DE212014000063U1 - Use of benzoic acid salt in the manufacture of a composition for the prevention or treatment of dementia or mild cognitive impairment - Google Patents

Abstract

Use of benzoic acid salt for the manufacture of a composition for the prevention or treatment of dementia or mild cognitive impairment.

Description

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION

The present invention relates to a novel treatment for dementia or mild cognitive impairment in general, and more particularly to a use of benzoic acid salt in the manufacture of a composition for the prevention or treatment of dementia or mild cognitive impairment.

Description of the Prior Art

The prevalence of dementia in the elderly is rapidly increasing with the age of society, with the worsening clinical history being a heavy burden on both the patients and their families. Early detection and intervention in Alzheimer's disease (hereinafter referred to as "AD") is critical to outcome (1). Mild cognitive impairment (hereinafter referred to as "MCI"), in particular amnestic MCI (hereinafter referred to as "aMCI"), is a risk factor and may be a precursor of AD. The common treatment for mild and moderate AD is an acetylcholinesterase inhibitor (hereinafter referred to as "AChEI"). However, its effectiveness and compatibility are unsatisfactory. In addition, AChEI shows no convincing efficacy against MCI (2-4), implying that another mechanism (s) may be subject to the pathogenesis of MCI.

Although NMDAR activity is crucial for cognitive function, its role in AD is not fully understood. NMDAR overactivation by glutamate leads to cell death. Excitotoxicity is one of the theories of AD, especially in the late stage (54). Based on the hypothesis of NMDAR overactivation (7), NMDAR antagonists are being developed for the treatment of AD. Memantine is a non-competitive NMDAR partial antagonist of low affinity, which can presumably block NMDAR overactivation by preventing excessive influx of calcium (8-10), and has been used for the treatment of moderate-grade AD. However, efficacy was limited to the early phase, including MCI and mild AD (12). NMDAR antagonists, such as MK-801, also induce apoptosis and neurodegeneration in both in vitro and in vivo studies (13). Ketamine, another NMDAR antagonist, interferes with spatial learning and verbal information capability in healthy people in a double-blind, randomized, placebo-controlled study (14). These findings raise concerns that an NMDA antagonist may affect cognition and memory in early AD.

Optimal NMDAR activation is crucial for synaptic plasticity (15), memory and cognitive function (16). The attenuation of NMDAR-mediated neurotransmission can result in the loss of neuronal plasticity and cognitive deficits in the aging brain, which can contribute to clinical deterioration and brain atrophy (17). Age-related decreases in the density of NMDAR in the cerebral cortex and hippocampus have been observed in humans (18). Previous studies have also found a decrease in glycine-dependent radioligand binding to the NMDAR in the cerebral cortex of post-mortem and neurosurgical tissue in patients with AD (19, 20). D-cycloserine, a partial agonist at the NMDAR glycine site, has been reported in some clinical trials to activate NMDAR in the brain of AD patients (21) and to classify it on the cognitive subscale "Alzheimer's Disease Assessment Scale "(ADAS-cog) (22) improved.

The current study suggests that NMDAR elevation is beneficial against early and mild dementia. There is an age-related decrease in glutamate content and synthesis in the human cerebral cortex and hippocampus (18, 55), the most significant and consistent finding being the decrease in the density of NMDAR in the elderly and in patients with AD (18). is. Low serum D-serine and serum L-serine levels have also been reported in patients with AD (56). Therefore, in addition to the cholinergic system, dysfunction of NMDA neurotransmission may play an important role in the pathophysiology of AD.

There are several ways to increase NMDA activation. One of them is the inhibition of the activity of D-amino acid oxidase (DAAO), a flavoenzyme of peroxisomes responsible for the degradation of D-serine and D-alanine (24-26), thereby reducing the levels of D-amino acid oxidase. Amino acids which are the neurotransmitters for the co-agonist NMDAR. Recent data indicate that aging is associated with decreased levels of D-serine, thereby affecting NMDAR transmission, and D-serine treatment significantly lowers the level of neuronal death, suggesting that Serine has a neuroprotective effect against apoptosis (27). In addition, neural stem cells from postnatal mouse forebrain can synthesize D-serine, thereby stimulating proliferation and neuronal differentiation of stem cells (28).

Increasing NMDAR by DAAO inhibition may be a safe way to reduce the nephrotoxicity of D-serine (29), especially in the elderly population.

Sodium benzoate is a DAAO inhibitor. Benzoic acid exists in many plants and is a natural component of food, including milk products (30). Benzoic acid and its salts, including sodium benzoate, which are generally recognized as safe (GRAS), are also food preservatives which are widely used in making groats, buffers, soy sauce, processed meat, etc. (31).

There are several other preclinical studies that support the CNS effects of DAAO inhibitors, although the memory effect has not been tested (32-34). N-methyl-D-aspartate receptor (NMDAR) -mediated neurotransmission is vital for learning and memory. The hypofunction of NMDAR has been reported to play a role in the pathophysiology of Alzheimer's disease (AD), especially in the early stages. Increasing NMDAR activity may be a new approach to treatment. One of the methods of increasing NMDAR activity is to increase the levels of NMDA co-agonists by blocking their metabolism. Sodium benzoate is effective in NMDAR models, such as pain relief (35, 36) and partially inhibited cell death in glial cells (37). The CNS bioavailability of benzoate is good (38). To test whether DAAO inhibition is beneficial for the early stage of dementia, the inventors performed this experiment to test the efficacy and safety of sodium benzoate in patients with aMCI or mild AD.

BRIEF SUMMARY OF THE INVENTION

Based on the supporting evidence, the inventors suggested that NMDA enhancers may be helpful for the early degressive process of AD and mild cognitive impairment due to their role in learning and memory as well as neurogenesis and neuroplasticity, and thus the present invention has been completed.

The present invention provides the use of benzoic acid salt in the manufacture of a composition for the prevention or treatment of dementia or mild cognitive impairment.

In one aspect of the present application, the benzoic acid salt may be sodium benzoate, potassium benzoate or calcium benzoate, and preferably the benzoic acid salt is sodium benzoate.

In another aspect of the present application, an effective amount of benzoic acid salt may be 200 milligrams (mg) / day to 2000 mg / day, preferably 500 mg / day to 900 mg / day, and more preferably 750 mg / day.

In another aspect of the present application, an effective amount of sodium benzoate is 200 mg / day to 2000 mg / day, preferably 500 mg / day to 900 mg / day, and more preferably 750 mg / day.

In one aspect of the present application, dementia includes early-stage dementia. In one embodiment of the present application, early-stage dementia includes mild Alzheimer's disease.

In one aspect of the present application, mild cognitive impairment includes amnestic mild cognitive impairment.

