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Cognitive Effects of Multi-Domain Interventions Among Pre-Frail and Frail Community-Living Older Persons: Randomized Controlled Trial

Cognitive Effects of Multi-Domain Interventions Among Pre-Frail and Frail Community-Living Older... Abstract Background Cognitive, physical, and nutritional interventions may produce different cognitive effects for different groups of older persons. We investigated simultaneously the cognitive outcomes of cognitive, physical, and nutritional interventions singly and in combinations in older persons with the physical frailty phenotype at particular risk of cognitive decline. Method Pre-frail and frail participants were randomly allocated to 24 weeks nutritional supplementation (N = 49), physical training (N = 48), cognitive training (N = 50), combination intervention (N = 49), or usual care control (N = 50). Cognitive domain and global functions were assessed at baseline (0M), 6 month (6M), and 12 month (12M). Results The control group showed declines in z-scores (from −0.100 to −0.244) of all domains. The cognitive training compared to control group showed the greatest increase in global cognition at 6M (0.094 vs −0.174, p = .006) and 12M (0.099 vs −0.142, p = .002), immediate memory at 6M (0.164 vs −0.211, p = .010) and 12M (0.182 vs −0.142, p = .040), delayed memory at 6M (p = .010), and attention at 6M (p = .025). Nutritional intervention showed benefits at 6M for immediate memory (p = .028) and delayed memory (p = .024), but physical training showed no positive effects. The combination group showed the greatest increase for visuospatial construction at 6M (0.215 vs −0.141, p = .010) and 12M (0.166 vs −0.180, p = .016), and for global cognition at 12M (p = .016) and language at 12M (p = .023). Conclusion Among frail older persons, cognitive training conferred the greatest cognitive benefits. Nutritional and physical interventions singly were associated with modest short-term or no cognitive benefits, but their combined effects on visuospatial construction should be further investigated. Frailty, Physical exercise, Cognitive training, Nutritional supplementation, Cognition Establishing the effects of different interventional approaches in reducing the risk of cognitive decline and dementia is important for designing programs of cognitive health for older persons. Epidemiological observational studies strongly indicate that physical, socially, and cognitively stimulating activities and nutritional factors are associated with lower risk of cognitive decline and possibly dementia (1). Evidence from randomized controlled trials are limited and mixed. As they are often interrelated, such interventions should arguably be investigated as a cluster for its pragmatic relevance. At the same time, investigating the individual effects of different interventions is important for understanding causal pathways and developing specific approaches for subgroups of at-risk elderly people. A vulnerable group at risk of cognitive decline and dementia are those with the physical frailty phenotype (2,3), Studies have shown a strong and intimate association of physical frailty with cognitive impairment, progression of mild cognitive impairment (MCI) to dementia and increased risk of developing dementia (4–6). Cognitive Interventions Systematic reviews and meta-analyses of randomized controlled trials consistently support the beneficial effects of cognitive training, in improving memory performance, executive functioning, processing speed, attention, fluid intelligence, and subjective cognitive performance in healthy older persons and those with MCI (7,8). However, these studies have typically found the largest effects for the cognitive domains that are specifically trained (trained effect) or near-transfer to tasks within the same cognitive domain, but little or no effects on far-transfer to entirely different nontrained cognitive domains (9). Also, the impact of cognitive interventions on the everyday functioning of healthy older adults remain unclear, as most trials do not include functional outcome measures (10). Physical Exercise Interventions Despite the strong epidemiological observational evidence of the association of habitual physical activity with less cognitive decline, (11) exercise intervention trials have yielded mixed results. Although there were some positive studies, many trials of aerobic, strength, and multicomponent exercise interventions on sedentary older persons have failed to show cognitive benefits (12–15), partly because of short duration intervention and questionable adherence. Nutritional Interventions Randomized controlled trials provide limited evidence in support of the cognitive benefits of folate, B12, and omega 3 fatty acid among nondemented older persons (16,17), but promising evidence in support of complex dietary regimens (such as a Mediterranean-like diet), milk protein concentrates and flavanols (18), and nutritionally complete oral nutritional supplements (ONS) among malnourished and cognitively impaired nursing home residents (19). Nutritional interventions may be more effective in individuals with poorer nutritional status, as multinutrient formulations or in combination with multidomain lifestyle interventions (20,21,22). In this paper, we report the results of secondary end-point analyses of changes in cognitive performance from a randomized controlled trial of nutritional, physical training, cognitive training and combination interventions aimed at reversing frailty among community-living pre-frail and frail older persons. Given the much stronger evidence in support of the positive effects of cognitive intervention, or cognitive-physical dual-tasking exercise intervention, and the limited evidence in support of physical exercise or nutritional interventions alone, we expected to observe that cognitive intervention singly and in combination with physical exercise to produce clearly more pronounced positive cognitive effects. Method Details of the Singapore Frailty Intervention Trial (S-FIT) (clinicaltrial.gov identifier NCT00973258) have been described in a previous publication (23). The study was approved by the National Health Group (NHG) Domain-Specific Review Board in Singapore. The study design was a parallel group, randomized controlled trial comparing multidomain lifestyle interventions of 6 months duration among community-dwelling pre-frail and frail older persons. The primary outcome was frailty and frailty components assessed at 0 month (0M), 3 month (3M), 6 month (6M), and 12 month (12M) post-intervention. Cognitive function was evaluated as secondary end-points at 0M, 6M, and 12M. Participants Between October 2009 and August 2012, community-living older persons were screened for the physical frailty phenotype using five criteria from Fried and colleagues (2): (i) unintentional weight loss, (ii) slow walking speed, (iii) weakness, (iv) self-reported exhaustion, and (v) low physical activity to define pre-frailty (score of 1–2) and frailty (score of 3–5). Details of the frailty measurements are found in the online Supplementary files. The inclusion criteria were: aged 65 and older, able to ambulate without personal assistance, and living at home. Exclusion criteria were: significant cognitive impairment (Mini-mental State Examination score ≤23), dementia, major depression, severe hearing or visual impairment, major stroke, Parkinson and other neurologic disease, terminal illness with life expectancy less than 12 months, and participation in other interventional studies. Randomization and Interventions Eligible participants (N = 246) provided informed consent and were randomized simultaneously to one of five interventions of 24 weeks duration each (23), as described in a previous publication, and are summarized below. Cognitive training was designed for multidomain skills to enhance short-term memory, attention, information processing skills, perceptual organizational tasks, reasoning and logic, and problem-solving abilities. Participants attended 2-hour duration weekly group training sessions (about 10 participants per group) with one-on-one help offered when participants needing greater assistance. The interactive training activities were conducted by a psychologist trainer and nurse facilitators, using materials (paper and pencil tasks, power-point projections, and cognitive games and block puzzles), with which participants learned strategies used to recall verbal and visual information, tasks such as “spot the differences”, categorical naming, and coding (used to enhance attention and processing speed); and matrix reasoning exercises, mazes, and tangram-like games (aimed at enhancing reasoning and problem-solving abilities). Activities were not planned to test specifically for skills tested on Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) although there were some resemblances in alternative versions of tasks such as learning of a word-list, digit span and the coding task using rehearsal, and visual/ auditory association strategies. Intensive training classes were conducted in the first 12 weeks, followed by subsequent 12 weeks where participants attended fortnightly 2-hour “booster” sessions where they reviewed and practiced the cognitive skills learned in the first 12 weeks. Physical training: Moderate intensity physical exercise, of 90-minute duration, on 2 days per week were performed in supervised groups for 12 weeks, followed by 12 weeks of home-based exercises. The exercise program was designed to improve strength and balance for older adults according to American College of Sports Medicine (ACSM) Guidelines for older adults, and included resistance exercises, integrated with functional tasks; and balance training exercises involving functional strength, sensory input, and added attentional demands. More details of the physical and nutritional interventions are described in the Supplementary Information available online. Nutritional intervention: Each participant was provided a commercial formula (Fortisip Multi Fibre, Nutricia), iron and folate supplement (Sangobion, Merck), vitamin B6 and vitamin B12 supplement (Neuroforte), calcium and vitamin D supplement (Caltrate) taken daily for 24 weeks, designed to augment caloric intake