Neuropsychopharmacology Unit

San Giovanni al Natisone, Italy

Neuropsychopharmacology Unit

San Giovanni al Natisone, Italy
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Maffioletti E.,Genetic Unit Irccs Centro S Giovanni Of Dio Fatebenefratelli | Maffioletti E.,University of Brescia | Tardito D.,University of Milan | Gennarelli M.,Genetic Unit Irccs Centro S Giovanni Of Dio Fatebenefratelli | And 2 more authors.
Frontiers in Cellular Neuroscience | Year: 2014

microRNAs (miRNAs) are small non-coding RNAs (20-22 nucleotides) playing a major role in post-transcriptional regulation of gene expression. miRNAs are predicted to regulate more than 50% of all the protein-coding genes. Increasing evidence indicates that they may play key roles in the biological pathways that regulate neurogenesis and synaptic plasticity, as well as in neurotransmitter homeostasis in the adult brain. In this article we review recent studies suggesting that miRNAs may be involved in the pathophysiology of neuropsychiatric disorders and in the action of psychotropic drugs, in particular by analyzing the contribution of genomic studies in patients' peripheral tissues. Alterations in miRNA expression have been observed in schizophrenia, bipolar disorder, major depression, Parkinson's disease, Alzheimer's disease and other neuropsychiatric conditions. In particular, intriguing findings concern the identification of disease-associated miRNA signatures in peripheral tissues, or modifications in miRNA profiles induced by drug treatments. Furthermore, genetic variations in miRNA sequences and miRNA-related genes have been described in neuropsychiatric diseases. Overall, though still at a preliminary stage, several lines of evidence indicate an involvement of miRNAs in both the pathophysiology and pharmacotherapy of neuropsychiatric disorders. In this regard, the data obtained in peripheral tissues may provide further insights into the etiopathogenesis of several brain diseases and contribute to identify new biomarkers for diagnostic assessment improvement and treatment personalization. © 2014 Maffioletti, Tardito, GennarelliandBocchio-Chiavetto.


Minelli A.,Genetic Unit | Zanardini R.,Neuropsychopharmacology Unit | Abate M.,Psychiatric Hospital Villa Santa Chiara | Bortolomasi M.,Psychiatric Hospital Villa Santa Chiara | And 3 more authors.
Progress in Neuro-Psychopharmacology and Biological Psychiatry | Year: 2011

Vascular endothelial growth factor (VEGF) is an angiogenic cytokine, which induces vasopermeability and facilitates neurogenesis and synaptic plasticity in the adult brain. Expression studies in animal models have reported that brain VEGF is regulated by electroconvulsive seizures (ECS), which are used in an experimental paradigm similar to clinical electroconvulsive therapy (ECT) a treatment for drug resistant depressed (TRD) patients. The aim of this study was to investigate putative modulations of ECT on VEGF serum levels in TRD patients. Nineteen patients were enrolled in the study; illness severity and VEGF serum contents were assessed before the treatment (T0), the day after the end of ECT (T1) and one month later the end of ECT (T2). ECT treatment improved depression symptomatology as measured by MADRS scores (p < 0.0001). No changes occurred in serum VEGF between T0 and T1, whereas a significant increase was observed between T0 and T2 (p = 0.042). Moreover a significant correlation was observed between the VEGF increase at T2 and the reduction in MADRS scores (p = 0.049). This study is the first to evaluate putative modulations of serum VEGF induced by ECT in TRD patients. © 2011 Elsevier Inc.


Bocchio-Chiavetto L.,Neuropsychopharmacology Unit | Bagnardi V.,University of Milan Bicocca | Bagnardi V.,Italian National Cancer Institute | Zanardini R.,Neuropsychopharmacology Unit | And 10 more authors.
World Journal of Biological Psychiatry | Year: 2010

