Effects of Molecular Hydrogen Assessed by an Animal Model and a Randomized Clinical Study on Mild Cognitive Impairment.

BACKGROUND: Oxidative stress is one of the causative factors in the pathogenesis of neurodegenerative diseases including mild cognitive impairment (MCI) and dementia. We previously reported that molecular hydrogen (H2) acts as a therapeutic and preventive antioxidant. OBJECTIVE: We assess the effects of drinking H2-water (water infused with H2) on oxidative stress model mice and subjects with MCI. METHODS: Transgenic mice expressing a dominant-negative form of aldehyde dehydrogenase 2 were used as a dementia model. The mice with enhanced oxidative stress were allowed to drink H2-water. For a randomized double-blind placebo-controlled clinical study, 73 subjects with MCI drank ~300 mL of H2-water (H2-group) or placebo water (control group) per day, and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) scores were determined after 1 year. RESULTS: In mice, drinking H2-water decreased oxidative stress markers and suppressed the decline of memory impairment and neurodegeneration. Moreover, the mean lifespan in the H2-water group was longer than that of the control group. In MCI subjects, although there was no significant difference between the H2- and control groups in ADAS-cog score after 1 year, carriers of the apolipoprotein E4 (APOE4) genotype in the H2-group were improved significantly on total ADAS-cog score and word recall task score (one of the sub-scores in the ADAS-cog score). CONCLUSION: H2-water may have a potential for suppressing dementia in an oxidative stress model and in the APOE4 carriers with MCI.

Impact of Depressive Symptoms on Conversion from Mild Cognitive Impairment Subtypes to Alzheimer's Disease: A Community-Based Longitudinal Study.

BACKGROUND: While longitudinal studies have investigated the relationships between mild cognitive impairment (MCI) subtypes and dementia subtypes, the results have been contradictory. In addition, some research shows that depression accompanied by MCI might increase the risk of Alzheimer's disease (AD). OBJECTIVE: The aim of this study is to longitudinally investigate the relationships between MCI subtypes and dementia subtypes, with special attention to the effect of comorbid depressive symptoms in a Japanese rural community. METHODS: Non-demented participants (n = 802) completed a baseline and follow-up study. Outcomes were conversion to dementia especially AD, MCI, or no conversion. A complementary log-log analysis was conducted to investigate the risk of dementia and AD in amnestic MCI (aMCI) compared to nonamnestic MCI (naMCI) groups. The impact of depressive symptoms on the transition from MCI to AD and from cognitively normal to MCI or AD was also analyzed. RESULTS: The risk of developing dementia, in particular AD, for the aMCI group was significantly higher than that for the naMCI group. In the aMCI group, the presence of depressive symptoms increased the risk of developing AD, but depressive symptoms in the naMCI group did not. In the cognitively normal group, the presence of depressive symptoms increased the risk of aMCI but not naMCI or AD. CONCLUSION: MCI subtyping could be useful in finding a prodrome for dementia and in particular for AD. The differing impacts of depressive symptoms on the development of AD suggest that the relationship between depressive symptoms and cognitive impairment could differ in aMCI and naMCI patients.

A comparative analysis of dementia inpatient characteristics: results from a nationwide survey of different care facilities in Japan.

