TWI573588B - Use of benzoic acid salt in the manufacture of a pharmaceutical composition for treating dementia or mild cognitive impairment - Google Patents

Description

Use of benzoate for the preparation of a pharmaceutical composition for treating dementia or mild cognitive impairment

The present invention relates generally to novel therapies for dementia or mild cognitive impairment, and more particularly to the use of benzoates for the manufacture of compositions for the prevention or treatment of dementia or mild cognitive impairment.

In an aging society, the prevalence of dementia among middle-aged people is rapidly increasing, and its deteriorating clinical process is a heavy burden for both patients and their families. Early detection and intervention of Alzheimer's disease (hereinafter referred to as "AD") is critical to the outcome (1). Mild Cognitive Impairment (hereinafter referred to as "MCI"), especially amnesiac MCI (hereinafter referred to as "aMCI"), is a risk factor and can be a prodromal phase of AD. The mainstream therapy for mild and moderate AD is an acetylcholinesterase inhibitor (hereinafter referred to as "AChEI"). However, the efficacy and tolerability of acetylcholinesterase inhibitors are not satisfactory. In addition, AChEI did not show convincing efficacy on MCI (2-4), suggesting that there are other mechanisms behind the onset of MCI.

Although the NMDA receptor (hereinafter referred to as NMDAR) activity is essential for cognitive function, it is not yet fully understood its role in AD. Excessive activation of NMDAR by glutamate causes cell death. Excitotoxicity is one of the theories of AD, especially in the advanced stage (54). Based on the hypothesis of NMDAR overactivation (7), NMDAR antagonists were developed to treat AD. Memantine is a non-competitive NMDAR partial antagonist with low affinity, which is said to block NMDAR overactivation (8-10) by preventing excessive calcium influx, and has been used for moderate-to-severe Treatment of AD. However, memantine has limited efficacy in the early stages (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 is another NMDAR antagonist that impairs spatial learning and verbal information in healthy humans in double-blind, randomized, and placebo-controlled trials (14). These findings raise concerns that NMDAR antagonists may impair cognitive and memory in early AD.

Optimal NMDAR activation is critical for synaptic plasticity (15), memory, and cognitive function (16). NMDAR-mediated attenuation of nerve conduction can cause loss of neural plasticity and cognitive deficits in aging brains, which may explain why clinical symptoms worsen and brain atrophy (17). NMDAR density reduction in the cerebral cortex and hippocampal gyrus is observed in humans to be age-related (18). Earlier studies also found a reduction in the binding of glycine-dependent radioconjugates to NMDAR in the cerebral cortex from necropsy and neurosurgical tissue in patients with AD (19, 20). D-cycloserine is a partial agonist at the glycine site of NMDAR and has been reported in several clinical studies. NMDAR (21) in the brain of patients with AD can be activated and the scores of these patients on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) are improved (22).

Current research suggests that NMDAR enhancement may be beneficial for early and mild dementia. The reduction in glutamate content and synthesis in the human cerebral cortex and hippocampus is age-related (18,55), with the most significant and consistent finding being a reduction in NMDAR density in elderly patients and patients with AD (18) . Lower amounts of D-serine and higher amounts of L-serine (56) were also observed in the serum of patients with AD. Therefore, in addition to the choline system, dysfunction of NMDA nerve conduction may also play an important role in the pathophysiology of AD.

There are many ways to enhance NMDA activation. One of them is to inhibit the activity of D-amino acid oxidase (DAAO), which is responsible for the decomposition of D-serine and D-alanine, the peroxisome flavin (24-26). The amount of D-amino acid (which is the neurotransmitter for the co-actinator position of NMDAR) is increased. Recent data indicate that aging is associated with a decrease in the amount of D-serine and thereby impairing NMDAR conduction, and D-serine treatment significantly reduces the extent of neuronal death, suggesting that D-serine has neuroprotective effects against apoptosis. (27). In addition, neural stem cells from the forebrain of the mouse after birth can synthesize D-serine to stimulate proliferation of stem cells and differentiation of nerve cells (28).

Enhancing NMDAR by inhibiting DAAO can 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 is found in many plants and is a natural component of foods (including dairy products) (30). Benzoic acid and its salts are generally It is considered safe (GRAS) and contains sodium benzoate. It is also a food preservative widely used in the manufacture of jelly, buffers, soy sauce, processed meat, etc. (31).