Objectives. Alterations of BDNF signalling in major depression (MD) are supported by studies demonstrating decreased levels of the neurotrophin serum and plasma content in MD patients. We conducted a replication study and we performed two meta-analyses on studies analysing serum and plasma BDNF levels in MD patients. Methods. The samples were composed by 489 patients/483 controls for the meta-analysis on serum and by 161 patients/211 controls for that on plasma levels. We performed also subgroup analyses to examine whether the decrease in BDNF levels in MD was influenced by gender. Results. In the replication study we found decreased serum BDNF levels in MD patients (P<0.01) and we demonstrated that is down-regulated the mature form of the neurotrophin (mBDNF). No significant difference was evidenced for plasma BDNF levels. The meta-analyses showed a reduction of both BDNF serum (P<0.0001) and plasma levels (P=0.02) in MD. No difference in the effect size on serum BDNF was observed between males and females (P=0.18). Conclusions. In conclusion, our results provide evidence of peripheral BDNF alteration in MD and support the rationale for further investigation aiming to the identification of biomarkers for differential diagnosis and personalization of therapies in this disorder. © 2010 Informa UK Ltd.


Agosta F.,San Raffaele Scientific Institute | Libera D.D.,San Raffaele Scientific Institute | Spinelli E.G.,San Raffaele Scientific Institute | Finardi A.,San Raffaele Scientific Institute | And 13 more authors.
Annals of Neurology | Year: 2014

Objectives: We have described cerebrospinal fluid (CSF) myeloid microvesicles (MVs) as a marker of microglia activation during neuroinflammation in Alzheimer disease (AD), and characterized their ability to produce toxic amyloid β1-42 (Aβ1-42 ) oligomers from aggregated or soluble substrate. The aim of this study is to investigate the association of CSF myeloid MVs with neuroimaging, clinical, and paraclinical data in AD and mild cognitive impairment (MCI).Methods: We collected CSF from 106 AD patients, 51 MCI patients, and 29 neurologically healthy controls. We examined CSF myeloid MV content and AD markers. A subgroup of 34 AD and 21 MCI patients underwent structural and diffusion tensor MRI.Results: Higher levels of myeloid MVs were found in the CSF of AD patients and MCI patients converting within 3 years relative to controls, but also, at a lower level, in MCI patients not converting to AD. CSF myeloid MVs were associated with Tau but not with Aβ 1-42 CSF levels. CSF MVs levels correlated with white matter (WM) tract damage in MCI, and with hippocampal atrophy in AD.Interpretation: Microglial MVs are neurotoxic and myelinotoxic in the presence of Aβ1-42 . CSF myeloid MVs, mirroring microglia activation and MV release, are associated with WM damage in MCI and hippocampal atrophy in AD. This suggests that hippocampal microglia activation, in the presence of Aβ1-42 in excess, produces neurotoxic and oligodendrotoxic oligomers that, through WM tract damage, spread disease to neighboring and connected areas, causing local microglia activation and propagation of disease through the same sequence of events. ©2014 American Neurological Association 813 Acknowledgment.


Minelli A.,Genetic Unit | Zanardini R.,Neuropsychopharmacology Unit | Bonvicini C.,Genetic Unit | Sartori R.,University of Verona | And 4 more authors.
European Archives of Psychiatry and Clinical Neuroscience | Year: 2011

Consisting evidence in animal models has suggested that alterations in brain-derived neurotrophic factor (BDNF) brain expression and release are involved in the pathogenesis of mental illnesses, such as, mood, anxiety, and eating disorders. This hypothesis is supported by data emerging from biochemical studies on serum BDNF levels and genetic studies on the functional polymorphism Val66Met in the BDNF gene in patients and control subjects. Anxiety-related personality traits are associated with several mental disorders. However, they are also measurable in non-affected subjects and, so, may represent a useful "endophenotype" to study the biological correlation of the vulnerability factors in the general population. In this study, we analyzed putative correlations in subjects unaffected by mental disorders between personality traits, serum BDNF levels (N = 107), and the BDNF Val66Met genotype (N = 217). Furthermore, we tested the possible interactions between these variables. A significant correlation has been observed between high scores of harm avoidance (HA) measured by the temperament and character inventory (TCI), and low BDNF serum concentration (r = -0.253, P = 0.009). In addition, an association has been evidenced between low BDNF levels in serum and the BDNF Val/Val genotype (P = 0.021). By analyzing putative concomitant effects of different variables on HA scores in a regression model, we observed a significant correlation only with BDNF serum concentrations (P = 0.022). The study results suggest that a decrease in serum BDNF concentrations may represent a biochemical marker associated with anxiety personality traits also retrievable in the general population. © 2011 Springer-Verlag.


