Precision Medicine of Sodium Benzoate for the Treatment of Behavioral and Psychological Symptoms of Dementia (BPSD)

Figures & data

Figure 1 Flow diagram and disposition of the two treatment groups.

Table 1 Results of Measures of Serum DAAO, Plasma Amino Acids, and Plasma Antioxidants Over the 6-Week Treatment Between Sodium Benzoate and Placebo Groups

Measures		Sodium Benzoate Mean ± SD	Placebo Mean ± SD	p value
DAAO protein, ng/mL	Baseline	46.3 ± 13.1	45.1 ± 17.2	0.304*
	Endpoint	45.7 ± 16.7	50.3 ± 20.7	0.349*
	Difference	−0.2 ± 13.8	2.8 ± 20.4	0.610*
L-Serine, ng/mL	Baseline	3562.7 ± 1274.6	3287.8 ± 1014.3	0.313*
	Endpoint	3569.6 ± 1187.2	3275.5 ± 958.6	0.403*
	Difference	−0.1 ± 1128.3	−70.7 ± 748.3	0.979*
D-Serine, ng/mL	Baseline	55.2 ± 35.0	53.4 ± 27.4	0.895*
	Endpoint	53.1 ± 25.9	47.4 ± 24.3	0.254*
	Difference	−2.7 ± 36.4	−6.1 ± 19.0	0.403*
Glycine, ng/mL	Baseline	4578.7 ± 1926.9	5117.0 ± 2495.6	0.298*
	Endpoint	5315.5 ± 2332.2	4730.8 ± 2054.3	0.154*
	Difference	649.8± 2757.6	−97.0 ± 2613.5	0.242*
L-Alanine, ng/mL	Baseline	13271.8 ±4401.9	12649.5 ± 3230.6	0.475*
	Endpoint	12351.0 ± 3933.7	12820.7 ± 4362.6	0.798*
	Difference	−1087.5 ± 4613.0	219.4 ± 3756.4	0.146*
D-Alanine, ng/mL	Baseline	42.4 ± 39.2	37.8 ± 26.2	0.976*
	Endpoint	34.5 ± 33.2	36.4 ± 39.9	0.930*
	Difference	−8.1 ± 51.9	−1.4 ± 31.7	0.484
SOD protein, U/mL	Baseline	0.04 ± 0.05	0.04 ± 0.06	0.805
	Endpoint	0.05 ± 0.06	0.06 ± 0.06	0.368
	Difference	0.01 ± 0.05	0.02 ± 0.05	0.346
CAT activity, nmol/min/mL	Baseline	55.3 ± 33.5	61.8 ± 32.9	0.278*
	Endpoint	61.5 ± 37.9	58.8 ± 31.0	0.948*
	Difference	6.5 ± 46.5	−0.6 ± 33.2	0.394*

Note: *Mann–Whitney U-test.

Abbreviations: DAAO, D-amino acid oxidase; SOD, superoxide dismutase; CAT, catalase.

Table 2 Zero-Order Correlations Among Laboratory and Clinical Measures at Baseline and Their Difference Values (Endpoint – Baseline)

Sodium Benzoate (N=49)	1	2	3	4	5	6	7	8	9	10
1 DAAO baseline	–
2 DAAO difference	−0.255	–
3 SOD baseline	−0.193	0.175	–
4 SOD difference	−0.072	0.080	−0.254	–
5 CAT baseline	0.108	0.280	0.005	0.032	–
6 CAT difference	0.109	−0.167	0.217	−0.268	−0.592***	–
7 BEHAVE-AD baseline	0.297*	−0.062	0.304*	−0.026	0.302*	−0.051	–
8 BEHAVE-AD difference	−0.138	0.001	0.095	−0.321*	−0.294*	0.432**	−0.461**	–
9 ADAS-cog baseline	0.215	0.081	−0.236	−0.006	0.167	−0.034	0.235	−0.239	–
10 ADAS-cog difference	−0.049	0.335*	0.068	−0.127	−0.027	0.185	−0.320*	0.323*	−0.123	–
Placebo (N=48)	1	2	3	4	5	6	7	8	9	10
1 DAAO baseline	–
2 DAAO difference	−0.450*	–
3 SOD baseline	0.057	−0.080	–
4 SOD difference	−0.104	0.192	−0.444**	–
5 CAT baseline	−0.046	0.129	0.053	0.106	–
6 CAT difference	−0.007	0.071	0.079	−0.164	−0.538***	–
7 BEHAVE-AD baseline	0.130	−0.062	0.150	−0.002	0.329*	−0.360*	–
8 BEHAVE-AD difference	−0.224	0.053	−0.232	−0.033	−0.160	0.230	−0.543***	–
9 ADAS-cog baseline	−0.279	0.115	−0.147	0.167	−0.048	−0.044	−0.241	0.194	–
10 ADAS-cog difference	−0.001	−0.143	0.166	0.052	−0.028	−0.146	−0.043	0.346*	−0.007	–

Notes: The zero-order correlations among amino acids levels and clinical measures were insignificant (data not shown). *p < 0.05; **p < 0.01; ***p < 0.001.