There are many other preclinical studies that support the CNS effect of DAAO inhibitors, but their effects on memory have not been tested (32-34). NMDAR-mediated nerve conduction is important for learning and memory. It has been reported that the insufficiency of NMDAR plays an important role in the pathophysiology of AD, especially in the early stages. Enhancing NMDAR activation can be a novel treatment modality. One of the ways to enhance NMDAR activity is to increase the amount of NMDA co-activator by blocking its metabolism. Sodium benzoate is effective in NMDAR mode-related effects such as pain relief (35, 36) and partially prevents cell death of glial cells (37). The CNS bioavailability of benzoate is good (38). To test whether DAAO inhibition is beneficial for the early stages of dementia, the inventors conducted this trial to test the efficacy and safety of sodium benzoate in patients with MCI or mild AD.

Based on the above evidence support, the inventors have proposed that NMDA promoters may be beneficial to the early decay process of AD and MCI due to their roles in learning and memory as well as neuronal and neuroplasticity, thus completing the present invention.

The present invention provides the use of a benzoate in the manufacture of a composition for the prevention or treatment of dementia or MCI.

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

In another aspect of the present application, the effective amount of the benzoate may range from 200 milligrams (mg) per day to 2000 mg per day, preferably from 500 mg per day to 900 mg per day. The day, and more preferably 750 mg / day.

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

In one aspect of this application, dementia includes early dementia. In one embodiment of the present application, early dementia includes mild AD.

In one aspect of the present application, the MCI includes amnesiac MCI.

Figure 1 shows the flow chart and configuration of two processing groups.

The following illustrative embodiments are provided to illustrate the disclosure of the present invention. These and other advantages and effects will be apparent to those of ordinary skill in the art of the invention.

Definition of Terms

As used herein, the term "dementia" means a collection of symptoms that severely affect intellectual and social ability to interfere with daily functions, including memory loss, language problems, inability to learn or remember new information (78). The term "early dementia" means a condition in which the CDR (Clinical Dementia Rating Scale) score of a patient suffering from dementia does not exceed one.

As used herein, the term "Alzheimer's disease (AD)" means a national institution and Az that may occur in middle or old age due to general degeneration of the brain, and which is consistent with neurological and communicative disorders and strokes. National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association) The progressive progressive mental deterioration of the disease. Excessive glutamate acid nerve conduction, particularly through the N-methyl-D-aspartate receptor (NMDAR), leads to neurotoxicity associated with the pathophysiology of AD (5,6), especially in advanced AD . The term "mild Alzheimer's disease" means a condition in which the CDR (Clinical Dementia Rating Scale) score of 0.5 or 1 in a patient suffering from dementia.

As used herein, the term "mild cognitive impairment (MCI)" means a cognitive disorder in which the CDR (Clinical Dementia Rating Scale) score is less than one. The term "amnesic mild cognitive impairment (aMCI)" means an MCI in which memory is primarily affected.

As used herein, the term "clinical dementia scale (CDR)" means an assessment system for assessing the severity of a period of dementia. The clinical dementia is a five-point scale, in which CDR-0 implies no cognitive impairment, and then the remaining four are divided into dementia in each period: CDRs within 0.5 to 1 = very mild to mild dementia, 1 to CDRs within 2 = mild to moderate, CDRs within 2 to 3 = moderate to severe, and CDR > 3 = severe.

Example

The present invention tests the efficacy and safety of sodium benzoate as a D-amino acid oxidase (DAAO) inhibitor in the treatment of amnesiac MCI (aMCI) and mild AD.

The inventors conducted randomized, double-blind, placebo-controlled trials in four major medical institutions in Taiwan. Sixty patients with aMCI or mild AD were treated with sodium benzoate or placebo at 250 to 750 mg/day for 24 weeks. Every 8 weeks, the Alzheimer's Assessment Scale-Cognitive Subscale (ADAS-cog, Measurements were made for the primary outcome determination project and the overall function (Clinician Interview Based Impression of Change plus Caregiver Input (CIBIC-plus) assessment). An additional cognition composite was performed at the start and end of the study.