BACKGROUND: In Japan, the number of dementia patients admitted to hospitals and other care facilities has been increasing and their hospital stays prolonged. Until now, there has been no study examining the differences between patients in psychiatric hospitals and other care facilities. Here we attempt a comparative analysis of characteristics of dementia patients in psychiatric hospitals and other types of facilities based on a nationwide survey. METHOD: A nationwide, cross-sectional survey was conducted in 2009-2011. Questionnaires were sent to randomly selected facilities and asked about each facility's status as of September 2009 and about individuals with dementia residing in each facility during the 2008 fiscal year. The portion about individuals consisted of items to assess eligibility for the Long-Term Care Insurance programme. Based on data from 6121 patients residing in seven different types of facilities, features of dementia patients in psychiatric hospitals and differences among facilities were analyzed. RESULTS: There was a significant difference in average age, activities of daily living level, and dementia severity level among the seven types of facilities. The average age in all types of facilities, except for psychiatric hospitals, was higher than the national average life expectancy of 82.59 years. The results of the study revealed that in psychiatric hospitals the proportion of men, those aged <75 years, demented patients with severe behavioural and psychological symptoms of dementia, and those with frontotemporal dementia was significantly greater than in other types of facilities. In other Long-Term Care Insurance care facilities, dementia patients >80 years and women accounted for 80% of all patients. CONCLUSION: Result showed that dementia patients in psychiatric hospitals had a higher proportion of men, younger age groups, and severe dementia than other types of facilities. These features contrast markedly with status of dementia patients in other Long-Term Care Insurance care facilities. In order to facilitate dementia patients' early discharge from psychiatric hospitals to other care facilities or to home, further fulfillment care services corresponding to severe dementia and early-onset dementia may be needed.

A combination of supplements may reduce the risk of Alzheimer's disease in elderly Japanese with normal cognition.

A number of studies have examined the effect of a single supplement against Alzheimer's disease (AD) with conflicting results. Taking into account the complex and multifactorial nature of AD pathogenesis, multiple supplements may be more effective. Physical activity is another prospect against AD. An open-label intervention study was conducted to explore a potential protective effect of multiple supplements and physical activity. Their interaction was also examined. Participants were community-dwelling volunteers aged 65 or older as of May 2001 in a rural area of Japan. Among 918 cognitively normal participants included in the analyses, 171 took capsules daily for three years that contained n-3 polyunsaturated fatty acid, Ginkgo biloba leaf dry extracts, and lycopene. Two hundred and forty one participants joined the two-year exercise intervention that included a community center-based and a home-based exercise program. One-hundred and forty eight participated in both interventions. A standardized neuropsychological battery was administered at baseline in 2001, the first follow-up in 2004-2005, and the second in 2008-2009. The primary outcome was AD diagnosis at follow-ups. A complementary log-log model was used for survival analysis. A total of 76 participants were diagnosed with AD during follow-up periods. Higher adherence to supplementation intervention was associated with lower AD incidence in both unadjusted and adjusted models. Exercise intervention was also associated with lower AD incidence in the unadjusted model, but not in the adjusted model. We hypothesized that the combination of supplements acted in a complementary and synergistic fashion to bring significant effects against AD occurrence.

Multicenter population-based study on the prevalence of early onset dementia in Japan: vascular dementia as its prominent cause.

AIM: In Japan, the government and media have become aware of the issues of early onset dementia (EOD), but policies for EOD have not yet been established and support systems are inadequate. To provide practical data about EOD, a two-step postal survey was performed. METHODS: A questionnaire requesting information on EOD cases was sent to target institutions in five catchment areas in Japan. According to the answers from the institutions, we estimated the prevalence of EOD using census data and determined the illnesses causing EOD. As a quality control study, the authors reviewed every diagnosis in a quarter of the reported cases using the medical and psychiatric records and neuroimaging data. This study was conducted from 2006 to 2007. RESULTS: Information from 2469 patients was collected from 12,747 institutions, and 2059 subjects with EOD were identified. The estimated prevalence of EOD was 47.6 per 100,000 (95% confidence interval, 47.1-48.1) for all of Japan. Of the illnesses causing EOD, vascular dementia (VaD) was the most frequent (39.8%), followed by Alzheimer's disease. CONCLUSIONS: The prevalence of EOD in Japan appeared to be similar to that in Western countries. However, unlike previously reported international experience, VaD was the most frequent cause of EOD in all catchment areas in Japan.

ApoE4 is not associated with depression when mild cognitive impairment is considered.