by about 20% and provide about one third of the recommended daily allowances of vitamins and minerals. Combination intervention: Participants in this group underwent all three aforementioned interventions. Control group: Participants had access to standard community-based social, recreational and day care rehabilitation services for older people, and were given placebo liquid capsules and tablet formulations. Treatment adherence was measured monthly by estimating the proportion of supplements consumed or training or home-based sessions completed. The mean levels of compliance were 91% for nutrition supplement, 85% for physical training, 79% for cognitive training, 88% for combination group, and 94% for control. Outcome Measures The efficacy outcome measure was the global and domain scores of the RBANS, a brief clinical neuropsychological testing battery that was developed specifically for assessing cognitive performance in elderly with dementia (24). The battery comprises 12 subtests that assess the domains of Immediate and Delayed Memory, Language, Attention and Visuospatial/Construction. Normative studies of the cross-cultural applicability of the RBANS in this elderly Chinese population has also been previously published (25). Raw scores obtained from these tasks were converted to standardized z-scores, used to derive five domain index scores: Attention (mean of ZForward digit span, longest span and ZCoding); Language (mean of Zpicture naming, Zsemantic fluency − fruits and vegetables); Visuospatial construction (mean of Zfigure copy and Zline orientation); Immediate memory (mean of Zlist learning and Zstory memory), and Delayed memory (mean of Zlist recall, Zstory recall, and Zfigure recall) and the global index score, with higher scores indicating better performance. Statistical Analysis Changes in cognitive performance were examined in efficacy analyses using intention-to-treat data including all subjects randomized to interventional arms. Differences in baseline characteristics among the intervention groups were compared using analysis of variance for continuous variables or Chi square for categorical variables. Efficacy analyses were performed using linear mixed models, accounting for correlations between the repeated measures for each participant. Subjects were treated as the random intercepts; time, treatment, and treatment × time interaction as fixed factors. A compound symmetry was specified for the variance–covariance matrix. Post-hoc analyses of between-treatment differences for each intervention versus the control group were performed using Bonferroni-corrected p values. Statistical significance tests were two-sided, and an alpha-level of .05 was considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics version 21 (IBM Corporation). Results Details of the participant flow of recruitment and screening have already been published (22). Of the total of 246 pre-frail and frail participants who were randomized to the intervention groups, 228 (93%) participants completed all follow-up assessments by 1 year. The number of drop outs (N = 20, 8%) were comparable across the five intervention groups. The participants (mean age 70.0 ± 4.7 standard deviation [SD], 61% female) included 28% who were “frail” (N = 68), and 72% who were pre-frail. Very few among them were hospitalized in the previous one year (N = 14, 6%) or were IADL dependent (N = 7, 3%). The mean MMSE score was 28.9 (SD 1.4), with 18 (7%) who were mildly impaired cognitively (MMSE between 24 and 26). Baseline frailty and other characteristics were comparable and no statistically significant differences were observed across the treatment groups (Table 1). Table 1. Baseline Characteristic of FIT Participants by Intervention Groups Control (N = 50) Nutrition (N = 49) Cognitive (N = 50) Physical (N = 48) Combination (N = 49) Male 21 (42.9) 16 (34.0) 12 (24.0) 23(43.8) 23 (46.9)  No education 10 (20.4) 12 (25.5) 9 (18.0) 13 (27.1) 6 (12.2)   1–6 years 29 (59.2) 19 (40.4) 27 (54.0) 22 (45.8) 22 (44.9)   7 or more 10 (20.4) 16 (34.1) 14 (28.0) 13 (31.1) 21 (44.9) Age 70.2 ± 5.0 69.6 ± 4.3 69.7 ± 4.3 70.2 ± 5.2 70.4 ± 4.7 GDS score 0.53 ± 0.87 0.55 ± 1.40 0.66 ± 0.82 0.60 ± 0.89 0.69 ± 1.75 MMSE 28.5 ± 1.8 29.0 ± 1.4 29.1 ± 1.3 29.1 ± 1.2 29.1 ± 1.1 RBANS Domain Index score  Immediate memory 101.2 (13.1) 100.3 (12.3) 99.8 (11.8) 96.9 (12.7) 101.7 (12.4)  Delayed memory 100.2 (10.2) 99.6 (10.5) 99.6 (8.8) 99.8 (10.8) 102.1 (9.5)  Attention 99.0 (11.1) 100.9 (11.2) 99.6 (10.7) 96.0 (16.3) 99.6 (14.2)  Language 100.4 (9.8) 100.5 (9.2) 98.5 (11.0) 100.5 (10.6) 101.3 (9.8)  Visuospatial 99.1 (12.5) 100.8 (9.2) 99.7 (12.7) 98.4 (14.0) 102.4 (10.1)  Total 100.3 (8.1) 100.6 (7.5) 99.3 (7.8) 98.1 (9.0) 101.3 (6.7) BMI, kg/m2 23.6 ± 3.35 24.0 ± 4.31 23.1 ± 2.70 23.5 ± 3.03 24.4 ± 3.79 Sitting systolic BP, mmHg 131.3 ± 16.5 130.2 ± 12.4 131.4 ± 17.2 132.0 ± 13.4 125.5 ± 13.9 Sitting diastolic BP, mmHg 81.3 ± 8.7 80.1 ± 7.9 79.1 ± 8.7 80.8 ± 7.5 78.1 ± 8.0  Fast gait speed, sec, (over 6m) 5.6 ± 2.07 5.8 ± 1.81 5.4 ± 1.16 6.1 ± 2.08 5.4 ± 1.25)  Knee extension, kg 15.5 ± 4.73 14.0 ± 5.27 12.9 ± 3.88 14.1 ± 4.63 14.9 ± 5.50  Energy score (0–15) 10.6 ± 1.55 10.7 ± 1.23 10.5 ± 1.20 10.8 ± 1.10 10.7 ± 1.38  PA score (min/day) 176.9 ± 111.0 165.7 ± 104.7 179.3 ± 113.3 162.5 ± 117.2 160.6 ± 116.0 Frailty status  Mean (SD) score, (range: 0–5) 1.8 (0.80) 2.1 (0.78) 2.0 (0.91) 2.2 (0.85) 2.1 (0.81)  Pre-frail, 43 (86.0) 33 (67.4) 37 (74.0) 29 (60.4) 36 (73.5)  Frail 7 (14.0) 16 (32.7) 13 (26.0) 19 (39.6) 13 (26.5) Frailty components  Weakness 20 (40.8) 26 (53.1) 28 (56.0) 26 (54.2) 25 (51.0)  Slowness 15 (30.0) 20 (40.8) 13 (26.0) 23 (47.9) 17 (34.7)  Weight loss 3 (6.0) 2 (4.1) 2 (4.0) 3 (6.3) 1 (2.0)  Exhaustion 6 (12.0) 7 (14.3) 10 (20.0) 7 (14.6) 8 (16.3)  Low physical activity 5 (10.0) 9 (18.4) 12 (24.0) 11 (22.9) 16 (32.7) Hospitalized in past 12 months 1 (2.0) 1 (2.0) 3 (6.0) 6 (12.5) 3 (6.1) IADL-ADL dependency 4 (8.0) 1 (2.0) 1 (2.0) 0 (0.0) 1 (2.0) Control (N = 50) Nutrition (N = 49) Cognitive (N = 50) Physical (N = 48) Combination (N = 49) Male 21 (42.9) 16 (34.0) 12 (24.0) 23(43.8) 23 (46.9)  No education 10 (20.4) 12 (25.5) 9 (18.0) 13 (27.1) 6 (12.2)   1–6 years 29 (59.2) 19 (40.4) 27 (54.0) 22 (45.8) 22 (44.9)   7 or more 10 (20.4) 16 (34.1) 14 (28.0) 13 (31.1) 21 (44.9) Age 70.2 ± 5.0 69.6 ± 4.3 69.7 ± 4.3 70.2 ± 5.2 70.4 ± 4.7 GDS score 0.53 ± 0.87 0.55 ± 1.40 0.66 ± 0.82 0.60 ± 0.89 0.69 ± 1.75 MMSE 28.5 ± 1.8 29.0 ± 1.4 29.1 ± 1.3 29.1 ± 1.2 29.1 ± 1.1 RBANS Domain Index score  Immediate memory 101.2 (13.1) 100.3 (12.3) 99.8 (11.8) 96.9 (12.7) 101.7 (12.4)  Delayed memory 100.2 (10.2) 99.6 (10.5) 99.6 (8.8) 99.8 (10.8) 102.1 (9.5)  Attention 99.0 (11.1) 100.9 (11.2) 99.6 (10.7) 96.0 (16.3) 99.6 (14.2)  Language 100.4 (9.8) 100.5 (9.2) 98.5 (11.0) 100.5 (10.6) 101.3 (9.8)  Visuospatial 99.1 (12.5) 100.8 (9.2) 99.7 (12.7) 98.4 (14.0) 102.4 (10.1)  Total 100.3 (8.1) 100.6 (7.5) 99.3 (7.8) 98.1 (9.0) 101.3 (6.7) BMI, kg/m2 23.6 ± 3.35 24.0 ± 4.31 23.1 ± 2.70 23.5 ± 3.03 24.4 ± 3.79 Sitting systolic BP, mmHg 131.3 ± 16.5 130.2 ± 12.4 131.4 ± 17.2 132.0 ± 13.4 125.5 ± 13.9 Sitting diastolic BP, mmHg 81.3 ± 8.7 80.1 ± 7.9 79.1 ± 8.7 80.8 ± 7.5 78.1 ± 8.0  Fast gait speed, sec, (over 6m) 5.6 ± 2.07 5.8 ± 1.81 5.4 ± 1.16 6.1 ± 2.08 5.4 ± 1.25)  Knee extension, kg 15.5 ± 4.73 14.0 ± 5.27 12.9 ± 3.88 14.1 ± 4.63 14.9 ± 5.50  Energy score (0–15) 10.6 ± 1.55 10.7 ± 1.23 10.5 ± 1.20 10.8 ± 1.10 10.7 ± 1.38  PA score (min/day) 176.9 ± 111.0 165.7 ± 104.7 179.3 ± 113.3 162.5 ± 117.2 160.6 ± 116.0 Frailty status  Mean (SD) score, (range: 0–5) 1.8 (0.80) 2.1 (0.78) 2.0 (0.91) 2.2 (0.85) 2.1 (0.81)  Pre-frail, 43 (86.0) 33 (67.4) 37 (74.0) 29 (60.4) 36 (73.5)  Frail 7 (14.0) 16 (32.7) 13 (26.0) 19 (39.6) 13 (26.5) Frailty components  Weakness 20 (40.8) 26 (53.1) 28 (56.0) 26 (54.2) 25 (51.0)  Slowness 15 (30.0) 20 (40.8) 13 (26.0) 23 (47.9) 17 (34.7)  Weight loss 3 (6.0) 2 (4.1) 2 (4.0) 3 (6.3) 1 (2.0)  Exhaustion 6 (12.0) 7 (14.3) 10 (20.0) 7 (14.6) 8 (16.3)  Low physical activity 5 (10.0) 9 (18.4) 12 (24.0) 11 (22.9) 16 (32.7) Hospitalized in past 12 months 1 (2.0) 1 (2.0) 3 (6.0) 6 (12.5) 3 (6.1) IADL-ADL dependency 4 (8.0) 1 (2.0) 1 (2.0) 0 (0.0) 1 (2.0) Note: Figures are mean ± SD or N (%). GDS = Geriatric Depression Score; IADL-ADL dependency = Instrumental or basic activity of daily living dependency; SD = standard deviation. View Large Table 1. Baseline Characteristic of FIT Participants by Intervention Groups Control (N = 50) Nutrition (N = 49) Cognitive (N = 50) Physical (N = 48) Combination (N = 49) Male 21 (42.9) 16 (34.0) 12 (24.0) 23(43.8) 23 (46.9)  No education 10 (20.4) 12 (25.5) 9 (18.0) 13 (27.1) 6 (12.2)   1–6 years 29 (59.2) 19 (40.4) 27 (54.0) 22 (45.8) 22 (44.9)   7 or more 10 (20.4) 16 (34.1) 14 (28.0) 13 (31.1) 21 (44.9) Age 70.2 ± 5.0 69.6 ± 4.3 69.7 ± 4.3 70.2 ± 5.2 70.4 ± 4.7 GDS score 0.53 ± 0.87 0.55 ± 1.40 0.66 ± 0.82 0.60 ± 0.89 0.69 ± 1.75 MMSE 28.5 ± 1.8 29.0 ± 1.4 29.1 ± 1.3 29.1 ± 1.2 29.1 ± 1.1 RBANS Domain Index score  Immediate memory 101.2 (13.1) 100.3 (12.3) 99.8 (11.8) 96.9 (12.7) 101.7 (12.4)  Delayed memory 100.2 (10.2) 99.6 (10.5) 99.6 (8.8) 99.8 (10.8) 102.1 (9.5)  Attention 99.0 (11.1) 100.9 (11.2) 99.6 (10.7) 96.0 (16.3) 99.6 (14.2)  Language 100.4 (9.8) 100.5 (9.2) 98.5 (11.0) 100.5 (10.6) 101.3 (9.8)  Visuospatial 99.1 (12.5) 100.8 (9.2) 99.7 (12.7) 98.4 (14.0) 102.4 (10.1)  Total 100.3 (8.1) 100.6 (7.5) 99.3 (7.8) 98.1 (9.0) 101.3 (6.7) BMI, kg/m2 23.6 ± 3.35 24.0 ± 4.31 23.1 ± 2.70 23.5 ± 3.03 24.4 ± 3.79 Sitting systolic BP, mmHg 131.3 ± 16.5 130.2 ± 12.4 131.4 ± 17.2 132.0 ± 13.4 125.5 ± 13.9 Sitting diastolic BP, mmHg 81.3 ± 8.7 80.1 ± 7.9 79.1 ± 8.7 80.8 ± 7.5 78.1 ± 8.0  Fast gait speed, sec, (over 6m) 5.6 ± 2.07 5.8 ± 1.81 5.4 ± 1.16 6.1 ± 2.08 5.4 ± 1.25)  Knee extension, kg 15.5 ± 4.73 14.0 ± 5.27 12.9 ± 3.88 14.1 ± 4.63 14.9 ± 5.50  Energy score (0–15) 10.6 ± 1.55 10.7 ± 1.23 10.5 ± 1.20 10.8 ± 1.10 10.7 ± 1.38  PA score (min/day) 176.9 ± 111.0 165.7 ± 104.7 179.3 ± 113.3 162.5 ± 117.2 160.6 ± 116.0 Frailty status  Mean (SD) score, (range: 0–5) 1.8 (0.80) 2.1 (0.78) 2.0 (0.91) 2.2 (0.85) 2.1 (0.81)  Pre-frail, 43 (86.0) 33 (67.4) 37 (74.0) 29 (60.4) 36 (73.5)  Frail 7 (14.0) 16 (32.7) 13 (26.0) 19 (39.6) 13 (26.5) Frailty components  Weakness 20 (40.8) 26 (53.1) 28 (56.0) 26 (54.2) 25 (51.0)  Slowness 15 (30.0) 20 (40.8) 13 (26.0) 23 (47.9) 17 (34.7)  Weight loss 3 (6.0) 2 (4.1) 2 (4.0) 3 (6.3) 1 (2.0)  Exhaustion 6 (12.0) 7 (14.3) 10 (20.0) 7 (14.6) 8 (16.3)  Low physical activity 5 (10.0) 9 (18.4) 12 (24.0) 11 (22.9) 16 (32.7) Hospitalized in past 12 months 1 (2.0) 1 (2.0) 3 (6.0) 6 (12.5) 3 (6.1) IADL-ADL dependency 4 (8.0) 1 (2.0) 1 (2.0) 0 (0.0) 1 (2.0) Control (N = 50) Nutrition (N = 49) Cognitive (N = 50) Physical (N = 48) Combination (N = 49) Male 21 (42.9) 16 (34.0) 12 (24.0) 23(43.8) 23 (46.9)  No education 10 (20.4) 12 (25.5) 9 (18.0) 13 (27.1) 6 (12.2)   1–6 years 29 (59.2) 19 (40.4) 27 (54.0) 22 (45.8) 22 (44.9)   7 or more 10 (20.4) 16 (34.1) 14 (28.0) 13 (31.1) 21 (44.9) Age 70.2 ± 5.0 69.6 ± 4.3 69.7 ± 4.3 70.2 ± 5.2 70.4 ± 4.7 GDS score 0.53 ± 0.87 0.55 ± 1.40 0.66 ± 0.82 0.60 ± 0.89 0.69 ± 1.75 MMSE 28.5 ± 1.8 29.0 ± 1.4 29.1 ± 1.3 29.1 ± 1.2 29.1 ± 1.1 RBANS Domain Index score  Immediate memory 101.2 (13.1) 100.3 (12.3) 99.8 (11.8) 96.9 (12.7) 101.7 (12.4)  Delayed memory 100.2 (10.2) 99.6 (10.5) 99.6 (8.8) 99.8 (10.8) 102.1 (9.5)  Attention 99.0 (11.1) 100.9 (11.2) 99.6 (10.7) 96.0 (16.3) 99.6 (14.2)  Language 100.4 (9.8) 100.5 (9.2) 98.5 (11.0) 100.5 (10.6) 101.3 (9.8)  Visuospatial 99.1 (12.5) 100.8 (9.2) 99.7 (12.7) 98.4 (14.0) 102.4 (10.1)  Total 100.3 (8.1) 100.6 (7.5) 99.3 (7.8) 98.1 (9.0) 101.3 (6.7) BMI, kg/m2 23.6 ± 3.35 24.0 ± 4.31 23.1 ± 2.70 23.5 ± 3.03 24.4 ± 3.79 Sitting systolic BP, mmHg 131.3 ± 16.5 130.2 ± 12.4 131.4 ± 17.2 132.0 ± 13.4 125.5 ± 13.9 Sitting diastolic BP, mmHg 81.3 ± 8.7 80.1 ± 7.9 79.1 ± 8.7 80.8 ± 7.5 78.1 ± 8.0  Fast gait speed, sec, (over 6m) 5.6 ± 2.07 5.8 ± 1.81 5.4 ± 1.16 6.1 ± 2.08 5.4 ± 1.25)  Knee extension, kg 15.5 ± 4.73 14.0 ± 5.27 12.9 ± 3.88 14.1 ± 4.63 14.9 ± 5.50  Energy score (0–15) 10.6 ± 1.55 10.7 ± 1.23 10.5 ± 1.20 10.8 ± 1.10 10.7 ± 1.38  PA score (min/day) 176.9 ± 111.0 165.7 ± 104.7 179.3 ± 113.3 162.5 ± 117.2 160.6 ± 116.0 Frailty status  Mean (SD) score, (range: 0–5) 1.8 (0.80) 2.1 (0.78) 2.0 (0.91) 2.2 (0.85) 2.1 (0.81)  Pre-frail, 43 (86.0) 33 (67.4) 37 (74.0) 29 (60.4) 36 (73.5)  Frail 7 (14.0) 16 (32.7) 13 (26.0) 19 (39.6) 13 (26.5) Frailty components  Weakness 20 (40.8) 26 (53.1) 28 (56.0) 26 (54.2) 25 (51.0)  Slowness 15 (30.0) 20 (40.8) 13 (26.0) 23 (47.9) 17 (34.7)  Weight loss 3 (6.0) 2 (4.1) 2 (4.0) 3 (6.3) 1 (2.0)  Exhaustion 6 (12.0) 7 (14.3) 10 (20.0) 7 (14.6) 8 (16.3)  Low physical activity 5 (10.0) 9 (18.4) 12 (24.0) 11 (22.9) 16 (32.7) Hospitalized in past 12 months 1 (2.0) 1 (2.0) 3 (6.0) 6 (12.5) 3 (6.1) IADL-ADL dependency 4 (8.0) 1 (2.0) 1 (2.0) 0 (0.0) 1 (2.0) Note: Figures are mean ± SD or N (%). GDS = Geriatric Depression Score; IADL-ADL dependency = Instrumental or basic activity of daily living dependency; SD = standard deviation. View Large The global and domain z-scores at 0M, 6M, and 12M across the five intervention groups are shown in Figure 1 and the Supplementary Table available online. The control group showed declines in all cognitive domain scores at 6M and 12M, whereas the cognitive training group showed the greatest increase in global cognition, attention, language, immediate memory and delayed memory, and the combination group showed the greatest increase for visuospatial construction. There was a main effect of treatment (p < .001) and treatment × time interaction (p = .013) for global cognition (Figure 1). Significant main effect of treatment (p = .004) and treatment × time interaction (p = .050) was also detected for immediate memory. For other cognitive domains, only a main effect of treatment (p = .004) was detected for visuospatial construction. Figure 1. View largeDownload slide Cognitive domain and global z-scores at 0 month, 6 month, and 12 month by intervention groups. Figure 1. View largeDownload slide Cognitive domain and global z-scores at 0 month, 6 month, and 12 month by intervention groups. Cognitive Training Intervention In post-hoc pairwise comparisons with Bonferroni-adjusted p values, the positive changes from 0M in global z-scores at 6M (0.094) and 12M (0.099) were significantly different from the changes in the control group at 6M (−0.174), p = .006, and 12M (−0.154), p = .002. Changes in immediate memory from 0M at 6M (0.164) and 12M (0.182) were also significantly different from the changes in the control group at 6M (−0.211), p = .010, and 12M (−0.142), p = .040. Changes from baseline at 6M were significantly different from the control group for delayed memory (p = .010) and attention (p = .025) (Table 2). Table 2. Change in RBANS Cognitive Domain z-Scores From Baseline at 6 Month and 12 Month by Interventional Groups Neurocognitive z scores Control Nutrition Cognitive Physical Combination Mean (95% CI) Mean (95% CI) p (vs ccontrol)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Global  Change (6M–0M) −0.174 (−0.280, −0.067) 0.025 (−0.089, 0.139) .13 0.094 (−0.014, 0.201) .006 −0.033 (−0.139, 0.072) .66 0.005 (−0.102, 0.112) .21  Change (12M–0M) −0.154 (−0.266, −0.042) −0.028 (−0.140, 0.084) .12 0.099 (−0.011, 0.208) .002 −0.090 (−0.197, 0.017) .42 0.039 (−0.070, 0.148) .016 Attention  Change (6M–0M) −0.162 (−0.331, 0.006) −0.041 (−0.220, 0.137) .33 0.109 (−0.059, 0.278) .025 −0.017 (−0.182, 0.147) .22 −0.055 (−0.221, 0.112) .37  Change (12M–0M) −0.121 (−0.301, 0.059) 0.074 (−0.104, 0.251) .13 0.027 (−0.147, 0.200) .24 −0.090 (−0.260, 0.079) .81 0.046 (−0.127, 0.19) .19 Language  Change (6M–0M) −0.126 (−0.31, 0.063) −0.030 (−0.023, 0.175) .49 0.085 (−0.105, 0.275) .12 0.021 (−0.165, 0.207) .27 −0.015 (−0.204, 0.173) .41  Change (12M–0M) −0.245 (−0.444, −0.046) −0.190 (−0.390, 0.011) .70 0.095 (−0.099, 0.288) .017 −0.003 (−0.192, 0.187) .084 0.076 (−0.115, 0.268) .023 Visuospatial/constructional  Change (6M–0M) −0.141 (−0.335, 0.054) 0.017 (−0.182, 0.216) .26 0.055 (−0.135, 0.245) .16 −0.159 (−0.346, 0.027) .89 0.215 (0.026, 0.404) .010  Change (12M–0M) −0.180 (−0.380, 0.020) 0.060 (−0.137, 0.258) .94 0.075 (−0.125, 0.275) .77 −0.126 (−0.320, 0.067) .70 0.166 (−0.028, 0.360) .016 Immediate memory  Change (6M–0M) −0.244 (−0.462, 0.027) 0.113 (−0.120, 0.347) .028 0.164 (−0.059, 0.387) .010 0.008 (−0.208, 0.224) .107 −0.009 (−0.227, 0.208) .13  Change (12M–0M) −0.142 (−0.364, 0.080) −0.031 (−0.253, 0.191) .48 0.182 (−0.034, 0.399) .040 −0.111 (−0.323, 0.102) .84 0.076 (−0.140, 0.293) .17 Delayed memory  Change (6M–0M) −0.211 (−0.383, −0.039) 0.076 (−0.104, 0.257) .024 0.114 (−0.061, 0.288) .010 −0.054 (−0.220, 0.113) .197 0.000 (−0.171, 0.171) .87  Change (12M–0M) −0.100 (−0.288, 0.088) −0.065 (−0.250, 0.121) .79 0.122 (−0.063, 0.308) .098 −0.101 (−0.281, 0.078) .99 −0.062 (−0.224, 0.120) .77 Neurocognitive z scores Control Nutrition Cognitive Physical Combination Mean (95% CI) Mean (95% CI) p (vs ccontrol)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Global  Change (6M–0M) −0.174 (−0.280, −0.067) 0.025 (−0.089, 0.139) .13 0.094 (−0.014, 0.201) .006 −0.033 (−0.139, 0.072) .66 0.005 (−0.102, 0.112) .21  Change (12M–0M) −0.154 (−0.266, −0.042) −0.028 (−0.140, 0.084) .12 0.099 (−0.011, 0.208) .002 −0.090 (−0.197, 0.017) .42 0.039 (−0.070, 0.148) .016 Attention  Change (6M–0M) −0.162 (−0.331, 0.006) −0.041 (−0.220, 0.137) .33 0.109 (−0.059, 0.278) .025 −0.017 (−0.182, 0.147) .22 −0.055 (−0.221, 0.112) .37  Change (12M–0M) −0.121 (−0.301, 0.059) 0.074 (−0.104, 0.251) .13 0.027 (−0.147, 0.200) .24 −0.090 (−0.260, 0.079) .81 0.046 (−0.127, 0.19) .19 Language  Change (6M–0M) −0.126 (−0.31, 0.063) −0.030 (−0.023, 0.175) .49 0.085 (−0.105, 0.275) .12 0.021 (−0.165, 0.207) .27 −0.015 (−0.204, 0.173) .41  Change (12M–0M) −0.245 (−0.444, −0.046) −0.190 (−0.390, 0.011) .70 0.095 (−0.099, 0.288) .017 −0.003 (−0.192, 0.187) .084 0.076 (−0.115, 0.268) .023 Visuospatial/constructional  Change (6M–0M) −0.141 (−0.335, 0.054) 0.017 (−0.182, 0.216) .26 0.055 (−0.135, 0.245) .16 −0.159 (−0.346, 0.027) .89 0.215 (0.026, 0.404) .010  Change (12M–0M) −0.180 (−0.380, 0.020) 0.060 (−0.137, 0.258) .94 0.075 (−0.125, 0.275) .77 −0.126 (−0.320, 0.067) .70 0.166 (−0.028, 0.360) .016 Immediate memory  Change (6M–0M) −0.244 (−0.462, 0.027) 0.113 (−0.120, 0.347) .028 0.164 (−0.059, 0.387) .010 0.008 (−0.208, 0.224) .107 −0.009 (−0.227, 0.208) .13  Change (12M–0M) −0.142 (−0.364, 0.080) −0.031 (−0.253, 0.191) .48 0.182 (−0.034, 0.399) .040 −0.111 (−0.323, 0.102) .84 0.076 (−0.140, 0.293) .17 Delayed memory  Change (6M–0M) −0.211 (−0.383, −0.039) 0.076 (−0.104, 0.257) .024 0.114 (−0.061, 0.288) .010 −0.054 (−0.220, 0.113) .197 0.000 (−0.171, 0.171) .87  Change (12M–0M) −0.100 (−0.288, 0.088) −0.065 (−0.250, 0.121) .79 0.122 (−0.063, 0.308) .098 −0.101 (−0.281, 0.078) .99 −0.062 (−0.224, 0.120) .77 Note: Estimates of changes in cognitive scores are adjusted for the levels of cognitive score at baseline. aAdjusted for multiple comparison with Bonferroni method. View Large Table 2. Change in RBANS Cognitive Domain z-Scores From Baseline at 6 Month and 12 Month by Interventional Groups Neurocognitive z scores Control Nutrition Cognitive Physical Combination Mean (95% CI) Mean (95% CI) p (vs ccontrol)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Global  Change (6M–0M) −0.174 (−0.280, −0.067) 0.025 (−0.089, 0.139) .13 0.094 (−0.014, 0.201) .006 −0.033 (−0.139, 0.072) .66 0.005 (−0.102, 0.112) .21  Change (12M–0M) −0.154 (−0.266, −0.042) −0.028 (−0.140, 0.084) .12 0.099 (−0.011, 0.208) .002 −0.090 (−0.197, 0.017) .42 0.039 (−0.070, 0.148) .016 Attention  Change (6M–0M) −0.162 (−0.331, 0.006) −0.041 (−0.220, 0.137) .33 0.109 (−0.059, 0.278) .025 −0.017 (−0.182, 0.147) .22 −0.055 (−0.221, 0.112) .37  Change (12M–0M) −0.121 (−0.301, 0.059) 0.074 (−0.104, 0.251) .13 0.027 (−0.147, 0.200) .24 −0.090 (−0.260, 0.079) .81 0.046 (−0.127, 0.19) .19 Language  Change (6M–0M) −0.126 (−0.31, 0.063) −0.030 (−0.023, 0.175) .49 0.085 (−0.105, 0.275) .12 0.021 (−0.165, 0.207) .27 −0.015 (−0.204, 0.173) .41  Change (12M–0M) −0.245 (−0.444, −0.046) −0.190 (−0.390, 0.011) .70 0.095 (−0.099, 0.288) .017 −0.003 (−0.192, 0.187) .084 0.076 (−0.115, 0.268) .023 Visuospatial/constructional  Change (6M–0M) −0.141 (−0.335, 0.054) 0.017 (−0.182, 0.216) .26 0.055 (−0.135, 0.245) .16 −0.159 (−0.346, 0.027) .89 0.215 (0.026, 0.404) .010  Change (12M–0M) −0.180 (−0.380, 0.020) 0.060 (−0.137, 0.258) .94 0.075 (−0.125, 0.275) .77 −0.126 (−0.320, 0.067) .70 0.166 (−0.028, 0.360) .016 Immediate memory  Change (6M–0M) −0.244 (−0.462, 0.027) 0.113 (−0.120, 0.347) .028 0.164 (−0.059, 0.387) .010 0.008 (−0.208, 0.224) .107 −0.009 (−0.227, 0.208) .13  Change (12M–0M) −0.142 (−0.364, 0.080) −0.031 (−0.253, 0.191) .48 0.182 (−0.034, 0.399) .040 −0.111 (−0.323, 0.102) .84 0.076 (−0.140, 0.293) .17 Delayed memory  Change (6M–0M) −0.211 (−0.383, −0.039) 0.076 (−0.104, 0.257) .024 0.114 (−0.061, 0.288) .010 −0.054 (−0.220, 0.113) .197 0.000 (−0.171, 0.171) .87  Change (12M–0M) −0.100 (−0.288, 0.088) −0.065 (−0.250, 0.121) .79 0.122 (−0.063, 0.308) .098 −0.101 (−0.281, 0.078) .99 −0.062 (−0.224, 0.120) .77 Neurocognitive z scores Control Nutrition Cognitive Physical Combination Mean (95% CI) Mean (95% CI) p (vs ccontrol)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Global  Change (6M–0M) −0.174 (−0.280, −0.067) 0.025 (−0.089, 0.139) .13 0.094 (−0.014, 0.201) .006 −0.033 (−0.139, 0.072) .66 0.005 (−0.102, 0.112) .21  Change (12M–0M) −0.154 (−0.266, −0.042) −0.028 (−0.140, 0.084) .12 0.099 (−0.011, 0.208) .002 −0.090 (−0.197, 0.017) .42 0.039 (−0.070, 0.148) .016 Attention  Change (6M–0M) −0.162 (−0.331, 0.006) −0.041 (−0.220, 0.137) .33 0.109 (−0.059, 0.278) .025 −0.017 (−0.182, 0.147) .22 −0.055 (−0.221, 0.112) .37  Change (12M–0M) −0.121 (−0.301, 0.059) 0.074 (−0.104, 0.251) .13 0.027 (−0.147, 0.200) .24 −0.090 (−0.260, 0.079) .81 0.046 (−0.127, 0.19) .19 Language  Change (6M–0M) −0.126 (−0.31, 0.063) −0.030 (−0.023, 0.175) .49 0.085 (−0.105, 0.275) .12 0.021 (−0.165, 0.207) .27 −0.015 (−0.204, 0.173) .41  Change (12M–0M) −0.245 (−0.444, −0.046) −0.190 (−0.390, 0.011) .70 0.095 (−0.099, 0.288) .017 −0.003 (−0.192, 0.187) .084 0.076 (−0.115, 0.268) .023 Visuospatial/constructional  Change (6M–0M) −0.141 (−0.335, 0.054) 0.017 (−0.182, 0.216) .26 0.055 (−0.135, 0.245) .16 −0.159 (−0.346, 0.027) .89 0.215 (0.026, 0.404) .010  Change (12M–0M) −0.180 (−0.380, 0.020) 0.060 (−0.137, 0.258) .94 0.075 (−0.125, 0.275) .77 −0.126 (−0.320, 0.067) .70 0.166 (−0.028, 0.360) .016 Immediate memory  Change (6M–0M) −0.244 (−0.462, 0.027) 0.113 (−0.120, 0.347) .028 0.164 (−0.059, 0.387) .010 0.008 (−0.208, 0.224) .107 −0.009 (−0.227, 0.208) .13  Change (12M–0M) −0.142 (−0.364, 0.080) −0.031 (−0.253, 0.191) .48 0.182 (−0.034, 0.399) .040 −0.111 (−0.323, 0.102) .84 0.076 (−0.140, 0.293) .17 Delayed memory  Change (6M–0M) −0.211 (−0.383, −0.039) 0.076 (−0.104, 0.257) .024 0.114 (−0.061, 0.288) .010 −0.054 (−0.220, 0.113) .197 0.000 (−0.171, 0.171) .87  Change (12M–0M) −0.100 (−0.288, 0.088) −0.065 (−0.250, 0.121) .79 0.122 (−0.063, 0.308) .098 −0.101 (−0.281, 0.078) .99 −0.062 (−0.224, 0.120) .77 Note: Estimates of changes in cognitive scores are adjusted for the levels of cognitive score at baseline. aAdjusted for multiple comparison with Bonferroni method. View Large Combination Intervention Changes from 0M in visuospatial construction at 6M (0.215) and 12M (0.166) were also significantly different from the changes in the control group at 6M (−0.141), p = .010, and 12M (−0.180), p = .016. Changes in global cognition (p = .016) and language (p = .023) were significantly more positive than the control group at 12 months. Nutritional Intervention Changes from baseline at 6M were significantly more positive from the control group for immediate memory (p = .028) and delayed memory (p = .024). Physical Training Intervention There were no significant differences in any neurocognitive scores compared to the control group. Discussion To our knowledge, this is the first time the individual effects of cognitive, physical, nutritional, and combination interventions versus control were evaluated simultaneously in a population group of pre-frail or frail older persons at high risk of cognitive decline. Recent studies have shown that physical frailty is associated with increased risks of cognitive decline and dementia (4,6). Consonantly in this study, pre-frail and frail study participants in the control group clearly demonstrated cognitive decline from follow-up measurements at 6 month and 12 month. For the most parts, the several multidomain interventions attenuated this cognitive decline to different degrees with cognitive training showing by far the most substantial increase in cognitive performance. Cognitive training was associated with significantly improved global and immediate memory performance at 6 months at the end of the active intervention period and which was sustained thereafter at 12 months, and additionally, there were improved performance for attention and delayed memory at 6 months, and language at 12 months. This adds to the findings from about 30 randomized controlled trials (RCTs) so far and several meta-analyses (7–10) that consistently document the beneficial effects of cognitive training in improving global cognition, memory, and measures of executive functioning (processing speed and working memory) in healthy older persons and those with MCI. Given the pragmatic design of this study, the multidomain cognitive interventions were designed to improve short-term memory, attention, processing speed, visuospatial skills and executive functions altogether. Hence, the cognitive effects observed undoubtedly represent trained or near-transfer effects, they could not be taken to demonstrate far-transfer effect, nor was there any impact on everyday cognitive functioning. At the other end, the distinct lack of a positive effect of physical training on cognition is in line with the preponderance of negative findings from well-designed RCTs of aerobic, strength, and multicomponent exercise interventions on sedentary older persons (12). In our study, the supervised physical training intervention was of relative low-to-moderate intensity and duration, and self-reported adherence to the home-based maintenance exercises may be questionable. Recent trials specifically among frail older adults (14,15) showed that a 3-month or 6-month supervised gym-based high frequency and high intensity resistance and aerobic training programs were effective in improving processing speed, attention, and working memory. However, longer duration (24 months) moderate-intensity aerobic and resistance training did not result in greater improvements in cognitive function more than controls (13). Nutritional intervention appeared to produce a modest short-term effect on immediate and memory performance only at 6 months for the duration of the nutritionally complete ONS, but no sustained effect at 12 months after discontinuing ONS. Given the pragmatic design of the trial and the multiple nutritional supplementation intervention, no cognitive effects could be attributed specifically to any nutritional component. However, our results are in agreement with positive results from interventions with multivitamins on immediate free recall memory only (20), and ONS on global cognitive performance among cognitively impaired frail older persons (21). Further studies may whether nutritional interventions in combined formulations are more effective compared to single-nutrient formulations. For the combination intervention, there was marked improvement in performance on visuospatial construction at both 6 months and 12 months. A synergistic effect of these interventions appears likely. Considering that nutritional and physical interventions singly were associated with modest short term or no cognitive benefits, and visuospatial construction effect was evident only in the combination intervention group and not in cognitive intervention group, it is possible that physical and nutritional interventions together may show visuospatial construction benefits. The relatively less pronounced effects on global and language function at 12 month were not anticipated. A possible reason is the uneven intensity of delivering the different components of the combination intervention due to logistical difficulties. Limitations As cognitive function was not the primary outcome of the study, the study sample size was based on physical frailty measures as the primary outcome, not cognitive function. The observed Cohen’s d effect sizes for cognitive benefits range approximately from 0.2 to 0.35. The number of subjects were adequate to provide the study with over 95% power to detect statistical significance at p <.05. Our cognitive training was carefully designed to avoid direct training skills to tasks tested on the RBANS (see online Supplementary Information). As previously reported, there were no major differences in the low frequencies of IADL functioning outcomes; hence, the functional significance of the observed neurocognitive effects is unclear. Of note, the findings in this study are related to frail and pre-frail older individuals, and their relevance to sedentary or nonsedentary older adults are unclear. The study participants included few (7%) who were mildly impaired cognitively (MMSE between 24 and 26) and hence were relatively cognitively healthy as a whole. Recent studies have shown that physical frailty with concomitant cognitive impairment considerably increasing the future risk of dementia. Further studies targeting older persons with “cognitive frailty” should be attempted, as it is possible that among more cognitively impaired frail older persons, a greater degree of cognitive benefits could be expected particularly with physical training and nutritional interventions. Supplementary Material Supplementary data is available at Journals of Gerontology, Series A: Biological Sciences and Medical Sciences online. Funding This work was supported by the National Medical Research Council, Singapore (NMRC/1108/2007). Conflict of Interest None reported. Acknowledgment We thank the following voluntary welfare organizations for their support: Geylang East Home for the Aged, Presbyterian Community Services, St Luke’s Eldercare Services, Thye Hua Kwan Moral Society (Moral Neighbourhood Links), Yuhua Neighbourhood Link, Henderson Senior Citizens’ Home, NTUC Eldercare Co-op Ltd, Thong Kheng Seniors Activity Centre (Queenstown Centre), and Redhill Moral Seniors Activity Centre. 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Cognitive Effects of Multi-Domain Interventions Among Pre-Frail and Frail Community-Living Older Persons: Randomized Controlled Trial

