Early-onset Alzheimer's disease with a de novo mutation in the presenilin 1 gene

A 32-year-old woman diagnosed with very rapidly progressing early-onset Alzheimer's disease (EOAD), age of onset 29 years, and S170F mutation in presenilin 1 gene (PSEN1) is presented. Neuroimaging conducted 2 years after the first symptoms was typical for the advanced stage of Alzheimer's disease (AD), showing cortical brain atrophy, particularly within hippocampus, frontal and temporal cortex. The unaffected parents of the proband are not carriers of the mutation. The paternity was confirmed by microsatellite typing, strongly suggesting de novo origin of S170F mutation. In silico modeling of S170F mutation impact on presenilin 1 (PS1) transmembrane structure indicates that the mutation considerably alters putative interactions of PS1 with other proteins within gamma-secretase complex.     

Death‐associated protein kinase 1 variation and Parkinson’s disease

Background and purpose: Mutations of the LRRK2 gene are now recognized as major risk factors for Parkinson’s disease. The Lrrk2 protein is a member of the ROCO family, which also includes Lrrk1 and Dapk1. Functional genetic variants of the DAPK1 gene (rs4877365 and rs4878104) have been previously associated with Alzheimer’s disease. Methods: Herein, we assessed the role of DAPK1 variants (rs4877365 and rs4878104) in risk of Parkinson’s disease with Sequenom iPLEX genotyping, employing one Taiwanese series (391 patients with Parkinson’s disease, 344 controls) and five separate Caucasian series’ (combined sample size 1962 Parkinson’s disease patients, 1900 controls). Results: We observed no evidence of association for rs4877365 and rs4878104 and risk of Parkinson’s disease in any of the individual series or in the combined Caucasian series under either an additive or recessive model. Conclusion: These specific DAPK1 intronic variants do not increase the risk of Parkinson’s disease. However, further functional studies are required to elucidate the potential therapeutic implications with the dimerization of the Dapk1 and Lrrk2 proteins.     

Frontotemporal dementia: An attempt at clinical characteristics.

The clinical recognition of frontotemporal dementia (FTD) depends on its differentiation from Alzheimer's disease (AD). From 212 patients primarily diagnosed as probable AD, 24 cases with mild dementia, absence of disturbances the presence of which would have prevented a full neuropsychological assessment, and brain CT with detailed visualization of hippocampus atrophy were chosen. On the basis of neuropsychological examination the patients were divided into two groups: 11 cases with predominant deficit in frontal system tasks (FTD group) and 13 cases with changes in cognitive functions typical of AD (AD group). Age at onset, duration, behavioral changes, psychotic symptoms, depression, speech disorders, neurologic deficit and hippocampal atrophy were analyzed in both groups. Statistically significant differences for behavioral disturbances and hippocampal atrophy were found. Early behavioral changes and lack of early hippocampal atrophy on CT may be useful features for differentiating between FTD and AD, especially when SPECT is not available.     

Identification of a late onset Alzheimer's disease candidate risk variant at 9q21.33 in polish patients

Late onset Alzheimer's disease (LOAD) accounts for about 95% of all Alzheimer's disease cases. While the APOE ε4 variant seems to have unparalleled influence on increased LOAD risk, it does not explain all of the heritability of LOAD. In this study, we present the application of a cost-effective, pooled DNA genome-wide association study (GWAS) to uncover genetic risk variants associated with LOAD in Polish women diagnosed with either mild cognitive impairment (MCI) or well-defined LOAD. A group of 141 patients (94 LOAD and 47 MCI), as well as 141 controls, were assayed using Affymetrix Genome-Wide Human SNP 6.0 arrays. Allele frequency distributions were compared using χ2-tests, and significantly associated SNPs at p < 0.0001 with a proxy SNP were selected. GWAS marker selection was conducted using PLINK, and selected SNPs were validated on DNA samples from the same cohort using KASPar Assays. In addition, to determine the genotype of APOE variants (rs429358, rs7412), a multiplex tetra-primer amplification refractory mutation system was applied. The GWAS revealed nine SNPs associated with MCI and/or LOAD. Of these, the association of seven SNPs was confirmed by genotyping of individual patients. Furthermore, the APOE ε4 appeared to be a risk variant for LOAD, while the APOE ε3 showed a protective effect. Multivariate analysis showed association between rs7856774 and LOAD, independently from the effect of APOE variation. Pooled DNA GWAS enabled the identification of a novel LOAD candidate risk variant, rs7856774 (9q21.33), tagging a possible genomic enhancer affecting proximal transcribed elements including DAPK1 gene.     

