Brain-derived neurotrophic factor gene polymorphisms and Alzheimer's disease.

Several lines of evidence have made brain-derived neurotrophic factor (BDNF) an important candidate gene conferring risk for Alzheimer's disease (AD). Recently, three studies reported an association between two single-nucleotide polymorphisms (SNP)--i.e., C270T and G196A--in the BDNF gene and AD. This attempt to confirm these associations in a larger AD sample included examination of the linkage disequilibrium of these two SNPs. Comparison of 487 Japanese AD subjects with 471 cognitively normal elderly controls showed higher frequencies of the G allele (60.5 vs. 55.5%, p = 0.028) and of both the GG and GA genotypes (85.8 vs. 79.8%, p = 0.025) of the G196A polymorphism in AD subjects than in controls and higher frequency of the T allele of the C270T polymorphism in AD subjects who were negative for apolipotrotein E4 (2.0 vs. 4.4%, p = 0.035) or positive for AD family history (2.8 vs. 7.1%, p = 0.046). These findings suggest that BDNF gene polymorphisms play some role in the development of AD.

Quantitative MRI findings and cognitive impairment among community dwelling elderly subjects.

OBJECTIVES: To study the factors which influence cognitive impairment among elderly subjects living in a local community, based on both MRI and clinical findings, to further elucidate the causes of dementia, and also to help develop strategies for its prevention. METHODS: Cranial MRI and other medical examinations were performed on non-demented elderly subjects who resided in one rural community. A total of 254 subjects aged from 60 to 91 years of age, with a mean age of 73.9 (SD 6.8) were examined. The mini mental state examination (MMSE) was used to identify cognitive impairment. White matter lesions and cerebral atrophy on MR images were measured quantitatively. A multivariate analysis was also performed with the existence of cognitive impairment as the dependent variable, and the MRI findings and clinical observations were used as the independent variables. RESULTS: Cognitive impairment was present in 46 subjects (18.1%). They were older, had a lower educational level, and more frequent hypertension compared with those without cognitive impairment. The packed cell volume was lower in the impaired group. In addition, their MRI findings showed significantly larger quantities of white matter lesions and cerebral atrophy, as well as more infarcts. A logistic regression analysis demonstrated a significant relation among such factors as white matter lesions (odds ratio (OR) 1.575, 95% confidence interval (95% CI) 1.123-2.208), cerebral atrophy (OR 0.761, 95%CI 0.587-0.987), and lower education (OR 0.682, 95%CI 0.544-0.855) for subjects with a cognitive impairment. CONCLUSIONS: White matter lesions and cerebral atrophy are factors which induce a cognitive impairment in community dwelling elderly subjects without dementia. It is important to carefully watch for any abnormalities in these factors, and to perform cohort studies to check for the above risk factors, to both prevent and make an early diagnosis of dementia.

Elevated plasma homocysteine levels and risk of silent brain infarction in elderly people.

BACKGROUND AND PURPOSE: Silent brain infarction (SBI) on MRI is common in elderly people, and recent studies have demonstrated that SBI increases the risk of progression to clinically apparent stroke and cognitive decline. Therefore, an early and accurate detection of SBI and a search for potential treatable risk factors may have a significant impact on public health. METHODS: Community-dwelling elderly people aged >/=66 years who participated in the present study (n=153) underwent brain MRI and standardized physical and neuropsychological examinations as well as blood biochemistry determinations, including total plasma homocysteine (pHcy), renal function, vitamin status, and polymorphisms of the methylenetetrahydrofolate reductase gene. RESULTS: SBI was found in 24.8% of the participants. In the univariate analysis, the pHcy levels in subjects with SBI (13.6+/-4.1 micromol/L) were significantly higher (P=0.0004) than those in subjects without SBI (11.0+/-3.3 micromol/L). When pHcy levels were stratified into high (>/=15.1 mmol/L), moderate (11.6 to 15.0 mmol/L), and low (

No association between DLST gene and Alzheimer's disease or Wernicke-Korsakoff syndrome.

Among many candidate genes for the genetically heterogeneous Alzheimer's disease (AD), only apolipoprotein E (ApoE) has been confirmed. Another candidate is the dihydrolipoyl succinyltransferase (DLST) gene, one of three components of thiamine-dependent mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC), because KGDHC activity is reported reduced in AD patients. Also characterized by reduced KGDHC activity is another neuropsychiatric disease, Wernicke-Korsakoff syndrome (WKS), which results from thiamine deficiency. Examination of specific DLST gene polymorphism in 247 Japanese AD patients, 53 alcoholic WKS patients, and 368 nondemented Japanese control subjects revealed no significant differences in DLST genotypes and failed to replicate the findings of earlier studies indicating an association between DLST gene polymorphism and AD.

Cranial MR imaging of sequelae of prefrontal lobotomy.

