Functional benefits of ultra‑high hydrostatic pressurized brown rice on cognition, apathy, and bone health in older adults: A 12‑month randomized controlled trial

Introduction

Geriatric syndromes such as cognitive decline, bone fragility, and mood disturbances often co-occur in older adults and may share overlapping pathophysiological pathways (1-5). For example, dementia, as typified by Alzheimer's disease (AD), and bone fragility are common among the elderly, and the causal relationship in their development has started to attract attention (1-3,5). In addition, cognitive impairment and bone fragility in the elderly have been linked to mental health conditions such as apathy and depression (2,6). Because these conditions are associated with severe morbidity, long-term disability, mortality, and significant socioeconomic impact, there is an urgent global need to develop effective strategies to address them.

Despite extensive research over the past 30 years, the development of fundamental treatments for geriatric diseases remains elusive. Consequently, interest is growing in comprehensive approaches to prevent geriatric diseases and extend healthy life expectancy through lifestyle modification, including daily diet (7,8). A variety of foods containing certain naturally occurring ingredients have the potential to prevent several diseases (9-11). For the past decade, we have been investigating functional foods that can be easily incorporated into the daily diet and may help prevent or manage various geriatric diseases (12-15). In this study, we focused on the functional properties of rice, a staple food for more than half of the global population. Generally, the rice consumed daily is white rice (WR) milled from brown rice (BR). The bran layer on BR is rich in various nutrients, including minerals, vitamins, and dietary fibers, and contains many substances that are considered effective against geriatric diseases, including γ-oryzanol, γ-aminobutyric acid (GABA), and ferulic acid (16-19). However, from a consumer perspective, regular BR has many drawbacks, such as a distinctive flavor and taste, hard texture, and low water absorbency, which makes it difficult to cook and hard to digest.

An ultrahigh hydrostatic pressure apparatus capable of applying water pressure of up to 6,000 atm (600 MPa) was recently developed (20,21). The ultra-high hydrostatic pressurized brown rice (UBR) obtained by processing with this equipment overcomes various drawbacks of BR. Compared with regular BR, UBR has improved water absorption, making it easier to cook, a less distinctive flavor, better texture, and is more easily digested (20,21). In addition, the ultrahigh hydrostatic pressure process confers an advantage in rice preservation by reducing the number of bacteria in the BR (20,21). We previously conducted a 24-month intervention trial of UBR intake in elderly participants, which was associated with the preservation or maintenance of cognitive function (22). A 12-month intake of UBR was associated with the maintenance of bone health in the elderly (23). Although previous findings have suggested that UBR may contribute to maintaining cognitive function and bone density, the interrelationship among these domains and the effects of UBR on mental health remain unclear. Therefore, we conducted a 12-month, randomized controlled trial to evaluate the effects of UBR intake on cognitive function, apathy, and bone health in older adults and to explore possible correlations among these outcomes.

Materials and methods

Study design and participants

This study was a 12-month, randomized controlled trial conducted in community-dwelling older adults aged 65-85 years. The intervention was carried out between October 2015 and March 2017 in Iinan Town, Shimane Prefecture, Japan. Although the study was conducted prior to trial registration, it was retrospectively registered in the UMIN Clinical Trials Registry (registration no. UMIN000053587, date: February 9th, 2024) before submission. The delay in registration occurred due to a lack of awareness of prospective trial registration requirements at the time of study initiation. We acknowledge this as a limitation and affirm that all future clinical trials will be prospectively registered in accordance with international standards. The study was approved by the Ethics Committee of the Shimane University School of Medicine (approval no. 1940-2504). The study adhered to the ethical principles outlined in the Declaration of Helsinki. Prior to study participation, all volunteers provided written informed consent. In this study, 54 healthy volunteers participated, and underwent physical examinations including anthropometry, medical interview by a physician and blood biochemical tests. Volunteers completed a lifestyle questionnaire covering medical and medication history. The following volunteers were excluded from the study: volunteers with any medical disorders, including cardiac, hepatic, renal, gastrointestinal, respiratory disease, diabetes mellitus, neurological disorders, and osteoporosis, metabolic, cancer, endocrine, or hematological disorders; those eating BR daily; those consuming medications/supplements to treat bone disorders or osteoporosis and/or improve cognitive and mental function that could affect the results of the study; those with allergies and hypersensitivity; smokers. Of the 54 volunteers screened for eligibility, 44 participants (mean age, 73.1±5.6 years) were enrolled into the study and assigned to either the WR-intake group (n=22) or the UBR intake group (n=22) (Fig. 1). Participants were diagnosed by a clinician to ensure they had no neuropsychiatric or other disorders. No volunteers had participated in any other clinical studies within the past year. Group allocation was conducted by stratified random assignment, as described previously (24,25). The randomization code lists were prepared by an independent clinical research advisor and concealed from the investigators, participants, outcome assessors, and data analysts. All assessments and data analyses were performed in a blinded manner, and group assignments were disclosed only after completion of the study. Although participants were not informed which intervention (UBR or WR) was considered active, the noticeable differences in color, texture, and flavor between the two made complete blinding of participants infeasible. Participants in the WR-intake group received 200 g of WR daily for 12 months; those in the UBR-intake group received 100 g of UBR and 100 g of WR daily for 12 months. The rice intake was voluntary for the participants. During the intervention period, participants were advised to avoid other BR products and functional foods potentially influencing cognitive or bone health. This request was made to reduce confounding factors, and adherence was encouraged without disrupting participants' usual lifestyle. Participants' adherence to rice consumption was daily investigated using a self-administered questionnaire.

