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CROSS-SECTIONAL ASSOCIATIONS OF SARCOPENIA AND ITS COMPONENTS WITH NEUROPSYCHOLOGICAL PERFORMANCE AMONG MEMORY CLINIC PATIENTS WITH MILD COGNITIVE IMPAIRMENT AND ALZHEIMER’S DISEASE

 

T. Sugimoto1,2, Y. Kuroda1, N. Matsumoto2, K. Uchida2,3, Y. Kishino2,4, N. Saji2, S. Niida5, T. Sakurai1,2,4

 

1. Department of Prevention and Care Science, Research Institute, National Center for Geriatrics and Gerontology, Obu, Japan; 2. Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, Obu, Japan; 3. Department of Public Health, Graduate School of Health Sciences, Kobe University, Kobe, Hyogo, Japan; 4. Department of Cognition and Behavior Science, Nagoya University Graduate School of Medicine, Nagoya, Japan; 5. Research Institute, National Center for Geriatrics and Gerontology, Obu, Japan

Corresponding Author: Taiki Sugimoto, 7-430 Morioka, Obu, Aichi, 474-8511, Japan. Tel.: +81 562 46 2311; Fax: +81 562 46 8394; E-mail: taiki-s@ncgg.go.jp.

J Frailty Aging 2022;in press
Published online January 4, 2022, http://dx.doi.org/10.14283/jfa.2022.3

 


Abstract

Background: The association of sarcopenia with cognitive function in its specific domains remains poorly understood.
Objectives: To investigate the association of sarcopenia and its components with neuropsychological performance among patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD).
Design: Cross-sectional design.
Setting: A memory clinic in Japan.
Participants: The study included 497 MCI/684 AD patients aged 65-89 years.
Measurements: Patients were assessed for muscle mass by bioelectrical impedance analysis, muscle strength by hand grip strength (HGS), and physical performance by timed up and go test (TUG). Sarcopenia was defined as presence of both low muscle strength and low muscle mass. The patients underwent neuropsychological tests, including logical memory, frontal lobe assessment battery, word fluency test, Raven’s colored progressive matrices, digit span, and the Alzheimer’s disease assessment scale-cognitive subscale (ADAS-cog).
Results: The prevalence of sarcopenia in men and women was 24.1% and 19.5%, respectively. In multiple regression analyses adjusting for confounders, unlike in men, sarcopenia was associated with memory function in women (ADAS-cog, memory domain, coefficient = 1.08, standard error (SE) = 0.36), which was thought likely due to the relationship between HGS and memory function (immediate recall of logical memory, coefficient = 0.07, SE = 0.03; ADAS-cog, memory domain, coefficient = -0.10, SE = 0.03). Of the components of sarcopenia in both sexes, HGS and TUG were associated with visuospatial function and frontal lobe function, respectively.
Conclusions: The specific association of sarcopenia and its components with cognitive domains may provide the key to elucidating the muscle-brain interactions in AD.

Key words: Sarcopenia, muscle strength, muscle mass, mild cognitive impairment, dementia.


 

