Association between nutritional status and gait performance in Alzheimer's disease

Abstract Aims This study aimed to comprehensively explore the nutrition and gait of AD patients at different stages and the relationship between them. Methods A total of 85 AD patients were consecutively enrolled in this cross‐sectional study and divided into the mild cognitive impairment (MCI) due to AD (AD‐MCI) and the dementia due to AD (AD‐D) groups. Demographic information, nutritional status, and gait performance were compared between the two groups, and the correlation between nutritional status and gait performance was subsequently analyzed by Pearson and Spearman correlation analyses. Results The AD‐D group had lower scores on Mini‐Nutritional Assessment (MNA) and MNAm scales, lower levels of urea nitrogen, folic acid, and vitamin B12 in blood, and higher homocysteine level than those in the AD‐MCI group (all p < 0.05). The AD‐D group had slower step speed, shorter step length, and shorter stride length than those in the AD‐MCI group (all p < 0.05). AD patients with decreased scores of MNA and MNAm scales, and declined levels of urea nitrogen and vitamin B12 in blood had reduced gait speed and gait cadence, and prolonged step length time and stride length time, whereas homocysteine showed the almost opposite results (all p < 0.05). In the AD‐MCI group, the score of scale was negatively correlated with the coefficient of variation (CV) of stride length, and the folic acid level was negatively correlated with the CV of stride length and cadence (all p < 0.05). Conclusions AD patients at the dementia stage had worse nutritional status and gait performance than those at the MCI stage, which was associated with worse global cognition and activities of daily living. Poorer nutritional status was associated with higher gait variability in patients at the MCI stage and with poorer gait performance in patients at the dementia stage. Early identification and intervention of patients with nutritional risk or malnutrition may improve gait performance, thus reducing the risk of falling and cognitive decline, as well as the mortality.


| BACKG ROU N D
The number of individuals with cognitive impairment is growing as the global aging process continues.Alzheimer's disease (AD) is the most common type of cognitive impairment, characterized by declines of multiple cognitive domains, and varying degrees of neuropsychiatric symptoms and compromised activities of daily living (ADL). 1 So far, there is no cure for AD.It is therefore crucial to early identify and intervene in the potential risk factors that may contribute to the onset and progression of AD.
According to recommendations from the European Society for Clinical Nutrition and Metabolism (ESPEN), malnutrition and weight loss are the most common nutritional conditions in dementia patients. 2In AD patients, malnutrition was associated with accelerated disease progression, and increased morbidity and mortality. 3,4Population-based studies found that weight loss was a predictor of both incident mild cognitive impairment (MCI) and dementia, which might be one of the first signs of cognitive decline. 5AD patients with severe dementia had a higher risk of malnutrition and lower body mass index (BMI) than those with MCI and mild dementia. 6There are several indicators that can reflect nutritional status, including weight loss, BMI, muscle mass, reduced food intake, burden/inflammation, rating scales, and laboratory variables, such as blood urea nitrogen and B vitamins.
Currently, there is a paucity of research that comprehensively assesses the nutritional status of AD patients.Given that nutrition is a modifiable risk factor for AD, one of the aims of this study was to holistically evaluate the nutritional status of AD patients at different stages from multiple perspectives.
Gait is a key indicator of overall health.Neural networks, including cortical, subcortical, and spinal cord structures, are involved in regulating gait control. 7AD patients had impaired balance control, slower gait speed, and greater gait variability than individuals with normal cognition. 8,9Abnormal gait increases the risk of falling in AD patients, resulting in increased mortality.
However, there are still limitations in current research on AD and gait performance.For instance, it is still unclear what the characteristics of gait variability among AD patients at different disease stages.The relationship between different gait parameters and neuropsychiatric symptoms as well as ADL of AD patients remained unknown.Furthermore, the gait parameters included in previous research were not comprehensive enough.This study therefore aimed to comprehensively investigate the relationship between multiple gait parameters and the different stages of AD, as well as its clinical symptoms.
Recently, a cross-sectional study based on cognitively healthy older adults showed that gait speed was twice as high in the well-nourished as in the malnourished. 10To date, however, the relationships between the nutritional status and gait performance in AD patients have not been studied.The aims of this study were therefore to comprehensively identify the characteristics and correlations of the nutritional status and gait performance in AD patients at different stages of disease.All subjects were diagnosed with MCI due to AD (AD-MCI) 11 or dementia due to AD (AD-D) of variation (CV) of stride length, and the folic acid level was negatively correlated with the CV of stride length and cadence (all p < 0.05).

| Subjects
Conclusions: AD patients at the dementia stage had worse nutritional status and gait performance than those at the MCI stage, which was associated with worse global cognition and activities of daily living.Poorer nutritional status was associated with higher gait variability in patients at the MCI stage and with poorer gait performance in patients at the dementia stage.Early identification and intervention of patients with nutritional risk or malnutrition may improve gait performance, thus reducing the risk of falling and cognitive decline, as well as the mortality.

