Metabolic changes in the plasma of mild Alzheimer's disease patients treated with Hachimijiogan.

Background: Alzheimer's disease (AD), the most prevalent form of dementia, is a debilitating, progressive neurodegeneration. Amino acids play a wide variety of physiological and pathophysiological roles in the nervous system, and their levels and disorders related to their synthesis have been related to cognitive impairment, the core feature of AD. Our previous multicenter trial showed that hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), has an adjuvant effect for Acetylcholine estelase inhibitors (AChEIs) and that it delays the deterioration of the cognitive dysfunction of female patients with mild AD. However, there are aspects of the molecular mechanism(s) by which HJG improves cognitive dysfunction that remain unclear. Objectives: To elucidate through metabolomic analysis the mechanism(s) of HJG for mild AD based on changes in plasma metabolites. Methods: Sixty-seven patients with mild AD were randomly assigned to either an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI (HJG:33, Control:34). Blood samples were collected before, 3 months, and 6 months after the first drug administration. Comprehensive metabolomic analyses of plasma samples were done by optimized LC-MS/MS and GC-MS/MS methods. The web-based software MetaboAnalyst 5.0 was used for partial least square-discriminant analysis (PLS-DA) to visualize and compare the dynamics of changes in the concentrations of the identified metabolites. Results: The VIP (Variable Importance in Projection) score of the PLS-DA analysis of female participants revealed a significantly higher increase in plasma metabolite levels after HJG administration for 6 months than was seen in the control group. In univariate analysis, the aspartic acid level of female participants showed a significantly higher increase from baseline after HJG administration for 6 months when compared with the control group. Conclusion: Aspartic acid was a major contributor to the difference between the female HJG and control group participants of this study. Several metabolites were shown to be related to the mechanism of HJG effectiveness for mild AD.

An exploratory, open-label, randomized, multicenter trial of hachimijiogan for mild Alzheimer's disease.

Background: Alzheimer's disease (AD) is a progressive neurodegeneration and is the most prevalent form of dementia. Intervention at an early stage is imperative. Although three acetylcholinesterase inhibitors (AChEIs) are currently approved for the treatment of mild AD, they are not sufficiently effective. Novel treatments for mild AD are of utmost importance. Objective: To assess the effectiveness of hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), in the treatment of mild AD. Methods: This exploratory, open-label, randomized, multicenter trial enrolled patients with mild AD whose score on the Mini Mental State Examination (MMSE) was over 21points. All participants had been taking the same dosage of AChEI for more than 3 months. The participants were randomly assigned to an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI. The primary outcome was the change from baseline to 6 months post treatment initiation on the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version(ADAS-Jcog). The secondary outcomes were change from baseline of the Instrumental Activity of Daily Life (IADL), Apathy scale, and Neuropsychiatric Inventory (NPI) -Q score. Results: Among the 77 enrollees, the data of 69(34 HJG and 35 control)were available for analysis. The difference in the change of ADAS-Jcog from baseline to 6 months of the HJG and control groups was 1.29 (90% Confidence interval (CI), -0.74 to 3.32 p = 0.293). In the subgroup analysis, the differences in the change from baseline to 3 and 6 months for women were 3.70 (90% CI ,0.50 to 6.91, p = 0.059) and 2.90 (90% CI,0.09 to 5.71, p = 0.090), respectively. For patients over 65 years, the difference at 3 months was 2.35 (90%CI, 0.01 to 4.68 p = 0.099). No significant differences were found between the HJG and control groups in IADL score, Apathy scale, or NPI-Q score. Conclusion: Although not conclusive, our data indicate that HJG has an adjuvant effect for acetylcholinesterase inhibitors and that it delays the deterioration of the cognitive dysfunction of mild Altzheimer's disease patients. Clinical Trial Registration: http://clinicaltrials.gov Japan Registry of clinical trials, identifier jRCTs 071190018.

Cognitive Function and Olfactory Impairment in Community-Dwelling Older Adults Attending a Salon.

BACKGROUND: Early detection, treatment, and care are important for the prevention of dementia. Though olfactory impairment has been reported to be associated with mild cognitive impairment (MCI), there are few reports involving community-dwelling older adults with no difficulty in daily life in Japan. OBJECTIVE: This study aimed to identify the frequency of MCI in community-dwelling elderly people attending community salons in a city with a high aging population, and to determine the usefulness of a pocket olfactory discrimination test. METHODS: We recruited 268 independent older adults attending community salons. The Japanese version of the MCI Screen was used to evaluate cognitive function, defining MCI as <49.8 out of 100 scores of the memory performance index (MPI). The Japanese version of the University of Pennsylvania Smell Identification Test (UPSIT-J) was used for olfactory discrimination and the number of correct answers out of 4 questions was noted. RESULTS: Of the salon participants, 138 (51.5%) were classified as having MCI. As the number of correct answers on the olfactory test decreased, the percentage of participants with MCI increased. The MPI score of the low UPSIT score group was significantly lower than that of the high UPSIT score group. CONCLUSIONS: This study revealed that approximately half of the elderly local residents living without daily problems were suspected of having MCI. The UPSIT-J-4 is a simple olfactory identification test, and can be used at any time and any place. It is useful for screening cognitive function via olfactory identification in a salon-like setting.