Introduction

With the average life expectancy increasing globally, sarcopenia and cognitive impairment now represent two of the four modern “giants of geriatrics”, alongside frailty and anorexia of aging (1). Sarcopenia is characterized by a progressive and generalized loss of skeletal muscle mass and strength with age, which is associated with increased risk of adverse health outcomes including falls, fractures, physical disability, and mortality (2). In this past decade, attention has been drawn to the association of sarcopenia with cognitive impairment, with a recent meta-analysis of 15 studies reporting that older adults with sarcopenia are at almost twice as likely to have cognitive impairment as those without sarcopenia (3). Additionally, this significant association was shown to be consistent across study populations and regions, and the definitions of sarcopenia and cognitive impairment (3).
Alzheimer’s disease (AD) is a growing health issue and the most common cause of dementia worldwide (4). In our previous study, patients with mild cognitive impairment (MCI) and AD had a higher prevalence of sarcopenia than those with normal cognition (5). Similarly, Ogawa et al. demonstrated that patients with AD or even early-stage AD showed a higher prevalence of sarcopenia than age-matched cognitive normal patients (6). Physical performance, e.g., gait performance, muscle strength, and balance function, is also shown to be decreased from an early stage of AD and worsen with disease progression (6-8). Although these results indicate a close association of sarcopenia with cognitive impairment, i.e., muscle-brain interactions in AD, their underlying mechanism still remains unclear.
To date, many studies have investigated the association of sarcopenia with global cognitive function and/or presence of MCI/dementia, the cognitive patterns of sarcopenia (i.e., association of sarcopenia with cognitive function in specific domains) have not been fully elucidated (9). A cross-sectional study of 5,038 participants from the ELSA-Brasil Study showed that sarcopenia was associated with poorer performance on the phonemic verbal fluency test which assessed language and executive learning (10). The I-Lan Longitudinal Aging Study involving 731 community-dwelling older adults showed that sarcopenia was associated with verbal fluency test, while dynapenia (i.e., weakness or slowness) was associated with multiple dimensions of cognitive function (11). The nationwide Korean Frailty and Aging Cohort Study showed that sarcopenia was associated with processing speed and executive function in older men (12). Although these studies seem to indicate a close association between sarcopenia and frontal lobe function, there is a paucity of supportive evidence.
Therefore, the aim of this study was to investigate the association of sarcopenia and its components (i.e., muscle mass, muscle strength and gait performance) with neuropsychological performance among memory clinic patients with MCI and AD. Identifying cognitive patterns of sarcopenia in AD may deepen our understanding of the muscle-brain interactions involved.

 

Methods

Design, setting, and participants

This cross-sectional study included outpatients who met the following inclusion criteria: 1) patients who presented to the Memory Clinic at the National Center for Geriatrics and Gerontology (NCGG) of Japan during the period from November 2010 to July 2017; 2) those aged 65-89 years at presentation; 3) those clinically diagnosed with MCI or possible or probable AD according to the criteria of the National Institute on Aging-Alzheimer’s Association (NIA/AA) workgroups (13, 14); 4) those with MCI or AD with a Mini-Mental State Examination (MMSE) score of 21–30 or 11-30 (15); 5) those who completed a comprehensive geriatric assessment (CGA) including physical performance (hand grip strength (HGS), timed up and go test (TUG)) and bioelectrical impedance analysis (BIA); 6) those who completed at least one of neuropsychological tests. The local Ethics Committee of the NCGG approved the study protocol (approval number: No.1400). The purpose, nature, and potential risks of the study were fully explained to the participants, and all participants gave written informed consent before participating in the study.

Definition of Sarcopenia

Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2)-suggested diagnostic flow (2). Low muscle strength was defined as low HGS measured with a digital force gauge (ZP-500N; Imada, Toyohashi, Japan) (16). Low HGS was defined as < 18 kg in women and < 28 kg in men, as suggested by the Asian Working Group for Sarcopenia (AWGS) (17). Low muscle mass was defined as low skeletal muscle mass index (SMI). Appendicular muscle mass (AMM) was measured by BIA using a Tanita body composition analyzer (MC-180; Tanita Corp., Tokyo, Japan). SMI was calculated as AMM divided by height squared (kg/m2). Low SMI was defined as SMI < 5.7 kg/m2 in women and < 7.0 kg/m2 in men (17). TUG was assessed as a measure of physical performance, with a TUG of 20.0 seconds or longer defined as low physical performance (2). According to the categorization suggested by the EWGSOP2 (2), patients with low muscle strength alone were defined as having probable sarcopenia. Sarcopenia was defined as simultaneous presence of low muscle strength and low muscle mass, and those who had low muscle strength, low muscle mass, and low physical performance simultaneously were considered to represent severe sarcopenia.

Neuropsychological assessment

Neuropsychological assessments were performed by trained clinical psychologists.

Logical memory Ⅰ and Ⅱ subset of the Wechsler Memory Scale-Revised

Verbal memory function was assessed using the logical memory (LM) Ⅰ and Ⅱ subsets of the Wechsler Memory Scale-Revised (18). In this test, two short stories were read to the participants to ask the participants to recall immediately (LM Ⅰ) and after 30 minutes (LM Ⅱ). Patients were scored for each story on a scale of 0 to 25, with the total score calculated by the sums of the two stories (0-50) in LM Ⅰ and Ⅱ.

Frontal assessment battery

Frontal lobe function was assessed by the frontal assessment battery (FAB) consisting of six subtests (conceptualization, mental flexibility, programming, sensitivity to interference, inhibitory control, and environmental autonomy) (19). Each subtest is scored from 0 to 3 and a higher total score (0-18) indicates better frontal lobe function. In statistical analyses, total FAB scores were used.