K E Y W O R D S
Alzheimer's disease, dementia, gait performance, gait variability, mild cognitive impairment, nutritional status into the AD-MCI group and the AD-D group, respectively.AD patients meeting the following criteria were excluded from this study: (1) patients with other neurological diseases that affected cognition, including Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, corticobasal degeneration, acute cerebrovascular disease involving the cerebral cortex, and acute stroke that was temporally associated with cognitive impairment; (2) patients with diseases affecting gait, including lower extremity fracture, femoral head necrosis, and lower extremity arteriosclerosis obliterans; (3) patients with other conditions leading to malnutrition, including hematological tumors, liver cirrhosis, severe systemic diseases, or subtotal gastrectomy; and (4) patients who were unable to cooperate with all the examinations for various reasons.

| Demographic data
The general demographic data, including sex, age, age of onset, education level, marital status, apolipoprotein E (APOE) genotype, and several comorbidities, including hypertension, hyperlipidemia, diabetes mellitus, hyperhomocysteinemia, myocardial infarction, atrial fibrillation, cerebral infarction, cerebral hemorrhage, thyroid disease, smoking, and drinking, were collected.
The following five aspects of nutrition-related demographic data were collected according to the Global Leadership Initiative on Malnutrition (GLIM) criterion 13 :

| Muscle mass
Circumferences of the arm, waist, hip, and calf were measured to reflect the muscle mass of patients.The waist circumference was measured at the narrowest point of the trunk between the ribs and the upper part of the hip bone.The hip circumference was measured at the widest point of the hip and buttock.The arm circumference was measured at the midpoint between the acromion and olecranon.
The calf circumference was measured at the location where the calf was thickest. 17

| Reduced food intake
Reduced food intake referred to a decrease in food intake over the past 3 months due to various reasons, including poor oral health, side effects of medication, depression, dysphagia, gastrointestinal complaints, anorexia, and insufficient nutrition support.It was classified into four categories: no reduction in intake, a 25%-50% reduction, a 50%-75% reduction, or a reduction of ≥75%. 18

| Burden/inflammation
Burden/inflammation was defined as patients with major infections, burns, trauma, closed head injury, fever, negative nitrogen balance, congestive heart failure, chronic obstructive pulmonary disease, rheumatoid arthritis, chronic kidney or liver diseases, or cancer. 13,18

| Clinical symptoms
The global cognition of patients was assessed by the scales of Mini-Mental State Examination (MMSE) 19 and the Montreal Cognitive Assessment (MoCA). 20Neuropsychiatric symptoms were assessed by the Neuropsychiatric Inventory (NPI) scale. 21ADL were assessed by the ADL scale, which includes basic ADL (BADL) and instrumental ADL (IADL). 22e nutritional status of patients was assessed by the Mini-Nutritional Assessment (MNA) scale. 23The scoring categorizes subjects: well-nourished (≥24 points), at risk of malnutrition (17-23.5   points), and malnourished (<17 points).To avoid interference of cognitive performance and depression with nutritional assessment, we also analyzed a modified MNA (MNA m ) scale, leaving out the question of "neuropsychological problem". 24e detailed description of these scales was provided in the Appendix S1.

| Nutrition-related laboratory variables
The venous blood samples of AD patients were collected from the median elbow under fasting condition the next morning after admission, and then sent to the clinical laboratory of Beijing Tiantan Hospital.
We collected a variety of nutrition-related laboratory variables in blood to assess the nutritional status of patients, including hemoglobin A1c, fasting blood glucose, hemoglobin, urea nitrogen, creatinine, albumin, prealbumin, homocysteine, folic acid, and vitamin B 12 , in serum.

| Gait parameters
The Codamotion 3D motion capture system (Charnwood Dynamics, Ltd., United Kingdom) was used to collect the bilateral gait parameters of patients by active infrared capture.
To record steady-state walking patterns, subjects were instructed to start walking approximately 1 m before entering the infrared capture range.A successful trial is defined as the acquisition of more than three consecutive complete cycles of stereo-motion data, and each task requires the acquisition of at least six successful trials.
The gait parameters, including speed (m/s), step length (m), step length time (s), stride length (m), stride length time (s), cadence (steps/ min), cadence (strides/min), and percentage of support (%), were collected.Cadence (steps/min) is defined as the number of steps per minute, and cadence (strides/min) is defined as the number of strides per minute.The variability of each gait parameter is represented by the coefficient of variation (CV): standard deviation (SD)/mean × 100. 25

| RE SULTS
A total of 149 patients diagnosed with AD were enrolled consecutively from September 2021 to November 2022, of which three patients who did not undergo nutritional assessment and 61 patients who did not undergo gait assessment were excluded.

