INTRODUCTION
Sarcopenia is associated with cognitive decline. Sarcopenia is a progressive, systemic skeletal muscle disease associated with an increased risk of adverse outcomes and is caused by aging, poor nutrition, low activity, and disease.1) Sarcopenia occurs in 1%–29% of community-dwelling older adults1,2) and is associated with decreased quality of life, falls, frailty,3,4) poor physical function, cognitive decline, hospitalization, and risk of death.5,6) In older people, sarcopenia is a risk factor for cognitive decline and has recently been shown to be a risk factor for the development of Alzheimer's disease and mild cognitive impairment.7) In contrast, post-stroke patients may present with a combination of cognitive impairments, including vascular dementia. Although the underlying pathologies differ, sarcopenia may contribute to cognitive dysfunction in both groups through mechanisms such as inflammation, decreased physical activity, and muscle-brain crosstalk. As a potential mechanism by which sarcopenia causes cognitive decline, it has been reported that muscle secretes hormone-like proteins that may reach cognitive brain regions via systemic circulation rather than via the central nervous system connection to affect cognition.7,8) Myokines secreted by muscles contribute to the regulation of hippocampal function.8) In addition, motor function is a complex volitional behavior, and impairment of this function leads to cognitive decline in many older people.9-11) In stroke patients with sarcopenia, cognitive decline may result from a combination of cerebrovascular damage and sarcopenia-related factors, such as reduced myokine secretion and physical inactivity.7,8,11)
Exercise is effective in improving cognitive function. Exercise may have a protective effect on cognitive function by (1) raising the levels of growth factors such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1), (2) regulating inflammatory cytokines, (3) relieving oxidative stress, and (4) increasing cerebral blood flow.12,13) Previous relevant studies have shown that specific types of exercise, such as resistance training14) and aerobic exercise,14,15) may be effective in improving cognitive function. In addition, group training has been reported to be beneficial in improving cognitive function16,17) and quality of life18) in cognitively impaired individuals.
However, the effect of exercise on the cognitive level of patients with sarcopenia is not clear. In previous studies of post-acute stroke patients admitted to rehabilitation hospitals, patients with sarcopenia have lower cognitive levels than patients without sarcopenia.19,20) On the other hand, studies in post-acute stroke patients have reported that chair-stand exercise was effective in improving activities of daily living (ADL), dysphagia, and sarcopenia in hospitalized patients.21,22) Theoretically, this exercise could be an effective adjunct to traditional rehabilitation programs to improve cognitive levels in patients with sarcopenia. However, evidence is currently lacking.
Therefore, this retrospective cohort study aimed to elucidate the effect of chair-stand exercise on the improvement of cognitive level in stroke patients with reduced cognitive level who were diagnosed with sarcopenia.
MATERIALS AND METHODS
Participants and Setting
This retrospective cohort study was conducted at Kumamoto Rehabilitation Hospital (Japan), a single facility with 225 beds, including 135 beds in three convalescent rehabilitation wards. All stroke patients were transferred in a medically stable condition from the stroke unit of the acute care hospital in a local medical cooperative system, and all new stroke patients admitted to the unit between 2015 and 2023 were included in the registry. Among the enrolled patients, those with sarcopenia and reduced cognitive level at admission were included in the analysis. Cognitive level was assessed by the cognitive items of the Functional Independence Measure (FIM)-cognitive,23) and FIM-cognitive score ≤23 was defined as cognitive decline in this study.24) In cases of aphasia, FIM-cognitive scores were carefully assessed by trained rehabilitation staff based on the patient’s actual ability to comprehend and interact in daily activities, with input from multidisciplinary discussions. Exclusion criteria were (1) altered consciousness (Japan Coma Scale 3-digit codes), (2) bioelectrical impedance analysis (BIA) unsuitable (e.g., pacemaker implantation), (3) not adapted for chair-stand exercise at the discretion of the attending physician, and (4) missing data.
Convalescent Rehabilitation
The convalescent rehabilitation program included rehabilitation, nutrition management, and medication management.