Category word fluency subset of the Hasegawa dementia scale-revised

The category word fluency test (CWFT) of the Hasegawa dementia scale-revised (20) was also used to assess frontal lobe function, especially executive function and language, where participants were asked to list as many vegetables as possible within one minute. The score was assigned according to the number of different words listed: 0-5 vegetables, 0 point; 6-10 or more, 1-5 points.

Raven’s Colored Progressive Matrices

Visuospatial function and reasoning ability were assessed using the Raven’s Colored Progressive Matrices (RCPM) (21) consisting of three 12-item subtests (A, AB, and B), where subtest A focuses on the concepts of difference, similarity, and identity; subtest AB assesses inferences about the orientation of pattern pieces; and subtest B emphasizes logical and spatial abilities. Total RCPM scores range from 0 to 36, with lower scores indicating impaired cognitive function. Total scores were used for statistical analyses.

Digit span forward and backward subtests of the Wechsler Adult Intelligence Scale-Ⅲ

Working memory and attention were assessed using the digit span forward and backward subsets of the Wechsler Adult Intelligence Scale-Ⅲ (WAIS-Ⅲ) (22), and their raw scores were used for statistical analyses.

Alzheimer’s Disease Assessment Scale-cognitive subscale

Global cognitive function was assessed using the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) (23), i.e., 11 tasks assessing the cognitive domains of memory (word recall, orientation, word recognition, remembering test instruction), language (spoken language ability, word finding difficulty, following commands, naming objects and fingers), and praxis (constructional and ideational praxis). A higher total score (0-70) indicates lower cognitive performance. In statistical analyses, total ADAS-cog and domain scores (memory (0-35), language (0-25), praxis (0-10)) were used.

Other variables

Information about the participants’ age, sex, education, smoking status (current smoker or not), alcohol consumption (drinking daily or not), physical activity (physical inactivity defined as those who did not engage in physical exercise at least once a week), body mass index (BMI) and comorbidities (diabetes mellitus, hypertension, dyslipidemia, overweight (BMI ≥ 25)) was obtained from their clinical charts. The basic activities of daily living, global cognitive function, and depressive mood were also assessed using the Barthel Index (24), MMSE (15), and the self-rated 15-item Geriatric Depression Scale (GDS-15) (25), respectively.

Statistical analysis

Given the sex differences in muscle profile, all analyses were performed by sex. Differences in demographic and clinical profiles between those with and without sarcopenia as well as between the sexes were examined using the Kruskal-Wallis test and χ2 test.
To clarify the association of sarcopenia with neuropsychological function, univariate and multivariate linear regression analyses were performed with sarcopenia as an independent variable. The total score or domain score for each neuropsychological test was entered as a dependent variable. Demographic data including age and education and confounding factors (smoking status, alcohol consumption, physical activity, comorbidities, and GDS-15) were forced into the multivariate analyses simultaneously. In addition, the Barthel index and MMSE were also entered as covariates to adjust for severity of dementia. The number of participants included in univariate and multivariate analyses ranged from 397 to 427 and 674 to 752 in men and women, respectively, due to missing data for neuropsychological tests resulting from their inability to complete tests and/or lack of time to do so in a clinical practice setting.
Moreover, to clarify which component of sarcopenia was associated with neuropsychological tests, univariate and multivariate linear regression models were also conducted with SMI, HGS, and TUG measured as continuous variables and entered as independent variables.
All statistical analyses were performed using STATA 14.2 (Stata Corp., College Station, Texas, USA). P-values < 0.05 were considered statistically significant.

 

