Yoshiki Adachi

Population-based door-to-door survey of migraine in Japan: The Daisen Study

Objectives.—To determine prevalence and characteristics of migraine in Japan, and to investigate use of medical care and whether food preference is associated with risk of migraine.

Huntington's disease–like 2 (HDL2) in North America and Japan

Huntingtons Disease–like 2 (HDL2) is a progressive, autosomal dominant, neurodegenerative disorder with marked clinical and pathological similarities to Huntingtons disease (HD). The causal mutation is a CTG/CAG expansion mutation on chromosome 16q24.3, in a variably spliced exon of junctophilin‐3. The frequency of HDL2 was determined in nine independent series of patients referred for HD testing or selected for the presence of an HD‐like phenotype in North America or Japan. The repeat length, ancestry, and age of onset of all North American HDL2 cases were determined. The results show that HDL2 is very rare, with a frequency of 0 to 15% among patients in the nine case series with an HD‐like presentation who do not have the HD mutation. HDL2 is predominantly, and perhaps exclusively, found in individuals of African ancestry. Repeat expansions ranged from 44 to 57 triplets, with length instability in maternal transmission detected in a repeat of 33 triplets. A younger age of onset is correlated with a longer repeat length (r2 = 0.29, p = 0.0098). The results further support the evidence that the repeat expansion at the chromosome 16q24.3 locus is the direct cause of HDL2 and provide preliminary guidelines for the genetic testing of patients with an HD‐like phenotype. Ann Neurol 2004

Estrogen receptor gene polymorphisms in patients with Alzheimer's disease, vascular dementia and alcohol-associated dementia

The association between the estrogen receptor (ER-α) gene and dementia was examined in 223 patients with Alzheimer’s disease (AD), 66 with vascular dementia (VD), 17 with alcohol-associated dementia (ALD) and 134 healthy elderly control subjects. The PvuII and XbaI restriction fragment length polymorphisms of the ER-α gene were represented as Pp (PvuII) and Xx (XbaI), with capital letters signifying the absence of restriction sites and small letters the presence of restriction sites. We found that the frequency of the ER-α gene P allele and X allele in the late-onset AD (LOAD) group (P allele was 0.51, X allele was 0.30) was significantly higher than that in controls (P 0.38, p < 0.01; X 0.20, p < 0.01), and that the frequency of the ER-α gene P allele and PP genotype was significantly different between apolipoprotein E ε4 carriers and noncarriers in LOAD. These findings suggest that the genotype of the ER-α gene may be specific in LOAD, and that the ER-α gene was an additional risk for LOAD.

Apolipoprotein E polymorphism in patients with Alzheimer's disease, vascular dementia and ischemic cerebrovascular disease.

Apolipoprotein E σ4 allele (ApoE σ4) is associated with Alzheimer’s disease (AD) in familial and sporadic cases, but the associations of ApoE σ4 allele and vascular dementia (VD) and/or ischemic cerebrovascular disease (ICVD) are still controversial. To clarify the associations of ApoE polymorphism with AD, VD and ICVD in Japanese, we examined ApoE polymorphism in samples of 255 patients with AD, 87 patients with VD, and 123 patients with ICVD, as compared with 117 age-matched healthy control subjects (CTL). The frequency of the ApoE σ4 allele was significantly higher in the VD group (0.21), the ICVD group (0.15) as well as in the AD group (0.26) than in the CTL subjects (0.08). These findings suggest that the genotype of ApoE σ4 is associated with not only AD but also VD and ICVD, and that ApoE σ4 plays an important role in the development of dementia and ICVD.

Positive association between an estrogen receptor gene polymorphism and Parkinson's disease with dementia.

Parkinsons disease (PD) is a common cause of dementia in the elderly. Dementia in Alzheimers disease (AD) and PD share common biologic and clinical features. The estrogen receptor (ER) gene is one of the susceptibility genes for AD. In order to test the hypothesis that the overlap between AD and PD may have a genetic basis, we determined ER gene polymorphisms in 13 PD patients with dementia (PDD) (age ± SD; 71.9 ± 5.5 years), 71 PD patients without dementia (PDND) (68.4 ± 7.5 years), 86 AD patients (76.8 ± 8.0 years) and 51 control subjects (CTL) (74.9 ± 6.9 years). ER genotypes were classified as a P or p allele on the basis of a Pvu II‐RFLP, and X and x on the basis of a Xba I‐RFLP. The frequency of the P allele in the PDD group as well as the AD group was higher than that in CTL. There was no significant difference in the distribution of the P allele between CTL and PDND. There were no significant differences in the distribution of the X allele among the PDD, PDND and CTL groups, whereas a higher incidence was found in AD. We conclude that the ER gene may be a common susceptibility gene for dementia in PD as well as AD.