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© The Author(s) 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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10.1093/gerona/glx207
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Abstract

Abstract Background Cognitive, physical, and nutritional interventions may produce different cognitive effects for different groups of older persons. We investigated simultaneously the cognitive outcomes of cognitive, physical, and nutritional interventions singly and in combinations in older persons with the physical frailty phenotype at particular risk of cognitive decline. Method Pre-frail and frail participants were randomly allocated to 24 weeks nutritional supplementation (N = 49), physical training (N = 48), cognitive training (N = 50), combination intervention (N = 49), or usual care control (N = 50). Cognitive domain and global functions were assessed at baseline (0M), 6 month (6M), and 12 month (12M). Results The control group showed declines in z-scores (from −0.100 to −0.244) of all domains. The cognitive training compared to control group showed the greatest increase in global cognition at 6M (0.094 vs −0.174, p = .006) and 12M (0.099 vs −0.142, p = .002), immediate memory at 6M (0.164 vs −0.211, p = .010) and 12M (0.182 vs −0.142, p = .040), delayed memory at 6M (p = .010), and attention at 6M (p = .025). Nutritional intervention showed benefits at 6M for immediate memory (p = .028) and delayed memory (p = .024), but physical training showed no positive effects. The combination group showed the greatest increase for visuospatial construction at 6M (0.215 vs −0.141, p = .010) and 12M (0.166 vs −0.180, p = .016), and for global cognition at 12M (p = .016) and language at 12M (p = .023). Conclusion Among frail older persons, cognitive training conferred the greatest cognitive benefits. Nutritional and physical interventions singly were associated with modest short-term or no cognitive benefits, but their combined effects on visuospatial construction should be further investigated. Frailty, Physical exercise, Cognitive training, Nutritional supplementation, Cognition Establishing the effects of different interventional approaches in reducing the risk of cognitive decline and dementia is important for designing programs of cognitive health for older persons. Epidemiological observational studies strongly indicate that physical, socially, and cognitively stimulating activities and nutritional factors are associated with lower risk of cognitive decline and possibly dementia (1). Evidence from randomized controlled trials are limited and mixed. As they are often interrelated, such interventions should arguably be investigated as a cluster for its pragmatic relevance. At the same time, investigating the individual effects of different interventions is important for understanding causal pathways and developing specific approaches for subgroups of at-risk elderly people. A vulnerable group at risk of cognitive decline and dementia are those with the physical frailty phenotype (2,3), Studies have shown a strong and intimate association of physical frailty with cognitive impairment, progression of mild cognitive impairment (MCI) to dementia and increased risk of developing dementia (4–6). Cognitive Interventions Systematic reviews and meta-analyses of randomized controlled trials consistently support the beneficial effects of cognitive training, in improving memory performance, executive functioning, processing speed, attention, fluid intelligence, and subjective cognitive performance in healthy older persons and those with MCI (7,8). However, these studies have typically found the largest effects for the cognitive domains that are specifically trained (trained effect) or near-transfer to tasks within the same cognitive domain, but little or no effects on far-transfer to entirely different nontrained cognitive domains (9). Also, the impact of cognitive interventions on the everyday functioning of healthy older adults remain unclear, as most trials do not include functional outcome measures (10). Physical Exercise Interventions Despite the strong epidemiological observational evidence of the association of habitual physical activity with less cognitive decline, (11) exercise intervention trials have yielded mixed results. Although there were some positive studies, many trials of aerobic, strength, and multicomponent exercise interventions on sedentary older persons have failed to show cognitive benefits (12–15), partly because of short duration intervention and questionable adherence. Nutritional Interventions Randomized controlled trials provide limited evidence in support of the cognitive benefits of folate, B12, and omega 3 fatty acid among nondemented older persons (16,17), but promising evidence in support of complex dietary regimens (such as a Mediterranean-like diet), milk protein concentrates and flavanols (18), and nutritionally complete oral nutritional supplements (ONS) among malnourished and cognitively impaired nursing home residents (19). Nutritional interventions may be more effective in individuals with poorer nutritional status, as multinutrient formulations or in combination with multidomain lifestyle interventions (20,21,22). In this paper, we report the results of secondary end-point analyses of changes in cognitive performance from a randomized controlled trial of nutritional, physical training, cognitive training and combination interventions aimed at reversing frailty among community-living pre-frail and frail older persons. Given the much stronger evidence in support of the positive effects of cognitive intervention, or cognitive-physical dual-tasking exercise intervention, and the limited evidence in support of physical exercise or nutritional interventions alone, we expected to observe that cognitive intervention singly and in combination with physical exercise to produce clearly more pronounced positive cognitive effects. Method Details of the Singapore Frailty Intervention Trial (S-FIT) (clinicaltrial.gov identifier NCT00973258) have been described in a previous publication (23). The study was approved by the National Health Group (NHG) Domain-Specific Review Board in Singapore. The study design was a parallel group, randomized controlled trial comparing multidomain lifestyle interventions of 6 months duration among community-dwelling pre-frail and frail older persons. The primary outcome was frailty and frailty components assessed at 0 month (0M), 3 month (3M), 6 month (6M), and 12 month (12M) post-intervention. Cognitive function was evaluated as secondary end-points at 0M, 6M, and 12M. Participants Between October 2009 and August 2012, community-living older persons were screened for the physical frailty phenotype using five criteria from Fried and colleagues (2): (i) unintentional weight loss, (ii) slow walking speed, (iii) weakness, (iv) self-reported exhaustion, and (v) low physical activity to define pre-frailty (score of 1–2) and frailty (score of 3–5). Details of the frailty measurements are found in the online Supplementary files. The inclusion criteria were: aged 65 and older, able to ambulate without personal assistance, and living at home. Exclusion criteria were: significant cognitive impairment (Mini-mental State Examination score ≤23), dementia, major depression, severe hearing or visual impairment, major stroke, Parkinson and other neurologic disease, terminal illness with life expectancy less than 12 months, and participation in other interventional studies. Randomization and Interventions Eligible participants (N = 246) provided informed consent and were randomized simultaneously to one of five interventions of 24 weeks duration each (23), as described in a previous publication, and are summarized below. Cognitive training was designed for multidomain skills to enhance short-term memory, attention, information processing skills, perceptual organizational tasks, reasoning and logic, and problem-solving abilities. Participants attended 2-hour duration weekly group training sessions (about 10 participants per group) with one-on-one help offered when participants needing greater assistance. The interactive training activities were conducted by a psychologist trainer and nurse facilitators, using materials (paper and pencil tasks, power-point projections, and cognitive games and block puzzles), with which participants learned strategies used to recall verbal and visual information, tasks such as “spot the differences”, categorical naming, and coding (used to enhance attention and processing speed); and matrix reasoning exercises, mazes, and tangram-like games (aimed at enhancing reasoning and problem-solving abilities). Activities were not planned to test specifically for skills tested on Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) although there were some resemblances in alternative versions of tasks such as learning of a word-list, digit span and the coding task using rehearsal, and visual/ auditory association strategies. Intensive training classes were conducted in the first 12 weeks, followed by subsequent 12 weeks where participants attended fortnightly 2-hour “booster” sessions where they reviewed and practiced the cognitive skills learned in the first 12 weeks. Physical training: Moderate intensity physical exercise, of 90-minute duration, on 2 days per week were performed in supervised groups for 12 weeks, followed by 12 weeks of home-based exercises. The exercise program was designed to improve strength and balance for older adults according to American College of Sports Medicine (ACSM) Guidelines for older adults, and included resistance exercises, integrated with functional tasks; and balance training exercises involving functional strength, sensory input, and added attentional demands. More details of the physical and nutritional interventions are described in the Supplementary Information available online. Nutritional intervention: Each participant was provided a commercial formula (Fortisip Multi Fibre, Nutricia), iron and folate supplement (Sangobion, Merck), vitamin B6 and vitamin B12 supplement (Neuroforte), calcium and vitamin D supplement (Caltrate) taken daily for 24 weeks, designed to augment caloric intake by about 20% and provide about one third