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1.209 Associations between multiple system atrophy and polymorphisms of SLC1A4, SQSTM1, and EIF4EBP1 genes
S62
Monday, 10 December 2007
1.206 Donepezil versus rivastigmine tolerability study in dementia with Lewy bodies and Alzheimer’s disease
1.208 APOE, CYP46, PRNP and PRND: Genetic polymorphisms in Alzheimer’s Disease and mild cognitive impairment
1 Lodz,
R. Magierski1° , T. Sobow, I. Kloszewska Poland
1 Lodz,
Objective: The comparative tolerability of donepezil and rivastigmine in a “real life” sample of patients diagnosed as having mild to moderate Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) have not been properly studied to date. Method: A retrospective, case record analysis of AD (N = 183) and DLB (N = 37) patients who had been prescribed with rivastigmine or donepezil was performed. Main outcome estimates were: the likelihood of achieving recommended doses for both drugs, the tolerability of the highest achieved dose, the frequency and profile of side effects, causes of drug discontinuation and the number of withdrawn cases. Results: Numerically, more subjects on rivastigmine than on donepezil were included. A maximum approved dose (10 mg for donepezil and 12 mg for rivastigmine) has been achieved by an equal proportion of patients on donepezil and on rivastigmine (differences not significant). The tolerability of the lowest tolerated dose was also similar in both compared groups. The side effects profiles of both drugs were similar and equally contributed to the drop-out rate. Conclusion: Donepezil and rivastigmine are comparably tolerated and of similar clinical benefits in a “real life” population of non-selected patients with mild to moderate AD and dementia with Lewy bodies. Cholinesterase inhibitors which are considered a gold standard in the treatment of AD might constitute therapeutical option in DLB as well.
Objective: The influence of genetic factors in the etiology of sporadic Alzheimer’s disease (AD) is estimated at 40−80%. The only widely confirmed sporadic AD genetic risk factor is the apolipoprotein E e4 allele. The results of numerous studies on various other genes are highly inconclusive. To date, genetic studies in mild cognitive impairment (MCI) are scarce. The aim of this study was to assess the influence of APOE, CYP46, PRNP, PRND genetic polymorphisms on the risk of AD and MCI. Method: To date, over 100 subjects with AD, amnestic form of MCI and healthy controls have been recruited for the study. To increase the homogeneity of the studied population subjects with comorbid vascular risk factors, family history of dementia and subjects satisfying criteria for non-AD dementias have been excluded from the study. RFLP and sequencing techniques were employed to assess various polymorphic sites in the CYP46, PRNP, PRND genes and APOE genotype. Results: As expected, the proportion of APOE e4 carriers was significantly higher in the AD group compared to controls. No statistically significant influence of polymorphisms in the CYP46, PRNP and PRND (codons 26, 56, 174) genes on the risk of either AD or MCI was observed. However, the odds ratio for PRNP codon 129 homozygosity was over fivefold higher in the AD group compared to other study groups. Heterozygosity in the 3 UTR region of the PRND gene was significantly more prevalent in the AD group than in MCI subjects or healthy controls. Conclusion: The significance of APOE genotype as an AD risk factor seems to be beyond controversy. Our results further confirm and strengthen this association. The role of other genes putatively involved in the pathobiology of neurodegenerative disorders seems vague at most. Further studies on much larger populations are required to estimate the true significance of these genetic variants in the etiology of AD.