Participant

From the four main medical institutions in Taiwan - the Department of Psychiatry and Neurology of Kaohsiung Chang Gung Memorial Hospital in Kaohsiung, the Department of Psychiatry of the Chinese Medical University in Taichung, the Ministry of Spirit of Taichung Veterans General Hospital in Taichung, and the Forest in Taichung The outpatient department of the Department of Neurology of the New Hospital recruited patients. The study was approved by the Human Research Committee (IRB) and was based on the revised Declaration of Helsinki. After a complete medical and neurological examination, the patient is evaluated by a research physician, including a psychiatrist and a neurologist.

If the patient meets the following criteria, they are invited to join the study: 1) meet the criteria for possible AD of NINCDS-ADRDA (National Institutions of Neurological and Communicative Disorders and Stroke and Association of Alzheimer's and Related Disorders) (39) and The Clinical Dementia Rating Scale (CDR) (40) score is 1, or meets the criteria for aMCI, which may be a degenerative course (41), which is defined as subjective memory complaints and overall cognitive and functional evidence as confirmed by the data provider. Sexual disorder complies with NINCDS-ADRDA criteria and has a CDR score of 0.5; 2) age is 50 to 90 years; 3) good health and all laboratory assessments (including urine/blood routine, biochemical tests, and electrocardiogram) are in the normal range 4) its Mini-Mental State Examination (MMSE) (42) score is 17 to 26; 5) an assessment that has sufficient educational standards to communicate effectively and complete the study; and 6) agree to participate in the study and sign the subject consent form. For patients who have undergone AChEI therapy, they must continue taking AChEI for at least three months prior to the study. The AChEI dose must remain unchanged during the study period. For patients who have not been treated with AChEI, AChEI or other anti-dementia medications are prohibited during the study period.

Exclusion criteria included a clear history of cerebrovascular disease; Hachinski Ischemic Score > 4; major neurological, psychiatric, or medical conditions other than AD; substance (including alcohol) abuse or dependence; Illusion or paralysis; severe visual or hearing loss; unable to follow the research procedure.

Research design

All patients were randomized to receive either 24-weth sodium benzoate or placebo in a double-blind manner. Efficacy and safety were assessed at the start of the study and at the end of weeks 8, 16 and 24. 250 mg of sodium benzoate or placebo was filled into the same capsule and placed in a coded vial. As for the dose, the first 8 weeks start with 250 to 500 mg / day (250 mg once or twice daily), then increase from 250 to 500 mg / day from the 9th week, and 250 to 500 mg / day from the 17th week. . Since the subjects in the study were older, the inventors used a dose of 250 to 750 mg/day. Subjects were randomized to receive either sodium benzoate or placebo in a 1:1 ratio by the study pharmacist.

Subjects, caregivers, and researchers were not aware of this assignment except for the study of pharmacists. Caregivers and research physicians closely monitor the subject's medical care Compliance and safety, and the pills are counted by the investigator.

Evaluation

The primary outcome was the Alzheimer's Assessment Scale-Cognitive Subscale (ADAS-cog) (43) measured at weeks 0, 8, 16 and 24. ADAS-cog is the most commonly used cognitive assessment method in AD clinical trials. It consists of 11 projects, including word recall, naming ability, command, constructional praxis, ideology (pration), orientation, word recognition, instruction memory, speaking ability, difficulty in finding words, and understanding. The ADAS-cog score ranges from 0 (best) to 70 (worst).

Secondary outcomes included a general change based on clinical visits measured at weeks 8, 16 and 24 - information provided by additional caregivers (CIBIC-plus) (44) and additional cognition at the start and end of the study Additional cognition composite.

CIBIC-plus is a holistic change assessment based on a comprehensive, semi-structured interview (including information provided by caregivers). The CIBIC-plus ranged from 1 to 7 for a 7-point scale, with 1 indicating a significant improvement; 4 indicating no change; and 7 indicating a significant deterioration.

Additional cognition composite is based on processing speed (language fluency), working memory (WMS-III, Spatial Span) (45), and oral learning and memory test (WMS-III, word The word test) (45) the average of the T scores. The processing speed, working memory, and the raw scores of the spoken and memory tests were normalized to a T score of 50 on average and a standard deviation of 10 to allow each trial to be compared to each other. Additional cognitive function tests combined with ADAS-cog can improve cognitive assessment whole. It has been found that a reduction in processing speed is associated with aging (46, 47). Working memory (48) and oral learning and memory (49) in patients with AD also declined.

Systemic side effects of treatment were at the start of the study and at weeks 8, 16 and 24, with physical and neurological examinations, laboratory tests including CBC and biochemistry, and Udvalg for Kliniske Undersogelser (UKU) side effects. Table (50) check.