BRIEF DESCRIPTION OF THE DRAWINGS

1 shows a flow chart and arrangement for two treatment groups.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following illustrative embodiments are provided to explain the disclosure of the present invention. These and other advantages and effects will become apparent to those skilled in the art after reading the disclosure of this specification.

definition of Terms

As used herein, the term "dementia" refers to a group of symptoms that interfere with intellectual and social skills that are severe enough to interfere with daily functioning, including memory loss, speech problems, inability to learn, or new ones To remember information, etc. (78). The term "early stage dementia" refers to the condition of dementia patients whose CDR (Clinical Dementia Rating) rating is not more than one.

As used herein, the term "Alzheimer's Disease (AD)" refers to a type of progressive, mentally debilitating disease that may occur in middle or old age due to general degeneration of the brain and the criteria of the National Institute of Neurological and Communicative Disorders and Stroke "and the" Alzheimer's Disease and Related Disorders Association ". Excessive glutamatergic neurotransmission, particularly through the N-methyl-D-aspartate receptor (NMDAR), leads to neurotoxicity (5, 6), which is implicated in the pathophysiology of AD, especially in the late phase. The term "mild Alzheimer's disease" refers to the condition of dementia patients whose CDR (Clinical Dementia Rating) rating is 0.5 or 1.

As used herein, the term "mild cognitive impairment (MCI)" refers to a type of mental deterioration with CDR (clinical dementia rating) rating of less than 1. The term "amnestic mild cognitive impairment (aMCI)" refers to a type of MCI in which memory is primarily influenced.

As used herein, the term "clinical dementia rating (CDR)" refers to a type of rating system to assess the degree of dementia. The Clinical Dementia Rating is a five-point scale in which CDR-0 does not mean cognitive impairment, and then the remaining four points are for different stages of dementia: CDR within 0.5-1 = very mild to mild dementia, CDR within 1-2 = easy to medium, CDR within 2-3 = medium to heavy, CDR> 3 = heavy.

example

The present invention tests the efficacy and safety of sodium benzoate, a D-amino acid oxidase (DAAO) inhibitor, for the treatment of amnestic mild cognitive impairment (aMCI) and mild AD.

The inventors conducted a randomized, double-blind, placebo-controlled trial in four major medical centers in Taiwan. Sixty patients with aMCI or mild AD were treated with 250-750 mg / day sodium benzoate or a placebo for 24 weeks. The Alzheimer's disease assessment scale - cognitive subscale (ADAS-cog, the primary result) and global function (assessed by a Clinician Interview Based Impression of Change plus Caregiver Input (CIBIC-plus)) were measured every 8 weeks , Additional cognitive complexes were measured at baseline and endpoint.

Attendees

Patients were removed from the outpatient departments at the Department of Psychiatry and Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Department of Psychiatry, China Medical University Hospital, Taichung, Department of Psychiatry, Taichung Veterans General Hospital, Taichung, and Department of Neurology , Lin-Shin Hospital, Taichung, which represent four major medical centers in Taiwan. The study was approved by the institutional IRB in four locations and carried out in accordance with the current revision of the Helsinki Declaration. Patients were evaluated by researching psychiatrists and neurologists after careful medical and neurological evaluation.

Patients were enrolled in this study if they: 1) NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association) (39) criteria for probable AD and a Clinical Dementia Rating (CDR) (40) - Classification of 1, or criteria for aMCI (41) of presumably degenerative nature, defined as subjective memory complaints, confirmed by an informant and insufficient overall cognitive and functional impairment to meet the NINCDS-ADRDA criteria and a CDR rating of 0 5, 2) 50-90 years old, 3) were physically healthy and had all laboratory assessments (including urine / blood routine, biochemical tests and electrocardiograph) within normal limits, 4) a mini-mental state examination (MMSE 5) had sufficient training to be able to communicate effectively and were able to complete the evaluations of the study, and 6) they were in agreement with the study and their informed To teach consent. For patients who were already on AChEI therapy, AChEI had to be continued for nearly three months before enrollment. The AChEI dose had to be kept unchanged during the study. For patients who did not have AChEI therapy, AChEI or other anti-dementia medication was banned during the study period.

Exclusion criteria closed the medical history of significant cerebrovascular disease; Hachinski ischemic classification> 4; severe neurological, psychiatric or medical conditions other than AD; Substance (including alcohol) abuse or dependence; Delusion, hallucination or delirium symptoms; severe vision or hearing loss; and inability to follow a protocol.

Program structure

All patients were randomly assigned to receive a 24-week treatment of sodium benzoate or placebo in a double-blind manner. Efficacy and safety were assessed on the baseline and at the ends of weeks 8, 16 and 24. Two hundred and fifty mg of sodium benzoate or placebo were packaged with identical capsules provided in coded containers. The dose was started at 250-500 mg / day (250 mg once or twice daily) in the first eight weeks, then increased by 250-500 mg / day from the 9th week and again by 250-500 mg / day of the 17th week of the study, if clinically indicated, further increased. The inventors decided to apply 250-750 mg / day, taking into account the higher age of the subjects in the present study. Patients were randomized in a cluster of 6 subjects to receive sodium benzoate or a placebo in a 1: 1 ratio from an independent investigational pharmacist.

Patients, carers and investigators, with the exception of the testing pharmacist, were all uninformed about the allocation. The patient's medical compliance and safety were closely monitored by supervisors and research physicians and tablet scores by the study staff.

reviews

The primary outcome was the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog) (43), measured at weeks 0, 8, 16 and 24. ADAS-cog is the most popular cognitive assessment tool used in clinical AD trials. It consists of 11 tasks, including word cueing, naming, commands, constructive apraktagnosia, ideator apraxia, orientation, word recognition, instruction reminder, spoken language ability, word difficulty and comprehension. His ratings range from 0 (best) to 70 (worst).

Measurements of the second result include the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus) (44), measured at weeks 8, 16 and 24, and the additional detection complex measured at baseline and endpoint (was measured at baseline) At the end of each measurement of the patient's additional detection complex).

CIBIC-plus is a comprehensive assessment of change based on a large, semi-structured interview, which includes nurse-assisted information. It is a 7-point rating scale that goes from 1-7, with 1 greatly improving; 4, no change and 7 clearly bad.

The additional recognition complex was calculated by the average of the T-ratings of speed of processing (category speech flow), working memory (WMS-III, spatial delineation) (45), and verbal learning and memory tests (WMS-III, word enumeration) (45). The rough grading of the speed of processing, working memory and verbal learning and memory tests were to become a T-score with a mean of 50 and a standard deviation of 10 for each test can be made comparable, standardized. The additional recognition complex was used in combination with ADAS-cog to complete the cognitive assessment. It has been found that the decrease in processing speed is associated with age (46, 47). Working memory (48) and verbal learning / memory (49) also decrease in patients with AD.