| Clinical characteristics of AD patients
The clinical characteristics of AD patients were shown in Table 1.
It was showed that 58.82% of patients were females, the average age was 64.13 ± 10.26 years old, the average age of onset was 59.54 ± 11.92 years old, and 32.90% of cases carried APOE ε4 allele.There were no statistically significant differences in all demographic variables between the AD-MCI and the AD-D groups.

| Global cognition, neuropsychiatric symptoms, and ADL of AD patients
The scores of MMSE and MoCA scales were lower (all p < 0.001), and the scores of NPI scale (p = 0.004) and ADL scale (p < 0.001) were higher in the AD-D group than that in the AD-MCI group (Table 2).

| The nutritional status of AD patients
Compared to the AD-MCI group, AD-D group had lower scores of MNA (p < 0.001) and MNA m scales (p = 0.006), and had higher proportion of at risk of malnutrition and malnutrition (p = 0.003) (Table 1).
As far as nutrition-related laboratory variables, the levels of urea nitrogen (p = 0.003), folic acid (p = 0.001), and vitamin B 12 (p = 0.001) in the AD-D group were all lower than those in the AD-MCI group, and the homocysteine level in the AD-D group was higher than that in the AD-MCI group (p < 0.001) (Table 1).
We further analyzed the relationship of the nutritional status with global cognition, neuropsychiatric symptoms, and ADL scale in AD patients.The results showed that the scores of MNA and MNA m scales, and the levels of folic acid and vitamin B 12 were positively correlated with the scores of MMSE scale, MoCA scale, and negatively correlated with the score of ADL scale, while homocysteine level was negatively correlated with the scores of MMSE and MoCA scales, and positively correlated with the ADL score (all p < 0.05).The score of MNA scale was also negatively correlated with the score of NPI scale (r = −0.331,p = 0.002) (Table S1).The variability of these gait parameters did not differ between the two groups.
In addition, step speed, step length, stride length, and cadence (steps/min) were positively associated with the scores of MMSE and MoCA scales, and negatively associated with the score of ADL scale (all p < 0.05) (Table S1).

| Association between nutritional status and gait performance of AD patients
The correlations between the nutritional status and gait performance in AD patients were shown in Figure 3.We further explored the differences in gait performance between the stages of MCI and dementia by dividing the patients into the well-nourished and undernourished risk/malnourished groups according to the score of the MNA scale.In the well-nourished subgroup, there were no statistical differences in gait parameters and their variability between the stages of MCI and dementia (Figure S1).
Nevertheless, in the undernourished risk/malnourished group, step speed (p = 0.007), step length (p = 0.027), and stride length (p = 0.034) in the AD-MCI group were all significantly lower than that in the AD-D group (Figure S2).

| DISCUSS ION
To our knowledge, this is the first study to elucidate the associations between nutritional status and gait performance in AD patients at different stages.We found that: (1) AD-D patients had significantly worse nutritional status and gait performance than AD-MCI patients, which were all significantly related to the worse cognition; (2) nutritional status of patients was markedly and negatively associated with gait variability in the MCI stage, and was remarkably and negatively associated with their gait performance

TA B L E 1 (Continued)
in the dementia stage; (3) in patients with undernourished risk/ malnourished, AD-D patients had worse gait performance than AD-MCI patients, which was however not found in the well-nourished patients.

