Facility-based and home-based multidomain interventions including cognitive training, exercise, diet, vascular risk management, and motivation for older adults: a randomized controlled feasibility trial

Retention rate and adherence

Between May 29 and August 20, 2019, 152 participants were randomly assigned to three groups: 51 to the FMI group, 51 to the HMI group, and 50 to the control group (Figure 1). The study ended in February 2020. Finally, 45, 49, and 42 participants completed the study in the FMI, HMI, and control groups, respectively. The retention rates at week 24 were 88.2%, 96.1%, and 84.0% in the FMI, HMI, and control groups, respectively. Differences in the retention rates of the groups were not significant (P = 0.13). The modified intention-to-treat (mITT) analysis participants were 48, 50, and 42 in the FMI, HMI, and control groups, respectively.

There were no significant differences in any demographic or clinical characteristics between the control and intervention groups in the mITT population (Table 1) or among the randomized participants (Supplementary Table 1). At baseline, there were no significant differences in age, sex, education, or scores on the Mini-Mental State Examination (MMSE) [12], Geriatric Depression Scale-15 items (GDS-15) [13], Clinical Dementia Rating-Sum of Boxes (CDR-SB) [14], Bayer-Activities of Daily Livings (ADL) [15], and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [16] between the mITT population and those excluded from the mITT analysis.

The total adherence rates were 94.5% (95% confidence interval [CI], 91.4-97.6%) in the FMI group and 96.8% (95% CI, 95.4-98.1%) in the HMI group. The adherence rates to the vascular and metabolic risk factor management program, cognitive training program using a tablet-based application or workbooks, social activity program, physical exercise program, nutritional program, and motivational enhancement program were 98.0%, 97.4%, 95.9%, 91.0%, 94.2%, and 97.7% in the FMI group, and 100%, 97.6%, 100%, 95.0%, 94.4%, and 99.4% in the HMI group (Figure 2).

RBANS

The RBANS total scale index score significantly improved by an average of 5.46 (SD = 7.50, P = 0.004) points in the FMI group and an average of 5.50 (SD = 8.14, P = 0.004) points in the HMI group compared to the control group with a decline by an average of 0.74 (SD = 11.51) points, at the end of the study (Figure 3). The Cohen’s d to represent intervention effect size was 0.64 and 0.63 for each FMI and HMI group. When comparing the index score for each cognitive domain of the RBANS with the control group, visuoconstruction ability in each intervention group, delayed memory in the FMI group, and attention in the HMI group were significantly improved (Table 2). Cognitive training using a tablet-based application was conducted with 67 participants, and 35 received cognitive training using workbooks. Participants using workbooks for cognitive training were older and more likely to be female than those using the cognitive training application. The change from baseline to the study endpoint in the RBANS total scale index score did not differ between participants using the cognitive training application and those using the workbooks after adjusting for their age, gender, and baseline scores (6.11 ± 8.09 vs. 4.24 ± 7.13, P = 0.28).

Secondary outcomes

Compared to the control group, depression, Quality of Life (QOL), control of vascular risk factors such as blood Pressure (BP) and body fat mass, dietary habits evaluated by Nutrition Quotient for the Elderly (NQ-E) [17], physical performance evaluated by Timed UP and Go (TUG) test, and motivation evaluated by the Self Determination Index (SDI) [18] were significantly improved in both the FMI and HMI groups (Table 3). Additionally, sleep quality, subjective memory impairment evaluated by the Prospective and Retrospective Memory Questionnaire (PRMQ) [19], and the Short Physical Performance Battery (SPPB) score [20] were significantly improved in the HMI group compared to the control group. Changes in additional vascular and nutritional factors and changes in the remainder of Korean National Physical Fitness Evaluation Program (K-NPFEP) are presented in Supplementary Table 2.

No significant differences were observed between the FMI group and the HMI group in retention rate, adherence rate, and changes in the RBANS total scale index score and secondary outcomes.

Exploratory blood biomarkers

Compared to the control group (54.18 ± 136.01 ng/mL), plasma cortisol levels were significantly decreased in both the FMI (-5.29 ± 154.01 ng/mL, P = 0.049) and HMI groups (-15.29 ± 172.09 ng/mL, P = 0.03) at the study endpoint (Figure 4 and Supplementary Table 2). Serum brain-derived neurotrophic factor (BDNF) levels were significantly increased in the FMI group compared to the control group (11.83 ± 20.06 ng/mL vs. -1.62 ± 19.01 ng/mL, P = 0.02). Serum chitinase-3-like protein 1 (YKL-40) levels decreased in the FMI and HMI groups and increased in the control group. Although not statistically significant, serum neurofilament light chain (NFL) levels decreased more in the FMI group than in the control group.

