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San Raffaele Cimena, Italy

Squitti R.,Fatebenefratelli Foundation for Health Research and Education | Squitti R.,Laboratorio Of Neurodegenerazione | Siotto M.,Don Carlo Gnocchi Foundation ONLUS | Polimanti R.,University of Rome Tor Vergata
Neurobiology of Aging | Year: 2014

Copper is an essential element, and either a copper deficiency or excess can be life threatening. Recent studies have indicated that alteration of copper metabolism is one of the pathogenetic mechanisms of Alzheimer's disease (AD). In light of these findings, many researchers have proposed preventive strategies to reduce AD risk. Because the general population comes in contact with copper mainly through dietary intake, that is, food 75% and drinking water 25%, a low-copper diet can reduce the risk of AD in individuals with an altered copper metabolism. We suggest that a diet-gene interplay is at the basis of the "copper phenotype" of sporadic AD. Herein, we describe the pathways regulating copper homeostasis, the adverse sequelae related to its derangements, the pathogenic mechanism of the AD copper phenotype, indications for a low-copper diet, and future perspectives to improve this preventive strategy. © 2014 Elsevier Inc. Source


Mariani S.,Neurology University Campus Biomedico | Ventriglia M.,Fatebenefratelli Foundation for Health Research and Education | Simonelli I.,AFaR Fatebenefratelli Association for the Research | Bucossi S.,Neurology University Campus Biomedico | And 3 more authors.
Rejuvenation Research | Year: 2015

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. © Mary Ann Liebert, Inc. Source


Squitti R.,Fatebenefratelli Foundation for Health Research and Education | Squitti R.,Laboratorio Of Neurodegenerazione
Journal of Trace Elements in Medicine and Biology | Year: 2014

Alzheimer's disease (AD) is the most common form of dementia. A myriad of complex factors contribute to AD, promoting the deposition in plaques of amyloid-beta (Aβ), which is the main constituent of this pathognomonic sign of AD at autopsy brain inspection. Aβ toxicity is related to oxidative stress, which results in synaptic loss in specific brain areas, eventually leading to cognitive decline. Metal, and especially copper, dyshomeostasis is a key factor in these processes. Recent studies have demonstrated that the serum fraction of copper that is not bound to ceruloplasmin (Non-Cp copper, also known as 'free' or labile copper) increases in a percentage of AD patients and mild cognitive impairment (MCI) subjects; this is considered a precursor of AD. Non-Cp copper is the exchangeable fraction of low molecular weight copper in serum. It is distinguished from the copper structurally bound to the ceruloplasmin protein, a master protein of iron metabolism. Non-Cp copper levels are higher than normal reference values (range 0-1.6. μmol/L) in about 50% of amnestic MCI subjects and 60% of AD patients, typifying them in a subset of AD. Meta-analyses, genetic studies and a prognostic study evaluating the predictive value of Non-Cp copper in MCI conversion to full AD demonstrate the existence of this copper phenotype of AD. © 2014 Elsevier GmbH. Source


Siotto M.,Don Carlo Gnocchi Foundation ONLUS | Pasqualetti P.,Fatebenefratelli Foundation for Health Research and Education | Marano M.,Biomedical University of Rome | Squitti R.,Fatebenefratelli Foundation for Health Research and Education | Squitti R.,Laboratorio Of Neurodegenerazione
Journal of Neural Transmission | Year: 2014

Ceruloplasmin (Cp) is a serum ferroxidase that plays an essential role in iron metabolism. It is routinely tested by immunoturbidimetric assays that quantify the concentration of the protein both in its active and inactive forms. Cp activity is generally analyzed manually; the process is time-consuming, has a limited repeatability, and is not suitable for a clinical setting. To overcome these inconveniences, we have set the automation of the o-dianisidine Cp activity assay on a Cobas Mira Plus apparatus. The automation was rapid and repeatable, and the data were provided in terms of IU/L. The assay was adapted for human sera and showed a good precision [coefficient of variation (CV) 3.7 %] and low limit of detection (LoD 11.58 IU/L). The simultaneous analysis of Cp concentration and activity in the same run allowed us to calculate the Cp-specific activity that provides a better index of the overall Cp status. To test the usefulness of this automation, we tested this assay on 104 healthy volunteers and 36 patients with Wilson’s disease, hepatic encephalopathy, and chronic liver disease. Cp activity and specific activity distinguished better patients between groups with respect to Cp concentration alone, and providing support for the clinical investigation of neurological diseases in which liver failure is one of the clinical hallmarks. © Springer-Verlag Wien 2014. Source


Marano M.,Biomedical University of Rome | Vespasiani Gentilucci U.,Biomedical University of Rome | Altamura C.,Biomedical University of Rome | Siotto M.,Don Carlo Gnocchi Foundation ONLUS | And 10 more authors.
Metabolic Brain Disease | Year: 2015

Dysfunctional metal homeostasis contributes to oxidative stress and neuronal damage. These have been implicated in hepatic encephalopathy pathogenesis. To investigate whether altered metal metabolism is associated with hepatic encephalopathy. Twenty-one controls and 34 HCV-cirrhotic patients (ENC/NEC patients according to presence/absence of previous overt episodes of hepatic encephalopathy) and a control group were studied. Serum iron, copper, ceruloplasmin, ceruloplasmin activity, transferrin, and ceruloplasmin/transferrin ratio were determined. Neuropsychological tests were performed by the repeatable battery of neuropsychological status. Magnetic resonance assessed basal ganglia volumes and metal deposition (pallidal index and T2*). Cirrhotic patients performed worse than controls at cognitive tests, especially ENC patients,. At biochemical analysis copper concentrations, ceruloplasmin activity and transferrin levels were lower in ENC than in NEC patients and controls (p < 0.05 and p < 0.01, respectively). Ceruloplasmin/transferrin ratio was higher in ENC compared to NEC patients (p < 0.05), and controls (p < 0.01). By brain magnetic resonance, ENC patients showed reduced caudate and globus pallidus volumes compared to controls (p < 0.05), and ENC and NEC patients an increased pallidal index compared to controls (p < 0.01). In ENC patients, ceruloplasmin activity correlated with caudate volume and pallidal index (ρ = 0.773 and ρ = −0.683, p < 0.05). Altered metal metabolism likely contributes to cirrhotic hepatic encephalopathy. © 2015, Springer Science+Business Media New York. Source

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