Results

A total of 8,962 patients visited the memory clinic at the NCGG from September 2010 to November 2017. Of these, 8,013 patients were 65–89 years of age, and among them, 4,196 patients were diagnosed with MCI (n = 1,368) or AD (n = 2,828). Furthermore, 143 MCI patients with MMSE scores of < 21 and 194 AD patients with MMSE scores of < 11 were excluded. The patients who did not complete the CGA, including assessments of sarcopenia (n = 2,052) and all neuropsychological tests (n = 626), were also excluded. Thus, a total of 1,181 patients (497 MCI and 684 AD patients) were included in the analyses. A flowchart of patient selection is shown in supplementary figure 1.
The 1,181 participants had a mean age of 77.7 ± 5.6 years, and 753 (63.8%) were women. The prevalence of sarcopenia in men and women was 24.1% and 19.5%, respectively, and was higher in those with AD than in those with MCI (men/women: MCI, 17.5%/12.7%; AD, 30.2%/23.8%) (Figure 1). Severe sarcopenia was also highly prevalent among those with AD (men/women, 5.9%/3.7%) than among those with MCI (men/women, 0.5%/1.0%). The sex differences in demographic and clinical characteristics are summarized in supplementary table 1. Notably, women were more likely to be diagnosed with AD (men/women, 51.9%/61.4%) and to have lower scores for almost all neuropsychological tests conducted, except for the CWFT.

Figure 1. Prevalence of sarcopenia according to cognitive status by sex

Percentages are rounded off to one decimal point. * Prevalence of severe sarcopenia. AD, Alzheimer’s disease; MCI, mild cognitive impairment

 

Clinical characteristics of participants with and without sarcopenia

Table 1 shows the clinical characteristics of the participants with and without sarcopenia. Regardless of sex, the participants with sarcopenia were more likely to be older and clinically diagnosed with dementia, and to have lower BMI, Barthel index and MMSE scores. Moreover, there were also differences in education and drinking status among men, as well as in GDS-15 among women.

Table 1. Characteristics of participants with and without sarcopenia (n = 1181)

Note. Data are rounded off to one decimal place; AD, Alzheimer’s disease; BMI, body mass index; GDS, geriatric depression scale; HGS, hand grip strength; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; SD, standard deviation; SMI, skeletal muscle mass index; TUG, timed up and go test

 

Neuropsychological profile of participants with and without sarcopenia

Table 2 shows the neuropsychological profile of the participants with and without sarcopenia. The participants with sarcopenia showed lower scores for almost all neuropsychological tests conducted, except for the digit span forward among men, and the RCPM and the digit span forward and backward among women.

Table 2. Neuropsychological characteristics of participants with and without sarcopenia (n = 1181)

Note. Data are rounded off to one decimal point; ADAS-cog, Alzheimer’s disease assessment scale-cognitive subscale; CWFT, category word fluency test; FAB, frontal assessment battery; RCPM, Raven’s colored progressive matrices

 

Association of sarcopenia, SMI, HGS and TUG with neuropsychological test

Table 3 shows the results of the linear regression analyses in men. Sarcopenia was significantly associated with lower performance in the LM Ⅰ, the FAB, the CWFT, the RCPM, the digit span backward, and the ADAS-cog in the non-adjusted model, while the adjusted model demonstrated no significant association between sarcopenia and any of the neuropsychological tests conducted. Of the components of sarcopenia, higher SMI was associated with higher performance in several tests in univariate analyses, while there was no association shown in the adjusted model. Higher HGS and slower TUG were shown to be associated with higher and lower performance in all neuropsychological tests in univariate analyses. In the adjusted model, however, HGS and TUG were shown to be only associated with the RCPM and the CWFT, respectively.

Table 3. Association of sarcopenia, hand grip strength, SMI, and TUG with neuropsychological function in men (n = 428) in linear regression analyses

Note. Data are presented as coefficient (standard error) and rounded off to two decimal points; Adjusted model: Adjusted for age, education, MMSE, Barthel Index, GDS-15, alcohol consumption, smoking status, inactivity, diabetes, hypertension, dyslipidemia, and overweight; * P < 0.05; † P < 0.01; ‡ P < 0.001; ADAS-cog, Alzheimer’s disease assessment scale-cognitive subscale; CWFT, category word fluency test; FAB, frontal assessment battery; GDS, geriatric depression scale; HGS, hand grip strength; MMSE, Mini-Mental State Examination; RCPM, Raven’s colored progressive matrices; SMI, skeletal muscle mass index; TUG, timed up and go test

 

Table 4 shows the results of the linear regression analyses in women. In univariate analyses, sarcopenia was shown to be significantly associated with lower performance in the LM Ⅰ and Ⅱ, the FAB, the CWFT, and the ADAS-cog. The adjusted model demonstrated a significant association between sarcopenia and ADAS-cog, especially memory domain. Of the components of sarcopenia, higher HGS was shown to be associated with higher performance in the LM Ⅰ, the RCPM and the ADAS-cog (all domains) in the adjusted model. Higher SMI was shown to be associated with higher performance in LM Ⅰ and Ⅱ and the CWFT in univariate analyses, and the association between sarcopenia and the CWFT remained significant in the adjusted model. Slower TUG was shown to be associated with lower performance in all neuropsychological tests in univariate analyses, while TUG was shown to be significantly associated with the FAB and the CWFT in multivariate analyses.

