Substantial evidence supports the hypothesis that impairment of mitochondrial function and increased oxidative damage are involved in the pathogenesis of several neurodegenerative disorders including ...Alzheimer's disease (AD). Manganese superoxide dismutase (MnSOD) plays a major role in protecting the mitochondrion from oxidative damage due to superoxide radicals and other excited oxygen species. Recent studies have indicated that MnSOD mRNA levels are significantly increased in the lymphocytes of AD patients, supporting the role of oxidative alterations in the pathogenetic mechanism underlying this neurodegeneration. A potentially functional amino acid polymorphism (Ala-9Val) has been described in the signal sequence of enzymes associated with decreased defense capacity against oxidative stress. The object of this study was to investigate the association between this polymorphism of the MnSOD gene and AD in the Italian population.
The Ala-9Val polymorphism was genotyped by PCR amplification and SSCP analysis in 227 AD patients and 198 healthy controls.
No significant differences in genotype or allele frequencies between cases and controls, even after stratification for APOE carrier status, were observed.
Our data suggest that the Ala-9Val polymorphism in the MnSOD gene is not associated with genetic susceptibility in AD patients.
Copper dyshomeostasis leading to a labile Cu(2+) not bound to ceruloplasmin ("free" copper) may influence Alzheimer's disease (AD) onset or progression. To investigate this hypothesis, we ...investigated ATP7B, the gene that controls copper excretion through the bile and concentrations of free copper in systemic circulation. Our study analyzed informative ATP7B single-nucleotide polymorphisms (SNPs) in a case-control population (n=515). In particular, we evaluated the genetic structure of the ATP7B gene using the HapMap database and carried out a genetic association investigation. Linkage disequilibrium (LD) analysis highlighted that our informative SNPs and their LD SNPs covered 96% of the ATP7B gene sequence, distinguishing two "strong LD" blocks. The first LD block contains the gene region encoding for transmembrane and copper-binding, whereas the second LD block encodes for copper-binding domains. The genetic association analysis showed significant results after multiple testing correction for all investigated variants (rs1801243, odds ratio OR=1.52, 95% confidence interval CI=1.10-2.09, p=0.010; rs2147363, OR=1.58, 95% CI=1.11-2.25, p=0.010; rs1061472, OR=1.73, 95% CI=1.23-2.43, p=0.002; rs732774, OR=2.31, 95% CI=1.41-3.77, p<0.001), indicating that SNPs in transmembrane domains may have a stronger association with AD risk than variants in copper-binding domains. Our study provides novel insights that confirm the role of ATP7B as a potential genetic risk factor for AD. The analysis of ATP7B informative SNPs confirms our previous hypothesis about the absence of ATP7B in the significant loci of genome-wide association studies of AD and the genetic association study suggests that transmembrane and adenosine triphosphate (ATP) domains in the ATP7B gene may harbor variants/haplotypes associated with AD risk.
A binary logistic regression analysis - with age, sex and MMSE as covariates - was applied to compare the AD subgroups for ATP7B and APOE4 frequencies. ATP7B and APOE4 frequencies were different ...between the two AD groups, with a significant increase of the rs1801243 CC, rs1061472 GG and rs732774 TT genotypes in the AD group with Non-Cp-Cu > 1.9 pm, accounting for a percentage of the disease risk.
Alzheimer’s disease (AD) is one of the most devastating epidemics of the twenty-first century, and no cure is currently available. One third of all AD cases can be attributed to modifiable risk ...factors (such as physical inactivity, smoking, hypertension, diabetes, and obesity in middle age). Accordingly, seven nutritional and lifestyle guidelines for the prevention of AD have been proposed to the public. The present review addresses the fifth guideline, which focuses on the significance of the breakdown of copper homeostasis as a risk factor for AD. Dietary copper in the human diet, the physiological pathway of copper in the body, copper metabolic abnormalities in AD (as revealed by clinical studies and large population datasets), and the onset of copper metabolic abnormalities (as a result of the interplay between copper intake and genetic defects linked primarily to the
ATP7B
gene) are reported herein. Data are discussed in the framework of evidence-based medicine to guide decision-making in AD clinical practice and prevention towards the adoption of an adequate dietary copper regimen in susceptible individuals.
To evaluate a possible involvement of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in susceptibility to Parkinson's disease (PD), we performed a meta-analysis of all studies on ...the topic published from 2002 to 2014. This article reviews and compares the data from two previous meta-analyses, including two studies not previously considered. We selected studies referring to a genetic comparison between PD patients and healthy controls, so 15 studies involving 3754 cases and 4026 controls were included in our meta-analysis. We found no association between the Val66Met polymorphism and the risk of developing PD in our overall analysis. The ethnicity-specific meta-analysis produced no significant association either. Our data do not support a major role for the BDNF Val66Met polymorphism in the pathogenesis of PD.