| The nutritional status of AD patients was related to disease severity
3][4] We found that lower score of MNA scale predicted the occurrence of dementia in AD patients.improve the reliability of the results, we adopted the revised MNA (MNA m ) scale and adjusted for sex, age, age of onset, educational level, the score of NPI scale, and the score of ADL scale, and still found a significant and negative association between score of MNA scale and dementia.
The lower scores of MNA and MNA m scales were associated with the lower scores of MMSE and MoCA scales.So far, the factors of malnutrition in AD are not fully clear.It was suggested that the factors that affected food intake, such as olfactory dysfunction, taste disorders, and compromised appetite were the primary reasons for malnutrition in the early stages of AD. [26][27][28] As the disease progressed, the chronic inflammatory response was gradually increased, leading to excessive protein and energy consumption as the primary cause of malnutrition in the middle and late stages of AD. 29,30 In addition, eating disorder, dysphagia, and neuropsychiatric symptoms at the later stage of AD exacerbated malnutrition. 31 addition, we analyzed the relationship between nutrition-related laboratory variables and dementia, and found that lower levels of blood urea nitrogen, folic acid, and vitamin B 12 , and higher homocysteine level had good predictive value for dementia.Blood urea nitrogen is the main end product of protein metabolism and one of the indicators reflecting the nutritional status of the body, which was influenced by multiple factors, including protein intake, dehydration, and gastrointestinal bleeding. 32When insufficient protein intake or excessive consumption, blood urea nitrogen level will decline.Up to now, almost no literature has reported the relationship between blood urea nitrogen and AD.In this study, the results showed that blood urea nitrogen level in AD-D patients was significantly lower than that in AD-MCI patients, and it is reasonable to speculate that this may be related to malnutrition caused by excessive protein and energy consumption at the dementia stage. 29vitamins, including vitamin B 12 and folic acid, are mainly derived from food intake and are indispensable substances for the metabolism of sugars, fats, and proteins in the human body.These are the components of mono-carbon metabolism and essential for maintaining cellular methylation capacity.33 Multiple studies suggested that low levels of plasma B vitamins in AD patients led to not only the disturbed metabolism of homocysteine but also the impaired release of docosahexaenoic acid and choline into blood, which resulted in increased homocysteine and decreased docosahexaenoic acid and choline, and thus impaired synaptic synthesis and cognition.[34][35][36] Homocysteine, a kind of sulfur-containing amino acid in the human body, is either metabolized to cysteine by the transsulfuration pathway or converted back to methionine through the remethylation pathway by using cofactors like folic acid and vitamin B 12 .It was recognized as proatherogenic and prothrombotic, and accepted in many studies as an independent risk for cardiovascular and cerebrovascular diseases.37 In addition, homocysteine was reported to be associated with dementia, such as AD-D, due to vascular damage and oxidative stress.38,39 Abnormal nutrition-related variables are modifiable risk factors for AD; hence, it is important to reveal whether there is a relation-

| The gait performance of AD patients was related to disease severity
Walking is a complex process related to cognitive ability as well as motor function, and it is sensitive to the loss of a higher level of cognitive control. 7,40Previous studies found that patients with cognitive impairment had worse gait performance than those with normal cognition, and poor gait performance acted as a factor predicting progression from MCI to dementia. 9,41,42In this study, we comprehensively analyzed the relationship between multiple gait parameters and different stages of AD, and found that slower step speed, shorter step length, and stride length significantly not found.These results suggested that gait variability might be more useful in distinguishing dementia from non-dementia than AD at different stages.

| The associations between nutritional status and gait performance in AD patients
This study for the first time found a significant correlation between nutritional status and gait performance in AD patients.Patients with lower scores of MNA and MNA m scales, and lower levels of urea nitrogen and vitamin B 12 had slower gait speed and gait cadence, and longer step length time and stride length time.Patients with higher homocysteine level had slower step speed and cadence, shorter step length and stride length, and longer stride length time.Poor nutritional status was associated with poor muscle strength, leading to poorer gait performance. 10,45 is worth noting that the correlation between nutrition and gait is more significant at the dementia phase than at the MCI phase.
Gait performance was worse, and the risk of falling was higher in the advanced-stage patients with AD. 9,41 The above results indicate that improving nutritional status of patients at the last stage has a greater benefit in improving gait performance, and consequently may be more effective in reducing the risk of falling and mortality compared to the patients at the early stage of AD.More interestingly, we found that nutritional status was markedly related to gait variability in patients at the MCI stage, which was revealed by the results that the score of MNA scale was significantly and negatively correlated with stride length CV, and the folic acid level was significantly and negatively correlated with stride length CV and cadence CV.However, the association was not significant in AD patients at the dementia stage, except that weight loss was negatively correlated with step speed CV.Higher gait variability was associated with worse gait rhythm, walking stability, and a higher risk of falling. 42,43The above results were critical for early identification of AD patients at high risk of falling and cognitive decline.
In this study, in AD patients with impaired nutrition, patients at the dementia stage had slower step speed, shorter step length, and stride length than those at the MCI stage; however, in the well-nourished AD patients, this differences in gait performance were not evident between the cases at different stages.We speculate that AD patients with malnutrition may have lower muscle mass and worse muscle strength, which may lead to impaired gait performance.
Thus, nutritional status may accelerate the deterioration of gait performance as the disease progresses. 10,45

| LI M ITATI O N
This study had limitations.First of all, the cross-sectional nature hampers causal interpretation of our findings, and further longitudinal studies with large samples are needed.Second, the differences of nutritional status and gait performance among the cognitively normal individuals, patients with other cognitive disorders, and AD patients need to be further explored in the future.