Systemic side effects of treatments were assessed by means of physical and neurological exams, laboratory tests, including CBC and biochemistry, and by applying the Side Effects Rating Scale according to the Udvalg for Kliniske Undersogelser (UKU) (50) on the baseline, week 8 , 16 and 24 examined.

Clinical evaluations were performed by research psychiatrists and neurologists who were trained and knowledgeable in the assessment scales. Interrater reliability or judgment was analyzed by the ANOVA test. Only assessors who achieved the intra-class correlation coefficients of ≥ 0.90 during pre-study training were allowed to evaluate the patients in the trials. In order to maintain high reliability between assessors and assessor compliance and to prevent assessor bias, the assessor visited at least once a training and reliability review center. To minimize variability between different assessors, each individual patient was evaluated by the same research psychiatrist or neurologist throughout the experiment.

data analysis

Chi-square test (or Fisher's exact test) was used to distinguish between category variables and Student's two-sample t-test (or Mann-Whitney U-test if the distribution was not normal) for continuous variables between to compare two treatment groups. Mean changes from the baseline in repeated measurement scores (ADAS-cog) were assessed using the "Generalized Estimating Equation" (GEE) procedure at treatment, visit and treatment-visit interaction as fixed effects and intersection as the only statistical or random effect; Baseline score as the covariance. The GEE analyzes were performed using SAS / STAT (SAS Institute, Cary, NC) "PROC GENMOD" method with AR (autoregressive) (l) working correlation structure using the boundary value model instead of the mixed-effect model carried out. Therapeutically effective quantities (Cohen's d) were used to determine the magnitude of the improvement for the continuous variables (51) resulting from the sodium benzoate treatment compared to a placebo.

Finally, all of the 60 randomized patients completed at least one repeat treatment, and 50 (90%) of them completed the 24-week trial (as in 1 shown). No imputation for the incomplete data was used for the GEE analysis.

There were no baseline ratings for the CIBIC-plus because this was considered an assessment of a baseline change. Differences in CIBIC-plus scores at week 8, 16, 24 and endpoint between groups were assessed by Student's two-sample t-test (or Mann-Whitney U-test if the distribution was abnormal).

Fisher's exact test was used to compare differences in dropout rates between the two groups. Cohen's w was used to determine the effect size of categorical variables (52). All data was analyzed by IBM SPSS Statistics (version 18.0, SPSS Inc.) or SAS version 9.3. All p-values for clinical measurements were based on two-tailed tests with a significance level of 0.05.

Results

Sixty patients were eligible and randomized (as in 1 shown). Demographic data, educational level, onset of illness, disease duration, CDR, body mass index (BMI) and baseline AChEI use were between the sodium benzoate group (N = 30) and the placebo group (N = 30 ) (p> 0.05) similar (as shown in Table 1). AChEI doses were within the therapeutic range and were similar between the two groups (as shown in Table 1). Mean doses of sodium benzoate at weeks 8, 16 and 24 were 275.0 ± 76.3, 525.0 ± 100.6 and 716.7 ± 182.6 mg / day, respectively. Table 1. Baseline demographic characteristics of the placebo or sodium benzoate treatment group treatment groups Benzoate (n = 30) Placebo (n = 30) p Demographic data Female, n (%) 18 (60,0) 19 (63,3) 1.0 ^a Male, n (%) 12 (40,0) 11 (36,7) 1.0 Age, years, average (SD) 70.7 (7.9) 69.7 (9.0) 0.64 ^b Age at onset, years, average (SD) 69.8 (7.1) 68.5 (8.9) 0.54 ^b Disease Duration, Months, Average (SD) 14.2 (15.6) 13.6 (17.9) 0.47 ^c CDR at output line, n (%) 1.0 ^a CDR 0.5 15 (50.0) 16 (53,3) CDR 1 15 (50.0) 14 (46,7) Education, Years, Average (SD) 5.9 (4.7) 7.5 (5.2) 0.36 ^c BMI, average (SD) 24.6 (4.1) 23.9 (3,4) 0.51 ^b Patients using AChEIs, n total 9 9 1.0 ^a Donepezil (dose, average ± SD) 7 (7.9 ± 2.7) 5 (8.0 ± 2.7) 1.0 ^c Rivastigmine (dose, average ± SD) 0 (0.0 ± 0.0) 3 (7.5 ± 2.6) N / A Galantamine (dose, average ± SD) 2 (16.0 ± 0.0) 1 (16.0 ± 0.0) 1.0 ^c AChEI, acetylcholinesterase inhibitor; BMI, body mass index; CDR, Clinical Dementia Rating; NA, not associated.
^a Fisher's exact test.
^b Independent t-test.
^c Mann-Whitney U-Test

The mean ± SD ratings for both primary and secondary outcomes, including ADAS-cog, additional recognition complex and CIBIC-plus, from the two groups of patients are shown in Table 2. At week 0 (baseline), there were no significant differences between the two groups in ADAS-cog and additional recognition complex (p = 0.75 and 0.27, respectively). Table 2. Average ± SD ratings of both primary and secondary outcomes

For the primary result, sodium benzoate produced a greater improvement in the ADAS-cog rating than the placebo therapy throughout the study (mean differences from baseline were 3.8, 5.4, 5.9 and 5.9 in the benzoate Group and 2,4, 1,7, 2,7 and 1,7 in the placebo group, at weeks 8, 16, 24 and endpoint, p = 0.3730, 0.0021, 0.0116 and 0, respectively , 0031), with effect score of 0.86 at the end of the study (as shown in Table 2). The results were similar when the baseline ADAS cog score was controlled in the GEE model (as shown in Table S1). Table S1. Results of measurements of ADAS-cog over the 24-week treatment using Generalized Estimating Equations (GEE) method set for the baseline effect scale Benzoate average ± SD (n) Placebo average ± SD (n) Estimate* SE Z P value ADAS-cog output line 15.6 ± 7.6 (30) 15.0 ± 7.3 (30) Week 8 11.6 ± 6.5 (30) 11.7 ± 8.5 (30) -2.6070 .8801 -2.96 0.0031 Week 16 9.8 ± 6.2 (29) 12.3 ± 9.1 (26) -1.3145 1.0526 -1.25 0.2118 Week 24 9.7 ± 6.4 (28) 11.3 ± 9.2 (25) -2.0495 .9114 -2.25 0.0245 endpoint 9.6 ± 6.2 (30) 12.4 ± 9.1 (30) -1.9247 .9507 -2.02 0.0429 medicine .5135 .3616 1.42 .1555 Week 8 × drug -1.2397 1.1366 -1.09 .2754 Week 16 × drug -4.4638 1.2601 -3.54 0.0004 Week 24 × drug -3.7523 1.2379 -3.03 0.0024 Endpoint × drug -3.6255 1.2278 -2.95 0.0031 * Estimate is the coefficient of treatment-visit-interaction term in the multiple linear regression model of the GEE procedure. An autoregressive AR (l) covariance matrix was adapted to the repeated measurements of a patient. The p-values were based on two-sided tests.
ADAS-cog: Alzheimers disease assessment scale-cognitive subscale.
Bolded P values indicate significance.

