Sarcopenic Obesity Tendency and Nutritional Status Is Related to the Risk of Sarcopenia, Frailty, Depression and Quality of Life in Patients with Dementia

The purpose of this study was to investigate the nutritional status of dementia patients and examine the correlation with sarcopenia, frailty, depression, and quality of life. We enrolled patients aged 60 years and over with Mini Mental State Examination (MMSE) scores ≤ 26 (Taiwan), and dementia diagnosed by a neurologist or psychiatrist. Nutritional status was assessed with the Mini Nutritional Assessment (MNA). Muscle mass was measured by dual-energy X-ray absorptiometry. Muscle strength and endurance were evaluated by handgrip, leg-back strength, dumbbell curls, sit to stand test, and gait speed. Quality of life, frailty, and depression status were measured by questionnaires. Patients with moderate dementia (MMSE ≤ 20) had a significantly lower MNA score, muscle function, and quality of life than patients with mild dementia (p < 0.01). A lower MNA score was significantly associated with the risk of frailty (odds ratio: 4.76, p < 0.01), depression (odds ratio: 3.17, p = 0.03), and poor quality of life (odds ratio: 2.73, p < 0.05), and sarcopenia (odds ratio: 3.97, p = 0.03) after adjusting for potential confounders. In conclusion, patients with dementia were at risk of malnutrition, and nutritional status was associated to the risk of sarcopenia, frailty, depression, and quality of life.


Introduction
The number of deaths from dementia has increased globally. The latest report of the World Health Organization (WHO) indicates that dementia was ranked as the 7th leading cause of death in 2019 [1]. Aging is one of the risk factors for dementia [2]. Throughout Asia, societies have aged, including in Taiwan. A report from Lin and Huang [3] indicated that the aging rate in Taiwan is more than twice that in European countries and the United States, and the number of people with dementia is increasing in Taiwan. According to the report from Taiwan Alzheimer Disease Association indicated that the prevalence of dementia in Taiwanese who aged ≥65 years is 7.71%, which means about 1 in 12 people over the age of 65 have dementia, and about 1 in 5 people who aged ≥80 [4].
Dementia is a term used for a group of symptoms with deterioration in cognition, memory, thinking, emotion, and the ability to perform daily activities [5]. Dementia may total cholesterol, were measured by an automated chemistry analyzer (Roche, Cobas c501, Rotkreuz, Switzerland).

Nutritional Status, Frailty, Depression and Quality of Life Measurements
The Mini Nutritional Assessment (MNA) was used to estimate the nutritional status of subjects. The MNA questionnaire consisted of 18 questions, including appetite, weight loss, mobility, physical and mental status, and dietary intake. The maximum total score of the screening tool is 30, and a score lower than 24 indicates malnutrition or risk of malnutrition [24]. Frailty was evaluated by the Study of Osteoporotic Fractures (SOF) questionnaire [25]. The SOF questionnaire consisted of 3 domains, including frailty, falls, and depression assessment (6 questions). A higher score of the SOF indicated the poor frailty status. The Geriatric Depression Scale [26] was used to assess the depression level. Higher score of geriatric depression indicate that subjects suffer from depression. The Quality of Life in Alzheimer's Disease scale was used to assess subjects' quality of life [27]. A higher quality of life score on the Alzheimer's Disease scale represents a better quality of life. All questionnaires were performed by the research assistant from asked the subjects or their caregiver.