Rehabilitation in the convalescent rehabilitation ward was provided by physiotherapists, occupational therapists, and speech therapists for up to 3 hours per day, depending on the patient's physical function and level of disability.25)
Nutritional management was based on functional and nutritional status.26) Nutritional management included nutritional support for malnourished patients (e.g., high-energy, high-protein diet), and protein administration to maintain muscle mass.
Medication management during hospitalization was provided by a multidisciplinary team that included a pharmacist. Multiple or inappropriate medications were corrected after screening, and medications that could affect physical activity or nutritional status were appropriately managed.27)
Group Chair-Stand Exercise
In addition to participating in the convalescent rehabilitation program, patients repeatedly performed "chair-stand exercise," which consisted of a sit-to-stand task from a chair, as a group training twice a day.21,22) This group training program was conducted for patients admitted to the convalescent rehabilitation wards, who gathered in the rehabilitation room in the morning and afternoon, respectively, and all participants performed the chair-stand exercise daily under the supervision and assistance of rehabilitation therapists, while timing their movements together. Each session lasted 20 minutes, and participants were asked to perform the task of continuously standing and sitting up to 120 times at a rate of approximately one every 8 seconds, with 2-seconds break in between. The frequency of chair-stand exercise performed was appropriately managed by the rehabilitation therapists according to each patient's ability, fatigue, and vital signs (Fig. 1). To avoid excessive physical burden, the duration of group chair-stand exercise was individually adjusted according to each patient's endurance and kept within 20 minutes. All staff involved were instructed to monitor participants' conditions closely and to modify the program as needed to maintain safety and feasibility. The number of chair-stand repetitions was accurately recorded in the electronic medical record by rehabilitation staff during each group session. All participating patients' data were documented precisely as a matter of institutional policy. Although the exercise was performed in groups, small subgroups were directly supervised by therapists to ensure accurate counting. The frequency reported in this study refers to the average number of repetitions per day, calculated by dividing the total repetitions during hospitalization by the number of hospital days. This level of frequency and repetition is considered moderate in intensity and is consistent with prior studies on resistance training in frail or post-stroke older adults.21,22)
Definition of Sarcopenia
Sarcopenia was diagnosed according to the consensus of the Asian Working Group for Sarcopenia (AWGS) in 2019.28) Patients were diagnosed with sarcopenia if they had low muscle strength as measured by handgrip strength (HG) and low skeletal muscle mass index (SMI) as measured by BIA. In post-stroke patients, HG was assessed using the non-paretic upper limb to avoid the influence of motor deficits. Although dominance of the arm may affect strength to some extent, the use of the non-paretic side was deemed appropriate to minimize stroke-related bias. This approach is consistent with prior studies evaluating sarcopenia in stroke patients using the AWGS 2019 criteria.28)
The cut-off values for HG were <28 kg for male and <18 kg for female.28) The cut-off values for SMI were <7.0 kg/m2 for male and <5.7 kg/m2 for female.28) BIA was performed by physiotherapists using the InBody S10 (InBody, Tokyo, Japan) with the patients in the supine position. In accordance with the AWGS 2019 criteria,28) sarcopenia was diagnosed based on the presence of both low HG and low SMI, without assessing physical performance, which was often difficult to evaluate in stroke patients with impaired mobility.
Data Collection
Baseline characteristics of participants include age, sex, stroke type, pre-stroke ADL by modified Rankin Scale (mRS),29) days from stroke onset to admission (onset-admission days), paralysis side, Brunnstrom Recovery Stage (BRS),30) FIM-total/motor/cognitive,23) Charlson Comorbidity Index (CCI),31) Mini Nutritional Assessment-Short Form (MNA-SF),32) Food Intake LEVEL Scale (FILS),33) body weight (BW), body mass index (BMI), appendicular skeletal muscle mass (SMM), SMI, HG, total number of drugs, laboratory data (albumin, hemoglobin, C-reactive protein), energy intake and protein intake were assessed. In addition, other parameters such as length of hospital stay and average number of rehabilitation units per day during hospitalization were evaluated. One rehabilitation unit was 20 minutes, with a maximum of 9 units per day provided to each patient under the supervision of a physiotherapist, occupational therapist, and speech therapist.