Safety

The safety analysis population was 152. Table 4 summarizes the adverse events (AEs) that occurred in three or more participants. The incidence of participants reporting at least one AE during the study period was 33.3%, 39.2%, and 24.0% in the FMI, HMI, and control groups, respectively (P = 0.26). There were no AEs with significant differences in incidence among the groups. Three cases of intervention-related AEs were reported: shoulder pain in the FMI group and knee pain and abdominal pain in the HMI group. Five serious AEs (SAEs) were reported. The SAEs occurring in the FMI group included rotator cuff tear surgery and obstructive prostate hypertrophy. The SAEs occurring in the control group included acute cerebral infarction, general weakness, and spinal compression fracture. None of the SAEs were reported to be related to the study.

Study design and participants

This study was a 24-week, multicenter, outcome assessor-blinded RCT with a multi-arm parallel design conducted in three hospitals and five public health centers across South Korea. The study protocol has previously been published [9]. Participants were recruited among older adults who visited outpatient clinics or public health centers for memory complaints.

The inclusion criteria were as follows: aged between 60 and 79 years; having at least one modifiable dementia risk factor such as hypertension [30], diabetes mellitus (DM) [31], dyslipidemia [32], smoking [33], obesity [34], abdominal obesity [35], metabolic syndrome [36], educational level of ≤ 9 years, social isolation [9], and physical inactivity [9]; a MMSE [12] Z score of ≥ -1.5; able to perform independent ADL; being able to pass a literacy test [37]; and having a reliable informant who can provide investigators with the requested information. The exclusion criteria were major psychiatric illness; overt dementia; other neurodegenerative diseases; malignancy within the last 5 years; cardiac stent or revascularization within the previous year; serious or unstable symptomatic cardiovascular diseases; other serious or unstable medical diseases; any conditions preventing cooperation with the interventions, as determined by a study doctor; a significant laboratory abnormality that may result in cognitive impairment; inability to safely participate in the exercise program; and simultaneous participation in any other intervention trial.

The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practices Guidelines [38]. Institutional review boards approved the protocol and consent forms at each institution before the study began. Written informed consent was obtained from all potential participants before their enrollment. This trial was registered with ClinicalTrials.gov (NCT03980392).

Randomization

In a 1:1:1 ratio, participants were randomly assigned to the FMI, HMI, and control groups at baseline. Randomization was achieved through a permuted block randomization method, with block sizes of three and six, through SAS macro programming, and was stratified by the participating center. The allocation sequence was known only to the independent statistical specialist. Cognitive outcome assessors remained blind to the assigned groups; they were not involved in the intervention activities. Participants were instructed not to discuss their study involvement with the outcome assessor.

Procedures

The FMI and HMI groups’ participants received the following five intervention components [9]: monitoring and management of metabolic and vascular risk factors, cognitive training and social activity, physical exercise, nutritional guidance, and motivational enhancement. The intervention period lasted for 24 weeks. The content of the five intervention components was the same between the FMI and HMI. Participants in the FMI group visited a facility three times a week to perform all intervention programs in a group or in individual sessions. Group sessions consisted of either 5 or 10 participants, depending on the size of the participating center. The HMI participants visited a facility once every 1-2 weeks to perform some programs in a group or in individual sessions and performed others at home. The detailed intervention is described in Table 5.

At baseline, the participants in the control group met a study doctor, were prescribed medication when necessary, and received educational booklets corresponding to their risk factors and a booklet on lifestyle guidelines to prevent dementia. They received usual care during the study period and were informed that they could participate in the multidomain intervention program after the study ended.

Outcomes

The primary outcome was feasibility measured through adherence, retention rates, and changes in the total scale index score of the RBANS with the normative data of Korean adults throughout the study [40]. The RBANS includes 12 subtests and evaluates five different cognitive domains: attention, language, visuoconstruction, immediate memory, and delayed memory. The index score (range 40-160) of each cognitive domain is separately scaled by age group to a scaled score mean of 100 with associated SD of 15. The total scale index score (range 40-160) is derived from the sum of five index scores, also with a normal mean of 100 and standard deviation of 15 [16].

Adherence to the intervention during sessions carried out at the facilities was assessed in real time. A tablet-based cognitive application was configured to allow administrators to view all participants’ data on the administration homepage. Study coordinators assessed adherence to tablet-based cognitive training home sessions on the administration homepage or by checking their cognition workbooks. They examined adherence to the exercise program’s home sessions by comparing the written self-reports with those recorded by a Fitbit smartwatch (Fitbit, Inc., San Francisco, CA, USA) on the participants’ wrists while they performed their daily activities. Participants wrote down the day and time when they performed the exercise program. We subsequently cross-checked their written self-report with the recorded Fitbit activity. Adherence to the nutritional and motivational home sessions was assessed by examining the participants’ homework. Furthermore, adherence to additional social activities (e.g., theater, meeting friends, etc.) was assessed by examining written self-reports. The retention rate was calculated as the percentage of participants in each group who did not discontinue the study.

