Laboratorio Of Neurodegenerazione

San Raffaele Cimena, Italy

Laboratorio Of Neurodegenerazione

San Raffaele Cimena, Italy

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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.


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.


PubMed | Don Carlo Gnocchi foundation ONLUS, Fatebenefratelli Hospital, Laboratorio Of Neurodegenerazione and Biomedical University of Rome
Type: Journal Article | Journal: 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 (=0.773 and =-0.683, p<0.05). Altered metal metabolism likely contributes to cirrhotic hepatic encephalopathy.


Ventriglia M.,San Giovanni Calibita Fatebenefratelli Hospital | Ventriglia M.,Fatebenefratelli Foundation | Brewer G.J.,University of Michigan | Simonelli I.,IRCCS San Raffaele Pisana | And 6 more authors.
Journal of Alzheimer's Disease | Year: 2015

To evaluate whether zinc levels in serum, plasma, and cerebrospinal fluid are altered in Alzheimer's disease (AD), we performed meta-analyses of 27 studies on the topic published from 1983 to 2014. The subjects' sample obtained by merging studies was a pooled total of 777 AD subjects and 1,728 controls for serum zinc studies, 287 AD subjects and 166 controls for plasma zinc, and of 292 AD subjects and 179 controls for CSF zinc. The main result of this meta-analysis is the very high heterogeneity among the studies either in demographic terms or in methodological approaches. Although we considered these effects in our analyses, the heterogeneity persisted and it has to be taken into account in the interpretation of the results. Our meta-analysis indicated that serum zinc appears significantly decreased in AD patients compared with healthy controls, and this result is confirmed when serum and plasma studies were analyzed together. If we considered the age-matched studies, the meta-analysis carried out on only six studies showed no significant difference in zinc levels between AD and healthy controls (SMD =-0.55, 95% CI (-1.18; 0.09); p = 0.094; I2 = 91%). In the light of these findings, we speculated about the possibility that the decreases observed could indicate a possible dietary zinc deficiency and we suggested that the possible involvement of zinc alterations in AD may have an interplay with copper metabolism. © 2015 - IOS Press and the authors. All rights reserved.


Mariani S.,Neurology University Campus Biomedico | Ventriglia M.,San Giovanni Calibita Fatebenefratelli Hospital | 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.


Squitti R.,San Giovanni Calibita Fatebenefratelli Hospital | 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.


Pal A.,PGIMER | Siotto M.,Don Carlo Gnocchi Foundation | Prasad R.,PGIMER | Squitti R.,Fatebenefratelli Hospital | Squitti R.,Laboratorio Of Neurodegenerazione
Journal of Alzheimer's Disease | Year: 2015

Copper is an essential micronutrient for physiological cell functioning and central nervous system (CNS) development. Indeed, it is a cofactor of many proteins and enzymes in a number of molecular pathways, including energy generation, oxygen transportation, hematopoiesis, cellular growth and metabolism, and signal transduction. This is because it serves as a catalyst of reduction-oxidation (redox) reactions in these processes. When copper is kept under control, bound to special proteins, it yields key properties. However, when it spirals out of control, it is exchanged among small compounds (it is loosely bound to them), and its redox activity makes it dangerous for cell viability, promoting oxidative stress. Copper homeostasis in the CNS is securely synchronized, and perturbations in brain copper levels are known to underlie the pathoetiology of wide spectrum of common neurodegenerative disorders, including Alzheimer's disease. The main objective of this review is to provide some of the most relevant evidence gleaned from recent studies conducted on animal models and humans, and to discuss the evidence as it pertains to a new concept: Aberrant copper metabolism, which appears to have a genetic basis, is a modifiable risk factor accelerating Alzheimer's disease and initiation/progression of cognitive deficits in a percentage of susceptible persons. © 2015 - IOS Press and the authors. All rights reserved.


Squitti R.,Afar San Giovanni Calibita Fatebenefratelli Hospital | Squitti R.,Laboratorio Of Neurodegenerazione | Polimanti R.,University of Rome Tor Vergata
American Journal of Neurodegenerative Diseases | Year: 2013

Alzheimer’s disease (AD) is the most common form of dementia. Several hypotheses have been put forward to explain the basis of disease onset and progression. Unfortunately, none of these seems to clarify the complexity of the pathogenesis. In fact, diverse and inde-pendent pathogenetic pathways can be disrupted at the same time, and each contributes to disease etiology. In recent years, researchers have begun studying biometals more deeply. A number of studies have shown that metal dyshomeostasis may enhance AD onset and pro-gression. Specifically, different authors have hypothesized that alterations in metal metabolism are associated with an increased in met-al- related oxidative stress and beta-amyloid oligomer formation and precipitation. Studies conducted in vivo, in vitro, in living patients and in silico studies have demonstrated that local and systemic defects in copper metabolism are characteristic signs of AD. This strongly supports the hypothesis that copper pathways may be disrupted by the disease. More specifically, a copper phenotype can be proposed for AD, based on defects found in genes involved in copper metabolism. In this review, we describe copper dyshomeostasis in AD patients and attempt to explain the basis of the AD copper phenotype. Dissecting copper pathways, we highlight mechanisms which may be at the basis of the disease. We also discuss various associated translation outcomes. © 2013 E-Century Publishing Corporation. All rights reserved.


Squitti R.,San Giovanni Calibita Fatebenefratelli Hospital | 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.

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