BIOELECTRICAL IMPEDANCE VECTOR ANALYSIS DETECTS LOW BODY CELL MASS AND DEHYDRATION IN PATIENTS WITH ALZHEIMER'S DISEASE

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1 MARINI:04 LORD_c 3/05/10 9:16 Page 1 BIOELECTRICAL IMPEDANCE VECTOR ANALYSIS DETECTS LOW BODY CELL MASS AND DEHYDRATION IN PATIENTS WITH ALZHEIMER'S DISEASE R. BUFFA, R.M. MEREU, P.F. PUTZU, G. FLORIS, E. MARINI Department of Experimental Biology, Anthropological Science Section, University of Cagliari, Italy (RB, GF, EM), Geriatric Division, SS Trinità Hospital, ASL 8, Cagliari, Italy (RMM, PFP). Correspondence address: Prof. Elisabetta Marini, Department of Experimental Biology, Anthropological Science Section, University of Cagliari, Cittadella Universitaria, Monserrato (Cagliari), Italy. Tel ; fax ; emarini@unica.it Abstract: Objectives: This paper evaluates the nutritional status in patients with mild-moderate and severe Alzheimer's disease (AD) by bioelectrical impedance vector analysis (BIVA). Design: Cross-sectional study. Setting: Alzheimer Center, SS. Trinità Hospital, Cagliari, and Monsignor Angioni Nursing Home, Quartu Sant'Elena (Cagliari, Italy). Participants: 83 free-living patients with mild-moderate Alzheimer's disease (29 men, 54 women), 9 institutionalized women in the severe stage; 468 age-matched controls (202 men, 266 women). Measurements: Mini Nutritional Assessment (MNA), anthropometric (height, weight, BMI), bioelectrical (R, Xc) and biochemical variables (serum albumin) were assessed. Results: Bioelectrical characteristics were significantly different in the patients with mild-moderate AD with respect to controls, indicating low body cell mass (men, T 2 = 12.8; women, T 2 =34.9; p<0.01). Women with severe AD showed low body cell mass and dehydration with respect to patients with mild-moderate AD (T 2 =17.1; p<0.01). The phase angle, R/H and Z/H were significantly correlated (p<0.05) with MNA (phase: r = 0.31; R/H: r =-0.37; Z/H: r =- 0.37) and albumin (phase: r=0.47; R/H: r=-0.36; Z/H: r=-0.36). Conclusion: Alzheimer's disease is characterized by a tendency to malnutrition, present even in the mild-moderate stages, and a tendency to dehydration that appears in the severe stage. The BIVA technique is a promising tool for the screening and monitoring of nutrition and hydration status in Alzheimer's disease. Key words: Alzheimer's disease, BIVA, nutritional status, hydration status Non-standard abbreviations: BIA: Bioelectrical Impedance Analysis; BIVA: Bioelectrical Impedance Vector Analysis; MNA: Mini Nutritional Assessment; CDR: Clinical Dementia Rating; NINCDS-ADRDA: National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders; MMSE: Mini Mental State Examination; R: Resistance; Xc: Reactance; Z: Impedance. Introduction Weight loss is a major clinical feature of Alzheimer's disease (AD). It affects between 30 and 40% of patients with mild to moderate forms (1) and becomes more common as AD progresses (2). However, current evidence regarding body composition variations is not conclusive. Weight loss may be associated with protein energy malnutrition (PEM). These conditions predict the progression of cognitive impairment and increase the risk of complications and mortality (1, 3, 4). In a recent review on the Mini Nutritional Assessment (MNA), Guigoz (5) reported a mean prevalence of risk of malnutrition of 51±0.5% and of malnutrition of 21±0.5%. Koopmans et al. (6) reported a frequency of 53.2% for dehydration in the final stages of AD. However, few studies have dealt with the initial stages of AD and the association between dehydration and progression of the disease. Practical guidelines for the diagnosis and management of malnutrition in Alzheimer's disease suggest a nutritional assessment at the time of diagnosis and in the follow-up and management of the disease (3). The indicators include at least weight and MNA. However, MNA is not applicable in patients with advanced stages of AD. Food intake assessment and plasma albumin are other important diagnostic tools. These techniques are not sensitive to body composition variations and thus do not record variations of soft tissue mass and body water. Practical guidelines also mention prevention of dehydration as a part of the management of