Figure 1 Flow diagram of the study. Of the 54 participants screened for eligibility, 44 participants were randomized into the WR (n=22) and UBR (n=22) treatment arms. In each group, 20 participants completed the 12-month intervention trial. WR, white rice; UBR, ultra-high hydrostatic pressurized brown rice.

Test foods

Both UBR and WR were supplied by NPO Satoyama Commission (Iinan-cho). To prepare UBR, BR was exposed to water at a hydrostatic pressure of 600 MPa for 5 s using a hydrostatic pressurizer (21). UBR and WR were both cultivated in Iinan-cho, Shimane, Japan, and produced from the same variety of rice. The nutrient content of WR and UBR was measured at Shimane Environment & Health Public Corporation and Shimane Institute for Industrial Technology and is summarized in Table I. Compared with WR, UBR was richer in lipids and dietary fiber and has a higher content of minerals, including magnesium (Mg), calcium (Ca), inorganic phosphorus (Pi), and iron (Fe). In addition, UBR is rich in vitamins B1, B6, and niacin, as well as bioactive substances such as GABA, inositol, and ferulic acid (Table I).

Table I Nutrients content of WR and UBR.

Table I

Nutrients content of WR and UBR.

Nutrients	WR	UBR
Protein, g	6.80	7.70
Carbohydrate, g	75.30	76.60
Dietary fiber, g	0.30	7.10
Lipid, g	1.30	3.00
GABA, mg	2.00	9.10
Inositol, mg	ND	202.00
Ferulic acids, mg	ND	12-50
Calcium, mg	2.00	9.00
Magnesium, mg	20.00	110.00
Phosphate, mg	140.00	290.00
Potassium, mg	110.00	230.00
Sodium, mg	2.00	1.89
Iron, mg	0.50	2.10
Zinc, mg	4.00	1.80
Vitamin B1, mg	0.12	0.51
Vitamin B2, mg	0.03	0.04
Vitamin B6, mg	0.05	0.32
Vitamin E, mg	0.40	ND
Niacin, mg	1.40	7.46

[i] Values shown are for 100 g. Part of the data within this table are adapted from J Nutr Sci Vitaminol (Tokyo). 2019;65:S88-S92 (23). WR, white rice; UBR, ultra-high hydrostatic pressurized brown rice; GABA, g-aminobutyric acid; ND, not detected.

Anthropometry

Height, waist circumference, and blood pressure were measured by trained nurses. Body weight and body fat were measured using a bioelectrical impedance analyzer (WB-150; TANITA Co.), as described previously (26). After these measurements, participants completed two self-administered questionnaires: a general lifestyle questionnaire, which included items on educational background and medical/medication history, and a brief diet history questionnaire, as described previously (22,26).

Blood biochemistry

At baseline and after 12 months of the intervention, blood samples were drawn by nurses in the morning after confirming whether participants had fasted. Serum was separated from whole blood samples and stored at -80˚C until use. Serum biochemical parameters were measured using an automated clinical chemistry analyzer TBA-c16000 (TOSHIBA); serum HbA1c level was determined with high-performance liquid chromatography (HPLC) using an HLC-723G9 (TOSOH); and blood sugar was measured using the GA08III automatic analyzer (A&T Co.), as described previously (7).

Safety assessment

Adverse events were monitored throughout the 12-month study period using structured monthly interviews and questionnaires. Participants were asked about specific symptoms including gastrointestinal issues (e.g., bloating, flatulence, diarrhea), allergic reactions, appetite changes, and bowel habit alterations. Any reported events were recorded and evaluated by the study physician to determine their relationship to the intervention.

Serum monoamine levels

The concentrations of monoamines, i.e., epinephrine (Epi), norepinephrine (NE), dopamine (DA), and serotonin (5-HT), in the serum were measured using a previously described HPLC method (22). Briefly, the serum was pretreated with a clean EG column (EICOM). The HPLC equipment consisted of an EICOM HTEC-500 (EICOM) equipped with a data processor (EICOM EPC-500 PowerChrom) and an automatic injector (EICOM M-514). Chromatographic separation was performed using an EICOMPAK CA-5ODS column (2.1x150 mm ID) linked to a precolumn (EICOM PREPAK PC-03-CA). PowerChrom software was used for data collection and analysis (EICOM). The mobile phase consisted of 0.1 M phosphate buffer (pH 5.7) containing 700 mg/l sodium 1-octanesulfonate, 12% methanol, and 50 mg/l EDTA disodium salt. The flow rate was set to 0.23 ml/min, and the applied potential was +450 mV with respect to an Ag/AgCl reference electrode. The column temperature was maintained at 25˚C.