Muscle Strength and Endurance Assessments
Tests of handgrip and leg-back strength were used to evaluate the upper and lower limb muscle strength, respectively. Handgrip strength was assessed by a handgrip dynamometer (TAKEI, TKK-5401, Niigata, Japan). Subjects were instructed to squeeze the device with the dominant hand as hard as they could. Leg-back strength was assessed by a back dynamometer (TAKEI, TKK-5402, Niigata, Japan). For the test, subjects stood on the base of the back dynamometer; knees and hips flexed slightly while the lower back was maintained upright, and grasped a bar attached to a chain and dynamometer. Then, subjects were asked to lift up the bar with maximal effort. Two measurements were taken with handgrip and leg-back strength tests, and the maximum measurement value was recorded for the analysis.
The dumbbell curls, sit to stand test, and gait speed were used to assess the upper and lower limb muscle endurance according to the Senior Fitness Test Manual [28]. Subjects were asked to flex and extend the elbow with their dominant hand holding an 8 lb dumbbell (for male patients) or a 5 lb dumbbell (for female patients). The number of repetitions of dumbbell curls in 30 s was recorded. For the assessment of the sit to stand test, subjects were instructed to stand from a chair and then return to the sitting position five times. In addition, the physical performance of subjects was assessed by the Short Physical Performance Battery (SPPB), which included a balance test, gait speed test, and chair-stand test [29]. Sarcopenia and its diagnostic components were defined according to the Asian Working Group for Sarcopenia [30], including the value of CC < 34 cm for males or <33 cm for females defined as low CC, the value of ASMI < 7.0 kg/m 2 for males or <5.4 kg/m 2 for females defined as low ASMI, the handgrip strength <28 kg for males or <18 kg for females defined as low handgrip, five-time sit to stand test ≥12 s defined as poor sit to stand test, the gait speed <1.0 m/s defined as low gait speed, and the SPPB score ≤9 defined as low SPPB. Sarcopenic obesity was defined as the subject meets the diagnosis of sarcopenia and obesity (body fat percentage ≥25% for males or ≥30% for females).

Statistical Analyses
SigmaPlot software (version 12.0, SYSTAT, San Jose, CA, USA) was used to examine all statistical tests in the present study. The descriptive statistics are presented as the means ± standard deviation (medians) or numbers of participants (percentages). We used the Shapiro-Wilk test to examine the normality of the distribution of the data. The independent t-test or Mann-Whitney rank sum test was used to compare the difference in continuous variables between the mild dementia and moderate dementia groups. A chi-square test or Fisher's exact test was used to examine the difference in categorical variables between the mild dementia and moderate dementia groups. The correlations between nutritional status, frailty, depression, quality of life, and muscle function were examined by Pearson correlation (a parametric test) or Spearman's rank order correlation (a non-parametric test) coefficient based on the normal or non-normal distribution of the data. Multiple logistic regression was used to examine the associations between MNA scores and frailty, depression, quality of life, and sarcopenia after adjusting for age, gender, and exercise habit. The logistic regression model's goodness of fit was evaluated by the value of Hosmer-Lemeshow test and calculate Nagelkerke R 2 value, which was examined by using IBM SPSS Statistics for Windows (version 20.0, Armonk, New York, NY, USA). The statistical significance level was set at a p value < 0.05.

Characteristics of Patients
The mean age of the participants was 76.5 ± 6.3 years, and the proportion of females was 72.5%. Table 1 shows the data on patient characteristics stratified by dementia severity. The patients with moderate dementia had significantly lower MMSE scores (p < 0.01); however, there was no significant difference in age, sex, blood pressure, biochemical data, education level, tobacco use, alcohol use, or exercise habits between patients with mild dementia and patients with moderate dementia. Although there was no significant difference in anthropometric data between the mild and moderate dementia groups, the values for waist circumferences in both genders and body fat percentage in females were higher than the reference values (waist, male < 90 cm, female < 80 cm; body fat, female < 30%). Additionally, there was a higher proportion of obesity in the moderate dementia group than in the mild dementia group (p = 0.09), which was slightly significant. Data was presented as means ± SD (medians). 1 A body fat percentage ≥25% in males and ≥30% in females. 2 Exercise habit was defined as patients with regular exercise at least 3 times a week. BMI, body mass index; DBP, diastolic blood pressure; GPT, glutamic pyruvic transaminase; SBP, systolic blood pressure. Table 2 shows the scores for nutritional status, frailty, depression, and quality of life of patients with dementia. Patients with moderate dementia had a significantly lower MNA score (p < 0.01) and quality of life (p < 0.01) than those with mild dementia. In addition, the proportion of malnutrition (MNA < 24 points, p = 0.02) was higher in the patients with moderate dementia than in those with mild dementia. Regarding muscle mass, strength, and endurance, patients with moderate dementia had significantly lower values of CC (p < 0.01), whole body muscle mass (p = 0.01), ASMI (p = 0.01), handgrip strength (p < 0.01), dumbbell curls (p = 0.04), leg-back strength (p = 0.02), and SPPB (p = 0.02) than those with mild dementia.   Figure 1 shows the proportion of sarcopenia components in patients with dementia. Patients with moderate dementia had a significantly higher proportion of poor sit-to-stand test results (55.0% vs. 42.5%, p = 0.04) and low SPPB scores (72.5% vs. 47.5%, p = 0.04) than patients with mild dementia. The proportion of low handgrip strength (75.0% vs. 52.5%, p = 0.06) and low CC (65.0% vs. 42.5%, p = 0.07) was slightly higher in the patients with moderate dementia than in those with mild dementia.  Figure 1 shows the proportion of sarcopenia components in patients with dementia. Patients with moderate dementia had a significantly higher proportion of poor sit-tostand test results (55.0% vs. 42.5%, p = 0.04) and low SPPB scores (72.5% vs. 47.5%, p = 0.04) than patients with mild dementia. The proportion of low handgrip strength (75.0% vs. 52.5%, p = 0.06) and low CC (65.0% vs. 42.5%, p = 0.07) was slightly higher in the patients with moderate dementia than in those with mild dementia.   4 Five-time sit to stand test ≥12 s. 5 The gait speed <1.0 m/s. 6 The SPPB score ≤9. *, p < 0.05; †, p = 0.06; ‡, p = 0.07. ASMI, appendicular skeletal muscle mass index; CC, calf circumference; SPPB, short physical performance battery.