For the secondary results, sodium benzoate was better than the placebo in the additional detection complex at the endpoint (p = 0.007, effect size = 0.78).

Benzoate treatment also produced greater improvement in CIBIC plus than placebo at week 16 (p = 0.015), week 24 (p = 0.016), and endpoint (p = 0.012, effect measure = 0.73 at endpoint). (as shown in Table 2).

The dropout rate (3.3%) of the sodium benzoate group was generally lower than that (16.7%) of the placebo group, yet not significant (p = 0.195).

For subgroup analysis, we continued to evaluate the efficacy of sodium benzoate versus placebo in CDR 0.5 and CDR 1 subgroups. For ADAS-cog, sodium benzoate produced greater improvement than placebo therapy at week 16, 24, and endpoint (p = 0.0151, 0.0387, and 0.0092, respectively) in the CDR 1 subgroup. However, sodium benzoate was not superior to placebo therapy in the CDR 0.5 subgroup throughout the study (p> 0.05) (as shown in Table 3).

Although ADAS-cog is widely used in clinical AD trials, it may be less sensitive to MCI (67). One of the strategies to improve the detection of responsiveness for MCI is to add additional cognitive testing. People with MCI have been found to be impaired in neuropsychological functions (68), such as speed of processing (69), working memory (70), and verbal learning and memory (71). In the aMCI subset of the present invention, sodium benzoate exhibited borderline significance in enhancing the additional recognition complex consisting of processing speed, working memory, and verbal learning / memory, but not the ADAS cog rating. Our result reflects the assumption that additional neuropsychological tests more sensitive to subtle defects should also be used in the trials for MCI. Table 3. Results of measurements of ADAS-cog over 24-week treatment with GEE procedures in subgroups scale Benzoate average ± SD (n) Placebo average ± SD (n) Estimate ^a SEM Z p CDR 0.5 output line 13.8 ± 6.1 (15) 11.9 ± 5.4 (16) reference .3560 Week 8 × drug 10.4 ± 6.0 (15) 8.3 ± 4.0 (16) 0.3213 .9690 0.33 .7402 Week 16 × drug 9.1 ± 6.1 (15) 10.2 ± 5.6 (15) -3.2694 1.9222 -1.70 .0890 Week 24 × drug 9.5 ± 6.2 (14) 8.7 ± 5.0 (14) -1.8480 1.7834 -1.04 .3001 Endpoint × drug 9.2 ± 6.1 (15) 9.8 ± 5.9 (16) -2.3444 1.9664 -1.19 .2332 CDR 1 output line 17.1 ± 8.6 (15) 16.7 ± 8.2 (14) reference .8910 Week 8 × drug 13.0 ± 7.1 (15) 15.6 ± 10.6 (14) -2.5727 2.0872 -1.23 .2177 Week 16 × drug 10.6 ± 6.4 (14) 15.2 ± 12.2 (11) -55.0788 2.0897 -2.43 0.0151 Week 24 × drug 9.9 ± 6.8 (14) 14.5 ± 12.3 (11) -4.6262 2.2375 -2.07 0.0387 Endpoint × drug 10.0 ± 6.6 (15) 15.4 ± 11.3 (14) -5.4755 2.1031 -2.60 0.0092

Abbreviations are the same as those in Tables 1 and 2.
^a Estimation is the coefficient of treatment-visit-interaction term in the multiple linear regression model of the GEE procedure. An autoregressive covariance matrix was adapted to the repeated measurements of a patient. The p-values were based on two-sided tests.

Sodium benzoate showed better efficacy in the CDR 1 subgroup (p = 0.041) and borderline significance in the CDR 0.5 subset (p = 0.063) in improving the additional recognition complex (as shown in Table 4). For CIBIC-plus, sodium benzoate produced greater improvement than placebo therapy at week 24 and endpoint (p = 0.040 and 0.018, respectively) in the CDR 1 subgroup but not in the CDR 0.5 subgroup (as shown in Table 5).

Sodium benzoate also did not improve the CIBIC-plus score in the aMCI subgroup. One possible explanation is a saturation effect in which functional impairment is minimal in the MCI individuals, thereby limiting space for further improvement. Table 4. Results of additional detection complex measurements over 24-week independent t-test treatment in subgroups scale Benzoate average ± SD (n) Placebo average ± SD (n) Cohen's d t p CDR 0.5 output line 49.0 ± 6.9 (14) 52.8 ± 7.6 (15) -1.395 , 174 endpoint 50.5 ± 7.1 (14) 50.8 ± 8.5 (15) - 108 915 difference 1.5 ± 3.5 (14) -1.9 ± 5.8 (15) , 7098 1,939 , 063 CDR 1 output line 48.8 ± 6.6 (12) 49.3 ± 9.3 (12) -, 150 , 882 endpoint 50.3 ± 6.1 (12) 48.0 ± 9.0 (12) , 742 , 466 difference 1.6 ± 2.8 (12) -1.3 ± 3.5 (12) , 9150 2,176 , 041

The p-values were based on two-sided tests. Additional recognition complex, the composition test classification of speed of processing, working memory and verbal learning and memory. CDR, Clinical Dementia Rating. Table 5. Clinical measurements of CIBIC-Plus over 24-week treatment with Mann-Whitney U-Test in subgroups scale Benzoate average ± SD (n) Placebo average ± SD (n) Cohen's d Z p CDR 0.5 Week 8 3.5 ±, 5 (15) 3,4 ±, 5 (16) , 1771 -, 508 , 611 Week 16 3.3 ±, 5 (15) 3.7 ±, 8 (15) -, 6042 -1.720 , 085 Week 24 3.3 ±, 5 (14) 3.6 ±, 6 (16) -, 4867 -1.260 208 endpoint 3.3 ±, 5 (15) 3.6 ±, 6 (16) -, 4086 -1.029 303 CDR 1 Week 8 3.3 ±, 5 (15) 3.6 ±, 6 (14) -, 6697 -1.719 , 086 Week 16 3.2 ±, 7 (15) 3.6 ±, 5 (11) -, 7374 -1.678 , 093 Week 24 3.1 ±, 8 (14) 3.8 ±, 9 (11) -, 8805 -2.052 , 040 endpoint 3.1 ±, 8 (15) 3.9 ±, 9 (14) -, 9494 -2.370 , 018

The p-values were based on two-sided tests. Mann-Whitney U test was used because the distribution of CIBIC-plus rating was abnormal.
CDR, Clinical Dementia Rating;
CIBIC-plus, Clinical Interview Based Impression of Change plus Caregiver Input.