Cognitive deficits and polymorphism of apolipoprotein E in Alzheimer's disease

The aim of this study was to test the relationship between apolipoprotein E (ApoE) genotypes and patterns of cognitive deficits in Alzheimer's disease (AD). All subjects were diagnosed as probable AD patients on the basis of the DSM-IV and NINCDS-ADRDA criteria. Each subject was examined for (1) ApoE genotype, (2) general level of mental activity (Global Deterioration Scale and Mini-Mental State Examination) and (3) cognitive functions by means of a battery of neuropsychological tests. On the basis of ApoE genotype, patients were subdivided into two groups: the first group consisted of patients with at least one epsilon4 allele (epsilon4+ group), while the second one consisted of patients without the epsilon4 allele (epsilon4- group). Our results showed that several cognitive processes depended on the ApoE genotype. In early stages of AD, patients from the epsilon4+ group had greater deficits in delayed recall of new information. On the other hand, working memory appeared to be more impaired in the epsilon4- group of patients. Independent of the genotype, both groups showed similar impairment of learning ability without, however, deficits in remote memory.     

Behavioural pathology in Alzheimer's disease with special reference to apolipoprotein E genotype

The aim of this study was to define the co-occurrence of behavioural symptoms and Alzheimer's disease (AD) in relation to apolipoprotein E (APOE) genotype. Probable AD patients from the Alzheimer's Day Clinic (n = 139) were assessed with the 'Behavioural Pathology in Alzheimer's Disease' rating scale, and their APOE genotype was determined. This study demonstrated no relationship between presence of the APOE epsilon4 allele and any of the behavioural symptoms assessed, including delusions, hallucinations, depression, activity disturbances, aggressiveness and anxiety. Activity disturbances, delusions, hallucinations and aggressiveness paralleled the severity of AD, increasing in frequency with the severity of the dementia. The prevalence of delusions, hallucinations, aggressiveness and depression were found to be associated with lower levels of education.     

The E318G substitution in PSEN1 gene is not connected with Alzheimer's disease in a large Polish cohort

Spinal cord injury (SCI) results in rapid and significant oxidative stress. We have previously demonstrated that polyethylene glycol (PEG) repairs neuronal membrane and inhibits lipid peroxidation in an in vitro model of SCI. In this study we tested the effects of PEG on oxidative stress in guinea pigs after SCI. Oxidative stress was assessed by lipid peroxidation, protein carbonyl and glutathione content. A compression injury of spinal cord at T10-11 induced a rapid and diffusive oxidative stress. Administration of PEG immediately after injury resulted in a marked decrease in oxidative stress both at the injury site and in its adjacent segments. These results, along with our previous findings, suggest that an early application of PEG can effectively suppress oxidative stress after SCI in vivo.     

Alpha2-macroglobulin gene polymorphism in patients with Alzheimer's disease

Recent studies suggest that alpha 2-macroglobulin (alpha 2 m) may play a role in the pathogenesis of Alzheimer's Disease (AD). The presence of alpha 2-macroglobulin G/G genotype is thought to increase the risk of AD. The aim of the study was to analyse alpha 2 m polymorphism in two groups: AD patients (n = 60, F = 41, M. = 19, mean age 73.3 +/- 6.3) and non-demented control group (n = 58, F = 36, M. = 22, mean age 73.1 +/- 8.3, mean MMSE score 27). Frequencies of genotypes A/A, A/G, G/G in AD group were: 0.46: 0.42: 0.12. In control group those frequencies were: 0.40: 0.48: 0.12. The lack of statistically significant difference between G/G frequencies in both groups of patients may suggest that alpha 2-macroglobulin G/G genotype is not a risk factor for AD.