OBJECTIVE: The aim of the study was to examine the relationship between apolipoprotein E4 allele (ApoE4) and depression among an older Japanese population. Mild cognitive impairment (MCI) was taken into consideration. METHODS: This is a community-based cross-sectional study. We assessed the mood and cognitive function of Japanese community-dwelling individuals aged 65 years or older. In the first phase of the study, we evaluated the mood and cognitive function. In the second phase, face-to-face structured interviews were conducted. Individuals with dementia and other mental diseases were excluded on the basis of a consensus meeting of psychiatrists and neuropsychologists; 738 subjects with full data were included in the analyses. We subdivided depression into major depressive episode (MDE) and depressive symptoms cases (DSCs). DSC was defined as a score of 6 or more on the Geriatric Depression Scale but not having a diagnosis of MDE. The relationship between depression (MDE and DSC) and ApoE4 was examined by multivariate logistic regression. RESULTS: The adjusted odds ratio (OR) of ApoE4 on DSC was not significant (OR = 0.82, 95%CI = 0.48-1.39, p < 0.46). Sex (OR = 2.53, 95%CI = 1.33-4.79, p < 0.01), MCI (1.95, 1.21-3.14, p < 0.01), years of education (0.87, 0.79-0.95, p < 0.01), and Nishimura's activities of daily living scores (0.75, 0.63-0.89, p < 0.01) significantly correlated with prevalence of DSC. There were no significant risk factors for MDE. CONCLUSION: Apolipoprotein E4 allele contributed to neither DSC nor MDE. The association of MCI with ApoE4 and DSC suggested that MCI is a confounder for the association between ApoE4 and DSC.

Combination of antioxidant supplements improved cognitive function in the elderly.

Although nutrients or agents with antioxidant properties were reported to show a preventive effect on cognitive decline in animal studies, epidemiologic data on select antioxidants have shown conflicting results. We investigated whether a combination of antioxidants from supplements is effective for the improvement of cognitive function of elderly. Forty-one subjects from a community dwelling aged 65 years and older took supplements containing n-3 polyunsaturated fatty acids (n-3 PUFA), lycopene, and Ginkgo biloba extracts (GE) daily for 3 years. The data of 622 subjects without supplement intake were used as control. We investigated the changes in cognitive function during a 3-year follow-up. We also investigated the influence of apolipoprotein E (APOE) genotype on the effect of antioxidants. We found that a combination of antioxidants improved cognitive function of aged persons after 3 years. Our present study also indicated this improvement in cognitive function with supplement intake in both APOE4 non-carrier (E4-) and APOE4 carrier (E4+) groups. Especially, in E4+, we found a large effect size of the improvement of cognition. When multiple antioxidants are used in combination, they protect against vulnerability to other agents and synergistically potentiate their antioxidant properties. These synergistically potentiated antioxidant effects of agents contribute to the improvement of cognitive function.

Multicentre population-based dementia prevalence survey in Japan: a preliminary report.

Community-based surveys were performed in seven rural areas in Japan to investigate the prevalence of dementia and illnesses causing dementia. A total of 5431 elderly subjects were selected based on census data from 1 October 2009. In total, 3394 participants were examined (participation rate: 62.5%), and 768 dementia cases and 529 mild cognitive impairment cases were identified. Of the illnesses causing dementia, Alzheimer's disease was the most frequent (67.4%), followed by vascular dementia (18.9%), dementia with Lewy body disease (4.6%), mixed dementia (4.2%) and other illnesses. The prevalence of dementia according to 5-year age strata between 65 and 99 years was 5.8-77.7% among the participants. The prevalence of dementia in this study was higher than in previous reports in Japan and other countries. To verify the upward trend of dementia prevalence and its background factors, we have scheduled surveys for three other urban areas in 2011-2012.

Effect of plasma lipids, hypertension and APOE genotype on cognitive decline.