Cognitive function and mental health assessment

Cognitive function was assessed using the Mini-Mental State Examination (MMSE) (27), the Revised Hasegawa's Dementia Scale (HDS-R) (28), the Frontal Assessment Battery (FAB) (29), and the Cognitive Assessment for Dementia, iPad version (CADi) (30). The MMSE is a cognitive function test consisting of 11 subitems. MMSE can be used to screen cognitive impairment, estimate the severity of cognitive impairment at a given point in time, track an individual's cognitive changes over time, and document an individual's response to treatment (27). A total MMSE score of 24 to 27 points is considered indicative of mild cognitive impairment (MCI), while a score below 23 suggests possible dementia (27). The HDS-R is commonly used for dementia screening in Japan and includes 9 items assessing orientation, memory, attention, and verbal fluency (28). Generally, a score below 20 is considered suggestive of dementia (28). The FAB, consisting of 6 subtests, is a cognitive test that incorporates several clinical assessments to screen for frontotemporal dementia, including S-word generation, similarities, Luria's test, grasp reflex, and the Go-No-Go test (29). The CADi consists of 10 items and is a useful tool for population screening for dementia and is known to correlate significantly with MMSE scores (30). In CADi, the time spent performing a task is also evaluated and used as an indicator of cognitive processing ability (30). Furthermore, mental condition, i.e., apathy and depression, was assessed using the Japanese version of the Starkstein apathy scale (31) and the Zung Self-Rating Depression Scale (SDS) (32), respectively. The Starkstein apathy scale is a subjective rating scale with scores ranging from 0 to 42; higher scores indicate less motivation and a greater apathy severity (31). The cutoff for the apathy scale is 16 points, and apathy is suspected in those who score 16 points or higher. The SDS is also a self-rating scale, comprising responses to 20 questions on a 4-point scale; a higher total score indicates a tendency toward depression (32). These tests are commonly used in clinical and interventional studies as they are relatively quick and can easily assess an individual's cognitive and mental function (12-15,22,25,26). All assessments were conducted by trained clinicians.

Quantitative ultrasound measurements of the calcaneum

To assess bone status, we used an ultrasonic bone densitometer (Venus-α; Nihon Kohden, Tokyo, Japan) to perform quantitative ultrasound (QUS) of the right calcaneus, as previously described (23). The device uses a combination of ultrasound pulse reflection and ultrasound pulse transmission methods to measure the speed of sound (SOS) and the bone width of the calcaneus and subsequently calculates the bone area ratio (BAR). QUS offers a quick and noninvasive method for evaluating bone health without the radiation exposure associated with dual-energy X-ray absorptiometry (DXA). The BAR values obtained with this device have been reported to correlate significantly with bone mineral density (BMD) measurements by DXA at the lumbar spine (r=0.77, P<0.01) and calcaneus (r=0.83, P<0.01) (33). For each participant, the BAR of the right calcaneus was measured at least three times and converted to the percentage of the young adult mean (%YAM), using reference data from Japanese adults aged 20-44, in which 100% represents the average bone density for that age group. %YAM is widely used in clinical practice in Japan as an index of bone status and allows for standardized comparisons across individuals (34,35).

Sample size power calculation

The sample size was calculated using PS: Power & Sample Size Calculation Software Version 3.1.2 (Vanderbilt University, Nashville, TN, USA). The primary outcomes were the change in MMSE scores after 12 months of intervention. Based on data from a previous randomized controlled trial involving a similar population (15,22), a mean difference of 1.4 points (SD=2.0) between groups was expected. Assuming two-sided α=0.05 and 90% power, a minimum of 20 participants per group was required using an independent t-test. To account for an anticipated dropout rate of 10%, we enrolled 22 participants per group.

Statistical analysis

All statistical analyses were conducted using IBM SPSS Statistics for Windows, version 26.0 (IBM Corp.). A per-protocol approach was adopted for efficacy analyses. Data were first assessed for normality using the Shapiro-Wilk test. All variables met normality assumptions and are presented as mean ± standard error of the mean (SEM). The primary outcomes were the MMSE score and Starkstein apathy scale score at 12 months. Secondary outcomes included other cognitive measures (CADi, HDS-R, FAB), additional mental health indicators (SDS), and bone health index (%YAM). To assess between-group differences at 12 months while controlling for potential baseline imbalances, analysis of covariance (ANCOVA) was employed. In the ANCOVA models, the 12-month score was entered as the dependent variable, group (UBR vs. WR) as the fixed factor, and baseline score and age as covariates. To examine time-by-group interaction effects across baseline and 12 months, two-way repeated measures ANOVA were used. When a significant interaction was found, post hoc comparisons were performed using Tukey's test. Between-group comparisons of change scores (Δ=12 months-baseline) were conducted using independent samples t-tests as supplementary analyses. While change scores are reported for descriptive purposes, interpretation of primary effects was based on ANCOVA results. Effect sizes for between-group comparisons were calculated using Cohen's d, with thresholds of 0.2, 0.5, and 0.8 representing small, medium, and large effects, respectively. Partial correlation analyses were conducted to explore the associations among cognitive, mental, and bone-related outcomes at 12 months, adjusting for age and baseline scores. All tests were two-tailed, and statistical significance was set at P<0.05.

Results

Adherence

Fig. 1 shows a flow diagram of this intervention study. During the 12-month intervention, four subjects (two in the WR-intake group and two in the UBR-intake group) retired for personal reasons (Fig. 1). Therefore, the 12-month intervention trial was completed by twenty participants both in the WR-intake group and UBR-intake group (Fig. 1). Participants demonstrated excellent adherence to the intervention protocol for 12 months (UBR: 95.5%, WR: 96.8%). Data from general questionnaires on lifestyle habits and medical/medication history showed no significant differences during 12 months of intervention (data not shown). Adverse effects disturbing participants' daily lives such as palpitation, anorexia, diarrhea, constipation, allergic reactions, and irritated stomach were not observed in both groups. The BDHQ survey showed no significant difference in mean dietary nutrient intake between the UBR-intake and WR-intake groups at 12 months (data not shown).