of the recommended daily allowances of vitamins and minerals. Combination intervention: Participants in this group underwent all three aforementioned interventions. Control group: Participants had access to standard community-based social, recreational and day care rehabilitation services for older people, and were given placebo liquid capsules and tablet formulations. Treatment adherence was measured monthly by estimating the proportion of supplements consumed or training or home-based sessions completed. The mean levels of compliance were 91% for nutrition supplement, 85% for physical training, 79% for cognitive training, 88% for combination group, and 94% for control. Outcome Measures The efficacy outcome measure was the global and domain scores of the RBANS, a brief clinical neuropsychological testing battery that was developed specifically for assessing cognitive performance in elderly with dementia (24). The battery comprises 12 subtests that assess the domains of Immediate and Delayed Memory, Language, Attention and Visuospatial/Construction. Normative studies of the cross-cultural applicability of the RBANS in this elderly Chinese population has also been previously published (25). Raw scores obtained from these tasks were converted to standardized z-scores, used to derive five domain index scores: Attention (mean of ZForward digit span, longest span and ZCoding); Language (mean of Zpicture naming, Zsemantic fluency − fruits and vegetables); Visuospatial construction (mean of Zfigure copy and Zline orientation); Immediate memory (mean of Zlist learning and Zstory memory), and Delayed memory (mean of Zlist recall, Zstory recall, and Zfigure recall) and the global index score, with higher scores indicating better performance. Statistical Analysis Changes in cognitive performance were examined in efficacy analyses using intention-to-treat data including all subjects randomized to interventional arms. Differences in baseline characteristics among the intervention groups were compared using analysis of variance for continuous variables or Chi square for categorical variables. Efficacy analyses were performed using linear mixed models, accounting for correlations between the repeated measures for each participant. Subjects were treated as the random intercepts; time, treatment, and treatment × time interaction as fixed factors. A compound symmetry was specified for the variance–covariance matrix. Post-hoc analyses of between-treatment differences for each intervention versus the control group were performed using Bonferroni-corrected p values. Statistical significance tests were two-sided, and an alpha-level of .05 was considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics version 21 (IBM Corporation). Results Details of the participant flow of recruitment and screening have already been published (22). Of the total of 246 pre-frail and frail participants who were randomized to the intervention groups, 228 (93%) participants completed all follow-up assessments by 1 year. The number of drop outs (N = 20, 8%) were comparable across the five intervention groups. The participants (mean age 70.0 ± 4.7 standard deviation [SD], 61% female) included 28% who were “frail” (N = 68), and 72% who were pre-frail. Very few among them were hospitalized in the previous one year (N = 14, 6%) or were IADL dependent (N = 7, 3%). The mean MMSE score was 28.9 (SD 1.4), with 18 (7%) who were mildly impaired cognitively (MMSE between 24 and 26). Baseline frailty and other characteristics were comparable and no statistically significant differences were observed across the treatment groups (Table 1). Table 1. Baseline Characteristic of FIT Participants by Intervention Groups Control (N = 50) Nutrition (N = 49) Cognitive (N = 50) Physical (N = 48) Combination (N = 49) Male 21 (42.9) 16 (34.0) 12 (24.0) 23(43.8) 23 (46.9)  No education 10 (20.4) 12 (25.5) 9 (18.0) 13 (27.1) 6 (12.2)   1–6 years 29 (59.2) 19 (40.4) 27 (54.0) 22 (45.8) 22 (44.9)   7 or more 10 (20.4) 16 (34.1) 14 (28.0) 13 (31.1) 21 (44.9) Age 70.2 ± 5.0 69.6 ± 4.3 69.7 ± 4.3 70.2 ± 5.2 70.4 ± 4.7 GDS score 0.53 ± 0.87 0.55 ± 1.40 0.66 ± 0.82 0.60 ± 0.89 0.69 ± 1.75 MMSE 28.5 ± 1.8 29.0 ± 1.4 29.1 ± 1.3 29.1 ± 1.2 29.1 ± 1.1 RBANS Domain Index score  Immediate memory 101.2 (13.1) 100.3 (12.3) 99.8 (11.8) 96.9 (12.7) 101.7 (12.4)  Delayed memory 100.2 (10.2) 99.6 (10.5) 99.6 (8.8) 99.8 (10.8) 102.1 (9.5)  Attention 99.0 (11.1) 100.9 (11.2) 99.6 (10.7) 96.0 (16.3) 99.6 (14.2)  Language 100.4 (9.8) 100.5 (9.2) 98.5 (11.0) 100.5 (10.6) 101.3 (9.8)  Visuospatial 99.1 (12.5) 100.8 (9.2) 99.7 (12.7) 98.4 (14.0) 102.4 (10.1)  Total 100.3 (8.1) 100.6 (7.5) 99.3 (7.8) 98.1 (9.0) 101.3 (6.7) BMI, kg/m2 23.6 ± 3.35 24.0 ± 4.31 23.1 ± 2.70 23.5 ± 3.03 24.4 ± 3.79 Sitting systolic BP, mmHg 131.3 ± 16.5 130.2 ± 12.4 131.4 ± 17.2 132.0 ± 13.4 125.5 ± 13.9 Sitting diastolic BP, mmHg 81.3 ± 8.7 80.1 ± 7.9 79.1 ± 8.7 80.8 ± 7.5 78.1 ± 8.0  Fast gait speed, sec, (over 6m) 5.6 ± 2.07 5.8 ± 1.81 5.4 ± 1.16 6.1 ± 2.08 5.4 ± 1.25)  Knee extension, kg 15.5 ± 4.73 14.0 ± 5.27 12.9 ± 3.88 14.1 ± 4.63 14.9 ± 5.50  Energy score (0–15) 10.6 ± 1.55 10.7 ± 1.23 10.5 ± 1.20 10.8 ± 1.10 10.7 ± 1.38  PA score (min/day) 176.9 ± 111.0 165.7 ± 104.7 179.3 ± 113.3 162.5 ± 117.2 160.6 ± 116.0 Frailty status  Mean (SD) score, (range: 0–5) 1.8 (0.80) 2.1 (0.78) 2.0 (0.91) 2.2 (0.85) 2.1 (0.81)  Pre-frail, 43 (86.0) 33 (67.4) 37 (74.0) 29 (60.4) 36 (73.5)  Frail 7 (14.0) 16 (32.7) 13 (26.0) 19 (39.6) 13 (26.5) Frailty components  Weakness 20 (40.8) 26 (53.1) 28 (56.0) 26 (54.2) 25 (51.0)  Slowness 15 (30.0) 20 (40.8) 13 (26.0) 23 (47.9) 17 (34.7)  Weight loss 3 (6.0) 2 (4.1) 2 (4.0) 3 (6.3) 1 (2.0)  Exhaustion 6 (12.0) 7 (14.3) 10 (20.0) 7 (14.6) 8 (16.3)  Low physical activity 5 (10.0) 9 (18.4) 12 (24.0) 11 (22.9) 16 (32.7) Hospitalized in past 12 months 1 (2.0) 1 (2.0) 3 (6.0) 6 (12.5) 3 (6.1) IADL-ADL dependency 4 (8.0) 1 (2.0) 1 (2.0) 0 (0.0) 1 (2.0) Control (N = 50) Nutrition (N = 49) Cognitive (N = 50) Physical (N = 48) Combination (N = 49) Male 21 (42.9) 16 (34.0) 12 (24.0) 23(43.8) 23 (46.9)  No education 10 (20.4) 12 (25.5) 9 (18.0) 13 (27.1) 6 (12.2)   1–6 years 29 (59.2) 19 (40.4) 27 (54.0) 22 (45.8) 22 (44.9)   7 or more 10 (20.4) 16 (34.1) 14 (28.0) 13 (31.1) 21 (44.9) Age 70.2 ± 5.0 69.6 ± 4.3 69.7 ± 4.3 70.2 ± 5.2 70.4 ± 4.7 GDS score 0.53 ± 0.87 0.55 ± 1.40 0.66 ± 0.82 0.60 ± 0.89 0.69 ± 1.75 MMSE 28.5 ± 1.8 29.0 ± 1.4 29.1 ± 1.3 29.1 ± 1.2 29.1 ± 1.1 RBANS Domain Index score  Immediate memory 101.2 (13.1) 100.3 (12.3) 99.8 (11.8) 96.9 (12.7) 101.7 (12.4)  Delayed memory 100.2 (10.2) 99.6 (10.5) 99.6 (8.8) 99.8 (10.8) 102.1 (9.5)  Attention 99.0 (11.1) 100.9 (11.2) 99.6 (10.7) 96.0 (16.3) 99.6 (14.2)  Language 100.4 (9.8) 100.5 (9.2) 98.5 (11.0) 100.5 (10.6) 101.3 (9.8)  Visuospatial 99.1 (12.5) 100.8 (9.2) 99.7 (12.7) 98.4 (14.0) 102.4 (10.1)  Total 100.3 (8.1) 100.6 (7.5) 99.3 (7.8) 98.1 (9.0) 101.3 (6.7) BMI, kg/m2 23.6 ± 3.35 24.0 ± 4.31 23.1 ± 2.70 23.5 ± 3.03 24.4 ± 3.79 Sitting systolic BP, mmHg 131.3 ± 16.5 130.2 ± 12.4 131.4 ± 17.2 132.0 ± 13.4 125.5 ± 13.9 Sitting diastolic BP, mmHg 81.3 ± 8.7 80.1 ± 7.9 79.1 ± 8.7 80.8 ± 7.5 78.1 ± 8.0  Fast gait speed, sec, (over 6m) 5.6 ± 2.07 5.8 ± 1.81 5.4 ± 1.16 6.1 ± 2.08 5.4 ± 1.25)  Knee extension, kg 15.5 ± 4.73 14.0 ± 5.27 12.9 ± 3.88 14.1 ± 4.63 14.9 ± 5.50  Energy score (0–15) 10.6 ± 1.55 10.7 ± 1.23 10.5 ± 1.20 10.8 ± 1.10 10.7 ± 1.38  PA score (min/day) 176.9 ± 111.0 165.7 ± 104.7 179.3 ± 113.3 162.5 ± 117.2 160.6 ± 116.0 Frailty status  Mean (SD) score, (range: 0–5) 1.8 (0.80) 2.1 (0.78) 2.0 (0.91) 2.2 (0.85) 2.1 (0.81)  Pre-frail, 43 (86.0) 33 (67.4) 37 (74.0) 29 (60.4) 36 (73.5)  Frail 7 (14.0) 16 (32.7) 13 (26.0) 19 (39.6) 13 (26.5) Frailty components  Weakness 20 (40.8) 26 (53.1) 28 (56.0) 26 (54.2) 25 (51.0)  Slowness 15 (30.0) 20 (40.8) 13 (26.0) 23 (47.9) 17 (34.7)  Weight loss 3 (6.0) 2 (4.1) 2 (4.0) 3 (6.3) 1 (2.0)  Exhaustion 6 (12.0) 7 (14.3) 10 (20.0) 7 (14.6) 8 (16.3)  Low physical activity 5 (10.0) 9 (18.4) 12 (24.0) 11 (22.9) 16 (32.7) Hospitalized in past 12 months 1 (2.0) 1 (2.0) 3 (6.0) 6 (12.5) 3 (6.1) IADL-ADL dependency 4 (8.0) 1 (2.0) 1 (2.0) 0 (0.0) 1 (2.0) Note: Figures are mean ± SD or N (%). GDS = Geriatric Depression Score; IADL-ADL dependency = Instrumental or basic activity of daily living dependency; SD = standard deviation. View Large Table 1. Baseline Characteristic of FIT Participants by Intervention Groups Control (N = 50) Nutrition (N = 49) Cognitive (N = 50) Physical (N = 48) Combination (N = 49) Male 21 (42.9) 16 (34.0) 12 (24.0) 23(43.8) 23 (46.9)  No education 10 (20.4) 12 (25.5) 9 (18.0) 13 (27.1) 6 (12.2)   1–6 years 29 (59.2) 19 (40.4) 27 (54.0) 22 (45.8) 22 (44.9)   7 or more 10 (20.4) 16 (34.1) 14 (28.0) 13 (31.1) 21 (44.9) Age 70.2 ± 5.0 69.6 ± 4.3 69.7 ± 4.3 70.2 ± 5.2 70.4 ± 4.7 GDS score 0.53 ± 0.87 0.55 ± 1.40 0.66 ± 0.82 0.60 ± 0.89 0.69 ± 1.75 MMSE 28.5 ± 1.8 29.0 ± 1.4 29.1 ± 1.3 29.1 ± 1.2 29.1 ± 1.1 RBANS Domain Index score  Immediate memory 101.2 (13.1) 100.3 (12.3) 99.8 (11.8) 96.9 (12.7) 101.7 (12.4)  Delayed memory 100.2 (10.2) 99.6 (10.5) 99.6 (8.8) 99.8 (10.8) 102.1 (9.5)  Attention 99.0 (11.1) 100.9 (11.2) 99.6 (10.7) 96.0 (16.3) 99.6 (14.2)  Language 100.4 (9.8) 100.5 (9.2) 98.5 (11.0) 100.5 (10.6) 101.3 (9.8)  Visuospatial 99.1 (12.5) 100.8 (9.2) 99.7 (12.7) 98.4 (14.0) 102.4 (10.1)  Total 100.3 (8.1) 100.6 (7.5) 99.3 (7.8) 98.1 (9.0) 101.3 (6.7) BMI, kg/m2 23.6 ± 3.35 24.0 ± 4.31 23.1 ± 2.70 23.5 ± 3.03 24.4 ± 3.79 Sitting systolic BP, mmHg 131.3 ± 16.5 130.2 ± 12.4 131.4 ± 17.2 132.0 ± 13.4 125.5 ± 13.9 Sitting diastolic BP, mmHg 81.3 ± 8.7 80.1 ± 7.9 79.1 ± 8.7 80.8 ± 7.5 78.1 ± 8.0  Fast gait speed, sec, (over 6m) 5.6 ± 2.07 5.8 ± 1.81 5.4 ± 1.16 6.1 ± 2.08 5.4 ± 1.25)  Knee extension, kg 15.5 ± 4.73 14.0 ± 5.27 12.9 ± 3.88 14.1 ± 4.63 14.9 ± 5.50  Energy score (0–15) 10.6 ± 1.55 10.7 ± 1.23 10.5 ± 1.20 10.8 ± 1.10 10.7 ± 1.38  PA score (min/day) 176.9 ± 111.0 165.7 ± 104.7 179.3 ± 113.3 162.5 ± 117.2 160.6 ± 116.0 Frailty status  Mean (SD) score, (range: 0–5) 1.8 (0.80) 2.1 (0.78) 2.0 (0.91) 2.2 (0.85) 2.1 (0.81)  Pre-frail, 43 (86.0) 33 (67.4) 37 (74.0) 29 (60.4) 36 (73.5)  Frail 7 (14.0) 16 (32.7) 13 (26.0) 19 (39.6) 13 (26.5) Frailty components  Weakness 20 (40.8) 26 (53.1) 28 (56.0) 26 (54.2) 25 (51.0)  Slowness 