It is crucial to identify AD and treat it as early as possible to potentially stop its progress (53). The present invention is the first to apply a DAAO hemimer, herein, sodium benzoate, as a new treatment for the early stage of cognitive decline. The result showed that sodium benzoate had better efficacy than placebo in improving the ADAS cog score, additional recognition complex (consisting of speed of processing, working memory, verbal learning and memory) and overall function in all subjects overall. Subgroup comparisons have shown that sodium benzoate was beneficial for all outcome measurements among patients with mild AD. In the aMCI subset, sodium benzoate showed borderline significance in improving the recognition complex. In addition, sodium benzoate also showed positive safety profiles.

Concerning the dosing strategy, sodium benzoate provided better efficacy than placebo at week 16 and week 24, with the average dose of 525 mg / day and 716 mg / day respectively, possibly implying that sodium benzoate at 500-750 mg / day is more effective than 250 mg /Day. Another possibility is that a longer sodium benzoate treatment time gives better treatment response.

AChEIs are commonly used for the treatment of AD (57, 58), but are not recommended for the treatment of MCI due to weak and beneficial effects and risk of side effects (59, 60). The consensus statement of the British Association for Psychopharmacology concludes that neither AChEIs nor memantine is effective in the treatment of MCI (61). Other compounds commonly used to treat MCI, such as vitamin E (62), folic acid (63), omega-3 fatty acid (64), piracetam (65), and ginkgo biloba (66), also fail to show convincing evidence of a reinforcing cognitive effect. Sodium benzoate is generally safe and its efficacy for aMCI achieved a trend of improvement in the current small size study.

Very high levels of DAAO are detected in the cerebellum of the adult brain, whereas the activity of DAAO in the forebrain, such as prefrontal cortex and hippocampus, is low despite stable expression (75, 76). The cellular localization and function of DAAO are probably different between forebrain and cerebellum: it is glial in the cerebellum, but mainly neuronal in the cerebral cortex. However, the effect of DAAO inhibitors on the forebrain D-serine level is inconsistent. Most DAAO inhibitors, except for some, can cause a measurable D-serine increase in the forebrain, as observed in the cerebellum (77). Nonetheless, the cerebellum is involved in cognition. Sodium benzoate can exert its procognitive effects through not only cerebral, but also cerebellar mechanism.

The present invention suggests that sodium benzoate, a DAAO inhibitor, is beneficial for cognitive and overall function in patients with early-stage AD and is potentially beneficial to aMCI. The use of sodium benzoate for early AD and aMCI gives hope for the growing aging population with cognitive decline. The results of the present application suggest that benzoate treatment for early-stage dementia may be due to activation of neurogenesis and anti-apoptosis.

Unfavorable effects

Both sodium benzoate and placebo were well tolerated. Only one patient in the placebo group reported dizziness at week 16. The adverse reaction was mild and did not justify medical treatment. There were no reported side effects in the sodium benzoate group, supported by the UKU side-effects rating scale at all visits. No dropouts due to side effect.

Routine blood cell count and chemistry were all within normal ranges and remained unchanged after treatment (data not shown).

This work was done by the National Science Council, Taiwan (NSC 99-3114-B-182A-003, NSC 101-2314-B-182A-073-MY2 and NSC-101-2325-B-039-009) . Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH102-TD-B-111-004) and China Medical University Hospital, Taiwan (CMU 101-AWARD-13, DMR-99-153) supported.

The foregoing descriptions of the embodiments in detail are merely illustrative of the disclosure of the principle and functions of the present invention and do not limit the scope of the present invention. It should be understood by those skilled in the art that all modifications and variations in accordance with the spirit and principle in the disclosure of the present invention should fall within the scope of the appended claims. It is intended that the specification and examples be considered as exemplary only, with a true scope of the invention being indicated by the following claims.

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• 3. Raschetti R, Albanese E, Vanacore N, Maggini M (2007): Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials. PLoS medicine. 4: e338 .
• 4. Birks J, Flicker L (2006): Donepezil for mild cognitive impairment. Cochrane Database Syst Rev.CD006104 .
• 5. Lipton SA, Rosenberg PA (1994): Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med. 330: 613–622 .
• 6. Kalia LV, Kalia SK, Salter MW (2008): NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol. 7: 742–755 .
• 7. Choi DW (1992): Excitotoxic cell death. Journal of neurobiology. 23: 1261–1276 .
• 8. Scarpini E, Scheltens P, Feldman H (2003): Treatment of Alzheimer'disease: current status and new perspectives. Lancet neurology. 2: 539–547 .
• 9. Gardoni F, Mauceri D, Malinverno M, Polli F, Costa C, Tozzi A, et al. (2009): Decreased NR2B subunit synaptic levels cause impaired long-term potentiation but no long-term depression. J Neurosci. 29: 669–677 .
• 10. Pallas M, Camins A (2006): Molecular and Biochemical Features in Alzheimer disease. Curr Pharm Des. 12: 4389–4408 .
• 11. Reisberg B, Doody R, Stöffler B, Schmitt F, Ferris S, Möbius HJ (2003): Memantine in Moderate-to-Severe Alzheimer Disease. N Engl J Med. 348: 1333–1341 .
• 12. Schneider LS, Dagerman KS, Higgins JP, McShane R (2011): Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol. 68: 991–998 .
• 13. Yoon WJ, Won SJ, Ryu BR, Gwag BJ (2003): Blockade of ionichtropic glutamate receptors produces neuronal apoptosis through the Bax-cytochrome C-caspase pathway: the causative role von Ca2+ deficiency. J Neurochem. 85: 525–533 .
• 14. Rowland LM, Astur RS, Jung RE, Bustillo JR, Lauriello J, Yeo RA (2005): Selective cognitive impairments associated with NMDA receptor blockade in humans. Neuropsychopharmacology. 30: 633–639 .
• 15. Mattson MP (2008): Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann N Y Acad Sci. 1144: 97–112 .
• 16. Tilleux S, Hermans E (2007): Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J Neurosci Res. 85: 2059–2070 .
• 17. Olney JW, Farber NB (1995): Glutamate receptor dysfunktion and schizophrenia. Arch Gen Psychiatry. 52: 998–1007 .
• 18. Segovia G, Porras A, Del Arco A, Mora F (2001): Glutamatergic neurotransmission in aging: a critical perspective. Mech Ageing Dev. 122: 1–29 .
• 19. Procter AW, Stirling JM, Stratmann GC, Cross AJ, Bowen DM (1989): Loss of glycine-dependent radioligand binding to the N-methyl-D-aspartate-phencyclidine receptor complex in patients with Alzheimer's disease. Neurosci Lett. 101: 62–66 .
• 20. Procter AW, Wong EH, Stratmann GC, Lowe SL, Bowen DM (1989): Reduced glycine stimulation of [3H]MK-801 binding in Alzheimers disease. J Neurochem. 53: 698–704 .
• 21. Chessell IP, Procter AW, Francis PT, Bowen DM (1991): D-cycloserine, a putative cognitive enhancer, facilitates activation of the N-methyl-D-aspartate receptor-ionophore complex in Alzheimer brain. Brain Res. 565: 345–348 .
• 22. Tsai GE, Falk WE, Gunther J, Coyle JT (1999): Improved cognition in Alzheimers disease with short-term D-cycloserine treatment. Am J Psychiatry. 156: 467–469 .
• 23. Lane HY, Lin CH, Green MF, Hellemann G, Huang CC, Chef PW, et al. (2013): A Randomized, Double-Blind, Placebo-Controlled Add-on Treatment of Benzoate, a D-Amino Acid Oxidase Inhibitor, for Schizophrenia. JAMA Psychiatry 70: 1267–1275 .
• 24. Fukui K, Miyake Y (1992): Molecular cloning and chromosomal localization of a human gene encoding D-amino-acid oxidase. The Journal of biological chemistry. 267: 18631–18638 .
• 25. Vanoni MA, Cosma A, Mazzeo D, Mattevi A, Todone F, Curti B (1997): Limited proteolysis and X-ray crystallography reveal the origin of substrate specificity and of the rate-limiting product release during oxidation of D-amino acids catalyzed by mammalian D-amino acid oxidase. Biochemistry. 36: 5624–5632 .
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• 33. Adage T, Trillat AC, Quattropani A, Perrin D, Cavarec L, Shaw J, et al. (2008): In vitro and in vivo pharmacological profile of AS057278, a selective d-amino acid oxidase inhibitor with potential anti-psychotic properties. Eur Neuropsychopharmacol. 18: 200–214 .
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• 37. Park HK, Shishido Y, Ichise-Shishido S, Kawazoe T, Ono K, Iwana S, et al. (2006): Potential role for astroglial D-amino acid oxidase in extracellular D-serine metabolism and cytotoxicity. Journal of biochemistry. 139: 295–304 .
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• 41. Lu PH, Edland SD, Teng E, Tingus K, Petersen RC, Cummings JL (2009): Donepezil delays progression to AD in MCI subjects with depressive symptoms. Neurology. 72: 2115–2121 .
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The references cited in the appendix are each incorporated by reference as if individually included.