Body composition, blood pressure, blood biochemistry, and serum monoamine levels

Table II shows the values for body composition, blood pressure, blood biochemistry, and serum monoamine levels of the participants at baseline and at 12 months after the intervention, as well as the changes during the intervention period. At baseline, there were no significant differences between the WR-intake and UBR intake groups in body weight, height, fat mass, BMI, waist circumference, or blood pressure (Table II). Similarly, no significant differences were observed between the groups for blood biochemical variables, aspartate transaminase (AST), alanine transaminase (ALT), γ-glutamyl transpeptidase (γ-GTP), albumin (ALB), total cholesterol (T-cho), triglyceride (TG), blood urea nitrogen (BUN), creatinine (CRE), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), blood sugar, or HbA1c levels at baseline (Table II). After 12 months of the intervention, the two groups did not differ in height, body weight, body fat mass, BMI, waist circumference, or blood pressure (Table II), and there were no significant differences in blood biochemistry parameters, blood sugar, or HbA1c. Furthermore, for each parameter, the change from baseline to 12 months was not significantly different (Table II). Serum EPi, NE, DA, and 5-HT levels did not differ between the groups at baseline, and long-term UBR intake had no effect. From baseline to 12 months, D5-HT levels were slightly increased in the UBR intake group, but the change was not statistically significant (P=0.081, Table II).

Table II Participants' characteristics and anthropometric biochemical variables.

Table II

Participants' characteristics and anthropometric biochemical variables.

	Baseline		Month 12		Change amount (Δ)
Characteristic	WR	UBR	WR	UBR	WR	UBR	P-value
N	22	22	20	20	-	-	-
Sex (male/female)	10/12	10/12	8/12	10/10	-	-	0.532
Age	75.2±1.3	70.8±1.2	75.7±1.4	72.4±1.3	-	-	0.038
Anthropometry
Height, cm	153.3±1.7	157.5±2.5	153.8±1.7	159.1±2.6	0.6±0.5	0.7±0.6	0.779
Body weight, kg	53.7±1.9	60.7±3.2	53.8±1.9	60.3±3.5	0.1±0.3	-0.4±0.5	0.094
BMI, kg/m2	22.8±0.6	23.9±0.7	22.6±0.5	23.8±0.7	1.7±3.9	4.7±4.6	0.924
Body fat, %	28.4±1.7	28.9±2.1	29.4±1.3	28.8±1.2	1.0±0.3	0.1±0.4	0.621
WC, cm	86.1±1.7	87.1±2.1	83.8±1.9	86.3±2.4	-2.4±0.9	-0.8±0.6	0.421
Blood pressure
SBP, mmHg	143.6±6.6	141.6±3.0	144.9±5.9	147.4±4.0	0.8±2.2	2.9±2.1	0.864
DPB, mmHg	76.4±3.6	78.7±2.1	78.6±3.2	82.2±2.3	1.1±0.2	2.0±0.2	0.119
Biochemistry
AST, IU/l	24.9±1.4	27.2±0.9	26.4±1.7	27.9±1.5	1.5±1.4	0.7±1.0	0.779
ALT, IU/l	16.1±1.9	20.8±1.9	18.7±2.1	21.3±1.5	1.6±1.6	0.4±1.3	0.383
γ-GTP, IU/l	31.9±8.6	41.9±10.4	32.8±9.3	45.1±11.9	0.8±1.6	2.5±2.9	0.461
ALB, g/dl	4.1±0.1	4.1±0.1	4.2±0.1	4.2±0.1	0.1±0.1	0.1±0.0	0.620
T-cho, mg/dl	192.2±5.3	191.6±6.0	196.6±6.6	197.5±5.4	4.3±6.0	5.9±2.8	0.998
TG, mg/dl	125.3±8.6	121.3±14.2	129.1±10.5	144.1±19.8	4.5±11.0	23.6±15.2	0.758
BUN, mg/dl	17.0±1.0	15.4±0.5	15.6±1.1	15.0±0.6	-1.3±0.8	-0.3±0.6	0.289
BS, mg/dl	113.9±6.3	100.9±6.2	118.6±7.0	109.1±4.9	4.9±8.7	8.1±4.3	0.968
CRE, mg/dl	0.7±0.0	0.7±0.0	0.7±0.0	0.7±0.0	0.0±0.0	0.0±0.0	0.814
HDL-C, mg/dl	65.1±2.0	62.8±2.3	66.2±3.9	64.2±2.8	1.8±1.9	1.9±1.5	0.779
LDL-C, mg/dl	102.1±5.4	106.2±6.1	104.7±5.3	104.5±6.5	1.7±7.0	-0.7±3.2	0.947
HbA1c, %	5.8±0.1	5.9±0.1	5.9±0.1	6.0±0.1	0.2±0.4	0.1±0.1	0.121
Serum monoamines
Epi, ng/ml	6.7±6.0	1.8±1.0	7.7±2.7	4.9±1.2	1.0±5.7	3.2±1.0	0.353
NE, ng/ml	45.9±6.9	55.5±4.2	102.8±6.8	112.6±5.4	67.0±10.3	56.9±4.9	0.752
DA, ng/ml	3.1±1.5	6.0±3.1	2.6±1.7	4.9±1.1	2.6±1.7	0.5±0.3	0.208
5-HT, ng/ml	10,470±986	11,313±1184	12,416±1274	14,448±810	1,690±631	3,305±650	0.087

[i] Data are shown as mean ± SEM. WR, white rice intake group; UBR, ultra-high hydrostatic pressurized brown rice intake group; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; AST, aspartate transaminase; ALT, alanine transaminase; γ-GTP, gamma-glutamyl transpeptidase; ALB, albumin; BUN, blood urea nitrogen; CRE, creatinine; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HbA1c, hemoglobin A1c; T-cho, total cholesterol; TG, triglyceride; Epi, epinephrine; NE, norepinephrine; DA, dopamine; 5-HT, serotonin.