15 (30.0) 20 (40.8) 13 (26.0) 23 (47.9) 17 (34.7)  Weight loss 3 (6.0) 2 (4.1) 2 (4.0) 3 (6.3) 1 (2.0)  Exhaustion 6 (12.0) 7 (14.3) 10 (20.0) 7 (14.6) 8 (16.3)  Low physical activity 5 (10.0) 9 (18.4) 12 (24.0) 11 (22.9) 16 (32.7) Hospitalized in past 12 months 1 (2.0) 1 (2.0) 3 (6.0) 6 (12.5) 3 (6.1) IADL-ADL dependency 4 (8.0) 1 (2.0) 1 (2.0) 0 (0.0) 1 (2.0) Control (N = 50) Nutrition (N = 49) Cognitive (N = 50) Physical (N = 48) Combination (N = 49) Male 21 (42.9) 16 (34.0) 12 (24.0) 23(43.8) 23 (46.9)  No education 10 (20.4) 12 (25.5) 9 (18.0) 13 (27.1) 6 (12.2)   1–6 years 29 (59.2) 19 (40.4) 27 (54.0) 22 (45.8) 22 (44.9)   7 or more 10 (20.4) 16 (34.1) 14 (28.0) 13 (31.1) 21 (44.9) Age 70.2 ± 5.0 69.6 ± 4.3 69.7 ± 4.3 70.2 ± 5.2 70.4 ± 4.7 GDS score 0.53 ± 0.87 0.55 ± 1.40 0.66 ± 0.82 0.60 ± 0.89 0.69 ± 1.75 MMSE 28.5 ± 1.8 29.0 ± 1.4 29.1 ± 1.3 29.1 ± 1.2 29.1 ± 1.1 RBANS Domain Index score  Immediate memory 101.2 (13.1) 100.3 (12.3) 99.8 (11.8) 96.9 (12.7) 101.7 (12.4)  Delayed memory 100.2 (10.2) 99.6 (10.5) 99.6 (8.8) 99.8 (10.8) 102.1 (9.5)  Attention 99.0 (11.1) 100.9 (11.2) 99.6 (10.7) 96.0 (16.3) 99.6 (14.2)  Language 100.4 (9.8) 100.5 (9.2) 98.5 (11.0) 100.5 (10.6) 101.3 (9.8)  Visuospatial 99.1 (12.5) 100.8 (9.2) 99.7 (12.7) 98.4 (14.0) 102.4 (10.1)  Total 100.3 (8.1) 100.6 (7.5) 99.3 (7.8) 98.1 (9.0) 101.3 (6.7) BMI, kg/m2 23.6 ± 3.35 24.0 ± 4.31 23.1 ± 2.70 23.5 ± 3.03 24.4 ± 3.79 Sitting systolic BP, mmHg 131.3 ± 16.5 130.2 ± 12.4 131.4 ± 17.2 132.0 ± 13.4 125.5 ± 13.9 Sitting diastolic BP, mmHg 81.3 ± 8.7 80.1 ± 7.9 79.1 ± 8.7 80.8 ± 7.5 78.1 ± 8.0  Fast gait speed, sec, (over 6m) 5.6 ± 2.07 5.8 ± 1.81 5.4 ± 1.16 6.1 ± 2.08 5.4 ± 1.25)  Knee extension, kg 15.5 ± 4.73 14.0 ± 5.27 12.9 ± 3.88 14.1 ± 4.63 14.9 ± 5.50  Energy score (0–15) 10.6 ± 1.55 10.7 ± 1.23 10.5 ± 1.20 10.8 ± 1.10 10.7 ± 1.38  PA score (min/day) 176.9 ± 111.0 165.7 ± 104.7 179.3 ± 113.3 162.5 ± 117.2 160.6 ± 116.0 Frailty status  Mean (SD) score, (range: 0–5) 1.8 (0.80) 2.1 (0.78) 2.0 (0.91) 2.2 (0.85) 2.1 (0.81)  Pre-frail, 43 (86.0) 33 (67.4) 37 (74.0) 29 (60.4) 36 (73.5)  Frail 7 (14.0) 16 (32.7) 13 (26.0) 19 (39.6) 13 (26.5) Frailty components  Weakness 20 (40.8) 26 (53.1) 28 (56.0) 26 (54.2) 25 (51.0)  Slowness 15 (30.0) 20 (40.8) 13 (26.0) 23 (47.9) 17 (34.7)  Weight loss 3 (6.0) 2 (4.1) 2 (4.0) 3 (6.3) 1 (2.0)  Exhaustion 6 (12.0) 7 (14.3) 10 (20.0) 7 (14.6) 8 (16.3)  Low physical activity 5 (10.0) 9 (18.4) 12 (24.0) 11 (22.9) 16 (32.7) Hospitalized in past 12 months 1 (2.0) 1 (2.0) 3 (6.0) 6 (12.5) 3 (6.1) IADL-ADL dependency 4 (8.0) 1 (2.0) 1 (2.0) 0 (0.0) 1 (2.0) Note: Figures are mean ± SD or N (%). GDS = Geriatric Depression Score; IADL-ADL dependency = Instrumental or basic activity of daily living dependency; SD = standard deviation. View Large The global and domain z-scores at 0M, 6M, and 12M across the five intervention groups are shown in Figure 1 and the Supplementary Table available online. The control group showed declines in all cognitive domain scores at 6M and 12M, whereas the cognitive training group showed the greatest increase in global cognition, attention, language, immediate memory and delayed memory, and the combination group showed the greatest increase for visuospatial construction. There was a main effect of treatment (p < .001) and treatment × time interaction (p = .013) for global cognition (Figure 1). Significant main effect of treatment (p = .004) and treatment × time interaction (p = .050) was also detected for immediate memory. For other cognitive domains, only a main effect of treatment (p = .004) was detected for visuospatial construction. Figure 1. View largeDownload slide Cognitive domain and global z-scores at 0 month, 6 month, and 12 month by intervention groups. Figure 1. View largeDownload slide Cognitive domain and global z-scores at 0 month, 6 month, and 12 month by intervention groups. Cognitive Training Intervention In post-hoc pairwise comparisons with Bonferroni-adjusted p values, the positive changes from 0M in global z-scores at 6M (0.094) and 12M (0.099) were significantly different from the changes in the control group at 6M (−0.174), p = .006, and 12M (−0.154), p = .002. Changes in immediate memory from 0M at 6M (0.164) and 12M (0.182) were also significantly different from the changes in the control group at 6M (−0.211), p = .010, and 12M (−0.142), p = .040. Changes from baseline at 6M were significantly different from the control group for delayed memory (p = .010) and attention (p = .025) (Table 2). Table 2. Change in RBANS Cognitive Domain z-Scores From Baseline at 6 Month and 12 Month by Interventional Groups Neurocognitive z scores Control Nutrition Cognitive Physical Combination Mean (95% CI) Mean (95% CI) p (vs ccontrol)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Global  Change (6M–0M) −0.174 (−0.280, −0.067) 0.025 (−0.089, 0.139) .13 0.094 (−0.014, 0.201) .006 −0.033 (−0.139, 0.072) .66 0.005 (−0.102, 0.112) .21  Change (12M–0M) −0.154 (−0.266, −0.042) −0.028 (−0.140, 0.084) .12 0.099 (−0.011, 0.208) .002 −0.090 (−0.197, 0.017) .42 0.039 (−0.070, 0.148) .016 Attention  Change (6M–0M) −0.162 (−0.331, 0.006) −0.041 (−0.220, 0.137) .33 0.109 (−0.059, 0.278) .025 −0.017 (−0.182, 0.147) .22 −0.055 (−0.221, 0.112) .37  Change (12M–0M) −0.121 (−0.301, 0.059) 0.074 (−0.104, 0.251) .13 0.027 (−0.147, 0.200) .24 −0.090 (−0.260, 0.079) .81 0.046 (−0.127, 0.19) .19 Language  Change (6M–0M) −0.126 (−0.31, 0.063) −0.030 (−0.023, 0.175) .49 0.085 (−0.105, 0.275) .12 0.021 (−0.165, 0.207) .27 −0.015 (−0.204, 0.173) .41  Change (12M–0M) −0.245 (−0.444, −0.046) −0.190 (−0.390, 0.011) .70 0.095 (−0.099, 0.288) .017 −0.003 (−0.192, 0.187) .084 0.076 (−0.115, 0.268) .023 Visuospatial/constructional  Change (6M–0M) −0.141 (−0.335, 0.054) 0.017 (−0.182, 0.216) .26 0.055 (−0.135, 0.245) .16 −0.159 (−0.346, 0.027) .89 0.215 (0.026, 0.404) .010  Change (12M–0M) −0.180 (−0.380, 0.020) 0.060 (−0.137, 0.258) .94 0.075 (−0.125, 0.275) .77 −0.126 (−0.320, 0.067) .70 0.166 (−0.028, 0.360) .016 Immediate memory  Change (6M–0M) −0.244 (−0.462, 0.027) 0.113 (−0.120, 0.347) .028 0.164 (−0.059, 0.387) .010 0.008 (−0.208, 0.224) .107 −0.009 (−0.227, 0.208) .13  Change (12M–0M) −0.142 (−0.364, 0.080) −0.031 (−0.253, 0.191) .48 0.182 (−0.034, 0.399) .040 −0.111 (−0.323, 0.102) .84 0.076 (−0.140, 0.293) .17 Delayed memory  Change (6M–0M) −0.211 (−0.383, −0.039) 0.076 (−0.104, 0.257) .024 0.114 (−0.061, 0.288) .010 −0.054 (−0.220, 0.113) .197 0.000 (−0.171, 0.171) .87  Change (12M–0M) −0.100 (−0.288, 0.088) −0.065 (−0.250, 0.121) .79 0.122 (−0.063, 0.308) .098 −0.101 (−0.281, 0.078) .99 −0.062 (−0.224, 0.120) .77 Neurocognitive z scores Control Nutrition Cognitive Physical Combination Mean (95% CI) Mean (95% CI) p (vs ccontrol)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Global  Change (6M–0M) −0.174 (−0.280, −0.067) 0.025 (−0.089, 0.139) .13 0.094 (−0.014, 0.201) .006 −0.033 (−0.139, 0.072) .66 0.005 (−0.102, 0.112) .21  Change (12M–0M) −0.154 (−0.266, −0.042) −0.028 (−0.140, 0.084) .12 0.099 (−0.011, 0.208) .002 −0.090 (−0.197, 0.017) .42 0.039 (−0.070, 0.148) .016 Attention  Change (6M–0M) −0.162 (−0.331, 0.006) −0.041 (−0.220, 0.137) .33 0.109 (−0.059, 0.278) .025 −0.017 (−0.182, 0.147) .22 −0.055 (−0.221, 0.112) .37  Change (12M–0M) −0.121 (−0.301, 0.059) 0.074 (−0.104, 0.251) .13 0.027 (−0.147, 0.200) .24 −0.090 (−0.260, 0.079) .81 0.046 (−0.127, 0.19) .19 Language  Change (6M–0M) −0.126 (−0.31, 0.063) −0.030 (−0.023, 0.175) .49 0.085 (−0.105, 0.275) .12 0.021 (−0.165, 0.207) .27 −0.015 (−0.204, 0.173) .41  Change (12M–0M) −0.245 (−0.444, −0.046) −0.190 (−0.390, 0.011) .70 0.095 (−0.099, 0.288) .017 −0.003 (−0.192, 0.187) .084 0.076 (−0.115, 0.268) .023 Visuospatial/constructional  Change (6M–0M) −0.141 (−0.335, 0.054) 0.017 (−0.182, 0.216) .26 0.055 (−0.135, 0.245) .16 −0.159 (−0.346, 0.027) .89 0.215 (0.026, 0.404) .010  Change (12M–0M) −0.180 (−0.380, 0.020) 0.060 (−0.137, 0.258) .94 0.075 (−0.125, 0.275) .77 −0.126 (−0.320, 0.067) .70 0.166 (−0.028, 0.360) .016 Immediate memory  Change (6M–0M) −0.244 (−0.462, 0.027) 0.113 (−0.120, 0.347) .028 0.164 (−0.059, 0.387) .010 0.008 (−0.208, 0.224) .107 −0.009 (−0.227, 0.208) .13  Change (12M–0M) −0.142 (−0.364, 0.080) −0.031 (−0.253, 0.191) .48 0.182 (−0.034, 0.399) .040 −0.111 (−0.323, 0.102) .84 0.076 (−0.140, 0.293) .17 Delayed memory  Change (6M–0M) −0.211 (−0.383, −0.039) 0.076 (−0.104, 0.257) .024 0.114 (−0.061, 0.288) .010 −0.054 (−0.220, 0.113) .197 0.000 (−0.171, 0.171) .87  Change (12M–0M) −0.100 (−0.288, 0.088) −0.065 (−0.250, 0.121) .79 0.122 (−0.063, 0.308) .098 −0.101 (−0.281, 0.078) .99 −0.062 (−0.224, 0.120) .77 Note: Estimates of changes in cognitive scores are adjusted for the levels of cognitive score at baseline. aAdjusted for multiple comparison with Bonferroni method. View Large Table 2. Change in RBANS Cognitive Domain z-Scores From Baseline at 6 Month and 12 Month by Interventional Groups Neurocognitive z scores Control Nutrition Cognitive Physical Combination Mean (95% CI) Mean (95% CI) p (vs ccontrol)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Global  Change (6M–0M) −0.174 (−0.280, −0.067) 0.025 (−0.089, 0.139) .13 0.094 (−0.014, 0.201) .006 −0.033 (−0.139, 0.072) .66 0.005 (−0.102, 0.112) .21  Change (12M–0M) −0.154 (−0.266, −0.042) −0.028 (−0.140, 0.084) .12 0.099 (−0.011, 0.208) .002 −0.090 (−0.197, 0.017) .42 0.039 (−0.070, 0.148) .016 Attention  Change (6M–0M) −0.162 (−0.331, 0.006) −0.041 (−0.220, 0.137) .33 0.109 (−0.059, 0.278) .025 −0.017 (−0.182, 0.147) .22 −0.055 (−0.221, 0.112) .37  Change (12M–0M) −0.121 (−0.301, 0.059) 0.074 (−0.104, 0.251) .13 0.027 (−0.147, 0.200) .24 −0.090 (−0.260, 0.079) .81 0.046 (−0.127, 0.19) .19 Language  Change (6M–0M) −0.126 (−0.31, 0.063) −0.030 (−0.023, 0.175) .49 0.085 (−0.105, 0.275) .12 0.021 (−0.165, 0.207) .27 −0.015 (−0.204, 0.173) .41  Change (12M–0M) −0.245 (−0.444, −0.046) −0.190 (−0.390, 0.011) .70 0.095 (−0.099, 0.288) .017 −0.003 (−0.192, 0.187) .084 0.076 (−0.115, 0.268) .023 Visuospatial/constructional  Change (6M–0M) −0.141 (−0.335, 0.054) 0.017 (−0.182, 0.216) .26 0.055 (−0.135, 0.245) .16 −0.159 (−0.346, 0.027) .89 0.215 (0.026, 0.404) .010  Change (12M–0M) −0.180 (−0.380, 0.020) 0.060 (−0.137, 0.258) .94 0.075 (−0.125, 0.275) .77 −0.126 (−0.320, 0.067) .70 0.166 (−0.028, 0.360) .016 