patients with AD (3). The diagnosis of dehydration is difficult because a reduced water volume does not result in evident and specific clinical manifestations, especially in mild and moderate cases. The difficulty is even greater in the elderly since physical signs of dehydration (e.g. reduced skin turgor and orthostatic hypotension) are often present in normally hydrated older people. Moreover, the dilution technique, considered the gold standard for the assessment of body water, is rather expensive, time-consuming and unsuitable for use in routine clinical practice. Bioelectrical impedance analysis (BIA) can be a valuable tool to assess changes in body composition. BIA is widely accepted as safe, time-saving and cost-effective, and can also be applied in bedridden subjects. The conventional BIA approach uses specific equations for the estimation of body composition. The predictive efficacy of the equations, which translate impedance values into Fat Free Mass (FFM), Lean Body Mass (LBM) or Total Body Water (TBW), depends on the similarity of the age and physical characteristics of the individual/group in examination with those of the sample used 1

2 MARINI:04 LORD_c 3/05/10 9:16 Page 2 BODY COMPOSITION IN ALZHEIMER'S DISEASE for validation, as well as on the criterion method. Therefore, the application of regression equations can lead to substantial estimation errors, particularly in older individuals, in which wide variability in the density of mineral mass, hydration and protein content of FFM has been observed (7). Considerably larger prediction errors are possible in pathological individuals (8). A variant of BIA, bioelectrical impedance vector analysis (BIVA), is more accurate, as it does not require the use of predictive equations (9). By an empirical approach, the direct analysis of the two components of the impedance vector (Z), resistance (R, Ohm) and reactance (Xc, Ohm), allows a semiquantitative evaluation of body composition in terms of body cell mass and hydration status. Resistance is related to the quantity of body fluids, being negatively correlated with the total body water and fat-free mass through which the current flows. Reactance is positively correlated with body cell mass. The length of the impedance vector (Z = (R 2 + Xc 2 ) 0.5 ) depends primarily on the resistance value and thus is negatively correlated with body fluids. The phase angle (arctan Xc/R) is indicative of cell number and integrity. Initially used to monitor dialysis patients, BIVA has proved particularly useful in pathological conditions with alterations of the water compartment (9-11). The validity of BIVA for nutritional assessment in older individuals was recently verified by studies of the pathological (12) and the healthy aged population (13), in which a significant association with multidimensional techniques was found. The aim of the present study was to compare the nutritional and hydration status of patients with Alzheimer's disease with that of a healthy control group selected on the basis of age and sex. This is the first application of bioelectrical impedance vector analysis in Alzheimer's disease. Materials and methods Subjects The pathological and control samples consisted of people resident in the province of Cagliari whose Sardinian origin was verified to the first parental generation. Patients with different stages of Alzheimer's disease were enrolled. The diagnosis of Alzheimer's disease was based on the DSM-IV and NINCDS- ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders) criteria. The CDR (Clinical Dementia Rating) scale was used to identify the stage of Alzheimer's disease. Patients with the mild-moderate stages of AD (CDR 1 and 2) and the severe stage (CDR 3) were selected for the study. Patients with mild-moderate AD were selected from the Alzheimer Center, SS. Trinità Hospital, ASL 8 of Cagliari (Italy). Patients with severe AD were selected from the Monsignor Angioni Nursing Home of Quartu Sant'Elena (Cagliari, Italy). The group with mild-moderate AD consisted of 83 free-living subjects (29 men and 54 women). The mean age was 79.0±6.6 years for men and 82.2±5.6 years for women. The Mini Mental State Examination (MMSE) score was 19.6±5.4 in the men and 19.2±4.9 in the