We examined the combined effect of plasma lipids/hypertension and apolipoprotein E (APOE) genotype on cognitive function in elderly individuals. Plasma concentrations of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), total cholesterol (TC), APOE, and history of hypertension were evaluated in 622 community-dwelling individuals aged 65 years and older. We investigated the associations between plasma lipids/hypertension and cognitive function in apolipoprotein E4 allele (APOE4) carrier (E4+) and APOE4 noncarrier (E4-) groups using 3-year longitudinal data. At baseline and 3 years later, cognitive scores were correlated with plasma APOE levels in both E4- and E4+, and HDL level in E4-. The combination of hypertension and E4+, but not E4-, was associated with a significant deterioration in cognitive function during the 3-year follow-up. Our findings suggest that an interaction between APOE and HDL is facilitated by APOE4, and is possibly linked with a protective effect on cognitive decline in later life. The findings also indicate a synergistic effect of an APOE4 allele and hypertension on the acceleration of cognitive decline.

Association between cognitive function and plasma lipids of the elderly after controlling for apolipoprotein E genotype.

OBJECTIVE: Although the relationship between cognitive function and plasma lipids has attracted attention, previous studies have shown conflicting results. One possible confounding factor is due to the influence of gene-related modulator. We investigated the relationship between cognitive function and lipid plasma levels of old age after controlling for apolipoprotein E (APOE) genotype. METHODS: One thousand three hundred ninety-five subjects without dementia age 65 and older participated in this study. They were divided into two groups, with and without APOE4 [E4 (+) and E4 (-)]. Plasma concentrations of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), total cholesterol (TC) and apolipoprotein E (apoE) were measured. Associations between plasma concentrations of lipids and cognitive function were investigated for each group. RESULTS: We found a positive association between cognitive scores and plasma apoE level in both E4 (-) and E4 (+) groups. A positive relationship was also observed between cognitive score and HDL level in the E4 (-) group, but not in the E4 (+) group. No substantial association between cognitive score and LDL, TG, and TC levels was found in either of the groups. CONCLUSIONS: Our findings suggest that plasma apoE have a positive influence on cognitive function in both E4 (-) and E4 (+) groups, whereas the positive influence of plasma HDL was shown only in E4 (-) group. The identification of the influences of (APOE) genotype and the intracellular linkage among apoE and HDL metabolism is hoped for new preventive and therapeutic strategies for cognitive change of elderly.

Prevalence of depression and depressive symptoms among older Japanese people: comorbidity of mild cognitive impairment and depression.

BACKGROUND: The aim of the study was to estimate the prevalence of DSM-III-R major depressive episodes (MDEs), depressive symptoms cases (DSCs) (defined as a score of ≥6 on the Geriatric Depression Scale but falling short of MDE), and coexisting mild cognitive impairment (MCI) among Japanese community-dwelling older people. METHODS: Prevalence was estimated based on screening evaluation, individual interviews, and door-to-door visits. MDE and DSC were diagnosed, and the cognitive status of the participants was determined to be dementia, MCI, or normal. RESULTS: A total of 1888 subjects of 2698 candidates (70.0%) participated. The prevalence of MDE and DSC were estimated to be 4.5% (95% CI, 3.4-6.0) and 11.5% (95% CI, 4.2-28.0), respectively. MCI was more prevalent in subjects with depression (26.2%) than those with normal mood (17.9%). Although no prototypical profile of cognitive dysfunction was revealed, multiple MCI was more prevalent in subjects with depression (12.2%) than subjects with normal mood (3.8%). Conversely, subjects with MCI (26.3%) were more likely to develop depression compared with those with normal cognitive function (18.0%). CONCLUSIONS: The prevalence of depression in our subjects seems to be similar with that of previous studies. MCI was more prevalent in subjects with depression than those with normal mood. Individuals with depression showed no particular association with any of the four MCIs. Given that depression and MCI are often associated with each other and that MCI is a predictor for development of dementia, the risk of developing dementia in the depressed older people with coexisting MCI should be acknowledged.

Prevalence and causes of early-onset dementia in Japan: a population-based study.