Safety assessment

Adverse events were monitored monthly using structured interviews. Participants were asked about common symptoms potentially associated with dietary fiber intake, such as bloating, diarrhea, and allergic reactions. No participants reported any adverse symptoms during the 12-month study period. These findings, together with the absence of unfavorable changes in clinical parameters (e.g., liver enzymes, kidney function, blood pressure), support the safety of long-term UBR intake.

Cognitive and mental health assessments

MMSE, CADi, HSD-R, and FAB were used to assess participants' cognitive function, and the results were summarized in Table III. In this study, all participants had MMSE scores of 24 or higher, Apathy scores of 16 or lower, and SDS scores of 40 or lower during the intervention period, suggesting that they were not suffering from dementia, apathy, or depression. At baseline, there were no significant differences between the groups for all measures of cognitive outcomes (Table III). At 12 months, MMSE and CADi total scores in the UBR-intake group were higher than in the WR-intake group. A two-way ANOVA revealed a significant group x time interaction for MMSE total scores, F(1,78)=7.67, P=0.021. Although the mean change in MMSE from baseline to 12 months was not statistically significant between the groups (P=0.142), ANCOVA adjusting for baseline value and age revealed that the 12-month MMSE score was significantly higher in the UBR group than in the WR group [F(1,36)=4.21, P=0.046, Cohen's d=0.72]. Sensitivity analyses using a simple comparison without covariates (P=0.034) and an alternative ANCOVA adjusting for age and sex (P=0.040) confirmed these results (Table SI). The absolute difference of 1.4 points, while statistically significant, was below the commonly cited in Minimal Clinically Important Difference (MCID) of 2-3 points, suggesting cognitive preservation rather than true improvement. Subitem analysis of the MMSE revealed no significant between-group difference in the change in ‘Recall 3 words’, a measure of recent memory (P=0.098, Table III). Regarding CADi, significant group x time interactions were observed for total score [F(1,78)=5.59, P=0.048] and execution time [F(1,78)=16.46, P=0.014]. At 12 months, CADi total score increased (P=0.038) and execution time decreased (P=0.008) in the UBR group compared to WR (Table III). The change in execution time (ΔCADi time) was significantly greater in the UBR group (Fig. 2A, P=0.026), and subitem analysis revealed a significant difference in ‘Delayed Recognition’ (Fig. 2B, P=0.027). For apathy, ANCOVA adjusting for baseline score and age showed a significantly lower 12-month score in the UBR group [F(1,36)=7.92, P=0.008; Cohen's d=0.89]. A two-way ANOVA also revealed a significant group x time interaction [F(1,78)=11.13, P=0.007], and Δapathy scores were significantly lower in the UBR group compared to the control (Fig. 2C, P=0.015), suggesting a potential benefit of UBR intake on motivational state. SDS values showed a non-significant trend toward reduction in the UBR group at 12 months (P=0.142), and between-group differences in change scores were not significant (P=0.294). HDS-R and FAB scores showed no significant differences. Sensitivity analyses for apathy and CADi confirmed consistent results across models (P=0.010-0.012 for apathy; P<0.05 for CADi), with moderate to large effect sizes (apathy: d=0.89; CADi: d=0.75-1.02). For HDS-R, FAB, and SDS, exploratory sensitivity analyses revealed small to moderate effect sizes (e.g., HDS-R: d=0.38) despite non-significant P-values (Table SII).

Figure 2 Change amount (Δ) in (A) CADi execution time (CADi time), (B) CADi time subitem ‘Delayed Recognition’ and (C) apathy score from baseline to 12 months. Data are the mean ± SEM. *P<0.05. CADi, Cognitive Assessment for Dementia, iPad version; WR, white rice intake group; UBR, ultra-high hydrostatic pressurized brown rice intake group.

Table III Cognitive and mental health assessments.

Table III

Cognitive and mental health assessments.

	Baseline		Month 12		Change amount (Δ)
Assessment	WR	UBR	WR	UBR	WR	UBR	P-value
MMSE	28.2±0.2	28.5±0.1	27.4±0.2	28.7±0.2a	-0.6±0.4	0.2±0.3	0.142
‘Recall 3 Words’	2.5±0.1	2.4±0.2	2.4±0.1	2.6±0.1	-0.1±0.1	0.2±0.1	0.098
CADi total	7.6±0.3	8.0±0.3	7.9±0.3	8.8±0.2a	0.3±0.3	0.6±0.2	0.439
‘Delayed Recognition’	0.63±0.1	0.61±0.1	0.60±0.1	0.91±0.1	-0.05±0.2	0.31±0.2	0.024
CADi time	141.0±8.2	127.6±10.3	151.7±11.2	108.6±6.7b	4.7±8.0	-19.1±5.0	0.026
‘Delayed Recognition’	18.6±2.3	16.7±1.3	18.3±2.3	12.2±1.2a	0.0±1.2	-4.0±1.2	0.016
FAB	14.7±0.3	15.2±0.5	15.1±0.4	15.6±0.4	0.5±0.3	0.4±0.3	0.775
HDS-R	27.7±0.5	28.9±0.2	27.5±0.5	28.9±0.4	-0.2±0.4	0.0±0.1	0.581
Apathy	11.1±1.0	9.8±1.2	11.3±1.2	6.6±1.0b,c	0.2±0.6	-2.9±0.3	0.015
SDS	33.6±1.5	32.8±1.6	32.5±1.4	29.0±1.6	-1.0±1.3	-3.6±1.1	0.294

[i] ^aP<0.05 and

[ii] ^bP<0.01 vs. WR (month 12);

[iii] ^cP<0.05 vs. baseline. MMSE, Mini-Mental State Examination; CADi, Cognitive Assessment for Dementia, iPad version; SDS, Self-rating Depression Scale. FAB, Frontal Assessment Battery; HDS-R, Hasegawa Dementia Scale-Revised; WR, white rice intake group; UBR, ultra-high hydrostatic pressurized brown rice intake group. Data are the mean ± SEM.