women. None of the patients received active nutritional interventions. The group with severe AD consisted of 9 institutionalized women, whose mean age was 82.7±6.4 years. Because of the severity of their psycho-physical conditions, it was not possible to record some variables (MMSE, MNA) or to collect measurements in men with severe AD. All of these patients received enteral nutrition support. The control group consisted of 468 healthy individuals (202 men and 266 women) chosen on the basis of age similarity from a large database of elderly Sardinians of both sexes, which also included personal, behavioral, medical history and biometric data. The mean age was 78.6±8.4 years for men and 80.7±8.2 years for women. Subjects who had been admitted to hospital in the 3 months before the investigation or currently under medical treatment were not included in the sample. Individuals with physical handicaps and/or with uncompensated chronic diseases (uncontrolled tumoral pathology, III-IV class cardiac decompensation, chronic gastrointestinal disease, renal or hepatic insufficiency) were also excluded. All subjects or their tutors were informed about the objectives and methods of the research and they consented to participate in the study. The procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in Methods Nutritional evaluation was performed by means of anthropometry, biochemical markers, mini nutritional assessment (MNA) (14) and bioelectrical impedance vector analysis (BIVA) (9). Biochemical and MNA data were collected only in the sample of patients with Alzheimer's disease. Anthropometry Anthropometric measurements were taken by an experienced and well-trained observer according to standard procedures (15). The values for the coefficient of reliability were at or above Height was measured with a portable anthropometer; subjects were asked to maintain a fully erect position during the measurement. In patients with severe AD, height was estimated from knee height measurements according to Chumlea and Guo (16). Body weight was measured to the nearest 0.1 kg with a movable spring scale. Body circumferences (waist, upper arm and calf) were taken with a metal tape measure. The Body Mass Index (BMI, kg/m 2 ) was calculated. The 20 kg/m² cut-off was adopted for the diagnosis of malnutrition as it is the most commonly used in older people (17). Moreover, the 24 kg/m² level was utilized for the classification of individuals at risk of malnutrition, as suggested by Beck and Ovesen (18). 2

3 MARINI:04 LORD_c 3/05/10 9:16 Page 3 Mini Nutritional Assessment (MNA) The MNA involves the compilation of a questionnaire consisting of 18 items divided into three sections: anthropometry (body mass index, mid-arm and calf circumference, weight loss); dietary habits (per day full meals, fluids, fruit or vegetables, markers for protein intake, mode of feeding, food intake decline); cognitive and disability status (mobility, psychological stress or acute disease, neuropsychological problems, independent living, drugs per day, pressure sores or skin ulcers, self- view of nutritional and health status) (14). A score lower than 17 indicates malnutrition, indicates a risk of malnutrition, and 24 or higher indicates normal nutrition. The sensitivity and specificity of MNA in detecting states of malnutrition are 96% and 98% respectively (19). The level of reliability (R) is 0.89 (20). The MNA form and the user guide are open access documents ( Biological markers Serum albumin (g/dl) was measured. A level of 3.5 g/dl was adopted as the cut-off for moderate malnutrition and 3.0 g/dl for severe malnutrition (17). Bioelectrical Impedance Vector Analysis (BIVA) The bioelectrical variables of resistance (R, Ohm) and reactance (Xc, Ohm) were measured with a single-frequency impedance analyzer (BIA 101, Akern, Florence, Italy) using an operating frequency of 50 khz at 800 µa. The accuracy was checked with a calibration circuit of known impedance (R: 380 Ohm, Xc: 47 Ohm; 1% error). Whole body impedance measurements were taken using the standard positions of outer and inner electrodes on the right hand and foot (21). The R and Xc values were standardized by height (H) to remove the effect of conductor length. According to Buffa et