Search

Meta-analyses show that nonbound ceruloplasmin (non-Cp) copper (also known as free or labile copper) in serum is higher in patients with Alzheimer disease (AD). It differentiates subjects with mild cognitive impairment (MCI) from healthy controls. However, a longitudinal study on an MCI cohort has not yet been performed to assess the accuracy of non-Cp copper for the prediction of conversion from MCI to AD during a long-term follow-up.

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.

The link between biometals and Alzheimer's disease (AD) has been investigated with a focus on local metal accumulations. In this work, we have looked at systemic metal changes and computed a score (M-score) based on metal disarrangements to discriminate patients with AD from patients with vascular dementia (VaD) and from controls. We measured serum levels of iron, copper, ceruloplasmin, transferrin, and total antioxidant capacity (TAS), performed Apolipoprotein E (APOE) genotyping and calculated non-ceruloplasmin copper ('free' copper') levels, transferrin saturation, total iron binding capacity, and ceruloplasmin-transferrin ratio (Cp/Tf) in 93 patients with AD, 45 patients with VaD, and 48 controls. All subjects underwent biochemical, neuroimaging and cognitive evaluations. Significant differences were observed among the tested groups for the levels of copper, free copper, peroxides, and TAS and for the Cp/Tf with disparity in couple comparison. On this basis we created the M-score as linear combination of biometal variables and APOE genotype. Besides its ability to discriminate AD patients vs. controls (ROC AUC=90%), M-score was able to distinguish AD vs. VaD (ROC AUC=79%). Moreover, we calculated the sensitivity and the specificity for M-score and for the other significant variables: M-score reached the highest sensitivity without a relevant loss in terms of specificity. When we compared M-score with APOE genotype and Medial Temporal Atrophy score, it resulted statistically better than these diagnostic markers. In conclusion, we confirm the link between biometals and AD and suggest its potential as diagnostic tool. Further studies may elucidate its potential role as reliable diagnostic test.

Due to growing evidence of sensorimotor integration impairment in focal task-specific hand dystonia, we aimed at describing primary sensory (S1) and primary motor (M1) cortex source activities and their functional cross-talk during a non-dystonia-inducing sensorimotor task free of biases generated by the interfering with the occurrence of dystonic movements.

Objective. To verify whether systemic biometals dysfunctions affect neurotransmission in living Alzheimer's disease (AD) patients. Methods. We performed a case-control study using magnetoencephalography to detect sensorimotor fields of AD patients, at rest and during median nerve stimulation. We analyzed position and amount of neurons synchronously activated by the stimulation in both hemispheres to investigate the capability of the primary somatosensory cortex to reorganize its circuitry disrupted by the disease. We also assessed systemic levels of copper, ceruloplasmin, non-Cp copper (i.e., copper not bound to ceruloplasmin), peroxides, transferrin, and total antioxidant capacity. Results. Patients' sensorimotor generators appeared spatially shifted, despite no change of latency and strength, while spontaneous activity sources appeared unchanged. Neuronal reorganization was greater in moderately ill patients, while delta activity increased in severe patients. Non-Cp copper was the only biological variable appearing to be associated with patient sensorimotor transmission. Conclusions. Our data strengthen the notion that non-Cp copper, not copper in general, affects neuronal activity in AD. Significance. High plasticity in the disease early stages in regions controlling more commonly used body parts strengthens the notion that physical and cognitive activities are protective factors against progression of dementia.

The link between biometals and Alzheimer's disease (AD) has been investigated with a focus on local metal accumulations. In this work, we have looked at systemic metal changes and computed a score (M-score) based on metal disarrangements to discriminate patients with AD from patients with vascular dementia (VaD) and from controls. We measured serum levels of iron, copper, ceruloplasmin, transferrin, and total antioxidant capacity (TAS), performed Apolipoprotein E (APOE) genotyping and calculated non-ceruloplasmin copper ('free' copper') levels, transferrin saturation, total iron binding capacity, and ceruloplasmin-transferrin ratio (Cp/Tf) in 93 patients with AD, 45 patients with VaD, and 48 controls. All subjects underwent biochemical, neuroimaging and cognitive evaluations. Significant differences were observed among the tested groups for the levels of copper, free copper, peroxides, and TAS and for the Cp/Tf with disparity in couple comparison. On this basis we created the M-score as linear combination of biometal variables and APOE genotype. Besides its ability to discriminate AD patients vs. controls (ROC AUC=90%), M-score was able to distinguish AD vs. VaD (ROC AUC=79%). Moreover, we calculated the sensitivity and the specificity for M-score and for the other significant variables: M-score reached the highest sensitivity without a relevant loss in terms of specificity. When we compared M-score with APOE genotype and Medial Temporal Atrophy score, it resulted statistically better than these diagnostic markers. In conclusion, we confirm the link between biometals and AD and suggest its potential as diagnostic tool. Further studies may elucidate its potential role as reliable diagnostic test.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. The causes of AD are very complex but there is general agreement about the existence of a link between Alzheimer's disease and oxidative stress. The Glutathione S-transferases (GSTs) act to detoxify products of oxidation that cause damage to macromolecules. Particular attention has been focused on GST genes because polymorphisms are important determinants of disease risk. To evaluate if GSTA1, GSTM1, GSTP1, and GSTT1 genes are associated with LOAD we screened a case-control population (n=311). Differences in genotype distributions between AD patients and controls were found only for the GSTM1 null genotype (P<0.001). In addition, a logistic regression analysis also conferred a positive association between the GSTM1 null genotype and LOAD after adjustment for age and gender (OR=2.09; 95%CI=1.31-3.35). The GSTM1 enzyme detoxifies substances such as exogenous and endogenous metabolites and plays a regulatory role in cellular signaling. Previous studies have highlighted that GSTM1 has a role in neurodegenerative disorders, but no data have associated the GSTM1 gene with AD risk. Our outcome suggests that the GSTM1 null genotype is a risk factor for AD in Italian patients.

It is now accepted that transition metals, such as iron and copper, are involved in the pathogenesis of the Alzheimer's disease (AD) through their participation in toxic oxidative phenomena. In this context, hemochromatosis (Hfe) and transferrin (Tf) genes are of particular importance, since they play a key role in iron homeostasis. Also, signs of liver distress which accompany metal dysmetabolisms have been shown to be linked to AD. In order to investigate whether and how all these factors are interconnected, in this study we have explored the relationship of the gene variants of Hfe H63D and C282Y and of Tf C2 with serum markers of iron status (iron, ferritin, TF, TF-saturation, ceruloplasmin -CP-, CP and TF serum concentrations (CP/TF) ratio), and of liver function (albumin, transaminases, prothrombin time-prothrombin time (PT)) in a sample of 160 AD patients and 79 healthy elderly controls. Albumin resulted in lower, PT longer and AST/ALT higher ratios in AD patients than in controls, indicating a distress of the liver. Also TF was lower and ferritin higher in AD. Multiple logistic regression backward analyses, performed to evaluate the effects of our biochemical variables upon the probability of developing AD, revealed that a one-unit TF serum-decrease increases the probability of AD by 80%, a one-unit albumin serum-decrease reduces this probability by 20%, and a one-unit increase of AST/ALT ratio generates a 4-fold probability increase. Patients who were carriers of the H63D mutation showed higher levels of iron, lower levels of TF and CP and higher CP/TF ratios, a panel resembling hemochromatosis. This picture was found neither in H63D non-carrier patients, nor in healthy controls. Our results suggest the existence of a link between Hfe mutations and iron abnormalities that increases the probability of developing AD when accompanied by a distress of the liver.