Assessment of bone status using quantitative ultrasound

Table IV presents the values of SOS and %YAM at baseline and after the 12-month intervention, along with the corresponding changes over time. At baseline, no significant differences were observed between the UBR and WR groups in SOS or %YAM. After 12 months, both SOS and %YAM values were higher in the UBR group compared to the WR group. A two-way ANOVA revealed a significant main effect of group for both SOS [F(1,78)=4.22, P=0.046] and %YAM [F(1,78)=4.64, P=0.043], indicating that participants in the UBR group maintained significantly greater bone status than those in the WR group. No significant group x time interaction effects were found for either SOS or %YAM (P>0.05). Post hoc comparisons showed that the %YAM at 12 months was significantly higher in the UBR group compared to the WR group (P=0.032). Similarly, SOS was significantly greater in the UBR group at 12 months (P<0.05). No significant difference in calcaneal bone width was detected between groups (data not shown). Fig. 3 illustrates the changes in SOS (ΔSOS) and %YAM (Δ%YAM) from baseline to 12 months. Both ΔSOS (P=0.035) and Δ%YAM (P=0.034) were significantly greater in the UBR group compared to the WR group, further supporting a potential benefit of UBR intake on bone health in older adults.

Figure 3 Change (Δ) in (A) calcaneal SOS and (B) %YAM from baseline to 12 months. Data are presented as mean ± SEM. *P<0.05. %YAM, percentage of the Young Adult Mean; SOS, speed of sound; WR, white rice intake group; UBR, ultra-high hydrostatic pressurized brown rice intake group.

Table IV Bone health assessment using quantitative ultrasound measurements.

Table IV

Bone health assessment using quantitative ultrasound measurements.

	Baseline		Month 12		Change amount (Δ)
Measurement	WR	UBR	WR	UBR	WR	UBR	P-value
SOS, m/sec	1,799.5±14.3	1,830.8±20.5	1,774.5±16.7	1,855.1±22.9a	-27.3±14.1	19.7±11.6	0.035
%YAM	85.6±2.4	88.6±2.4	82.4±2.0	91.5±2.7a	-3.1±1.8	2.3±1.3	0.034

[i] ^aP<0.05 vs. WR at 12 months. WR, white rice intake group; UBR, ultra-high hydrostatic pressurized brown rice intake group; %YAM, percentage of the Young Adult Mean; SOS, speed of sound. Values are the mean ± SEM.

Correlation analysis

Partial correlation analyses adjusting for age and baseline values revealed significant associations between cognitive and mental health indicators. After 12 months of intervention, MMSE score had significant negative correlations with the apathy score (Fig. 4A, r=-0.513, P=0.001) and SDS (Fig. 4B, r=-0.472, P=0.002). A strong positive correlation was observed between apathy and depression levels (Fig. 4C, r=0.769, P<0.0001). Moreover, %YAM had a significant negative correlation with CADi time (Fig. 4D, r=-0.283, P=0.046) and a positive correlation with CADi total (Fig. 4E, r=0.369, P=0.021). The %YAM had significant negative correlations with SDS (Fig. 4F, r=-0.439, P=0.005) and apathy score (Fig. 4G, r=-0.331, P=0.039) after 12 months of intervention. The apathy score showed a significant negative correlation with MMSE subitem ‘Recall 3 words’ (Fig. 4H, r=-0.499, P<0.001), and a significant positive correlation with CADi time subitem ‘Delayed Recognition’ (Fig. 4I, r=0.372, P=0.019). A full matrix of partial correlation coefficients is presented in Table SIII.

Figure 4 Scatter plots showing partial correlations adjusted for age and baseline values after 12 months of intervention: (A) MMSE vs. apathy score; (B) MMSE vs. SDS; (C) apathy score vs. SDS; (D) %YAM vs. CADi time; (E) %YAM vs. CADi total; (F) %YAM vs. SDS; (G) %YAM vs. apathy score; (H) MMSE subitem ‘Recall 3 words’ vs. apathy score; (I) CADi subitem ‘Delayed Recognition’ vs. apathy score. Open circles=WR intake group; gray circles=UBR intake group. MMSE, Mini-Mental State Examination; CADi, Cognitive Assessment for Dementia, iPad version; SDS, Self-rating Depression Scale; %YAM, percentage of the Young Adult Mean.