BW, BMI, SMM, SMI, and HG were measured within 3 days of admission, and BMI and SMI were calculated by dividing BW (kg) and SMM (kg), respectively, by the square of height (m2). Each body composition value was measured by InBody S10. All measurements were taken at least 2 hours after the last meal, and patients were on bed rest and limited fluid intake for 1 hour before measurement. Patients with pacemakers and those who could not remain at rest during measurements were excluded.
HG value was measured with a Smedley hand dynamometer (TTM Tsutsumi Co. Ltd., Tokyo, Japan). Measurements were taken in the standing or sitting position, depending on the patient's condition, with both arms extended on the side without paralysis, and the maximum value was recorded.
Chair-stand exercise was evaluated for the frequency with which each participant performed it per day during hospitalization (frequency/day).
Outcomes
The primary outcome was the "FIM-cognitive at discharge" to assess the cognitive level. The FIM consisted of 18 items on a 7-point ordinal scale ranging from total assistance to complete independence. The sum of the 18 items was recorded as the FIM-total score. The FIM-total score was subdivided into the FIM-motor score, calculated from the total score of 13 items corresponding to motor items, including self-care, and the FIM-cognitive score, calculated from the total score of 5 items corresponding to cognitive items.23)
Secondary outcomes were two variables: "HG at discharge" to assess muscle strength and "FIM-motor at discharge" to assess ADL.
Sample Size Calculation
Sample size determination was based on information from our previous study,34) which showed that FIM-cognitive score of hospitalized post-stroke patients followed a normal distribution with a standard deviation of 9.0. Assuming that the true mean difference in FIM-cognitive between high- and low-frequency groups for the chair-stand exercise is 3, which is considered a minimally clinically significant difference for patients with post-stroke sequelae,35) a minimum sample size of 111 patients per group is required to achieve statistical power of 0.8 and alpha error of 0.05 to reject the null hypothesis.
Statistical Analysis
Data were presented as mean±standard deviation for parametric data, median and 25th-75th percentile (interquartile range [IQR]) for nonparametric data, and number (%) for categorical data. For univariate analysis, patients were divided into two groups, one with a high frequency of chair-stand exercise and one with a low frequency of chair-stand exercise, using the median frequency of chair-stand exercise as the cut-off value. The two groups were then compared for differences in baseline characteristics of participants and outcomes. For outcomes, comparisons between the two groups were made by sex, taking into account the difference in HG. Comparisons between groups were made using the t-test, Mann-Whitney U test, and χ2 test based on measures of normality and variables.
Multiple linear regression analysis was used to determine whether the frequency of chair-stand exercise was independently associated with FIM-cognitive at discharge, HG at discharge, and FIM-motor at discharge. The covariates selected for bias adjustment were age, sex, stroke type, FIM-motor, FIM-cognitive, CCI, MNA-SF, total number of drugs, and HG at baseline. These potential confounders were identified by discussion among the investigators and review of a previous study.36,37) Multicollinearity was assessed using the variance inflation factor (VIF): the VIF between 1 and 10 indicates no multicollinearity. All analyses were performed in IBM SPSS version 21 (IBM, Armonk, NY, USA); p-value <0.05 was considered statistically significant.
Ethics
The study was approved by the Institutional Review Board (ID: 218-230414) of the Kumamoto Rehabilitation Hospital, Japan. Participants were offered the opportunity to withdraw from the study at any time through an opt-out procedure. The study complied with the Ethical Guidelines for Medical and Health Research Involving Human Subjects, in accordance with the tenets of the Declaration of Helsinki of 1964 and subsequent amendments.
RESULTS
A total of 1,220 new stroke patients were admitted to the units during the study period. Patients with altered consciousness (n=32), BIA unsuitable (n=108), not adapted for chair-stand exercise (n=13), and missing data (n=257) were excluded from the analysis. After applying the exclusion criteria, 810 patients were assessed for sarcopenia at baseline, of whom 367 (45%) had sarcopenia. Of these, 273 (74%) were found to be cognitively impaired (FIM-cognitive score ≤23) by cognitive level assessment and were included in the subsequent analyses (Fig. 2).