Correlations between Nutrition Status and the Severity of Dementia, Frailty, Depression and Quality of Life
The correlations between MNA score and the severity of dementia, frailty, depression, and quality of life in patients with dementia are shown in Figure 2. The MNA score was significantly positively correlated with the MMSE (r = 0.42; p < 0.01) and quality of life (r = 0.44; p < 0.01) and significantly negatively correlated with frailty (r = −0.35; p < 0.01) and depression (r = −0.42; p < 0.01).

and Quality of Life
The correlations between MNA score and the severity of dementia, frailty, depression, and quality of life in patients with dementia are shown in Figure 2. The MNA score was significantly positively correlated with the MMSE (r = 0.42; p < 0.01) and quality of life (r = 0.44; p < 0.01) and significantly negatively correlated with frailty (r = −0.35; p < 0.01) and depression (r = −0.42; p < 0.01).  Table 3 shows the correlations between MNA score, frailty, depression, quality of life and muscle mass, strength, and endurance in patients with dementia. The MNA score was significantly positively correlated with muscle mass, muscle strength (handgrip strength), and endurance (dumbbell curls and gait speed) (p < 0.05). The frailty score was significantly correlated with muscle strength and endurance (p < 0.05). The depression and quality of life scores were significantly correlated with muscle endurance (p < 0.05).

MNA Score
Frailty Score Depression Score Quality of Life Score  Table 3 shows the correlations between MNA score, frailty, depression, quality of life and muscle mass, strength, and endurance in patients with dementia. The MNA score was significantly positively correlated with muscle mass, muscle strength (handgrip strength), and endurance (dumbbell curls and gait speed) (p < 0.05). The frailty score was significantly correlated with muscle strength and endurance (p < 0.05). The depression and quality of life scores were significantly correlated with muscle endurance (p < 0.05).   Table 4 examines the associations between nutritional status and frailty, depression, quality of life, and sarcopenia. Patients with a lower MNA score were significantly associated with increased risk of frailty (odds ratio: 4.76, p < 0.01), depression (odds ratio: 3.17, p = 0.03), poor quality of life (odds ratio: 2.73, p < 0.05), low CC (odds ratio: 3.11, p = 0.02) and low handgrip (odds ratio: 2.52, p = 0.07). Additionally, after adjusting for potential confounders, a lower MNA score was significantly associated with an increased risk of low ASMI (odds ratio: 3.54, p = 0.04) and sarcopenia (odds ratio: 3.97, p = 0.03) in patients with dementia. In the adjusted regression models, the Hosmer and Lemeshow tests were all above 0.05, indicating that it was a goodness of fit test for logistic regression, and the values of Nagelkerke R 2 for frailty, poor quality of life, low CC, low ASMI, and sarcopenia were 22.1%, 24.9%, 18.6%, 27.9%, and 29.8%, respectively.  9 The gait speed <1.0 m/s. 10 The SPPB score ≤9. 11 Low ASMI and low muscle strength and endurance according to the Asian Working Group for Sarcopenia. 12 Adjusted for age, gender, and exercise habit. ASMI, appendicular skeletal muscle mass index; CC, calf circumference; CI, confidence interval; MNA, mini nutritional assessment; SPPB, short physical performance battery.