al. (22), bioelectrical values were also adjusted for body circumferences (upper arm, waist and calf circumferences) by covariance analysis in order to eliminate the effect of transverse measures. Mean impedance vectors were plotted in the Cartesian plane defined by the R/H and Xc/H axes (R/Xc graph). Statistical Analyses Statistical analyses were performed separately in the two sexes. ANOVA was applied to compare patients with Alzheimer's disease and controls. The differences between the mean impedance vectors in the Alzheimer s and control groups were assessed with Hotelling s T 2 test, a multivariate generalization of the univariate t-test, and graphically with 95% probability confidence ellipses. Mahalanobis distance D was also calculated. The linear relationship between bioelectrical and nutritional variables was assessed with Pearson correlation analysis. Statistical analyses were carried out with Statistica 4.0 (Statsoft Inc.). BIVA was performed with an open source specific software (23). Results In the patients with mild-moderate AD, the nutritional variables were in the normal range, except for mean MNA in women (MNA<24), which indicates a risk of malnutrition (Table 1). Four individuals (5% of women) were classified as malnourished (MNA<17) and 27 (20.7% of men and 38.9% of women) at risk of malnutrition (17 MNA<24). In women with severe AD, the mean albumin level was significantly lower than for patients with mild-moderate AD and below the threshold for the diagnosis of moderate malnutrition in older people (17) (table 1). Age and stature were not significantly different between patients with AD and controls (table 2). In both sexes, waist, upper arm and calf circumferences, weight and BMI values tended to be lower in patients with AD than in controls. The differences were significant when all females were considered, when weight and waist circumference were compared between women with mild-moderate AD and controls, and when upper arm and calf circumferences were compared between women with mild-moderate and severe AD (table 2). Five of the patients with mild-moderate AD (3.4% of men and 7.4% of women) were classified as malnourished (BMI< 20 kg/m 2 ) and 23 (31.0% of men and 25.9% of women) at risk of malnutrition according to the cut-off suggested by Beck and Ovesen (18) for the aged population (BMI< 24 kg/m 2 ). Three of the women with severe AD (33.3%) were classified as malnourished (BMI< 20 kg/m 2 ) and 3 (33.3%) at risk of malnutrition (BMI< 24 kg/m 2 ). Figure 1 Mean impedance vector and confidence ellipses of the patients with Alzheimer's disease and the control group. T 2, Hotelling's statistic; D, Mahalanobis distance between two groups defined by the two correlated variables, resistance/height (R/H) and reactance/height (Xc/H) The phase angle was significantly lower in patients with mild-moderate AD than in controls (table 2). In women, Xc and Xc/H were also significantly lower. The bioelectrical variables 3

4 MARINI:04 LORD_c 3/05/10 9:16 Page 4 BODY COMPOSITION IN ALZHEIMER'S DISEASE Table 1 Descriptive and comparative statistics for albumin and MNA in patients with Alzheimer's disease Malnutrition cut-offs Mild-moderate AD Severe AD Men (N=29) Women (N=54) Women (N=9) Undernutrition 'at risk' Mean s.d. Mean s.d. Mean s.d. F MNA a score Albumin g/dl * a. Mini Nutritional Assessment; *p<0.05. Table 2 Descriptive and comparative statistics for the anthropometric and bioelectrical variables in patients with Alzheimer's disease and controls Men Women Controls Alzheimer Controls vs. Controls Alzheimer Alzheimer Controls vs. Mild- All groups (N=202) mild-moderate mild-moderate (N=266) mild-moderate severe stage mild- moderate vs stage (N=29) stage (N=54) (N=9) moderate severe stage stage Mean s.d. Mean s.d. F Mean s.d. Mean s.d. Mean s.d. F F F Age (y) Stature (cm) Weight (kg) * ** Waist crf a (cm) ** ** Arm crf a (cm) ** 6.136** Calf crf a (cm) ** 6.212** BMI (kg/m 2 ) * R b (Ω) ** ** Xc c (Ω) ** ** Z d (Ω) ** ** Phase ( ) * ** ** ** R/H e (Ω /m) ** 9.589** Xc/H f (Ω /m) ** ** Z/H g (Ω /m) ** 9.403** *p<0.05; **p<0.01; a. circumference; b. resistance; c. reactance; d. impedance; e. resistance/height; f. reactance/height; g. impedance/height showed a significant tendency to a