The secondary outcomes were derived from measures that evaluated the effectiveness of the intervention’s components. The measurement tools included the following: MMSE [12], CDR-SB [14], Prospective Memory Test (PMT) modified from the Royal Prince Alfred PMT [10, 41], PRMQ for evaluating memory problems perceived by a proxy [19], cognitive complaint interview for evaluating subjective memory problems [42], GDS-15 [13], Bayer-ADL [15], and QOL-Alzheimer’s disease (QOL-AD) [43]. Participants’ physical functioning was assessed with the Global Physical Activity Questionnaire [44], SPPB [20], and K-NPFEP. The K-NPFEP measures grip power, sit-to-stand for 30 sec, walk in place for 2 min, bending the upper body forward, TUG test, quickly walking along a figure-eight track, and bioelectrical impedance analysis. Dietary intake was assessed with the Mini Nutritional Assessment [45] and NQ-E [17]. The NQ-E was developed by the Korean Nutritional Society to assess how often participants eat vegetables, fruit, beans, fish, milk, dairy products, eggs, water, fast food, pastries, and sweets [17]. Motivation was assessed by the SDI [18]. Changes in BP, body mass index, waist circumference, smoking, and alcohol consumption were evaluated. Blood tests were performed to assess folate, vitamin B12, 25-hydroxyvitamin D, homocysteine, and lipid and glucose levels.

The RBANS and PMT were assessed at baseline and within 4 weeks after the last intervention. Other secondary outcomes were assessed within 4 weeks before the intervention and within 4 weeks after the last intervention. Participants who withdrew prematurely were asked to complete all endpoint assessments at the point of early termination. Study coordinators evaluated the occurrences of AEs when participants visited a facility, when AEs took place, and at the end of the study.

Exploratory outcomes of blood biomarkers

We performed exploratory studies to investigate the mechanism by which multidomain intervention works in the brain [9]. Changes in plasma total cortisol, a major hormonal byproduct of the HPA axis system [26], serum BDNF as a biomarker of neuroplasticity, NFL as a biomarker of neurodegeneration, and YKL-40 as a neuroinflammatory marker were investigated after the multidomain intervention Fasting blood samples were collected from all participants at approximately 9 o’clock in the morning in serum separator tubes (SSTs) and in K2EDTA tubes within 4 weeks before baseline and at the study endpoint. The SSTs were maintained at room temperature for 30 min. The SSTs and K2EDTA tubes were centrifuged for 10 min at 3000 rpm. In 0.5 mL aliquots, serum and plasma samples were stored in cryovial tubes at ≤ -70° C until analysis. Serum BDNF, NFL, and YKL-40 were measured via a quantitative sandwich enzyme-linked immunosorbent assay using DBD00 and DC3L10 (R&D Systems, Inc., Minneapolis, MN, USA) for BDNF and YKL-40, respectively, and LS-F6701 (LifeSpan BioSciences, Inc., Seattle, WA, USA) for NFL, according to the manufacturers’ instructions. Plasma total cortisol levels were determined by liquid chromatography-selected reaction monitoring quantification using a QTrap5500 mass spectrometer (ABSciex, Foster City, CA, USA). The detailed method is described in the Supplementary Method.

Statistical analysis

Since the purpose of this feasibility trial was to estimate retention and adherence rates, the sample size was calculated using the 95% CI for the rates. Based on the recommendations of sample size calculations for feasibility studies from the National Institute for Health Research [46], we could estimate the retention and adherence rates of 75% when the sample size was 50 and within a 95% CI of ± 12%. Therefore, the required sample size was determined to be 150, with 50 participants in each group.

The adherence rate was calculated by adding the number of sessions completed and dividing by the number of interventions assigned to each intervention component: vascular and metabolic risk factor management (6 sessions), cognitive training (48 sessions), additional social activity (5 sessions), physical exercise (72 sessions), nutrition education (10 sessions), and motivational enhancement (4 education sessions and 24 self-assessments of dementia prevention activities). The total adherence rate was calculated by adding the number of sessions completed across all intervention components and dividing by the total number of interventions (169 sessions) assigned without modifying the weight of each intervention component. Regarding the participants who dropped out of the study, adherence rates were calculated until the dropout point. The chi-square test was used to compare the retention rates between the intervention and control groups.

The RBANS, secondary outcomes, and exploratory blood biomarkers were analyzed using a mITT population. This population was defined as all participants who received baseline evaluation and at least one postbaseline assessment and participated at least once in the intervention program. We used a chi-square test for categorical variables and a one-way analysis of variance for continuous variables to compare baseline characteristics between the groups. Analysis of covariance (ANCOVA), with a baseline score as a covariate, was used to compare changes from baseline to the study endpoint in the RBANS, secondary outcomes, and exploratory blood biomarkers between each intervention group and the control group. P values in the analysis regarding changes in the RBANS total scale index score were adjusted for multiple comparisons by the Bonferroni correction, accounting for the fact that the two intervention groups were compared with one control group.

The safety analysis was conducted on participants who underwent at least one safety evaluation after baseline and participated at least once in the intervention program. The chi-square test was used to compare the prevalence of AEs between the intervention and control groups. Statistical analyses were performed using SPSS 26.0 (SPSS, Chicago, IL, USA). P < 0.05 was considered significant.