Cerebrospinal fluid tau in dementia disorders: a large scale multicenter study by a Japanese study group

A large scale multicenter study of cerebrospinal fluid (CSF) tau levels was conducted to determine the cut-off value, sensitivity and specificity for clinical usage as a biomarker of Alzheimers disease (AD). Its use for early and differential diagnosis and the factors that increase CSF tau levels were also examined. CSF samples from a total of 1,031 subjects including 366 patients with AD, 168 patients with non-Alzheimer type dementia (NA), 316 patients with non-dementia neurological diseases (ND) and 181 normal controls (NC) were measured using ELISA for tau. The cut-off value of tau, 375 pg/ml, showed 59.1% sensitivity and 89.5% specificity for diagnosis of AD compared with the other groups. The tau levels were increased from the early to late stages of AD. Elevation of CSF tau in the non-tauopathy and tauopathy dementia groups, chronic and acute damage to the cerebrum, and meningeal disturbance were other factors that required attention for clinical practice. Measurement of CSF tau was useful as a biomarker for early and differential diagnosis of AD.

High Expression of Apolipoprotein E mRNA in the Brains with Sporadic Alzheimer’s Disease

In order to study progressive dementia in Alzheimer’s disease (AD) patients, we analyzed the gene expression of apolipoprotein E (apoE). ApoE mRNA level in the brains of patients with AD was determined by the reverse transcriptase-polymerase chain reaction (RT-PCR) method. ApoE genotype and the promoter polymorphisms (–491A/T, Th1/E47cs) were determined by the PCR restriction fragment length polymorphism method. The apoE mRNA level was significantly higher in the AD group than the control group (p < 0.05). ApoE mRNA in the AD group with apoE Ε4 was also significantly higher than that in the control group with apoE Ε4 (p < 0.05). Our result did not indicate the possibility that the promoter polymorphisms modulate the apoE mRNA level. The higher level of apoE mRNA in AD with apoE Ε4 may play an important role in the development of AD.

Prognosis of Parkinson's disease in Japan

Therapy for Parkinsons disease (PD) has been progressing. However, the prognosis for patients with PD is still unclear. We studied the course of PD in patients in the San-in Area of Japan over a long time period. The main purpose of this study was to see whether there was a difference in survival between PD patients and the general population. Information on 114 deceased PD patients, who died between 1989 and 1996, was collected from hospitals belonging to the Tottori University Parkinsons Disease Epidemiology Study Group. Although the duration of illness was prolonged, the survival of PD patients was still poorer than that of the general population. The most common cause of death was pneumonia. The main cause of death in young PD patients was also pneumonia. In order to improve the survival of PD patients, PD-related conditions should be treated more extensively, especially pneumonia.

Genetic Analysis of Vascular Factors in Alzheimer's Disease

Abstract: Genetic risk factors for Alzheimers disease (AD) have been extensively examined. Several risk factors for AD are shared with vascular dementia (VaD). We performed genetic case‐control studies on polymorphisms of the apolipoprotein E (ApoE) gene, the methylene tetrahydrofolate reductase (MTHFR) gene, and the angiotensin‐converting enzyme (ACE) gene. The most acceptable genetic risk factor for the development of AD is the ApoE epsilon‐4 (ApoE ε4) allele. ApoE promoter polymorphisms have also been reported to be associated with AD. As expected, the ApoE ε4 allele had strong association with AD in our samples. The ApoE ε4 allele was also estimated as a risk factor for VaD. An ApoE promoter polymorphism (−291T/G) did not show positive association with AD or any other diseases. Common MTHFR phenotypes are thought to genetically regulate blood homocysteine level, which has been associated with AD. We failed to show independent associations between AD and the common MTHFR polymorphisms (C677T and A1298C). A deletion polymorphism at intron 16 of the ACE gene has also been associated with AD. In our study, we found a significant ethnic difference of the genotype distribution, but failed to replicate the positive association between the I allele and AD.

Prevalence of dementia in the rural island town of Ama-cho, Japan.

Background: With the striking increase in the number of elderly people in Japan, dementia has not only become a medical but also a social issue. Methods: We studied the prevalence of dementing disorders in a rural island town of Japan (Ama-cho), using a door-to-door 2-phase design. Results: Of the 120 persons screened as having cognitive impairment, 104 people were diagnosed as having dementia. The prevalence (cases/100 persons aged 65 years and older) was 11.0 for all types of dementia, 7.0 for Alzheimer’s disease, 1.7 for vascular dementia, 0.53 for dementia with Lewy bodies, 0.74 for Parkinson’s disease dementia, 0.21 for progressive supranuclear palsy, 0.11 for frontotemporal lobar degeneration and 0.74 for other dementia. The overall prevalence was higher in women for Alzheimer’s disease and Parkinson’s disease dementia, and in men, for vascular dementia and dementia with Lewy bodies. Conclusion: We confirmed the overall prevalence of dementia in the elderly population aged 65 years and older to be 11.0. This finding is higher compared with previous reports in Japan.