The Proportion of Sarcopenic Obesity in Patients with Dementia
A total of twenty-four patients with sarcopenia in the present study. We further calculated the proportion of sarcopenic obesity in patients with dementia (Figure 3). Fiftyeight percent of dementia patients had sarcopenic obesity ( Figure 3A). A total of 71.4% and 44.6% of patients had sarcopenic obesity in moderate and mild dementia, respectively (p = 0.13, Figure 3B). performance battery.

The Proportion of Sarcopenic Obesity in Patients with Dementia
A total of twenty-four patients with sarcopenia in the present study. We further calculated the proportion of sarcopenic obesity in patients with dementia (Figure 3). Fiftyeight percent of dementia patients had sarcopenic obesity ( Figure 3A). A total of 71.4% and 44.6% of patients had sarcopenic obesity in moderate and mild dementia, respectively (p = 0.13, Figure 3B).

Discussion
In the present study, we found that patients with dementia were suffering from malnutrition. Our study noted that patients with moderate dementia had a significantly lower MNA score ( Table 2), 55% of patients with moderate dementia were at risk for malnutrition status (MNA < 24), and malnutrition was associated with the progression of the disease (Figure 2A). From the MNA questionnaire, we found that patients with dementia had a lower MNA score due to digestive problems, chewing or swallowing difficulties, weight loss during the last 3 months, neuropsychological problems, BMI < 19 kg/m 2 , and a lower intake of daily food such as dairy products, vegetables, and fruits (Supplementary Table  S1). A previous study indicated that patients with dementia often face eating behavior disturbances, loss of independence, and depression, which may be predictors of malnutrition [31]. According to the report of the 2013-2016 National Nutrition Survey of Taiwan