Clinical evaluation is performed by a research psychiatrist and neurologist who is trained and has experience in using the assessment scale. The inter-rater reliability was analyzed by ANOVA assay. Reached only during pre-study training The scorer of the correlation coefficient within the order of 0.90 can score the subject. The scorer meets at least once a quarter for training and reliability retesting to maintain high-scoring inter-personal confidence and avoid scorer drift. Individual patients were assessed by the same study psychiatrist or neurologist throughout the trial to minimize inter-rater variability.

data analysis

Use the chi-square test (or Fisher's exact test) to compare the differences between the category variables, using the Student's two-sample t -test (Student's two-sample t- test) (if the distribution is abnormal) Then, the Mann-Whitney U test was used to compare the continuous variables between the two groups. The generalized estimating equation (GEE) method (with treatment, visit and treatment-visit interaction as a fixed effect, intercept as the only random effect, and the reference value as a covariate) was compared from the benchmark in the repeated measures assessment (ADAS-cog). The mean value of the line change was analyzed by the SAE/STAT (SAS Institute, Cary, North Carolina) "PROC GENMOD" AR (autoregressive) ( 1 ) work-related structure of the GEE analysis, but the mixed mode was replaced by the marginal mode. A therapeutically effective extent (Keen Shi d (Cohen's d)) is determined compared to a placebo treatment, sodium benzoate and the magnitude of the improvement is generated (51) of continuous variables.

Eventually, all 60 randomly assigned patients completed at least one follow-up, and 50 of them (90%) completed the 24-week trial (shown in Figure 1). There is no imputation for incomplete data in the GEE analysis.

CIBIC-plus has no score for the starting point of the study because its score is based on changes from the starting point. Student assessed the CIBIC-plus score difference between the two groups at weeks 8, 16, 24 and the end point with a two-sample t-test (or a Mann-Whit U test if the distribution was abnormal).

The difference between the exit rates between the two groups was compared by Fisher's precision check. In Keen Shi w (Cohen's w) measured effectiveness (52) category of variables. All data was analyzed using IBM SPSS Statistics (version 18.0; SPSS Inc.) or SAS 9.3. All p values for clinical measurements were based on a two-tailed assay with a significance level of 0.05.

result

Sixty patients were eligible and randomized (shown in Figure 1). Demographic characteristics, educational attainment, age at onset, duration of disease, CDR score, body mass index (BMI), and AChEI between the sodium benzoate group (N=30) and the placebo group (N=30) at the start of the study The use was similar ( p > 0.05) (shown in Table 1). The AChEI dose was within the therapeutic range and the AChEI doses were similar between the two groups (shown in Table 1). At weeks 8, 16 and 24, the average dose of sodium benzoate was 275.0 ± 76.3, 525.0 ± 100.6 and 716.7 ± 182.6 mg / day, respectively.

AChEI represents an acetylcholinesterase inhibitor; BMI represents body mass Index; CDR indicates clinical dementia scale; NA indicates no association.

^a Fisher's precision check.

^b Independent t test.

^c Man-Hui Ne U test.

Table 2 shows the mean ± SD scores for both primary and secondary outcomes for both groups, including ADAS-cog, additional cognitive function tests, and CIBIC-plus. At week 0 (study starting point), there was no significant difference in ADAS-cog and additional cognitive function tests between the two groups ( p = 0.75 and 0.27, respectively).

Measurement of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and clinical physician visit as a basis for overall change during the 24-week treatment period using the Generalized Estimation Formula (GEE) - provided by additional caregivers The result of the measurement of CIBIC-plus. Additional cognitive function tests: composite test scores for processing speed, working memory, and spoken language learning and memory.

^a Estimated value is the coefficient of treatment-visit interaction in the multiple linear regression model of the GEE method. The first order autoregressive covariance matrix is used for repeated measurements within the patient. The p value is based on a two-tailed test.

^b Independent t test.

^c Use the Man-Huinet U test because the distribution of the CIBIC-plus score is abnormal.

As for the primary outcome, sodium benzoate improved the ADAS-cog score better throughout the study compared to placebo (at the 8th, 16th, and 24th week and at the end of the study, the sodium benzoate group from the starting point of the study) The mean difference was 3.8, 5.4, 5.9, and 5.9, respectively, while the placebo group was 2.4, 1.7, 2.7, and 1.7, respectively; p = 0.3730, 0.0021, 0.0116, and 0.0031, respectively, and the effective level at the end of the study was 0.86 ( Shown in Table 2). The ADAS-cog scores at the starting point of the study were controlled in the GEE mode and the results were similar (shown in Table S1).