• 1. Budd D, Burns LC, Guo Z, L'Italy G, Lapuerta P (2011): Impact of early intervention and disease modification in patients with dementia Alzheimer's disease: a Markov model simulation. ClinicoEconomics and outcomes research: CEOR. 3: 189-195 ,
• Second Loy C, Schneider L (2006): Galantamine for Alzheimer's Disease and mild cognitive impairment. Cochrane Database System Rev.CD001747 ,
• Third Raschetti R, Albanese E, Vanacore N, Maggini M (2007): Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomized trials. PLoS medicine. 4: e338 ,
• 4th Birks J, Flicker L (2006): Donepezil for mild cognitive impairment. Cochrane Database System Rev. CD006104 ,
• 5th Lipton SA, Rosenberg PA (1994): Excitatory amino acids as a final common pathway for neurological disorders. N Engl J Med. 330: 613-622 ,
• 6th Kalia LV, Kalia SK, Salter MW (2008): NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol. 7: 742-755 ,
• 7th Choi DW (1992): Excitotoxic cell death. Journal of neurobiology. 23: 1261-1276 ,
• 8th. Scarpini E, Scheltens P, Feldman H (2003): Treatment of Alzheimer's Disease: current status and new perspectives. Lancet neurology. 2: 539-547 ,
• 9th Gardoni F, Mauceri D, Malinverno M, Polli F, Costa C, Tozzi A, et al. (2009): Decreased NR2B subunit synaptic levels cause long term impairment but no long term depression. J Neurosci. 29: 669-677 ,
• 10th Pallas M, Camins A (2006): Molecular and Biochemical Features in Alzheimer Disease. Curr Pharm Des. 12: 4389-4408 ,
• 11th Reisberg B, Doody R, Stöffler B, Schmitt F, Ferris S, Möbius HJ (2003): Memantine in Moderate-to-Severe Alzheimer Disease. N Engl J Med. 348: 1333-1341 ,
• 12th Schneider LS, Dagerman KS, Higgins JP, McShane R (2011): Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol. 68: 991-998 ,
• 13th Yoon WJ, Won SJ, Ryu BR, Gwag BJ (2003): Blockade of ionichtropic glutamate receptors produces neuronal apoptosis through the Bax-cytochrome C-caspase pathway: the causative role of Ca2 + deficiency. J Neurochem. 85: 525-533 ,
• 14th Rowland LM, Astur RS, Jung RE, Bustillo JR, Lauriello J, Yeo RA (2005): Selective cognitive impairments associated with NMDA receptor blockade in humans. Neuropsychopharmacology. 30: 633-639 ,
• 15th Mattson MP (2008): Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann NY Acad Sci. 1144: 97-112 ,
• 16th Tilleux S, Hermans E (2007): Neuroinflammation and regulation of glutamate uptake in neurological disorders. J Neurosci Res. 85: 2059-2070 ,
• 17th Olney JW, Farber NB (1995): Glutamate receptor dysfunction and schizophrenia. Arch gene psychiatry. 52: 998-1007 ,
• 18th Segovia G, Porras A, Del Arco A, Mora F (2001): Glutamatergic neurotransmission in aging: a critical perspective. Mech Aging Dev. 122: 1-29 ,
• 19th Procter AW, Stirling JM, Stratmann GC, Cross AJ, Bowen DM (1989): Loss of glycine-dependent radioligand binding to the N-methyl-D-aspartate-phencyclidine receptor complex in patients with Alzheimer's disease. Neurosci Lett. 101: 62-66 ,
• 20th Procter AW, Wong EH, Stratmann GC, Lowe SL, Bowen DM (1989): Reduced glycine stimulation of [3H] MK-801 binding in Alzheimer's disease. J Neurochem. 53: 698-704 ,
• 21st Chessell IP, Procter AW, Francis PT, Bowen DM (1991): D-cycloserine, a putative cognitive enhancer, initiating activation of the N-methyl-D-aspartate receptor-ionophore complex in Alzheimer brain. Brain Res. 565: 345-348 ,
• 22nd Tsai GE, Falk WE, Gunther J, Coyle JT (1999): Improved cognition in Alzheimer's disease with short-term D-cycloserine treatment. At J Psychiatry. 156: 467-469 ,
• 23rd Lane HY, Lin CH, Green MF, Hellemann G, Huang CC, Chief PW, et al. (2013): A Randomized, Double-Blind, Placebo-Controlled Add-on Treatment of Benzoate, a D-Amino Acid Oxidase Inhibitor, for Schizophrenia. JAMA Psychiatry 70: 1267-1275 ,
• 24th Fukui K, Miyake Y (1992): Molecular cloning and chromosomal localization of a human gene encoding D-amino acid oxidase. The Journal of biological chemistry. 267: 18631-18638 ,
• 25th Vanoni MA, Cosma A, Mazzeo D, Mattevi A, Todone F, Curti B (1997): Limited proteolysis and X-ray crystallography reveal the origin of substrate specificity and the rate-limiting product release during the oxidation of D-amino acids catalyzed by mammalian D-amino acid oxidase. Biochemistry. 36: 5624-5632 ,
• 26th Sasabe J, Miyoshi Y, Suzuki M, Mita M, Konno R, Matsuoka M, et al. (2012): D-amino acid oxidase controls motoneuron degeneration through D-serine. Proc Natl Acad Sci USA. 109: 627-632 ,
• 27th Esposito S, Pristera A, Maresca G, Cavallaro S, Felsani A, Florenzano F, et al. (2012): Contribution of serine racemase / d-serine pathway to neuronal apoptosis. Aging Cell 11: 588-598 ,
• 28th Huang X, Kong H, Tang M, Lu M, Ding JH, Hu G (2012): D-serine regulates proliferation and neuronal differentiation of neural stem cells from postnatal mouse forebrain. CNS Neurosci Ther. 18: 4-13 ,
• 29th Smith SM, Uslaner JM, Hutson PH (2010): The Therapeutic Potential of D-Amino Acid Oxidase (DAAO) Inhibitors. The open medicinal chemistry journal. 4: 3-9 ,
• 30th WHO-Concise International Chemical Assessment Document No. 26. WHO G, 2000 http://www.inchem.org/documents/cicads/cicads/cicad26.htm ,
• 31st World Health Organization (2000): Concise International Chemical Assessment. Document No. 26. Geneva: World Health Organization. Available at: http://www.who.int/ipcs/publications/cicad/cicad26_rev_1.pdf ,
• 32nd Smith SM, Uslaner JM, Yao L, Mullins CM, Surles NO, Huszar SL, et al. (2009): The behavioral and neurochemical effects of a novel D-amino acid oxidase inhibitor compound 8 [4H-thieno [3,2-b] pyrrole-5-carboxylic acid] and D-serine. The Journal of pharmacology and experimental therapeutics. 328: 921-930 ,
• 33rd Adage T, Trillate AC, Quattropani A, Perrin D, Cavarec L, Shaw J, et al. (2008): In vitro and in vivo pharmacological profile of AS057278, a selective d-amino acid oxidase inhibitor with potential anti-psychotic properties. Eur Neuropsychopharmacol. 18: 200-214 ,
• 34th Hashimoto K, Fujita Y, Horio M, Kunitachi S, Iyo M, Ferraris D, et al. (2009): Co-administration of a D-amino acid oxidase inhibitor potentiates the efficacy of D-serine in attenuating prepulse inhibition deficits after administration of dizocilpine. Biol Psychiatry. 65: 1103-1106 ,
• 35th Zhao WJ, Gao ZY, Wei H, Never HZ, Zhao Q, Zhou XJ, et al. (2010): Spinal D-amino acid oxidase contributes to neuropathic pain in rats. The Journal of pharmacology and experimental therapeutics. 332: 248-254 ,
• 36th Gong N, Gao ZY, Wang YC, Li XY, Huang JL, Hashimoto K, et al. (2011): A series of D-amino acid oxidase inhibitors specifically prevents and reverses formalin-induced tonic pain in rats. The Journal of pharmacology and experimental therapeutics. 336: 282-293 ,
• 37th Park HK, Shishido Y, Ichise-Shishido S, Kawazoe T, Ono K, Iwana S, et al. (2006): Potential role for astroglial D-amino acid oxidase in extracellular D-serine metabolism and cytotoxicity. Journal of biochemistry. 139: 295-304 ,
• 38th Batshaw ML, Hyman SL, Coyle JT, Robinson MB, Qureshi IA, Mellits ED, et al. (1988): Effect of sodium benzoate and sodium phenylacetate on brain serotonin turnover in the ornithine transcarbamylase-deficient sparse-fur mouse. Pediatric research. 23: 368-374 ,
