 52/29/19 57/26/17 55/26/19 Marital status (% living together) 75 68 69 73 a th 44 (10–155) 39 (11–120) 45 (13–155) 38 (9–111) b 46/8/0 48/8/0 49/9/0 45/7/0 c 27 23 27 23 d 27* 14 25 16 2 26.7 (23.1–31.5) 26.6 (23.5–32.7) 26.5 (23.3–32.8) 26.7 (23.5–31.2) Smoking (% smokers) 13 15 17 11 e 52/42/6 69/27/4 66/28/6 55/41/4 WP = Walking Program, PAP = Placebo Activity Program, FA/B12/B6 = Folic Acid, Vitamin B12, Vitamin B6 supplementation, MMSE = Mini Mental State Examination, Education: low = no education, primary education, lower vocational training; intermediate = intermediate level secondary education, intermediate vocational training; high = higher level secondary education, higher vocational training, university training. BMI = Body Mass Index a  b  c  d  e P Statistical analyses t U 2 t 14 26 27 Data were analyzed using SPSS for Windows (release 12.0.1). A significance level of 5% was used for between group comparisons and of 10% for interaction terms. For all analyses, regression coefficients and 95% confidence intervals for the adjusted models were reported, with the regression coefficients directly indicating the difference in QoL ratings between the WP and the PAP or the FA/B12/B6-supplementation versus placebo supplementation. In the case of significant interaction, regression coefficients and the 95% confidence intervals of the interaction terms were reported. Results Patient characteristics P P 1 2 3 Table 3 a  WP  PAP FA/B12/B6  Placebo  n n n n n n n n n n n n D-QoL sumscore 3.5 (0.26) 3.5 (0.29) 3.5 (0.27) 3.5 (0.32) 3.5 (0.34) 3.5 (0.34) 3.5 (0.32) 3.5 (0.32) 3.5 (0.33) 3.4 (0.24) 3.5 (0.31) 3.5 (0.27) D-QoL aesthetics 3.5 (0.63) 3.5 (0.64) 3.6 (0.60) 3.5 (0.70) 3.5 (0.71) 3.5 (0.65) 3.5 (0.64) 3.5 (0.68) 3.6 (0.61) 3.4 (0.68) 3.5 (0.67) 3.6 (0.64) D-QoL belonging 3.7 (0.50) 3.7 (0.49) 3.7 (0.44) 3.8 (0.45) 3.7 (0.47) 3.7 (0.46) 3.8 (0.50) 3.6 (0.50) 3.6 (0.48) 3.7 (0.44) 3.8 (0.45) 3.8 (0.40) D-QoL negative affect 2.7 (0.45) 2.7 (0.46) 2.8 (0.50) 2.7 (0.55) 2.8 (0.54) 2.8 (0.52) 2.7 (0.54) 2.8 (0.47) 2.8 (0.53) 2.7 (0.47) 2.7 (0.53) 2.8 (0.49) D-QoL positive affect 3.8 (0.39) 3.7 (0.46) 3.8 (0.40) 3.8 (0.40)  3.7 (0.44) 3.8 (0.43) 3.8 (0.41) 3.7 (0.47) 3.8 (0.44) 3.8 (0.39) 3.8 (0.43) 3.8 (0.39) D-QoL self esteem 3.6 (0.45) 3.8 (0.41) 3.8 (0.40) 3.7 (0.48) 3.7 (0.49) 3.8 (0.48) 3.8 (0.48)* 3.8 (0.48) 3.9 (0.48) 3.6 (0.43) 3.7 (0.43) 3.7 (0.38) SF12-MCS 54.6 (6.85) 55.6 (6.40) 55.3 (4.39) 54.7 (8.07) 55.0 (7.34) 55.3 (6.24) 55.5 (7.49) 55.9 (6.91) 55.8 (4.90) 53.8 (7.36) 54.6 (6.86) 54.8 (5.76) SF12-PCS 48.2 (7.15) 48.1 (7.57) 50.5 (6.13)  48.7 (7.86) 48.8 (8.47) 49.8 (7.04) 47.9 (8.20) 47.4 (8.79) 49.8 (6.68) 49.1 (6.67) 49.6 (7.00) 50.6 (6.49) MCI = Mild Cognitive Impairment, WP = Walking Program, PAP = Placebo Activity Program, FA/B12/B6= Folic Acid, Vitamin B12, Vitamin B6 supplementation, D-QoL = Dementia Quality of Life, SF12-MCS = Short Form 12 Mental Component Summary, SF12-PCS = Short Form 12 Physical Component Summary a  P Attendance to the WP and the PAP n P n P P P Compliance with the (FA/B12/B6)supplementation P Modified intention to treat analyses 4 P P P P P Table 4 Results of longitudinal multi level analyses on the effect of the WP and FA/B6/B12 supplementation on change in QoL (adjusted model)   WP versus PAP Beta (95%CI) P FA/B12/B6 versus placebo Beta (95%CI) P D-QoL sumscore 0.04 (−0.03;0.10) 0.25 −0.06 (−0.12;0.004)  0.07 D-QoL aesthetics 0.06 (−0.07;0.20) 0.37 −0.07 (−0.20;0.07) 0.33 D-QoL belonging 0.00 (−0.11;0.11) 0.96 −0.18 (−0.29; −0.07) 0.00 D-QoL negative affect −0.02 (−0.12;0.08) 0.65 0.04 (−0.05;0.14) 0.37 D-QoL positive affect 0.04 (−0.04;0.13) 0.34 −0.04 (−0.12;0.04) 0.33 D-QoL self esteem 0.08 (−0.02;0.18) 0.11 0.00 (−0.10;0.11) 0.94 SF12-PCS 0.66 (−1.23;2.54) 0.49 −0.73 (−2.65;1.19) 0.45 SF12-MCS* Men −0.82 (−2.24;0.60) 0.25 0.25 (−1.31;1.81) 0.76  Women 1.66 (−1.50;4.81) 0.30 1.32 (−1.93;4.56) 0.42 WP = Walking Program, PAP = Placebo Activity Program, FA/B12/B6= Folic Acid, Vitamin B12, Vitamin B6 supplementation, D-QoL = Dementia Quality of Life, SF12-MCS = Short Form 12 Mental Component Summary, SF12-PCS = Short Form 12 Physical Component Summary * Interaction WP and gender Per protocol analyses n P P Discussion No positive main effect of walking or daily FA/B6/B12 supplementation was observed on QoL in community-dwelling adults with MCI. However, ratings of overall QoL (i.e., feelings of belonging, positive affect) and the mental component of health-related QoL improved slightly with increasing attendance to the walking program. In a subgroup that attended at least 75% of the sessions, a beneficial effect of the walking program was observed on positive affect and self esteem. 2 28 29 30 31 7 32 31 8 7 7 8 33 7 30 34 35 Nevertheless, several outcomes improved with increasing attendance to the walking program. In the per protocol analyses a beneficial effect was observed on positive affect. Self esteem also tended to improve. However, observed differences were small and approximated 5% differences from baseline QoL ratings. As a rule of thumb, a minimal change of 5% has been mentioned to signify clinical relevance. To obtain a change of 5% by increasing attendance, the required increase in attendance would be 62% for D-QoL-belonging and 94% for D-QoL-positive affect and the SF12-MCS. Therefore, it can be questioned whether the observed effects are clinically relevant. 11 n n 11 n 13 36 To conclude, the walking program and vitamin B supplementation were not effective in improving QoL in community-dwelling older adults with MCI within 1 year. However, increasing attendance to moderate intensity physical activity may benefit certain aspects of QoL.