* Estimated as the coefficient of treatment-visit interaction in the multiple linear regression model of the GEE method. The autoregressive covariance matrix is used for repeated measurements within the patient. The p value is based on a two-tailed test.

ADAS-cog: Alzheimer's Disease Assessment Scale - Cognitive Subscale.

The bold p value indicates statistical significance.

As for the secondary outcome, the additional cognitive function test for sodium benzoate at the end of the study was better compared to placebo ( p = 0.007, effective = 0.78). Compared with placebo treatment, sodium benzoate treatment also produced a better CIBIC-plus score at week 16 ( p = 0.015), week 24 ( p = 0.016), and study end point ( p = 0.012, effective = 0.73). (Displayed in Table 2).

The withdrawal rate of the sodium benzoate group (3.3%) was lower than that of the placebo group (16.7%), but did not reach a statistically significant difference ( p = 0.195).

For subgroup analysis, we further examined the efficacy of sodium benzoate in the CDR 0.5 and CDR 1 subpopulations relative to placebo. In the ADAS-cog, sodium benzoate produced greater improvement at the 16th, 24th, and end of study than placebo treatment in the CDR 1 subpopulation ( p = 0.0151, 0.0387, and 0.0092, respectively). However, in the CDR 0.5 subpopulation, sodium benzoate was not superior to placebo ( p > 0.05) throughout the study (shown in Table 3).

Although ADAS-cog is widely used in AD clinical trials, it may be less sensitive to MCI (67). One of the strategies to improve the responsiveness of detecting MCI is to add additional cognitive tests. Those with MCI have been found to have impaired neuropsychological function (68), such as speed of treatment (69), working memory (70), and oral learning and memory (71). In the aMCI subgroup of the present invention, sodium benzoate exhibits marginal significance in terms of additional cognitive function tests (which consist of processing speed, working memory, and spoken language learning/memory), but not in terms of ADAS-cog scores. Our results echo the recommendations of the MCI trial for additional neuropsychological testing that is more sensitive to subtle defects.

The abbreviations are the same as those in Tables 1 and 2.

^a Estimated value is the coefficient of treatment-visit interaction in the multiple linear regression model of the GEE method. The first order autoregressive covariance matrix is used for repeated measurements within the patient. The p value is based on a two-tailed test.

In terms of improving the additional cognitive function test, sodium benzoate showed better efficacy in the CDR 1 subpopulation ( p = 0.041) and marginal significance in the CDR 0.5 subpopulation ( p = 0.063) (shown in Table 4). As for CIBIC-plus, at week 24 and at the end of the study, sodium benzoate produced a greater improvement in the CDR 1 subgroup than placebo treatment ( p = 0.040 and 0.018, respectively), but not in the CDR 0.5 subgroup. (Displayed in Table 5).

Sodium benzoate also did not improve the CIBIC-plus score in the aMCI subpopulation. One possible explanation is the ceiling effect produced by the tiny impairment of functional impairment in MCI individuals, thus limiting the room for further improvement.

The p value is based on a two-tailed test. The additional cognitive function test represents a composite test score for processing speed, working memory, spoken language learning, and memory. The CDR represents the clinical dementia scale.

The p value is based on a two-tailed test. Utilizing the Man-Hui-U test, the distribution of CIBIC-plus scores is abnormal.

CDR represents the clinical dementia scale;

CIBIC-plus represents the overall change that the clinician visits as a basis - information provided by additional caregivers.

It is important to identify and treat AD as early as possible to potentially prevent its course of disease (53). The present invention is the first to administer a DAAO inhibitor, herein referred to as sodium benzoate, as a novel therapy for early cognitive attenuation. The results showed that sodium benzoate was more effective in improving the ADAS-cog score, the additional cognitive function test (which consists of processing speed, working memory, oral learning, and memory) and overall sexual function compared to all subjects. The agent is better. Subgroup comparisons found that sodium benzoate was better measured in all outcomes in patients with mild AD. In the aMCI subgroup, sodium benzoate showed marginal significance in improving the additional cognitive function test. In addition, sodium benzoate also shows good safety.