Abbreviations: DAAO, D-amino acid oxidase; SOD, superoxide dismutase; CAT, catalase; BEHAVE-AD, Behavioral Pathology in Alzheimer’s Disease Rating Scale; ADAS-cog, Alzheimer’s disease assessment scale-cognitive subscale.

Table 3 Multiple Linear Regression Analyses of Independent Factors Associated with ADAS-Cog and BEHAVE-AD Improvements (Score Reduction from Baseline to Endpoint) in Sodium Benzoate Group (Stepwise)

ADAS-Cog Improvement
Variable	B (SE)	t	p
Baseline BEHAVE-AD Score	0.371 (0.107)	3.471	0.001
DAAO level difference	−0.196 (0.061)	−3.210	0.003
BMI	0.631 (0.249)	2.530	0.016
Gender, female vs male	3.642 (1.699)	2.143	0.040
Antipsychotic use	4.321 (1.695)	2.496	0.018
Age	−0.263 (0.121)	−2.172	0.037
Adjusted R Square = 0.464
BEHAVE-AD Improvement
Variable	B (SE)	t	p
Baseline BEHAVE-AD score	0.487 (0.106)	4.570	<0.001
CAT Level Difference	−0.043 (0.019)	−2.324	0.026
BMI	0.561 (0.269)	2.087	0.044
Adjusted R Square = 0.446

Notes: The variables were demographic and clinical characteristics (including gender, age, age at illness onset, education, BMI, anti-dementia medication use, antipsychotics use, baseline ADAS-cog score, baseline BEHAVE-AD score, and laboratory parameters at baseline and their difference values (endpoint – baseline) including DAAO, amino acids (L-serine, D-serine, glycine, L-alanine, and D-alanine), and antioxidants (SOD and CAT)). Significant variables are shown in the Table (p < 0.05).

Abbreviations: ADAS-cog, Alzheimer’s disease assessment scale-cognitive subscale; BEHAVE-AD, Behavioral Pathology in Alzheimer’s Disease Rating Scale; BMI, body mass index; DAAO, D-amino acid oxidase; SOD, superoxide dismutase; CAT, catalase.

Table 4 Multiple Linear Regression Analyses of Independent Factors Associated with ADAS-Cog and BEHAVE-AD Improvements (Score Reduction from Baseline to Endpoint) in Placebo Group (Stepwise)

ADAS-Cog Improvement
Variable	B (SE)	t	p
Gender, female vs male	−5.393 (1.880)	−2.868	0.007
Baseline D-alanine Level	−0.073 (0.033)	−2.186	0.036
Adjusted R Square = 0.228
BEHAVE-AD Improvement
Variable	B (SE)	t	p
Baseline BEHAVE-AD score	0.655 (0.109)	6.032	<0.001
Glycine Level Difference	0.001 (0.000)	2.448	0.020
Adjusted R Square = 0.490

Notes: The variables were demographic and clinical characteristics (including gender, age, age at illness onset, education, BMI, anti-dementia medication use, antipsychotics use, baseline ADAS-cog score, baseline BEHAVE-AD score, and laboratory parameters at baseline and their difference values (endpoint – baseline) including DAAO, amino acids (L-serine, D-serine, glycine, L-alanine, and D-alanine) and antioxidants (SOD and CAT)). Significant variables are shown in the Table (p < 0.05).

Abbreviations: ADAS-cog, Alzheimer’s disease assessment scale-cognitive subscale; BEHAVE-AD, Behavioral Pathology in Alzheimer’s Disease Rating Scale; BMI, body mass index; DAAO, D-amino acid oxidase; SOD, superoxide dismutase; CAT, catalase.

Data Availability Statement

The protocol of this study is online (https://clinicaltrials.gov/ct2/show/NCT02103673). The individual de-identified participant data are available to qualified investigators on request to the corresponding author after the request is approved by the Institutional Review Board and Data Safety Monitoring Board of Kaohsiung Chang Gung Memorial Hospital, Institutional Review Board and Data Safety Monitoring Board of China Medical University Hospital, and Institutional Review Board and Data Safety Monitoring Board of Lin-Shin Hospital.