Table 1 shows the baseline characteristics of participants stratified by frequency of chair-stand exercise. Of the total 273 patients, the mean age was 80±10 years, and 48% were male. The mean duration of the chair-stand exercise intervention was 111±45 days. The median frequency of chair-stand exercise among eligible patients was 43 (IQR 20–71), and this value was used as a cut-off value to stratify 140 patients into the high-frequency group and 133 into the low-frequency group. Univariate analysis of baseline patient characteristics showed that the high-frequency group had significantly higher age, percentage of male, BRS, FIM, MNA-SF, FILS, SMM, SMI, HG, albumin, energy intake, protein intake, and frequency of chair-stand exercise and significantly lower C-reactive protein than the low-frequency group.
Table 2 shows the results of the univariate analyses for outcomes between high- and low-frequency groups for the chair-stand exercise by sex. Univariate analysis showed that the high-frequency group had significantly higher FIM-cognitive, HG, and FIM-motor at discharge than the low-frequency group for each sex.
Table 3 shows the results of the multiple linear regression analysis. After adjusting for the effect of potential confounders, the frequency of chair-stand exercise was associated with FIM-cognitive at discharge (β=0.217, B [95% CI] 0.047 [0.023–0.070], p<0.001), HG and at discharge (β=0.146, B [95% CI] 0.041 [0.011–0.071], p=0.008) and FIM motor at discharge (β=0.295, B [95% CI] 0.203 [0.142–0.264], p<0.001). No multicollinearity was observed for any of the variables (VIF<10).
DISCUSSION
The aim of this study was to evaluate the effect of chair-stand exercise in post-acute stroke patients with decreased cognitive level and diagnosed sarcopenia. The analysis revealed three novel findings: (1) chair-stand exercise was positively associated with improvement in cognitive level, (2) chair-stand exercise was positively associated with improvement in muscle strength, and (3) chair-stand exercise was positively associated with improvement in ADL.
The first finding was that chair-stand exercise was significantly associated with improved cognitive level. To our knowledge, this is the first cohort study to evaluate the beneficial effects of a specific exercise program on cognitive level in patients with sarcopenia in a clinical rehabilitation setting. There are anecdotal reports that exercise intervention has improved cognitive decline after stroke38) and cognitive decline in older patients with sarcopenia.39) Sarcopenia has been associated with an increased prevalence of cognitive impairment, while brain-derived neurotrophic factors released by skeletal muscle contraction are involved in synaptic and structural connections.40) Possible mechanisms by which chair-stand exercise improved cognitive function in subjects include (1) improved neuroplasticity and brain health, (2) improved muscle function and physical performance, and (3) attenuation of sarcopenia and frailty. Active resistance training may have increased cerebral blood flow and promoted the secretion of growth factors such as BDNF and IGF-1 in the subjects.13) However, as reported in previous studies,12,13) neurotrophic factors such as BDNF and IGF-1 are influenced by exercise intensity. Whether low-intensity chair-stand exercises can sufficiently promote their secretion in post-stroke elderly individuals remains unclear, and further investigation is warranted. In addition, the effect of group training16,17) may have been effective in improving the cognitive level of the subjects. People who exercise with others have been shown to further improve attention, memory, visuospatial function, and overall cognitive function compared to those who exercise alone.41,42) In addition, compared to our previous study,22) which included a broader patient population, the present study specifically targeted individuals with cognitive impairment at admission. This difference in inclusion criteria likely contributed to the observed significant improvements in FIM-cognitive scores. These improvements may also have been influenced by other factors such as individualized rehabilitation or the natural course of recovery; therefore, future prospective studies are warranted to determine the independent contribution of chair-stand exercise. On the other hand, because this study included stroke patients, it was difficult to assess cognitive function in detail due to the effects of aphasia and higher brain dysfunction, so the cognitive level adapted to daily life was used as the outcome. Although cognitive screening tools such as the Mini-Mental State Examination and Montreal Cognitive Assessment are widely used in geriatric populations, they were not suitable for many of our patients due to impaired language and cognitive functions. Therefore, we relied on a clinical assessment of cognitive level reflecting the patient’s functional performance in daily activities, which was more feasible in this rehabilitation setting. A detailed analysis of how the changes in cognitive function of each patient affected the improvement in cognitive level is needed in the future.