Discussion

This study investigated the effects of daily UBR consumption over a 12-month period on cognitive performance, mental health, and bone status in community-dwelling older adults. The results indicated that MMSE scores at 12 months were significantly higher in the UBR group compared to the WR group, although the change from baseline was not statistically significant. In contrast, UBR intake was associated with the preservation of CADi total scores and a slower execution time, suggesting a potential benefit in cognitive processing speed and memory-related tasks. Additionally, apathy scores significantly decreased in the UBR group over the intervention period, while no significant changes were observed in depression scores (SDS). Importantly, CADi and apathy scores were significantly correlated with bone health indices (%YAM), highlighting a potential interplay between cognitive-motivational function and bone density. Although causal relationships cannot be inferred from the present analyses, the observed partial correlations between cognitive/apathy scores and %YAM may indicate a potential association among cognitive, motivational, and skeletal health in older adults. These findings warrant further investigation in studies with longitudinal mediation models. No serious adverse events were reported, and UBR consumption did not result in notable changes in hepatic or renal markers, body composition, or metabolic parameters, suggesting that the intervention was well tolerated and safe for long-term intake.

Cognitive impairment and fragility fractures mainly affect the elderly population and significantly increase the prevalence and incidence of dementia and osteoporosis. Because of the severe morbidity, long-term disability, and mortality associated with these conditions, as well as their socioeconomic impact, there is an urgent global need to develop strategies to prevent these diseases (5). Although the causal relationship between dementia and bone fragility is still under debate, several clinical and epidemiological reports have shown that patients with dementia, including AD, exhibit lower BMD, higher susceptibility to falls, and an increased propensity for fracture compared with their healthy counterparts (5,36). Retrospective and prospective studies consistently highlight cognitive decline as a risk factor for bone fracture, with both sexes experiencing dementia and osteoporosis as the most common condition (5,37-39). In a longitudinal study (the Rotterdam Study), Xiao et al. (3) found that individuals with lower BMD were more likely to develop dementia later in life, suggesting that bone fragility may be a risk factor for dementia. The relationship between dementia and osteoporosis in treatment can be seen with raloxifene, an osteoporosis drug shown to reduce the risk of vertebral fractures (40). The analysis of cognitive function in postmenopausal women, raloxifene was found to reduce the risk of dementia, especially in women with MCI (40,41). Furthermore, a systematic review also showed that raloxifene reduced the risk of MCI and lowered the risk of AD (42). Thus, ingredients that improve bone density may also have beneficial effects on cognition. Although a causal relationship cannot be established, the observed associations suggest that UBR intake may contribute to the preservation of both cognitive and bone health. However, further research is needed to fully understand the complex relationship between cognitive impairment, BMD decline, and the mechanism of action of UBR.

Typically, even healthy older adults without MCI or dementia experience various changes in cognitive abilities as they age, one of which is decline in recent memory (43). In this study, CADi analysis showed that UBR intake was associated with an increase in total scores and a significant reduction in execution time. Furthermore, the CADi subitem analysis shows a significant increase in ‘Delayed Recognition’ in the UBR group compared to the WR group. A trend toward improvement with UBR-intake was also observed in changes in the MMSE subitem ‘Recall 3 words’ (recent memory scale). These findings suggest that UBR intake may support recent memory in older individuals. It is also of interest that UBR intake was associated with a significant reduction in apathy scores in the elderly; moreover, these results were significantly correlated with cognitive abilities and %YAM. In the elderly, several brain areas (including the prefrontal cortex, anterior cingulate cortex, temporal lobe and hippocampus) atrophy with age, leading to MCI and the subsequent onset of AD, the most common form of neurodegenerative disease (44). The earliest pathogenesis of AD is the accumulation of β-amyloid (Aβ) plaques in the brain, which begin to form more than 20 years before onset of the disease (44). Aβ deposition and corticolimbic dysfunction have also been shown to be positively correlated with the development of apathy and depression (45,46). In addition, apathy and depression have been linked with frailty and lower BMD, suggesting that a comprehensive approach is required to combat dementia (47,48). In a preclinical study, Okuda et al. reported that chronic administration of UBR in a mouse model of AD (senescence-accelerated mouse prone-8) suppressed Aβ accumulation in the brain and improved cognitive function (49). Therefore, the observed preservation of cognitive function and reduction in apathy in the UBR intake group may, at least in part, be associated with the potential role of UBR in attenuating amyloid burden.

The molecular mechanisms through which UBR may contribute to cognitive, motivational, and bone-related benefits remain unclear; however, several bioactive components in UBR are hypothesized to play a role in these effects. For example, UBR is richer in minerals (e.g., Ca, Mg, Pi, and Fe) than WR (Table I). Mineral deficiencies can affect memory function and are a likely cause of age-related cognitive impairment and mental illness (50-55). Deficiencies in nutrients also pose serious problems for bone health in the elderly (56). In addition, UBR is richer in lipids and dietary fiber than WR and contains bioactive substances such as ferulic acid, GABA and g-Oryzanol (Table I). Ferulic acid has been reported to induce an increase in blood estradiol and alkaline phosphatase activity in castrated female rats, consequently preventing a decrease in BMD (54). Ferulic acid has also been reported to have beneficial effects in dementia and depression and to inhibit Ab aggregation, oxidative stress and inflammatory responses (19,55). GABA, a major inhibitory neurotransmitter, is known for its neuroprotective properties and potential to preserve cognitive function (17,57-59). g-Oryzanol has been shown to exert neuroprotective effects by reducing oxidative stress and neuroinflammation, thereby supporting cognitive function, and may also contribute to bone health by inhibiting osteoclast differentiation and reducing bone resorption through its anti-inflammatory properties (60,61). Together, these components could synergistically contribute to preserving cognitive function, reducing apathy via neurotransmitter modulation, and supporting bone quality through anti-inflammatory and antioxidant mechanisms. In addition, B vitamins, which are abundant in UBR (Table I), are known to be closely involved in the formation of collagen crosslinks in bone, and a high correlation has been reported between insufficient vitamin B6 intake and decreased bone density (62,63). Recently, elevated serum homocysteine levels due to vitamin B6 deficiency have been shown to have a negative impact on bone metabolism and result in an increased fracture risk (64,65). Increased homocysteine levels due to a deficiency of B vitamins increase the risk of dementia and other related diseases (66). Various functional components in UBR, along with their potential synergistic interactions, may help prevent cognitive decline and bone loss. These findings underscore the need for further mechanistic research to clarify the biological pathways involved.