Table 4. Association of sarcopenia, hand grip strength, SMI, and TUG with neuropsychological function in women (n = 753) in linear regression analyses

Note. Data are presented as coefficient (standard error) and rounded off to two decimal places; Adjusted model: Adjusted for age, education, MMSE, Barthel Index, GDS-15, alcohol consumption, smoking status, inactivity, diabetes, hypertension, dyslipidemia, and overweight; * P < 0.05; † P < 0.01; ‡ P < 0.001; ADAS-cog, Alzheimer’s disease assessment scale-cognitive subscale; CWFT, category word fluency test; FAB, frontal assessment battery; GDS, geriatric depression scale; HGS, hand grip strength; MMSE, Mini-Mental State Examination; RCPM, Raven’s colored progressive matrices; SMI, skeletal muscle mass index; TUG, timed up and go test

 

Discussion

The present study investigated the cross-sectional association of sarcopenia and its components with neuropsychological functions among the memory clinic patients with MCI and AD. In men, HGS and TUG were associated with RCPM and CWFT scores, respectively, although sarcopenia was not associated with any cognitive domains. In women, sarcopenia was associated with ADAS-cog scores, especially memory domain. HGS was associated with several neuropsychological tests, which included the LM Ⅰ, the RCPM, and the ADAS-cog (all domains). SMI and TUG were associated with the frontal lobe function as assessed by the CWFT and the FAB.
Sarcopenia was associated with ADAS-cog, especially with memory domain, in women alone. This significant association may be mainly due to the relationship between HGS and memory function, given that HGS was also associated with LM Ⅰ and memory domain of ADAS-cog in women alone. To date, HGS has been reported to be associated with several cognitive domains including memory function (26). Additionally, Moon et al. reported that muscle strength as assessed with an isokinetic knee extensor was related to hippocampal atrophy, which is closely associated with memory deficits, in 28 probable AD (27). Our results supported these findings in a larger number of MCI and AD patients, although a systematic review article showed that the association of muscle strength with brain regional atrophy was inconclusive (28).
Besides the significant association of sarcopenia and HGS with memory function, women demonstrated an association between SMI and the CWFT, although men did not. A meta-analysis of seven studies, of which five studies focused on community-dwelling older adults, concluded that the significant association of sarcopenia with cognitive impairment was independent of several confounding factors including sex (29). Sex differences in our results might be due to differences in clinical characteristics, especially in neuropsychological tests. Indeed, women were more likely to be diagnosed with dementia and have lower scores for almost all neuropsychological tests compared to men (supplementary table 1). Additionally, a previous study using nearly 1,500 postmortem data demonstrated that women had higher levels of AD pathology, especially tau tangles, compared to men after adjustment for age and education (30). Given that these AD pathologies are also associated with components of frailty and sarcopenia, i.e., grip strength and gait performance (31, 32), sex differences in pathological features, as well as in cognition, may also contribute to differences in the association of sarcopenia with cognition, but remains a matter of speculation. Further studies investigating the relevance of AD pathologies, cognition, and sarcopenia by sex may deepen our understanding of the muscle-brain interactions in AD.
As expected in both sexes, TUG was associated with the CWFT, which is thought to be a measure of executive function and language. In women, TUG was also associated with the FAB. The association of gait performance and frontal lobe function, especially attention and executive function, has been widely established (33, 34). Our findings were not only consistent with these previous findings but showed that they applied to memory clinic populations with MCI and AD. Cognitive and gait dysfunction may have common underlying pathophysiological mechanisms and brain pathologies. In fact, white matter hyperintensities especially in the frontal lobe, which are found in cerebral small vessel disease and increased in AD, have a critical effect on gait performance (35), and this effect might be mediated by executive function (36). Additionally, accumulation of beta amyloid as well as reduced gray and white matter volumes have been involved in common pathologies of gait and cognitive dysfunction (32, 34, 37).