1.207 Mortality in a community based cohort of Parkinson’s disease patients with and without dementia in a rural area of North Wales in the United Kingdom P. Hobson1° , J. Meara United Kingdom
M. Flirski1° , E. Golanska, T. Sobow, P. Liberski, I. Kloszewska Poland
1 Rhyl,
Objective: The aim of this study was to compare the mortality rate in cases of Parkinson’s disease (PD), with and without significant cognitive impairment at baseline, to the age and sex matched United Kingdom England and Wales population. Method: A cohort of clinically probable PD patients (n = 166) aged 53−91, based on UK Brain Bank criteria, were drawn from a community based register. The England and Wales mortality rates for both genders were used as controls. Results: A total of 166 PD patients were identified and followed for a mean of 4.4 years, during which period 91 died, giving a cumulative mortality of 54.8%. Within this cohort, 80 fulfilled criteria for dementia, and 86 did not. The cumulative mortality in the demented cohort was 81% and for the non-demented cohort it was 30% (p < 0.05). The standardized mortality ratio (SMR) for the total cohort was 2.06 and was increased for both sexes (Male = 1.74, female 2.29). Controlling for dementia cases at baseline (demented n = 80, not demented n =86), found that the mortality in the demented cohort the SMR was 3.05 and in the non-demented cohort it was 1.14. A cox proportional hazard model revealed that dementia was an independent predictor for mortality. Conclusion: These findings suggest that despite modern pharmacological treatments, mortality remains much higher in PD compared to the general population. PD patients with a diagnosis of dementia appear to be at increased risk of mortality compared to non-demented patients and the general population
1.209 Associations between multiple system atrophy and polymorphisms of SLC1A4, SQSTM1, and EIF4EBP1 genes H. Soma1° , I. Yabe, A. Takei, N. Fujiki, T. Yanagihara, H. Sasaki Japan
1 Sapporo,
Objective: Multiple system atrophy (MSA) is an adult-onset sporadic neurodegenerative disease. Although the etiology of MSA remains obscure, recent studies suggest that oxidative stress is associated with the pathogenesis of MSA. The aim of this study was to evaluate genetic associations between the candidate genes involved in oxidative stress and MSA in a case-control study. Method: We examined 119 Japanese patients with MSA and 123 controls, and genotyped single nucleotide polymorphisms (SNPs) of the following eight genes: CCAAT/enhancer-binding protein homologous protein (CHOP), activating transcription factor 3 (ATF3), CCAAT/enhancerbinding protein-b (CEBPB), sequestosome 1 (SQSTM1), cysteinyl-tRNA synthetase (CARS), solute carrier family 1A4 (SLC1A4), activating transcription factor 4 (ATF4), and eukaryotic translation initiation factor 4Ebinding protein 1 (EIF4EBP1). Results: SLC1A4 SNP +28833 (V398I, rs759458, genotype: Pc = 0.0186, allele: Pc = 0.0303, Pc: p-value with Bonferroni correction), two major haplotypes of SLC1A4 “T-C-C-G” and “T-C-T-A” (Pc = 0.0261 and 0.000768), two-SNP haplotypes of SQSTM1 “C-T” and “A-T” (Pc = 0.0136 and 0.0369), and the most common haplotype of EIF4EBP1 “C-T-G-C” (Pc = 0.0480) showed significant associations. Conclusion: This study revealed genetic associations of SLC1A4, SQSTM1, and EIF4EBP1 with MSA. These results may lend genetic support to the hypothesis that oxidative stress is associated with the pathogenesis of MSA.
Monday, 10 December 2007
1.206 Donepezil versus rivastigmine tolerability study in dementia with Lewy bodies and Alzheimer’s disease
1.208 APOE, CYP46, PRNP and PRND: Genetic polymorphisms in Alzheimer’s Disease and mild cognitive impairment
1 Lodz,
R. Magierski1° , T. Sobow, I. Kloszewska Poland
1 Lodz,
Objective: The comparative tolerability of donepezil and rivastigmine in a “real life” sample of patients diagnosed as having mild to moderate Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) have not been properly studied to date. Method: A retrospective, case record analysis of AD (N = 183) and DLB (N = 37) patients who had been prescribed with rivastigmine or donepezil was performed. Main outcome estimates were: the likelihood of achieving recommended doses for both drugs, the tolerability of the highest achieved dose, the frequency and profile of side effects, causes of drug discontinuation and the number of withdrawn cases. Results: Numerically, more subjects on rivastigmine than on donepezil were included. A maximum approved dose (10 mg for donepezil and 12 mg for rivastigmine) has been achieved by an equal proportion of patients on donepezil and on rivastigmine (differences not significant). The tolerability of the lowest tolerated dose was also similar in both compared groups. The side effects profiles of both drugs were similar and equally contributed to the drop-out rate. Conclusion: Donepezil and rivastigmine are comparably tolerated and of similar clinical benefits in a “real life” population of non-selected patients with mild to moderate AD and dementia with Lewy bodies. Cholinesterase inhibitors which are considered a gold standard in the treatment of AD might constitute therapeutical option in DLB as well.