The benefits of regular intake of BR for human physiology and disease prevention have been well studied (10,67,68). However, continuous intake of regular BR is often difficult for various reasons, and in some cases, it has been associated with health concerns such as digestive malabsorption (69). In this study, long-term consumption of UBR showed no difference between the two groups in terms of changes in liver function, renal function, lipid metabolism, and carbohydrate metabolism before and after intervention (Table II). Furthermore, participant adherence was high, and no physical complaints related to chronic intake were reported during the intervention period. These results demonstrate that the long-term consumption of UBR does not interfere with daily life in the elderly individuals and that UBR is a sustainable and safe staple food. Given its low cost, wide availability, and ease of daily consumption, UBR may serve as a feasible dietary approach for older adults. Compared to pharmaceutical interventions, UBR may offer a more accessible and sustainable strategy for maintaining cognitive and bone health, particularly in community-dwelling populations.

Despite the encouraging findings, this study has several limitations. First, the relatively small sample size may have limited the power to detect subtle effects and increases the risk of type II error. For example, the MMSE difference, while statistically significant, did not exceed the established MCID (2-3 points), suggesting limited clinical relevance. Similarly, some secondary outcomes showed non-significant results despite small to moderate effect sizes. These findings should be interpreted cautiously, and future studies with larger samples are needed to validate these effects. Second, the trial was retrospectively registered, which we acknowledge as a limitation. Future studies should ensure prospective registration to enhance transparency, reduce reporting bias, and strengthen the credibility of the findings. Third, the assessment of bone health relied solely on calcaneal QUS, using %YAM as the endpoint. While %YAM is widely used in Japan for screening purposes, it is not a direct measure of BMD and lacks internationally standardized diagnostic thresholds. Unlike DXA, which is the gold standard for diagnosing osteoporosis, QUS primarily reflects bone quality and structural integrity. Furthermore, the QUS device used in this study did not generate validated T-scores, which are essential for classification based on WHO criteria. As such, clinical interpretation of bone status and risk based solely on %YAM should be approached with caution. This limitation underscores the need for future studies to incorporate DXA or QUS devices that provide validated T-scores to allow for more clinically meaningful assessment of bone health. Fourth, although the sample size limited stratified analysis, the effects of UBR intake may vary according to baseline characteristics such as age, sex, physical activity, vitamin D exposure, and dietary patterns. These potential effect modifiers should be considered in future studies with larger and more diverse populations. Fifth, although complete participant blinding was not feasible due to perceptible differences between UBR and WR, all outcome assessments and data analyses were conducted by staff who were blinded to group allocation, minimizing assessment bias. Finally, the lack of mechanistic investigation limits our ability to draw conclusions about the underlying biological effects of UBR.

In conclusion, daily intake of UBR over 12 months was associated with preservation of cognitive function, reduced apathy, and maintenance of bone-related parameters in older adults, without adverse effects. While causality cannot be established, these findings support the potential of UBR as a functional staple food to help mitigate age-related declines in cognition and bone health. Further large-scale, mechanistically informed studies are needed to confirm and expand upon these observations.

Supplementary Material

Sensitivity analyses of between-group differences in MMSE endpoint under alternative models.

Exploratory sensitivity analyses and corresponding effect sizes for secondary outcomes at 12 months

Partial correlation coefficients between cognitive, emotional and bone-related outcomes at 12 months.

Acknowledgements

Not applicable.

Funding

Funding: This work was supported in part by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education Culture, Sports, Science and Technology of Japan (grant no. 26500008).

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Author's contributions

MH contributed to the conceptualization, design of the study and was responsible for project administration, including ethical approvals and coordination among research sites. KM, SY, YK and MH contributed to formal analysis, data interpretation, and data curation. KM, SY, YK and MH were involved in clinical assessments. KM and MH contributed to the development of the study methodology, including the design of outcome measures and statistical analysis plans. SY, OS, KY, HKis and MH provided essential experimental equipment and resources required for the conduct of the study. HN, TM, and HKin managed rice processing and the provision of test food. TM, HKin and MH coordinated participant recruitment. KM, YK, HN, TM, HKin and MH contributed to data acquisition through participant support and intervention management. TM, HKin, KY and MH contributed to the design and interpretation of nutritional analysis. KM wrote the first draft of the manuscript and performed data visualization. SY, OS, HKis and MH contributed to the interpretation of results and critical review of the manuscript. MH secured the research funding. SY, OS, KY, HKis and MH supervised the study. KM, YK and MH confirmed the authenticity of all raw data. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Shimane University School of Medicine (approval no. 1940-2504). All procedures were conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants prior to their inclusion in the study.

Patient consent for publication

All participants provided written informed consent for participation in the study and for the publication of anonymized data.

Competing interests

The authors declare that they have no competing interests.

Authors' information

ORCID: Kentaro Matsuzaki, 0000-0002-5942-8840; Shozo Yano, 0000-0002-9210-2949; Hiroko Kishi, 0000-0003-2896-7355; Michio Hashimoto, 0000-0002-3726-4347.

References