• 39th McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984): Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease , Neurology. 34: 939-944 ,
• 40th Morris JC (1993): The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 43: 2412-2414 ,
• 41st Lu PH, Edland SD, Teng E, Tingus K, Petersen RC, Cummings JL (2009): Donepezil delays progression to AD in MCI subjects with depressive symptoms. Neurology. 72: 2115-2121 ,
• 42nd Folstein MF, Folstein SE, McHugh PR (1975): "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. Journal of psychiatric research. 12: 189-198 ,
• 43rd Rosen WG, Mohs RC, Davis KL (1984): A new rating scale for Alzheimer's disease. At J Psychiatry. 141: 1356-1364 ,
• 44th Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, et al. (1997): Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 11 Suppl 2: 522-32 ,
• 45th Changer D (1997): Changer Memory Scale, 3rd ed. Psychological Association, San Antonio, TX: Psychological Association ,
• 46th Salthouse TA (1996): The processing-speed theory of adult age differences in cognition. Psychological review. 103: 403-428 ,
• 47th Habekost T, Vogel A, Rostrup E, Bundesen C, Kyllingsbaek S, Garde E, et al. (2013): Visual processing speed in old age. Scandinavian journal of psychology. 54: 89-94 ,
• 48th Carlesimo GA, Mauri M, Graceffa AM, Fadda L, Loasses A, Lorusso S, et al. (1998): Memory performance in young, elderly, and very old healthy individuals versus patients with Alzheimer's disease: evidence for discontinuity between normal and pathological aging. Journal of clinical and experimental neuropsychology. 20: 14-29 ,
• 49th Chef P, Ratcliff G, Belle SH, Cauley JA, DeKosky ST, Ganguli M (2001): Patterns of cognitive decline in presymptomatic Alzheimer's disease: a prospective community study. Arch gene psychiatry. 58: 853-858 ,
• 50th Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K (1987): The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta psychiatrica Scandinavica Supplementum. 334: 1-100 ,
• 51st Rosenthal R RR (1991): Essentials of Behavioral Research: Methods and Data Analysis. 2nd Ed. New York: McGraw Hill ,
• 52nd Cunningham JB M-GE (2007): Power, effect and sample size using GPower: practical issues for researchers and members of research ethics committees. Evidence Based Midwifery 5: 132-136 ,
• 53rd Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. (2011): Toward the preclinical stages of Alzheimer's disease: recommendations from the National Institute of Aging Alzheimer's Association on Alzheimer's disease. Alzheimer's & dementia: the journal of the Alzheimer's Association. 7: 280-292 ,
• 54th Huang YJ, Lin CH, Lane HY, Tsai GE (2012): NMDA Neurotransmission Dysfunction in Behavioral and Psychological Symptoms of Alzheimer's Disease. Current neuropharmacology. 10: 272-285 ,
• 55th Riederer P, Hoyer S (2006): From benefit to damage. Glutamate and advanced glycation end products in Alzheimer brain. J Neural Transm. 113: 1671-1677 ,
• 56th Hashimoto K, Fukushima T, Shimizu E, Okada S, Komatsu N, Okamura N, et al. (2004): Possible role of D-serine in the pathophysiology of Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry. 28: 385-388 ,
• 57th Birks J (2006): Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database System Rev. CD005593 ,
• 58th Burns A, O'Brien J, Auriacombe S, Ballard C, Broich K, Bullock R, et al. (2006): Clinical practice with anti-dementia drugs: a consensus statement from the British Association for Psychopharmacology. J Psychopharmacol. 20: 732-755 ,
• 59th Fellgiebel A (2007): [Alzheimer's - Medication in Mild Cognitive Impairment]. Neuropsychiatry: Clinic, Diagnostics, Therapy and Rehabilitation: Organ of the Society of Austrian Nerve Physicians and Psychiatrists. 21: 230-233 ,
• 60th Russ TC, Morling JR (2012): Cholinesterase inhibitors for mild cognitive impairment. Cochrane Database System Rev. 9: CD009132 ,
• 61st O'Brien JT, Burns A (2011): Clinical practice with anti-dementia drugs: a revised (second) consensus statement from the British Association for Psychopharmacology. J Psychopharmacol. 25: 997-1019 ,
• 62nd Farina N, Isaac MG, Clark AR, Rusted J, Tabet N (2012): Vitamin E for Alzheimer's dementia and mild cognitive impairment. Cochrane Database System Rev. 11: CD002854 ,
• 63rd Malouf R, Grimley Evans J (2008): Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and elderly people. Cochrane Database System Rev. CD004514 ,
• 64th Sydenham F, Dangour AD, Lim WS (2012): Omega 3 fatty acids for the prevention of cognitive decline and dementia. Cochrane Database Syst Rev. 6: CD005379 ,
• 65th Flicker L, Grimley Evans G (2001): Piracetam for dementia or cognitive impairment. Cochrane Database System Rev. CD001011 ,
• 66th Birks J, Grimley Evans J (2009): Ginkgo biloba for cognitive impairment and dementia. Cochrane Database System Rev. CD003120 ,
• 67th Skinner J, Carvalho JO, Potter GG, Thames A, Zelinski F, Crane PK, et al. (2012): The Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-Plus): Expansion of the ADAS-Cog to Improve Responsiveness in MCI. Brain imaging and behavior. 6: 489-501 ,
• 68th Salmon DP (2012): Neuropsychological features of mild cognitive impairment and preclinical Alzheimer's disease. Current topics in behavioral neurosciences. 10: 187-212 ,
• 69th Price SE, Kinsella GJ, Ong B, Storey F, Mullaly F, Phillips M, et al. (2012): Semantic verbal fluency strategies in amnestic mild cognitive impairment. Neuropsychology. 26: 490-497 ,
• 70th Rios C, Pascual LF, Santos S, Lopez F, Fernandez T, Navas I, et al. (2001): [Working memory and complex activities of daily life in the early stages of Alzheimer's disease]. Revista de neurologia. 33: 719-722 ,
• 71st Espinosa A, Alegret M, Valero S, Vinyes-Junque G, Hernandez I, Mauleon A, et al. (2013): A longitudinal follow-up of 550 mild cognitive impairment patients: evidence of major adverse events. J Alzheimer's Dis. 34: 769-780 ,
• 72nd Albert M, Blacker D, Moss MB, Tanzi R, McArdle JJ (2007): Longitudinal change in cognitive performance among individuals with mild cognitive impairment. Neuropsychology. 21: 158-169 ,
• 73rd Perneczky R, Pohl C, Sorg C, Hartmann J, Komossa K, Alexopoulos P, et al. (2006): Complex activities in mild cognitive impairment: conceptual and diagnostic issues. Age and aging. 35: 240-245 ,
• 74th Lai CH, Lane HY, Tsai GE (2012): Clinical and cerebral volumetric effects of sodium benzoate, a D-amino acid oxidase inhibitor, in a drug-naive patient with major depression. Biol Psychiatry. 71: e9-e10 ,
• 75th Kapoor R, Lim KS, Cheng A, Garrick T, Kapoor V (2006): Preliminary evidence for a link between schizophrenia and NMDA-glycine site receptor ligand metabolic enzymes, d-amino acid oxidase (DAAO) and kynurenine aminotransferase-1 (KAT -1). Brain Res. 1106: 205-210 ,
• 76th Verrall L, Walker M, Rawlings N, Benzel I, Kew JN, Harrison PJ, et al. (2007): d-amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia. The European journal of neuroscience. 26: 1657-1669 ,
• 77th Knit CA, Li C, Scott L, Harvey B, Hajos M, Steyn Si, et al. (2011): Modulation of NMDA receptor function by inhibition of D-amino acid oxidase in rodent brain. Neuropharmacology. 61: 1001-1015 ,
• 78th http://www.mayoclinic.org/diseases-conditions/alzheimers-disease/expert-blog/dementia-definitions/bgp-20055922