Objective: The influence of genetic factors in the etiology of sporadic Alzheimer’s disease (AD) is estimated at 40−80%. The only widely confirmed sporadic AD genetic risk factor is the apolipoprotein E e4 allele. The results of numerous studies on various other genes are highly inconclusive. To date, genetic studies in mild cognitive impairment (MCI) are scarce. The aim of this study was to assess the influence of APOE, CYP46, PRNP, PRND genetic polymorphisms on the risk of AD and MCI. Method: To date, over 100 subjects with AD, amnestic form of MCI and healthy controls have been recruited for the study. To increase the homogeneity of the studied population subjects with comorbid vascular risk factors, family history of dementia and subjects satisfying criteria for non-AD dementias have been excluded from the study. RFLP and sequencing techniques were employed to assess various polymorphic sites in the CYP46, PRNP, PRND genes and APOE genotype. Results: As expected, the proportion of APOE e4 carriers was significantly higher in the AD group compared to controls. No statistically significant influence of polymorphisms in the CYP46, PRNP and PRND (codons 26, 56, 174) genes on the risk of either AD or MCI was observed. However, the odds ratio for PRNP codon 129 homozygosity was over fivefold higher in the AD group compared to other study groups. Heterozygosity in the 3 UTR region of the PRND gene was significantly more prevalent in the AD group than in MCI subjects or healthy controls. Conclusion: The significance of APOE genotype as an AD risk factor seems to be beyond controversy. Our results further confirm and strengthen this association. The role of other genes putatively involved in the pathobiology of neurodegenerative disorders seems vague at most. Further studies on much larger populations are required to estimate the true significance of these genetic variants in the etiology of AD.
1.207 Mortality in a community based cohort of Parkinson’s disease patients with and without dementia in a rural area of North Wales in the United Kingdom P. Hobson1° , J. Meara United Kingdom
M. Flirski1° , E. Golanska, T. Sobow, P. Liberski, I. Kloszewska Poland
1 Rhyl,
Objective: The aim of this study was to compare the mortality rate in cases of Parkinson’s disease (PD), with and without significant cognitive impairment at baseline, to the age and sex matched United Kingdom England and Wales population. Method: A cohort of clinically probable PD patients (n = 166) aged 53−91, based on UK Brain Bank criteria, were drawn from a community based register. The England and Wales mortality rates for both genders were used as controls. Results: A total of 166 PD patients were identified and followed for a mean of 4.4 years, during which period 91 died, giving a cumulative mortality of 54.8%. Within this cohort, 80 fulfilled criteria for dementia, and 86 did not. The cumulative mortality in the demented cohort was 81% and for the non-demented cohort it was 30% (p < 0.05). The standardized mortality ratio (SMR) for the total cohort was 2.06 and was increased for both sexes (Male = 1.74, female 2.29). Controlling for dementia cases at baseline (demented n = 80, not demented n =86), found that the mortality in the demented cohort the SMR was 3.05 and in the non-demented cohort it was 1.14. A cox proportional hazard model revealed that dementia was an independent predictor for mortality. Conclusion: These findings suggest that despite modern pharmacological treatments, mortality remains much higher in PD compared to the general population. PD patients with a diagnosis of dementia appear to be at increased risk of mortality compared to non-demented patients and the general population
1.209 Associations between multiple system atrophy and polymorphisms of SLC1A4, SQSTM1, and EIF4EBP1 genes H. Soma1° , I. Yabe, A. Takei, N. Fujiki, T. Yanagihara, H. Sasaki Japan
1 Sapporo,
Objective: Multiple system atrophy (MSA) is an adult-onset sporadic neurodegenerative disease. Although the etiology of MSA remains obscure, recent studies suggest that oxidative stress is associated with the pathogenesis of MSA. The aim of this study was to evaluate genetic associations between the candidate genes involved in oxidative stress and MSA in a case-control study. Method: We examined 119 Japanese patients with MSA and 123 controls, and genotyped single nucleotide polymorphisms (SNPs) of the following eight genes: CCAAT/enhancer-binding protein homologous protein (CHOP), activating transcription factor 3 (ATF3), CCAAT/enhancerbinding protein-b (CEBPB), sequestosome 1 (SQSTM1), cysteinyl-tRNA synthetase (CARS), solute carrier family 1A4 (SLC1A4), activating transcription factor 4 (ATF4), and eukaryotic translation initiation factor 4Ebinding protein 1 (EIF4EBP1). Results: SLC1A4 SNP +28833 (V398I, rs759458, genotype: Pc = 0.0186, allele: Pc = 0.0303, Pc: p-value with Bonferroni correction), two major haplotypes of SLC1A4 “T-C-C-G” and “T-C-T-A” (Pc = 0.0261 and 0.000768), two-SNP haplotypes of SQSTM1 “C-T” and “A-T” (Pc = 0.0136 and 0.0369), and the most common haplotype of EIF4EBP1 “C-T-G-C” (Pc = 0.0480) showed significant associations. Conclusion: This study revealed genetic associations of SLC1A4, SQSTM1, and EIF4EBP1 with MSA. These results may lend genetic support to the hypothesis that oxidative stress is associated with the pathogenesis of MSA.