Regardless of sex, HGS was associated with the RCPM, which is widely used to evaluate visuospatial function and reasoning ability. Visuospatial function is considered to rely on parietal lobe function and structure, which are reported to be damaged in early-stage AD (38, 39). A recent study also demonstrated that sarcopenia was independently associated with parietal atrophy in older adults (40), although, again, the association of muscle health and with brain regional atrophy remains still inconclusive (28). Collectively, AD-related functional and structural changes in parietal lobe could be a common underlying mechanism responsible for declines in HGS and visuospatial function among AD patients. Although our study highlighted the association of HGS and visuospatial function, HGS was shown to be associated with frontal lobe functions, such as information processing speed and executive function in a previous study involving 309 memory clinic patients with subjective cognitive decline and MCI (41). Our present study may suffer from lack of measurements of processing speed and executive function, such as the Letter Digit Substitution Test, the Stroop Color Word Test, and the Trail Making Test, thus resulting in inconsistent results, and further studies involving comprehensive psychological tests are needed.
The current study showed that specific components of sarcopenia, namely hand grip strength and gait performance, rather than muscle mass, were especially associated with neuropsychological performance. These results seem to support the concept of “physio-cognitive decline syndrome (PCDS),” defined as the simultaneous presence of cognitive impairment in any domain and physical decline (weakness or slowness, i.e., dynapenia) among older adults without dementia (42). The results extend the notion of a close association of dynapenia and cognitive performance in older adults with MCI and AD. PCDS is based on the evidence that dynapenia is associated with cognitive decline and reduced gray matter volume in several regions (43-46). Liu et al. in 2020 conducted a study among 1,196 community-dwelling adults aged 50 years or older and demonstrated that PCDS was associated with lower gray matter volume in the bilateral amygdala and thalamus, right hippocampus, right temporo-occipital cortex, and left cerebellum VI and V regions, as well as disrupted hippocampus-amygdala-cerebellum connections (47). These neuroanatomical changes may reflect the pathophysiological processes associated with physical and cognitive decline. Further studies investigating the mechanisms underlying the close associations between physical and cognitive declines in MCI and AD using multimodal brain imaging and dementia-related biomarkers are needed.
This present study has several limitations. First, since our study was a cross-sectional study, the temporal association of sarcopenia and its components with neuropsychological performance remains unclear. Second, given the focus on outpatients presenting to the Memory Clinic, the study results may not be readily generalizable to other populations. Third, we were unable to obtain biomarker information for AD pathology or other pathologies that ensures a reliable diagnosis of dementia. Moreover, this study did not involve brain imaging analysis, which could clarify specific neuroimaging patterns related to the association of sarcopenia and its components with neuropsychological performance.
Despite these limitations, however, the present study is the first to demonstrate a significant association of sarcopenia and its components with neuropsychological functions among memory clinic patients with MCI and AD.
In conclusion, sarcopenia was associated with memory function in women with MCI and AD, but not in men, and this might be due to the association of HGS with memory function in women. In both sexes, muscle strength and gait performance were associated with visuospatial function and frontal lobe functions, respectively. These specific associations may help elucidate the muscle-brain interactions in AD. Further studies are needed to investigate the relevance of AD-related biomarkers (brain images, neurodegenerative pathologies), cognition, and sarcopenia.

 

Funding: This work was supported by funds from the Research Funding for Longevity Sciences (grant number 21-28) from the National Center for Geriatrics and Gerontology. The funders had no role in study design, methods, data collection/analysis, and preparation of this manuscript.

Acknowledgments: The authors thank the BioBank at the National Center for Geriatrics and Gerontology for the quality control of the clinical data.

Conflict of Interest: None.

Ethical standards: The local Ethics Committee of the National Center for Geriatrics and Gerontology approved the study (approval number: No.1400).

Author Contributions: T.Su. designed the analysis and study design, organized data, and wrote the manuscript. T.Sa. designed the analysis and study design, contributed statistical support, and reviewed/edited the manuscript. Y.Ku., N.M., K.U., S.N. reviewed/edited the manuscript and contributed to the discussion. Y.Ki., N.S., T.Sa. ascertained patients and follow them, collected data, reviewed/edited the manuscript, and contributed to the discussion. T.Su. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

 

SUPPLEMENTARY MATERIAL1

SUPPLEMENTARY MATERIAL2

 

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