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

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• http://www.mayoclinic.org/diseases-conditions/alzheimers-disease/expert-blog/dementia-definitions/bgp-20055922 [0062]

Claims (12)

Use of benzoic acid salt for the manufacture of a composition for the prevention or treatment of dementia or mild cognitive impairment. Use according to claim 1, wherein the benzoic acid salt is sodium benzoate, potassium benzoate or calcium benzoate. Use according to claim 1, wherein the benzoic acid salt is sodium benzoate. Use according to claim 1, wherein the dementia is early-stage dementia. Use according to claim 4, wherein the early phase dementia comprises mild Alzheimer's disease. The use of claim 1, wherein the mild cognitive impairment comprises amnestic mild cognitive impairment. Use according to claim 1, wherein an effective amount of benzoic acid salt is 200 milligrams (mg) / day to 2000 mg / day. Use according to claim 1, wherein an effective amount of benzoic acid salt is 500 mg / day to 900 mg / day. Use according to claim 1, wherein an effective amount of benzoic acid salt is 750 mg / day. Use according to claim 3, wherein an effective amount of sodium benzoate is 200 mg / day to 2000 mg / day. Use according to claim 3, wherein an effective amount of benzoic acid salt is 500 mg / day to 900 mg / day. Use according to claim 3, wherein an effective amount of sodium benzoate is 750 mg / day.

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