Toru Kinoshita

A randomized cross-over study of a traditional Japanese medicine (kampo), yokukansan, in the treatment of the behavioural and psychological symptoms of dementia

The effectiveness and safety of yokukansan (TJ-54), a traditional Japanese medicine (kampo) for the treatment of the behavioural and psychological symptoms of dementia (BPSD), were evaluated in 106 patients diagnosed as having Alzheimers disease (AD) (including mixed-type dementia) or dementia with Lewy bodies. Patients were randomly assigned to group A (TJ-54 treatment in period I and no treatment in period II; each period lasting 4 wk) or group B (no treatment in period I and TJ-54 treatment in period II). BPSD and cognitive functions were evaluated using the Neuropsychiatric Inventory (NPI) and the Mini-Mental State Examination (MMSE), respectively. Activities of daily living (ADL) were evaluated using Instrumental Activities of Daily Living (IADL) in outpatients and the Barthel Index in in-patients. For the safety evaluation, adverse events were investigated. Significant improvements in mean total NPI score associated with TJ-54 treatment were observed in both periods (Wilcoxon test, p=0.040 in period I and p=0.048 in period II). The mean NPI scores significantly improved during TJ-54 treatment in groups A and B (p=0.002 and p=0.007, respectively) but not during periods of no treatment. Among the NPI subscales, significant improvements were observed in delusions, hallucinations, agitation/aggression, depression, anxiety, and irritability/lability. The effects of TJ-54 persisted for 1 month without any psychological withdrawal symptoms in group A. TJ-54 did not show any effect on either cognitive function or ADL. No serious adverse reactions were observed. The present study suggests that TJ-54 is an effective and well-tolerated treatment for patients with BPSD.

A new EEG method for estimating cortical neuronal impairment that is sensitive to early stage Alzheimer's disease

OBJECTIVES To test the hypothesis that elecetroencephalographic (EEG) analysis is sensitive to cortical neuronal impairment in early stage Alzheimers disease (AD), and that this analysis correlates with corresponding changes in cerebral blood flow. METHODS We examined an EEG measure of neuronal impairment in the cerebral cortex in terms of its ability to detect very mild AD. This measure, the mean value of the resting state EEG alpha dipolarity (D(alpha)), approaches unity without cortical sulcal lesions, whereas brains with randomly distributed cortical sulcal lesions lower D(alpha) values well below unity. D(alpha) was evaluated in 25 patients with very mild AD, 33 patients with moderately severe AD, and 56 normal age-matched subjects. These subjects also received SPECT, and strong correlation between D(alpha) and regional cerebral blood flow (rCBF) was observed. RESULTS D(alpha) values greater than 0.977 correctly classified normal subjects, but also included 10% of very mild AD. D(alpha) values less than 0.952 correctly classified very mild AD as well as moderately severe AD, but also included 10% of normal subjects. D(alpha) values also correlated positively with bilateral temporal-parietal rCBF (a characteristic finding in AD patients); both declined with increasing dementia severity. CONCLUSIONS Analysis of D(alpha) in this sample supports the hypothesis that early stages of AD can be discriminated from normal aging using measures of cortical neuronal impairment. Furthermore, dementia severity, as reflected by the degree of impairment, is reflected in declining D(alpha) values and increasing variance (greater spread of the D(alpha) values).

Prevalence of Dementia and Distribution of ApoE Alleles in Japanese Centenarians: An Almost-Complete Survey in Yamanashi Prefecture, Japan

OBJECTIVE: To determine the prevalence and types of dementia in centenarians and to examine whether the ApoE 4 allele has significant impact on the development of Alzheimers disease (AD) in the population.

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

The results of previous reports estimating the prevalence of mild cognitive impairment (MCI) have varied widely according to the criteria used to define MCI.

Mitochondrial DNA variants in a Japanese population of patients with Alzheimer's disease.

The evidence for the role of mitochondria in Alzheimers disease (AD) has been well investigated, based on the amyloid hypothesis and its relation to the mitochondrial dysfunction due to oxidative stress. However, contrasting reports describe an unclear picture on the relationship between AD and mitochondrial DNA (mtDNA) variations. Therefore, we analyzed complete mtDNA sequences from 153 AD patients and 129 normal control subjects to determine if inherited mtDNA polymorphisms or rare variants, or both contribute to the etiology of late-onset AD. The results reported herein indicate that inherited mtDNA common polymorphisms could not be the single major causes of AD but that some rare variants in the protein-coding-region may have protective effects for high-risk populations with the APOE e4 allele. Furthermore, our results support the idea that the np956-965 poly-c insertion and 856A>G variant might be a riskfactor for AD.

Dementia and mild cognitive impairment among non-responders to a community survey

We aimed to estimate the prevalence of mild cognitive impairment (MCI) among elderly non-responders to a community-based survey. We conducted a two-phase, population-based cross-sectional study of community-dwelling individuals aged 65 years or older in Tone, located in central Japan. The first phase of the study consisted of physical and cognitive examinations of individuals who responded to the first recruitment (quick-responders), whereas the second phase included individuals who did not respond in the first phase (delayed-responders). We compared the prevalence of MCI and dementia between delayed-responders and quick-responders. Of the 2,698 potential candidates, 1,888 (1,619 quick-responders, 225 delayed-responders, and 44 nursing home residents) were enrolled (70.0%). The prevalence of MCI was 2.3-fold increased in delayed-responders compared to the quick-responders (OR=2.27, 95% CI: 1.37-3.77, p=0.002, aged< or =74). In order to develop a method for the early detection of dementia, we must pay more attention to delayed-or non-responders.

Apolipoprotein E allele in centenarians.

Sobel et al., 1 reporting the prevalence of apolipoprotein E (apoE) genotypes among Finnish centenarians, noted that the presence of the e4 allele does not necessarily lead to Alzheimers disease (AD) in this population and suggested that the relationship between the apoE e4 allele and AD may be age-dependent. Recently, we also carried out an almost complete survey of centenarians living in Yamanashi prefecture, a district of Japan with a population of 0.87 million, and determined the prevalence of apoE …

ApoE epsilon 4 allele and cognitive decline in patients with Alzheimer's disease

Many clinical and basic studies have confirmed an association between the apolipoprotein E (apoE) epsilon 4 allele and the development of Alzheimers disease (AD). Corder et al. [1] reported that survival from onset was unrelated to epsilon 4 gene dose. In this issue, Kurz et al. [2] report that no association of the apoE epsilon 4 allele with cognitive decline was found in AD subjects. We examined the relationship between apoE alleles and the rate of cognitive decline in a longitudinal study of up to 3 years. Between February and October 1992, 105 subjects with probable AD diagnosed on the basis of NINCDS-ADRDA [3] criteria entered the study. All the subjects underwent a …

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

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.

Decreased ventilatory response to hypercapnia in dementia with Lewy bodies

A systematic autonomic dysfunction observed among patients with dementia with Lewy bodies (DLB) has recently attracted close attention. Here, we compare cardiovascular and pulmonary autonomic functions among patients with DLB, patients with Alzheimers disease, and healthy control subjects. All 15 DLB patients demonstrated severely low ventilatory response to hypercapnia, whereas none of the other subjects demonstrated abnormal results. The majority of the DLB patients showed impaired heart rate variability, low uptake on 123I‐metaiodobenzylguanidine myocardial scintigraphy, and orthostatic hypotension. Ventilatory response to hypercapnia as a marker of respiratory autonomic function is a promising diagnostic tool for DLB. Ann Neurol 2009;65:614–617