| CON CLUS ION
AD patients at the dementia stage had both poorer nutritional status and worse gait performance than those at the MCI stage, which were associated with worse global cognition and ADL.
Poorer nutritional status was associated with higher gait variability in patients at the MCI stage, and poorer gait performance in patients at the dementia stage.Nutrition is one of the risk factors that can be intervened with, and early identification and intervention of AD patients with nutritional risk or malnutrition may improve gait performance, thus reducing the risk of falling, delaying the progression of AD symptoms, and decreasing the mortality of AD patients.

A
total of 85 subjects with AD were consecutively enrolled in the cross-sectional study between September 2021 and November 2022 from the Center for Cognitive Neurology, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University.
Statistical analyses were performed by SPSS Statistics 25.0 (IBM Corporation, New York, USA).Statistical significance was defined as a two-sided p < 0.05.Data were tested for normal distribution using the Kolmogorov-Smirnov test.Clinical characteristics, nutritional status, and gait performance were compared between the AD-MCI and the AD-D groups.Continuous variables conforming to normal distribution were presented as means ± SD and compared by two-tailed t test, non-normal distributed variables were presented as median (quartile) and compared by non-parametric test, and categorical variables were presented as number (percentage) and compared by chi-squared test.Binary logistic regression analyses were performed to assess the association of nutritional status and gait performance with dementia, with Model 1 was adjusted for age and gender, and Model 2 was further adjusted for age of onset, educational level, and the scores of NPI and ADL scales based on Model 1. Pearson correlation analysis and Spearman correlation analysis were performed to evaluate the correlations between nutritional status and gait performance in the total patients, the AD-MCI group, and the AD-D group, respectively, and the results were presented by heat maps.

Finally, 85 | 5 of 13 HE
patients with AD were enrolled in this study, with 34 cases in the AD-MCI group and 51 cases in the AD-D group (Figure 1).F I G U R E 1 Study flow chart.AD, Alzheimer's disease; MCI, mild cognitive impairment.et al.
ship between the levels of above variables and dementia.In this study, AD patients in the dementia stage exhibited lower levels of folic acid and vitamin B 12 .Furthermore, the increased homocysteine and decreased folic acid and vitamin B 12 were associated with worse global cognition and ADL.These results could potentially be attributed to decreased food intake and increased protein and energy consumptions, which were common in the stage of dementia.The reduced folic acid and vitamin B 12 in turn impaired homocysteine synthesis, resulting in higher homocysteine level during the dementia stage.

F I G U R E 2
Comparison of Gait performance between the AD-MCI and AD-D groups.Comparisons of step speed (A), step length (B), step length time (C), cadence (steps/min) (D), stride length (E), stride length time (F), cadence (strides/min) (G), percentage of support (H), and CV of A-G (I-O) between the groups of AD-MCI and AD-D.AD, Alzheimer's disease; CV, coefficient of variation; MCI, mild cognitive impairment.*p < 0.05, **p < 0.01.

F I G U R E 4 | 11 of 13 HE
predicted dementia and were associated with worse global cognition and ADL.Altered gait variability is a common feature of several neurodegenerative diseases, including AD, and its increase reflected worse gait rhythm and was associated with the increased risk of falling, and a harbinger of cognitive decline and disease severity.42,43A previous study found increased gait variability in AD patients compared to cognitively normal individuals, and might distinguish MCI from cognitively normal individuals.44However, the underlying mechanisms of altered gait variability in AD patients are poorly understood.In this study, gait variability between AD-MCI and AD-D patients was not different and the association of gait variability with cognition, neuropsychiatric symptoms, and ADL was F I G U R E 3 Heat map of correlations between the nutritional status and gait performance in patients with AD.BMI, body mass index; CV, coefficient of variation; MNA, Mini-Nutritional Assessment.*p < 0.05, **p < 0.01.Heat maps of correlations between the nutritional status and gait performance in the AD-MCI and AD-D groups.BMI, body mass index; CV, coefficient of variation; MNA, Mini-Nutritional Assessment.*p < 0.05, **p < 0.01.et al.
Association of nutritional status and gait performance with dementia in AD patients.Model 1 was adjusted for sex and age; Model 2 was adjusted for sex, age, age of onset, educational level, and the scores of NPI and ADL scale.
| 9 of 13 HE et al.