longer impedance vector (R, R/H, Z, Z/H) and a smaller phase angle with progression of the disease (table 2). With respect to the controls, the confidence ellipses of the patients with AD were significantly shifted towards the region of the RXc graph corresponding to low body cell mass (reduction of the phase angle) (figure 1). The women with severe AD showed a further significant tendency to dehydration (lengthening of the impedance vector) (figure 1). The phase angle, R/H and Z/H were significantly correlated (p<0.05) with MNA (phase: r = 0.31; R/H: r = -0.37; Z/H: r = ) and albumin (phase: r = 0.47; R/H: r = ; Z/H: r = ). Discussion Low body weight and weight loss are well documented in Alzheimer's disease (1, 2, 24, 25). However, current evidence regarding body composition variations is not conclusive. Various studies agree on a decrease of fat mass (26-28) and some report reduced fat-free mass (28) or fat-free soft tissue mass (27). Other studies have not found this reduction in either the fat-free soft component (26) or the lean body mass (29, 30). The association between progression of AD and worsening nutritional status has been found in studies based on anthropometric indicators (1, 2, 25, 31-33) and MNA (33). Dehydration is frequent in the final phases of AD and, together with cachexia, is the main cause of death (6). The results of this study show a tendency to malnutrition in both men and women with AD; it is present in the early phases of the disease and increases as it progresses. The bioelectrical characteristics (low reactance and phase angle) of patients with both mild-moderate and severe AD can be interpreted as a low number of cells per unit volume, as these parameters are a measure of the capacitance produced by cell membranes. Similar bioelectrical characteristics have been observed in other pathological conditions, e.g. in critically ill patients, in uremic hemodialysis patients, in HIV-infected patients, in cancer patients, in gastrointestinal disease patients, where they indicate a condition of cachexia (7, 34). Migration of the impedance vector toward the region of the RXc graph corresponding to low body cell mass has also been observed in normal ageing, where it indicates sarcopenia (22). The further reduction of the phase angle in patients with severe AD indicates a worsening of 4

5 MARINI:04 LORD_c 3/05/10 9:16 Page 5 the nutritional status. Interestingly, the mean phase angle, as low as 4.5 degrees, corresponds to the critical prognostic value suggested by Toso et al. (34) on the basis of data from patients with lung cancer, renal failure and HIV. The significant lengthening of the impedance vector in patients with severe AD, related to an increase in resistance, is attributable to reduction of the fluid compartment. A similar BIVA pattern has been observed in other pathological conditions characterized by dehydration, such as cholera (35) and renal disease after hemodialysis (10). The bioelectrical variables (phase angle and Z/H) were correlated with the nutritional indicators (MNA, albumin), confirming the suitability of BIVA in the assessment of nutritional status (7). Moreover, BIVA showed significant differences in the nutritional status between patients with mildmoderate AD and controls; such differences were not detected by BMI. In conclusion, this study shows that Alzheimer's disease is characterized by a tendency to malnutrition, with a decrease in body cell mass, which is already present in the initial stages. The significant shift of the mean Z vector in patients with severe AD, with a further reduction of the phase angle and lengthening of the modulus, indicates a worsening of the nutritional status and a tendency to dehydration. The BIVA technique is a promising tool for the screening and monitoring of nutrition and hydration status in Alzheimer's disease. Acknowledgments: We thank the patients who participated in the study. This research was financially supported by the University of Cagliari. The study sponsor had no role in the study design, in the collection, analysis and interpretation of the data, in the writing of the manuscript, or in the decision to submit the manuscript for publication. 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