BACKGROUND AND PURPOSE: Although prefrontal lobotomy is an obsolete treatment for schizophrenia, we still encounter patients who have undergone this procedure. The purpose of this study was to describe the MR imaging findings of sequelae of prefrontal lobotomy. METHODS: We retrospectively reviewed cranial MR images of eight patients with schizophrenia who underwent prefrontal lobotomy approximately 50 years previously. RESULTS: In all patients, a bilateral cavitary lesion with a thick wall was found in the frontal white matter. The genu of the corpus callosum was mildly to markedly atrophic. The size and location of the cavity and the degree of callosal atrophy were correlated. CONCLUSION: MR imaging is useful for the diagnosis of sequelae of prefrontal lobotomy, including cavitary lesions with dense walls of gliosis and secondary degeneration of the genu of the corpus callosum.

Alpha2-macroglobulin gene polymorphisms show racial diversity and are not associated with Alzheimer's disease.

Two genetic markers of the plasma protein alpha2-macroglobulin, a 5 bp deletion/insertion at the 5' splice site of exon 18 (A2MI) and the GTC/ATC (VaIIO00IIe) in exon 24 (A2M2), may have roles in the development of Alzheimer's disease (AD). Genotyping and linkage analysis of these markers in 426 Japanese sporadic AD patients, 85 autopsy-confirmed Caucasian AD cases, and, as controls, 382 Japanese and 65 Caucasians who were cognitively normal and 140 Japanese Parkinson's disease patients showed racial diversity in the frequencies and relationship of the two markers. Comparison of genotype and allele frequencies, stratification of the samples by the presence of the apolipoprotein E epsilon4 allele, and logistic regression analysis revealed no association of these markers with AD in either racial group.

Phosphorylation of MARCKS in Alzheimer disease brains.

Activation of the amyloid beta-protein precursor, secretary pathway through alpha-secretase has been reported to increase the secretion of neuroprotective amyloid precursor protein and preclude the formation of amyloid beta-protein. Activation of protein kinase C has been shown to accelerate this secretory pathway. These results prompted us to focus on a potential links between protein kinase C and the amyloid beta-protein-related pathology of Alzheimer disease (AD). Although protein kinase C is reported to occur in senile plaques, its catalytic activity has not been investigated. As the phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) has been used as a marker for activation of protein kinase C in vivo, we examined its phosphorylation in brain tissues obtained from seven AD patients and five non-demented subjects using an antibody that specifically recognized MARCKS phosphorylated by protein kinase C. Phosphorylation of MARCKS in cortical neurons in AD brains was weaker than that in control brains. Interestingly, however, phosphorylation of MARCKS was detected in microglia and dystrophic neurites within neuritic plaques, a mature form of amyloid beta-protein deposits. These results suggest that protein kinase C alteration is associated with AD pathology and that protein kinase C is activated in microglia and dystrophic neurites by amyloid beta-protein in AD brains.

Cerebral blood flow in nondemented elderly subjects with extensive deep white matter lesions on magnetic resonance imaging.

Our previous study showed that deep white matter lesions (DWML) were associated with subtle cognitive decline in community-dwelling elderly people. However, even extensive (EXT)-DWML, found in 7 (4%) of 178 subjects aged 60 years or older, did not cause dementia. The purpose of the present study was to investigate brain circulation in nondemented elderly subjects with EXT-DWML. We compared cerebral blood flow in the deep white matter and frontal cortex between 5 subjects with EXT-DWML and 5 without such lesions, using a xenon-enhanced computed tomography (CT) method. Although the difference of deep white matter findings on magnetic resonance imaging (MRI) was the greatest possible (i.e., extensive v no or minimum lesions), cerebral blood flow values in anterior deep white matter and frontal cortex were 21.4 ± 5.3 standard deviation (SD) mL/100 g/minute and 42.7 ± 4.1, respectively, in subjects with extensive lesions, which were not significantly different from 24.3 ± 4.3 and 44.0 ± 7.1 in subjects without DWML. The present study suggests that EXT-DWML in nondemented elderly individuals do not necessarily indicate apparent hypoperfusion or marked cognitive decline.

No evidence of association between apolipoprotein E gene regulatory region polymorphism and Alzheimer's disease in Japanese.

The reported association between -491 A/T polymorphism in the regulatory region of the apolipoprotein E gene (APOE) and increased risk for Alzheimer's disease (AD) is controversial: Studies of different racial and ethnic populations have found both positive and negative associations. Examination of -491 A/T polymorphism in 216 patients with sporadic AD and 157 age- and gender-matched controls from the Japanese population revealed that, in contrast to findings for Caucasian populations, the -491 T allele, but not the A allele, was significantly more prevalent in patients with AD than in controls. This difference disappeared when the subjects were stratified by the gene dose of the APOE epsilon4 allele. Moreover, logistic regression analysis, controlling for age, sex, and the presence of the APOE epsilon4 allele, showed no association between the -491 polymorphism and AD. These results suggest that -491 polymorphism does not independently confer susceptibility to AD, but that this polymorphism is in partial linkage disequilibrium with the APOE epsilon2/3/4 polymorphism.