Discussion
In the present study, we found that patients with dementia were suffering from malnutrition. Our study noted that patients with moderate dementia had a significantly lower MNA score ( Table 2), 55% of patients with moderate dementia were at risk for malnutrition status (MNA < 24), and malnutrition was associated with the progression of the disease (Figure 2A). From the MNA questionnaire, we found that patients with dementia had a lower MNA score due to digestive problems, chewing or swallowing difficulties, weight loss during the last 3 months, neuropsychological problems, BMI < 19 kg/m 2 , and a lower intake of daily food such as dairy products, vegetables, and fruits (Supplementary Table S1). A previous study indicated that patients with dementia often face eating behavior disturbances, loss of independence, and depression, which may be predictors of malnutrition [31]. According to the report of the 2013-2016 National Nutrition Survey of Taiwan also noted that malnutrition is prevalent in the Taiwanese elderly [32]. Although the assessment of nutritional status that we used in the present study (MNA) is different from the National Nutrition Survey of Taiwan, the MNA nutritional assessment is widely used in long-term care and in clinical application. Likewise, patients with dementia who suffer from malnutrition may have faster cognitive decline and worse functional impairment in the progression of dementia [33]. Thus, we suggest that nutritional assessment should be a standard approach in patients with dementia (particular they are elderly) and that follow-up processes work to prevent malnutrition's contribution to disease progression.
Patients with dementia face not only malnutrition but also the risk of sarcopenia. In our study, more than half of the patients with moderate dementia had low muscle mass, strength, and endurance ( Figure 1). It is worth noting that the proportion of low gait speed in both mild and moderate dementia patients was very high (mild vs. moderate: 87.5% vs. 82.5%). In addition, the amount of muscle mass, strength and endurance were significantly lower with the progression of the disease (Table 2), which may be associated to nutritional status (Table 4). From the data of the nutritional status assessment questionnaire (MNA), we found that 76.3% of patients with dementia did not consume at least one serving of dairy products per day, 21.3% of patients did not consume meat, fish, or poultry every day, and 42.5% of patients did not consume two or more servings of fruit or vegetables per day (Supplementary Table S1), it reflects our patients may have insufficient intake of proteinrich food, especially from dairy. Recently, a systematic review and meta-analysis reported that total protein consumption was associated with body mass increase in a dose-response relationship [34]. As a result, we recommend that patients with dementia need to intake sufficient protein to sustain and improve their muscle mass. Additionally, it should be noted that up to 58.3% of dementia patients with sarcopenia were obese ( Figure 3A), and 71.4% of patients with sarcopenic obesity had moderate dementia ( Figure 3B). Based on the data (Figure 3), we theorize that the cause of malnutrition in patients with dementia is an unbalanced diet. In addition, as dementia is an aging-related disease, the basal metabolic rate and energy requirement may decrease in these elderly patients [35]. The volume of skeletal musculature decreases and the percentage of fat tissue increases with aging. In fact, we suspect that the risk of malnutrition from MNA in the present study was underestimated. The change in weight in the MNA questionnaire only assessed "weight loss" during the last three months. We suggest that the MNA include a scoring item for "weight gain". Nutritional management should be integrated into dementia care [7]. A regular nutritional status assessment in patients with dementia may be useful in predicting the progression of the disease and may provide a target for clinical intervention.
Depression is a cause and consequence of dementia [36] and is associated with reduced quality of life [37] and increased risk of frailty [38]. In our study, we found that frailty, depression, and quality of life in patients with dementia were significantly related to nutritional status ( Figure 2 and Table 4). Nutritional health is an essential component of quality of life in an aging population [39]. In our study, higher nutritional status was positively associated with muscle mass, strength, and endurance, and the muscle function was also related to frailty, depression, and quality of life in patients with dementia (Table 3). It is interesting to note that muscular endurance parameters, such as dumbbell curls, sitstand tests, gait speed, and SPPB, were significantly associated with nutritional status, frailty, depression, and quality of life (Table 3). The muscle endurance may respond to the individual nutritional status and frail state, and further influence the quality of life, including mood state, particularly in older people [40,41]. A cross-sectional study that enrolled community-dwelling older adults in Taiwan also observed that physical fitness was related to quality of life [42]. In the elderly, declining muscle strength and endurance status have been found to further impact personal physical activity, negatively affecting depression and long-term quality of life [43,44]. Since dementia is an aging-related disease, assessing the muscle strength and endurance of patients with dementia should be included in dementia care in order to reduce the risk of frailty and depression and slow the decline in quality of life.
In the present study, a high prevalence of sarcopenia was found in dementia patients, with sarcopenia worsening as the disease progresses. We have demonstrated that nutritional status is related to the risk of sarcopenia, frailty, depression, and quality of life in patients with dementia. Most of the patients with dementia in this study suffered from sarcopenic obesity, which implies that dementia patients not only face skeletal musculature loss but also face accumulation of body fat. The limitations of this study include that the patients were from a single Taiwanese medical center, and a lack of a control group (without dementia) to compare, and we cannot clarify the causal relationship between nutritional status and dementia in this cross-sectional study. Second, the critical cause of dementia including Alzheimer's disease or vascular dementia had not been confirmed.
Although the small sample size was one of the limitations in the present study, we have tried to perform the post hoc tests to calculate the statistical power of the sample size and found the statistical power for correlations between MNA score and these outcomes such as muscle mass, frailty, depression, and quality of life have reached 0.89-0.99. Large-scale and case-control studies are needed to detect the differences in nutritional status between patients with dementia and non-dementia. Third, although we did not examine the reliability of the questionnaires (MNA, SOF, geriatric depression scale, and quality of life), these questionnaires were well developed and validated in clinical practice; besides, all questionnaires were performed by the research assistant from asked the subjects or their caregiver carefully to reduce the reported error. Regarding the reliability of the questionnaires, these questionnaires detected similar domains, such as body weight changes, activity, and mood states. We attempted to examine the consistency of MNA, SOF, GDS, and, QOL on similar questions and we found the consistency for the response status of the cases were high (>90%). So, the response status of our cases in the present was consistent.

Conclusions
In patients with dementia, the risk of malnutrition was significantly correlated with muscle function, as well as the risk of sarcopenia, frailty, depression, and decreased quality of life, all of which worsen with the severity of the disease. Thus, we suggest that in patients with dementia, nutritional status should be monitored regularly to prevent the risk of sarcopenia and improve quality of life along with slowing the progression of dementia. Lifestyle interventions, including caloric restriction, protein supplementation, and physical activity consisting of aerobic and resistance exercise, have been considered the cornerstone of the treatment of sarcopenic obesity [19]. Thus, future studies should clarify the effect of nutritional intervention on the risk of sarcopenic obesity in patients with dementia. Informed Consent Statement: Written informed consent was provided from each subject in the present study.

Data Availability Statement:
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.