In terms of dose, sodium benzoate had better efficacy than placebo at weeks 16 and 24, with average doses of 525 mg/day and 716 mg/day, respectively, suggesting that 500 to 750 mg/day of sodium benzoate is more than 250 mg/day. More effective. Another possibility for longer sodium benzoate treatment during treatment Good treatment response.

AChEI is often used to treat AD (57, 58), but is not recommended for the treatment of MCI due to its weak efficacy and risk of side effects (59, 60). A consensus statement from the British Association for Psychopharmacology states that both AChEI and memantine are ineffective for treating MCI (61). Other compounds commonly used to treat MCI, such as vitamin E (62), folic acid (63), omega-3 fatty acids (64), piracetam (65), and ginkgo (66), have no clear evidence of cognitive enhancement. Sodium benzoate is generally safe, and in this small sample size study, the efficacy of sodium benzoate for aMCI has improved.

Very high concentrations of DAAO are detected in the cerebellum of the adult brain, whereas in the forebrain (such as the prefrontal cortex and hippocampus), although their performance is strong, their activity is low (75, 76). The cellular localization and function of DAAO between the forebrain and cerebellum may be different: DAAO is glia in the cerebellum, but mainly neuronal in the cerebral cortex. However, the effects of DAAO inhibitors on the amount of D-serine in the forebrain are inconsistent. Most DAAO inhibitors cause a measurable increase in D-serine in the forebrain (as observed in the cerebellum), but some DAAO inhibitors may not (77). However, the cerebellum is involved in cognitive function. Sodium benzoate may exert its cognitive effects not only through the brain mechanism but also through the cerebellar mechanism.

The present invention means that sodium benzoate, which is a DAAO inhibitor, is beneficial for cognition and overall function in patients with early AD, and may be beneficial for aMCI. The use of sodium benzoate in early AD and aMCI will bring hope to an increasing number of aging communities with cognitive decline. This application The result of the case means that sodium benzoate treatment for early dementia may be due to activation of nerve regeneration and anti-apoptosis.

Adverse effects

Both sodium benzoate and placebo are well tolerated. Only one patient in the placebo group reported dizziness at week 16. This side effect is mild and does not require medical treatment. No side effects were reported in the sodium benzoate group after evaluation by the UKU Side Effects Assessment Scale in each visit. There are no exits due to side effects.

Both routine blood counts and biochemical tests were within the normal range and remained unchanged after treatment (data not shown).

This research was carried out by the Ministry of Science and Technology of Taiwan (NSC 99-3114-B-182A-003, NSC 101-2314-B-182A-073-MY2 and NSC-101-2325-B-039-009), Taiwan Excellence Clinical Trial Supported by the Research Center (DOH102-TD-B-111-004) and the Hospital of China Medical University of Taiwan (CMU 101-AWARD-13, DMR-99-153).

The above detailed description is merely illustrative of the principles and functions of the invention and is not intended to limit the scope of the invention. It is to be understood by those of ordinary skill in the art that all modifications and changes in the spirit and scope of the present invention are intended to fall within the scope of the appended claims. The specification and examples are to be considered as illustrative only, and the scope of the invention

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Claims (12)

A use of a benzoate for the manufacture of a pharmaceutical composition for the treatment of dementia or mild cognitive impairment, wherein the effective amount of the benzoate is from 200 mg/day to 2000 mg/day. The use according to claim 1, wherein the benzoate is sodium benzoate, potassium benzoate or calcium benzoate. The use according to claim 1, wherein the benzoate is sodium benzoate. The use of the first aspect of the patent application, wherein the dementia is early dementia. The use of claim 4, wherein the early dementia comprises mild Alzheimer's disease. The use of claim 1, wherein the mild cognitive impairment comprises amnesia mild cognitive impairment. The use according to claim 1, wherein the effective amount of the benzoate is from 500 mg/day to 1000 mg/day. The use according to claim 1, wherein the effective amount of the benzoate is from 500 mg/day to 900 mg/day. The use according to claim 1, wherein the effective amount of the benzoate is 750 mg/day. The use according to claim 3, wherein the effective amount of the sodium benzoate is from 500 mg/day to 1000 mg/day. The use according to claim 3, wherein the effective amount of the sodium benzoate is from 500 mg/day to 900 mg/day. The use according to claim 3, wherein the effective amount of the sodium benzoate is 750 mg/day.