The second finding was that chair-stand exercise was significantly associated with improved muscle strength. Resistance training provides the necessary stimuli to promote muscle hypertrophy through multiple signaling pathways.43,44) In addition, muscle contraction causes the release of myokines that affect these signaling pathways and thereby have a positive effect on muscle growth.45) On the other hand, studies in patients with sarcopenia have shown that muscle strength can be further improved by adding leucine-enriched protein to resistance training,46) making the combination of chair-stand exercise and nutritional intervention important in the treatment of sarcopenia.46) In accordance with the AWGS 2019 criteria28) and our previous study,22) HG was selected as the representative indicator of muscle strength. Quantitative assessments of lower limb strength were not uniformly performed in the study. However, as chair-stand exercises may improve lower limb strength, future studies should include objective measures of lower limb muscle function to explore potential mechanisms of cognitive improvement. Furthermore, future studies should clarify the detailed mechanisms by which chair-stand exercise contributes to improved muscle strength in patients with sarcopenia.
The third finding was that chair-stand exercise was significantly associated with improved ADL. Chair-stand exercise has been reported to be an effective exercise program for improving muscle strength and ADL in patients with physical disability.22,47) In addition, dysphagia in stroke patients is negatively associated with improved cognitive level and ADL.48) On the other hand, whole-body exercise, including chair-stand exercise, is effective in improving dysphagia,21,49) and furthermore, the improvement effect on cognitive level shown in this study may have contributed to the improvement of ADL in the subjects. Additionally, a recent narrative review emphasized that resistance exercise has the potential to improve cognitive function in older adults with sarcopenia, supporting the rationale for incorporating such interventions into rehabilitation programs.50) In this study, the amount of rehabilitation therapy provided per day was equivalent between the high and low frequency groups—median 8 (IQR 7–8) units/day in both groups; p=0.587. This suggests that the observed differences in ADL improvement were unlikely to be attributable to differences in the total rehabilitation dosage. However, due to the retrospective design of this study, potential differences in the quality or content of rehabilitation interventions could not be thoroughly evaluated, and further investigation is warranted. Furthermore, although we adjusted for baseline functional status using FIM scores at admission, we were unable to include standardized stroke severity scales such as the National Institutes of Health Stroke Scale or mRS in the analysis due to the unavailability of consistent data. As stroke severity may influence both exercise tolerance and recovery outcomes, further investigation incorporating these severity indices is warranted. In addition, this study included only patients who were able to participate in the chair-stand exercise program. Therefore, those with more severe strokes who could not tolerate the exercise were likely excluded from the analysis. This may limit the generalizability of our findings to post-stroke patients with relatively preserved mobility. In the future, it is expected that the effect of chair-stand exercise on ADL in stroke patients with sarcopenia will be analyzed in detail by high-quality prospective studies.
This present study had some limitations. First, the study was conducted in a single rehabilitation hospital in Japan, which limits the generalizability of the results. Future multicenter studies are needed to clarify whether similar results can be obtained in different populations. Second, because of the retrospective study design, we were unable to obtain detailed information on whether the quality and quantity of rehabilitation for cognitive impairment during hospitalization, as well as the type and duration of prescribed medications, affected outcomes. Furthermore, the influence of cognitive medications cannot be ruled out. However, due to considerable variability in drug types, timing, dosages, and administration periods among individuals, these medications could not be included as covariates in this analysis. Future prospective studies should systematically examine the potential impact of such medications. Third, because of the observational study design, causal relationships cannot be determined. Future high-quality prospective and interventional studies are needed to adjust for these confounding factors.
In conclusion, the results suggest that group chair-stand exercise may have a positive effect on improving cognitive level, muscle strength, and ADL in sarcopenic stroke patients with decreased cognitive level. The results of this study suggest that, in addition to conventional rehabilitation, active chair-stand exercise in conjunction with sarcopenia treatment may lead to a good prognosis in stroke patients.
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