The efficacy and safety of hachimijiogan for mild Alzheimer disease in an exploratory, open standard treatment controlled, randomized allocation, multicenter trial: A study protocol.

BACKGROUND: Dementia among the Japanese aged 65 years or over population is estimated to approach about 700 million cases by 2025, and a corresponding rapid increase in Alzheimer disease (AD) can also be expected. The ballooning number of dementia patients, including AD, is creating major medical and social challenges. At present, only 3 drugs are recognized for the treatment of mild AD, and these are only used to alleviate symptoms. Although new therapies are needed to treat mild AD, insufficient development of disease-modifying drugs is being done. METHODS/DESIGN: The aim of this exploratory, open standard, treatment-controlled, randomized allocation, multicenter trial is to determine the efficacy of the traditional Japanese Kampo medicine hachimijiogan (HJG) on the cognitive dysfunction of mild AD.Eighty-six patients with AD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and as mild AD according to the Mini Mental State Examination (MMSE ≥21) will be included. All will already have been taking the same dose of Donepezil, Galantamine, or Rivastigmine for more than 3 months. The patients will be randomly assigned to receive additional treatment with HJG or to continue mild AD treatment without additional HJG. The primary endpoint is the change from baseline of the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version (ADAS-Jcog). ADAS-Jcog is a useful index for detecting change over time that investigates memory and visuospatial cognition injury from the early stage. The secondary endpoints are the changes from baseline of the Instrumental Activity of Daily Life, Apathy scale, and Nueropsychiatric Inventory scores. In this protocol, we will examine the Geriatric depression scale and do Metabolome analysis as exploratory endpoints. The recruitment period will be from August 2019 to July 2021. DISCUSSION: This is the first trial of Kampo medicine designed to examine the efficacy of HJG for the cognitive dysfunction of patients with mild AD. TRIAL REGISTRATION: This trial was registered on the Japan Registry of Clinical trials on 2 August 2, 2019 (jRCTs 071190018).

A diagnosis of depression should be considered in patients with multiple physical symptoms in primary care clinics.

Although the vast majority of depressed patients visit primary health care clinics, they often remain undiagnosed and untreated. Therefore, early detection in primary care settings is important. There is a high correlation between number of physical symptoms and the presence of depression, yet little has been reported regarding this relationship in Japanese primary care clinics. We examined number of physical symptoms and depression in a department of general medicine of a Japanese hospital. We included patients with unexplained symptoms after multiple tests to rule out organic diseases. Twenty-one common symptoms were assessed using a symptom checklist. Depression was diagnosed using the Patient Health Questionnaire-9, a self-administered questionnaire designed to diagnose depression. Among 386 patients, 105 (27.2%) (average age: 49.7 ± 20.9 years, 28 men and 77 women) met the criteria for depression. Among the 21 symptoms, 14 were significantly more frequent in patients with depression than in those without depression. When patients had neither general fatigue, nor sleep disturbance nor appetite loss, none met the criteria for depression. Number of symptoms was significantly higher in patients with compared with those without depression. The prevalence of depression increased with number of symptoms: 2% (2/100) for 0 or 1 symptom, 42.4% (42/99) for four to five symptoms and 68.7% (22/32) for more than nine symptoms. Japanese primary care physicians can often rule out depression when patients have neither general fatigue, nor sleep disturbance nor appetite loss. A diagnosis of depression should be considered in patients who report multiple physical symptoms.

The value of ethyl cysteinate dimer single photon emission computed tomography in predicting antidepressant treatment response in patients with major depression.

OBJECTIVE: The purpose of this study is to examine whether the reversal of compromised regional cerebral blood flow (rCBF) in older patients with major depressive disorder (MDD) is dependent on specific parameters of selective serotonin reuptake inhibitor (SSRI) treatment and to examine the efficacy of such treatment. METHODS: Forty-five patients with moderate MDD were studied following 8 weeks of treatment with SSRIs. Twelve patients displayed a positive response to SSRIs, whereas 33 patients did not respond to SSRI treatment. A comparison group of 30 healthy volunteers was also studied. The age of all participants was greater than 50 years. Age, gender, and the Hamilton Rating Scale for Depression scores were examined. The rCBF was assessed using 99mTc-ethyl cysteinate dimer single photon emission computed tomography after SSRI treatment. RESULTS: The rCBF levels in the right middle frontal cortex in non-responsive MDD patients were lower compared with responsive MDD patients. Compared with healthy controls, non-responders had significantly lower rCBF levels in the bilateral middle frontal cortex and insula and had significantly higher rCBF levels in the bilateral inferior frontal cortex and left middle temporal cortex. Compared with healthy controls, responders had significantly higher rCBF levels in the left inferior frontal, middle temporal, precentral, and fusiform gyrus. We found no changes in single photon emission computed tomography between pre-treatment and post-treatment stages for the responders to SSRI treatment. CONCLUSION: Hypoperfusion in older, non-responsive MDD patients was primarily localized in the middle frontal cortex. It is possible that the responders to SSRI treatment at baseline already displayed higher rCBF values in the frontal regions.