Immediate memory  Change (6M–0M) −0.244 (−0.462, 0.027) 0.113 (−0.120, 0.347) .028 0.164 (−0.059, 0.387) .010 0.008 (−0.208, 0.224) .107 −0.009 (−0.227, 0.208) .13  Change (12M–0M) −0.142 (−0.364, 0.080) −0.031 (−0.253, 0.191) .48 0.182 (−0.034, 0.399) .040 −0.111 (−0.323, 0.102) .84 0.076 (−0.140, 0.293) .17 Delayed memory  Change (6M–0M) −0.211 (−0.383, −0.039) 0.076 (−0.104, 0.257) .024 0.114 (−0.061, 0.288) .010 −0.054 (−0.220, 0.113) .197 0.000 (−0.171, 0.171) .87  Change (12M–0M) −0.100 (−0.288, 0.088) −0.065 (−0.250, 0.121) .79 0.122 (−0.063, 0.308) .098 −0.101 (−0.281, 0.078) .99 −0.062 (−0.224, 0.120) .77 Neurocognitive z scores Control Nutrition Cognitive Physical Combination Mean (95% CI) Mean (95% CI) p (vs ccontrol)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Mean (95% CI) p (vs control)a Global  Change (6M–0M) −0.174 (−0.280, −0.067) 0.025 (−0.089, 0.139) .13 0.094 (−0.014, 0.201) .006 −0.033 (−0.139, 0.072) .66 0.005 (−0.102, 0.112) .21  Change (12M–0M) −0.154 (−0.266, −0.042) −0.028 (−0.140, 0.084) .12 0.099 (−0.011, 0.208) .002 −0.090 (−0.197, 0.017) .42 0.039 (−0.070, 0.148) .016 Attention  Change (6M–0M) −0.162 (−0.331, 0.006) −0.041 (−0.220, 0.137) .33 0.109 (−0.059, 0.278) .025 −0.017 (−0.182, 0.147) .22 −0.055 (−0.221, 0.112) .37  Change (12M–0M) −0.121 (−0.301, 0.059) 0.074 (−0.104, 0.251) .13 0.027 (−0.147, 0.200) .24 −0.090 (−0.260, 0.079) .81 0.046 (−0.127, 0.19) .19 Language  Change (6M–0M) −0.126 (−0.31, 0.063) −0.030 (−0.023, 0.175) .49 0.085 (−0.105, 0.275) .12 0.021 (−0.165, 0.207) .27 −0.015 (−0.204, 0.173) .41  Change (12M–0M) −0.245 (−0.444, −0.046) −0.190 (−0.390, 0.011) .70 0.095 (−0.099, 0.288) .017 −0.003 (−0.192, 0.187) .084 0.076 (−0.115, 0.268) .023 Visuospatial/constructional  Change (6M–0M) −0.141 (−0.335, 0.054) 0.017 (−0.182, 0.216) .26 0.055 (−0.135, 0.245) .16 −0.159 (−0.346, 0.027) .89 0.215 (0.026, 0.404) .010  Change (12M–0M) −0.180 (−0.380, 0.020) 0.060 (−0.137, 0.258) .94 0.075 (−0.125, 0.275) .77 −0.126 (−0.320, 0.067) .70 0.166 (−0.028, 0.360) .016 Immediate memory  Change (6M–0M) −0.244 (−0.462, 0.027) 0.113 (−0.120, 0.347) .028 0.164 (−0.059, 0.387) .010 0.008 (−0.208, 0.224) .107 −0.009 (−0.227, 0.208) .13  Change (12M–0M) −0.142 (−0.364, 0.080) −0.031 (−0.253, 0.191) .48 0.182 (−0.034, 0.399) .040 −0.111 (−0.323, 0.102) .84 0.076 (−0.140, 0.293) .17 Delayed memory  Change (6M–0M) −0.211 (−0.383, −0.039) 0.076 (−0.104, 0.257) .024 0.114 (−0.061, 0.288) .010 −0.054 (−0.220, 0.113) .197 0.000 (−0.171, 0.171) .87  Change (12M–0M) −0.100 (−0.288, 0.088) −0.065 (−0.250, 0.121) .79 0.122 (−0.063, 0.308) .098 −0.101 (−0.281, 0.078) .99 −0.062 (−0.224, 0.120) .77 Note: Estimates of changes in cognitive scores are adjusted for the levels of cognitive score at baseline. aAdjusted for multiple comparison with Bonferroni method. View Large Combination Intervention Changes from 0M in visuospatial construction at 6M (0.215) and 12M (0.166) were also significantly different from the changes in the control group at 6M (−0.141), p = .010, and 12M (−0.180), p = .016. Changes in global cognition (p = .016) and language (p = .023) were significantly more positive than the control group at 12 months. Nutritional Intervention Changes from baseline at 6M were significantly more positive from the control group for immediate memory (p = .028) and delayed memory (p = .024). Physical Training Intervention There were no significant differences in any neurocognitive scores compared to the control group. Discussion To our knowledge, this is the first time the individual effects of cognitive, physical, nutritional, and combination interventions versus control were evaluated simultaneously in a population group of pre-frail or frail older persons at high risk of cognitive decline. Recent studies have shown that physical frailty is associated with increased risks of cognitive decline and dementia (4,6). Consonantly in this study, pre-frail and frail study participants in the control group clearly demonstrated cognitive decline from follow-up measurements at 6 month and 12 month. For the most parts, the several multidomain interventions attenuated this cognitive decline to different degrees with cognitive training showing by far the most substantial increase in cognitive performance. Cognitive training was associated with significantly improved global and immediate memory performance at 6 months at the end of the active intervention period and which was sustained thereafter at 12 months, and additionally, there were improved performance for attention and delayed memory at 6 months, and language at 12 months. This adds to the findings from about 30 randomized controlled trials (RCTs) so far and several meta-analyses (7–10) that consistently document the beneficial effects of cognitive training in improving global cognition, memory, and measures of executive functioning (processing speed and working memory) in healthy older persons and those with MCI. Given the pragmatic design of this study, the multidomain cognitive interventions were designed to improve short-term memory, attention, processing speed, visuospatial skills and executive functions altogether. Hence, the cognitive effects observed undoubtedly represent trained or near-transfer effects, they could not be taken to demonstrate far-transfer effect, nor was there any impact on everyday cognitive functioning. At the other end, the distinct lack of a positive effect of physical training on cognition is in line with the preponderance of negative findings from well-designed RCTs of aerobic, strength, and multicomponent exercise interventions on sedentary older persons (12). In our study, the supervised physical training intervention was of relative low-to-moderate intensity and duration, and self-reported adherence to the home-based maintenance exercises may be questionable. Recent trials specifically among frail older adults (14,15) showed that a 3-month or 6-month supervised gym-based high frequency and high intensity resistance and aerobic training programs were effective in improving processing speed, attention, and working memory. However, longer duration (24 months) moderate-intensity aerobic and resistance training did not result in greater improvements in cognitive function more than controls (13). Nutritional intervention appeared to produce a modest short-term effect on immediate and memory performance only at 6 months for the duration of the nutritionally complete ONS, but no sustained effect at 12 months after discontinuing ONS. Given the pragmatic design of the trial and the multiple nutritional supplementation intervention, no cognitive effects could be attributed specifically to any nutritional component. However, our results are in agreement with positive results from interventions with multivitamins on immediate free recall memory only (20), and ONS on global cognitive performance among cognitively impaired frail older persons (21). Further studies may whether nutritional interventions in combined formulations are more effective compared to single-nutrient formulations. For the combination intervention, there was marked improvement in performance on visuospatial construction at both 6 months and 12 months. A synergistic effect of these interventions appears likely. Considering that nutritional and physical interventions singly were associated with modest short term or no cognitive benefits, and visuospatial construction effect was evident only in the combination intervention group and not in cognitive intervention group, it is possible that physical and nutritional interventions together may show visuospatial construction benefits. The relatively less pronounced effects on global and language function at 12 month were not anticipated. A possible reason is the uneven intensity of delivering the different components of the combination intervention due to logistical difficulties. Limitations As cognitive function was not the primary outcome of the study, the study sample size was based on physical frailty measures as the primary outcome, not cognitive function. The observed Cohen’s d effect sizes for cognitive benefits range approximately from 0.2 to 0.35. The number of subjects were adequate to provide the study with over 95% power to detect statistical significance at p <.05. Our cognitive training was carefully designed to avoid direct training skills to tasks tested on the RBANS (see online Supplementary Information). As previously reported, there were no major differences in the low frequencies of IADL functioning outcomes; hence, the functional significance of the observed neurocognitive effects is unclear. Of note, the findings in this study are related to frail and pre-frail older individuals, and their relevance to sedentary or nonsedentary older adults are unclear. The study participants included few (7%) who were mildly impaired cognitively (MMSE between 24 and 26) and hence were relatively cognitively healthy as a whole. Recent studies have shown that physical frailty with concomitant cognitive impairment considerably increasing the future risk of dementia. Further studies targeting older persons with “cognitive frailty” should be attempted, as it is possible that among more cognitively impaired frail older persons, a greater degree of cognitive benefits could be expected particularly with physical training and nutritional interventions. Supplementary Material Supplementary data is available at Journals of Gerontology, Series A: Biological Sciences and Medical Sciences online. Funding This work was supported by the National Medical Research Council, Singapore (NMRC/1108/2007). Conflict of Interest None reported. Acknowledgment We thank the following voluntary welfare organizations for their support: Geylang East Home for the Aged, Presbyterian Community Services, St Luke’s Eldercare Services, Thye Hua Kwan Moral Society (Moral Neighbourhood Links), Yuhua Neighbourhood Link, Henderson Senior Citizens’ Home, NTUC Eldercare Co-op Ltd, Thong Kheng Seniors Activity Centre (Queenstown Centre), and Redhill Moral Seniors Activity Centre. 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The Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences – Oxford University Press

Published: Oct 24, 2017

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