BACKGROUND AND PURPOSE: Few studies are available that have addressed the prevalence of early-onset dementia (EOD), including early-onset Alzheimer disease and other forms of dementia in Japan. METHODS: A 2-step postal survey was sent to all of the 2475 institutions providing medical or care services for individuals with dementia in Japan's Ibaraki prefecture (population, 2 966 000) requesting information on EOD cases. Data were then reviewed and collated. RESULTS: We identified 617 subjects with EOD. The estimated prevalence of EOD in the target population was 42.3 per 100 000 (95% CI, 39.4 to 45.4). Of the illnesses that cause EOD, vascular dementia was the most frequent (42.5%) followed by Alzheimer disease (25.6%), head trauma (7.1%), dementia with Lewy bodies/Parkinson disease with dementia (6.2%), frontotemporal lobar degeneration (2.6%), and other causes (16.0%). CONCLUSIONS: The prevalence of EOD in Japan appeared to be similar to that in Western countries with the notable exception that vascular dementia was the most frequent cause of EOD in Japan.

Prevalence of four subtypes of mild cognitive impairment and APOE in a Japanese community.

BACKGROUND: The results of previous reports estimating the prevalence of mild cognitive impairment (MCI) have varied widely according to the criteria used to define MCI. METHODS: We assessed the cognitive function of Japanese community-dwelling individuals >or=65 years old and attempted to estimate the prevalence of four MCI subtypes (amnestic single, amnestic multiple, nonamnestic single, and nonamnestic multiple) using two cutoffs (1 and 1.5 SD) below normative standard. Presence of apolipoprotein E4 allele (APOE4), which is known as a strong risk factor for AD, is reportedly associated with high risk of conversion from MCI to AD. We therefore calculated the frequency of APOE4 carriers for each MCI subtype. RESULTS: Initially 1888 (70%) of 2698 baseline samples participated, and 1433 (53%) subjects who had complete clinical data including APOE typing remained for the final analysis. The prevalence of MCI subtypes varied within the range of 1.7-16.6%, depending on the criteria applied. Prevalence of MCI was higher using a cutoff at -1.0 SD than at -1.5 SD, and prevalence of amnestic MCI single at -1.5 SD was lowest among all subtypes of MCI. Frequency of APOE4 was higher for amnestic MCI than for non-amnestic MCI or the cognitively normal group. CONCLUSION: The prevalence of MCI was highly dependent on the diagnostic criteria applied. A higher frequency of APOE4 in participants with amnestic MCI subtype suggested a greater risk of future AD. For future interventions to delay the onset of dementia, targeting individuals with amnestic MCI multiple at -1 SD might be desirable.

Reliability and validity of questionnaire for neurobehavioral disability following traumatic brain injury.

The neurobehavioral disability recognized in traumatic brain injury (TBI) is a severe sequela, but there is no appropriate classification due to its various manifestations. In the present study a questionnaire for a simple investigation of this disability was prepared, and its reliability and validity verified. The survey was conducted on 72 patients with TBI by the caregiver of each patient. As a result, good reliability was indicated by the split-half method (coefficient of reliability: 0.95, obtained using Spearman-Brown correction formula). The total score of the questionnaire had a significant correlation with the total score of the simultaneously conducted Japanese version of Neuropsychiatry Inventory at the 0.01 level (Spearman's rank correlation, 0.47). It also had a significant correlation with the total score of the simultaneously conducted Japanese version of the Dysexecutive Questionnaire at the 0.05 level (Spearman's rank correlation, 0.36). Six factors constituting this neurobehavioral disability were extracted from a factor analysis of the questionnaire survey. These factors are angry outburst, avolition, deficits of sympathy, depressed mood, discourse deficits, and degradation of appearance. Each factor indicated good internal consistency (Cronbach alpha, 0.86-0.94). The present results indicate that this questionnaire has good reliability and validity, therefore it can be a significant indicator in TBI neurobehavioral disability study.