Semicarbazide-sensitive amine oxidase (SSAO) metabolizes the oxidative deamination of primary aromatic and aliphatic amines. The final cytotoxic products of its catalysis contribute to diseases ...involving vascular degeneration. The increasing interest in measuring SSAO activity has led to the development of several different methods. Herein, we compare SSAO activity results obtained with radiometric and fluorimetric methods in 49 plasma samples. Although not interchangeable, a significant correlation was obtained between methods. Considering these limitations, the fluorimetric method might replace the radioisotopic one.
Deregulation of iron metabolism has been observed in patients with neurodegenerative diseases. We have carried out a molecular analysis investigating the interaction between iron specific gene ...variants transferrin (TF, P589S), hemochromatosis (HFE) C282Y and (H63D), iron biochemical variables iron, Tf, ceruloplasmin (Cp), Cp:Tf ratio and % of Tf saturation (% Tf-sat) and apolipoprotein E (APOE) gene variants in 139 Alzheimer's disease (AD), 27 Mild Cognitive Impairment (MCI), 78 Parkinson's disease (PD) patients and 139 healthy controls to investigate mechanisms of iron regulation or toxicity. No difference in genetic variant distributions between patients and controls was found in our Italian sample, but the stratification for the APOEε4 allele revealed that among the APOEε4 carriers was higher the frequency of those carriers of at least a mutated TF P589S allele. Decreased Tf in both AD and MCI and increased Cp:Tf ratio in AD vs. controls were detected. A multinomial logistic regression model revealed that increased iron and Cp:Tf ratio and being man instead of woman increased the risk of having PD, that increased values of Cp:Tf ratio corresponded to a 4-fold increase of the relative risk of having MCI, while higher Cp levels were protective for PD and MCI. Our study has some limitations: the small size of the samples, one ethnic group considered, the rarity of some alleles which prevent the statistical power of some genetic analysis. Even though they need confirmation in larger cohorts, our data suggest the hypothesis that deregulation of iron metabolism, in addition to other factors, has some effect on the PD disease risk.
The hypoxic brain damage induced by stroke is followed by an ischemia–reperfusion injury modulated by oxidative stress. Magnetoencephalographic (MEG) recording of rest and evoked cortical activities ...is a sensitive method to analyse functional changes following the acute ischemic damage. We aimed at investigating whether MEG signals are related to oxidative stress compounds in acute stroke.
Eighteen stroke patients and 20 controls were enrolled. All subjects underwent MEG assessment to record background activity and somatosensory evoked responses (M20 and M30) of rolandic regions, neurological examination assessed by National Institute of Health Stroke Scale (NIHSS) and plasmatic measurement of copper, iron, zinc, ceruloplasmin, transferrin, total peroxides and Total Anti-Oxidant Status. Magnetic Resonance was performed to estimate the lesion site and volume.
Delta power and M20 equivalent current dipole (ECD) strength in the affected hemisphere (AH) correlated with NIHSS scores (respectively, rho
=
.692,
p
=
.006 and rho
=
−
.627,
p
=
.012) and taken together explained 67% of NIHSS variability (
p
=
.004). Higher transferrin and lower peroxides levels correlated with better clinical status (respectively, rho
=
−
.600,
p
=
.014 and rho
=
.599,
p
=
.011). Transferrin also correlated with AH M20 ECD strength (rho
=
.638
p
=
.014) and inversely with AH delta power (rho
=
−
.646
p
=
.023) and the lesion volume, especially in cortico-subcortical stroke (
p
=
.037).
Our findings strengthen MEG reliability in honing the evaluation of neuronal damage in acute ischemic stroke also demonstrating an association between the MEG parameters most representing the clinical status and the oxidative stress compounds. Our results meet at a possible protective role of transferrin in limiting the oxidative damage in acute stroke.
Different factors interact to develop neurodegeneration in patients with dementia and other neurodegenerative disorders. Oxidative stress and the ε4 allele of apolipoprotein E (ApoE) are associated ...with significant alteration in lipid metabolism, in turn connected to a variety of neurodegenerative diseases and aging. Thus, a better understanding of the pathogenetic pathways associated with lipid dyshomeostasis may elucidate the causes of neurodegenerative processes. To address this issue, we evaluated the effects of antioxidant status and APOE genotype on neurodegeneration in patients with dementia of the Alzheimer type (AD), with vascular dementia (VaD), and in elderly healthy controls. Eighty-two AD, 42 VaD patients, and 26 healthy controls were recruited and underwent medial temporal lobe atrophy (MTA) assessment, white matter hyperintensities rating (WMH), serum total antioxidant status assaying (TAS), and APOE genotyping. A logistic regression algorithm applied to our data revealed that a 0.01 mmol/L decrease of TAS concentration increased the probability of MTA by 24% (p=0.038) and that carriers of the APOE ε4 allele showed higher WMH scores (p=0.018), confirming that small variations in antioxidant systems homeostasis are associated with relevant modifications of disease risk. Furthermore, in individuals with analogous TAS values, the presence of the ε4 allele increased the predicted probability of having MTA. These outcomes further sustain the interaction of oxidative stress and APOE genotype to neurodegeneration.
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