The relationship between Helicobacter pylori infection and Alzheimer's disease in Japan.

Although two studies have indicated a possible link between Alzheimer's disease (AD) and Helicobacter pylori (H. pylori) infection, these were reported from Europe, where the prevalence of H. pylori infection is not very high. In this study, the prevalence of H. pylori infection was examined in AD patients in Japan, where there is a high prevalence of H. pylori. Consecutive patients referred to the Memory and Dementia Outpatient Clinic from August 2002 to March 2009 were studied. H. pylori infection status was determined by measuring urinary levels of anti-H. pylori antibody (RAPIRUN(®)). Multiple stepwise logistic regression analyses were used to examine the associations of AD with the main predictor variables. Of the 917 patients who visited the clinic, 385 were diagnosed as having AD. Ninety-seven patients did not have dementia and were considered controls. On univariate analysis, average age and the proportion of males were significantly higher in AD patients than in controls. There was no difference in the prevalence of H. pylori infection between patients with AD and controls (62.0% vs. 59.7%, p = 0.67, crude odds ratio (OR), 1.10). Multiple logistic regression analysis showed that older age and male sex, but not H. pylori status, were significantly associated with AD (p < 0.001, p = 0.01, p = 0.83, respectively). The prevalence of H. pylori infection did not differ between AD patients and controls among Japanese subjects. The high prevalence of H. pylori in controls may contribute to the discrepancy with previous reports.

Evaluation of Helicobacter pylori status and endoscopic findings among new outpatients with dyspepsia in Japan.

PURPOSE: The 2005 ACG guidelines for the management of dyspepsia recommend eradication and proton pump inhibitors for patients who are H. pylori-positive and-negative, respectively. To establish Japanese guidelines for dyspepsia, we evaluated H. pylori status and endoscopic findings among outpatients with dyspepsia. METHODS: The status of H. pylori in dyspeptic patients was determined by measuring urinary levels of anti-H. pylori antibody (RAPIRAN). We then compared the endoscopic findings between H. pylori-positive and -negative patients. RESULTS: The prevalence of H. pylori among 258 dyspeptic patients was 47.8%, and increased with age (11.1% at age 10-19 years; >50% at age >50 years). The prevalence of H. pylori in each age-group tended to be lower among male than female dyspeptic patients. Endoscopy (n = 138) showed that H. pylori-negative patients rarely had peptic ulcers or gastric cancer, and 84.7% had no endoscopic findings, which was significantly higher when compared to H. pylori-positive patients (67.3%) (p = 0.029). CONCLUSIONS: Over half of the dyspeptic Japanese patients examined were negative for H. pylori. Patients who are H. pylori-positive should undergo endoscopy to rule out gastric malignancy, peptic ulcers and other diseases.

Guidelines for the management of Helicobacter pylori infection in Japan: current status and future prospects.

In the years that followed the issuance in 2000 of the Guidelines for the Management of Helicobacter pylori Infection in Japan by the Japanese Society for Helicobacter Research (JSHR), a number of major issues arose, including the emergence of H. pylori strains resistant to clarithromycin as part of primary eradication therapy, and this led to the Guidelines being revised by the JSHR in 2003. While the JSHR aimed in the 2000 Guidelines to prepare clinicians for the task ahead in view of H. pylori eradication therapy becoming available, the JSHR went a step further in the 2003 Guidelines to include more evidence-based recommendations to address clinical and institutional challenges and issues of interest in the management of H. pylori infection in Japan. Thus, a number of diseases were upgraded to either class A or B indications for H. pylori eradication, including mucosa-associated lymphoid tissue lymphoma (class A), and after endoscopic mucosal resection for early gastric cancer, atrophic gastritis, and gastric hyperplastic polyp (all class B), with further diseases such as extragastric disease also included as class C indications requiring further examination. Concern was expressed over reliance on a single diagnostic test for H. pylori infection, which is in place due to institutional constraints. Metronidazole was also recommended for use in the place of clarithromycin as part of a second-line eradication regimen in light of increasing clarithromycin resistance, although metronidazole remains to be approved for health insurance coverage. Finally, areas requiring further clinical research and endeavors, including establishment of second-line eradication therapy, were also proposed in the 2003 Guidelines to point the way for the future.