Bocchio-Chiavetto L.,Neuropsychopharmacology Unit | Maffioletti E.,Neuropsychopharmacology Unit | Maffioletti E.,University of Brescia | Bettinsoli P.,Neuropsychopharmacology Unit | And 7 more authors.
European Neuropsychopharmacology | Year: 2013

MicroRNAs (miRNAs) are potent modulators of protein expression that play key roles in brain pathways regulating neurogenesis and synaptic plasticity. These small RNAs may be critical for the pathophysiology of mental disorders and may influence the effectiveness of psychotropic drugs. To investigate the possible involvement of miRNAs in the mechanism of action of antidepressants (AD), we conducted a whole-miRNome quantitative analysis with qRT-PCR of the changes in the blood of 10 depressed subjects after 12 weeks of treatment with escitalopram. Thirty miRNAs were differentially expressed after the AD treatment: 28 miRNAs were up-regulated, and 2 miRNAs were strongly down-regulated. miRNA target gene prediction and functional annotation analysis showed that there was a significant enrichment in several pathways associated with neuronal brain function (such as neuroactive ligand-receptor interaction, axon guidance, long-term potentiation and depression), supporting the hypothesis that the differentially regulated miRNAs may be involved in the AD mechanism. © 2012 Elsevier B.V. and ECNP.


Maina G.,University of Turin | Rosso G.,University of Turin | Zanardini R.,Neuropsychopharmacology Unit | Bogetto F.,University of Turin | And 3 more authors.
Journal of Affective Disorders | Year: 2010

Background: There is lack of data regarding BDNF serum levels in patients with obsessive-compulsive disorder (OCD). The aims of the present study were: 1) to assess the serum BDNF content in a sample of drug-naïve patients with OCD and 2) to assess whether putative alterations in peripheral BDNF may be associated to OCD severity and clinical characteristics. Methods: Twenty-four drug-naïve patients with a principal diagnosis of OCD were recruited. In parallel, a control group of 24 unrelated volunteers matched for gender and age was enrolled. Serum BDNF levels were measured by ELISA method. Results: The results showed that BDNF levels were decreased in OCD patients when compared to controls (36.90 ± 6.42 ng/ml versus 41.59 ± 7.82 ng/ml; p = 0.043). No correlations were evidenced between serum BDNF content and the severity of OCD symptoms measured as Y-BOCS scores or other clinical variables. Limitations: The choice of drug-naïve patients with obsessive-compulsive disorder had limited the size of the sample and excluded the recruitment of patients with a severe symptomatology. Conclusions: Our findings reveal for the first time in OCD patients a decrease in serum BDNF levels. These data corroborate the hypothesis of a dysfunction in the neurotrophin expression in the OCD pathogenetic mechanism and provide the rationale for further investigations directed to the identification of novel biomarkers and new therapeutic strategies for antiobsessional treatments. © 2009 Elsevier B.V. All rights reserved.


Cattaneo A.,Genetics Unit | Bocchio-Chiavetto L.,Neuropsychopharmacology Unit | Zanardini R.,Neuropsychopharmacology Unit | Milanesi E.,Genetics Unit | And 4 more authors.
International Journal of Neuropsychopharmacology | Year: 2010

Consistent data coming from biochemical studies have evidenced a brain-derived neurotrophic factor (BDNF) serum reduction in depressed patients compared to controls and a restoration following antidepressant treatment. However, to date, no study has evaluated whether BDNF synthesis in leukocytes could contribute to such modulation. Therefore, in this study, we analysed BDNF mRNA levels in leukocytes from 21 depressed patients prior to and during escitalopram treatment and from 23 control subjects showing that BDNF mRNA levels were decreased in drug-free depressed patients and that 12 wk escitalopram treatment was able to reverse this deficit. Interestingly, changes in BDNF mRNA levels paralleled BDNF serum increase during antidepressant treatment, and were correlated with symptoms improvement. Our results indicate that BDNF serum modulation observed in depressed patients is associated with BDNF synthesis alteration in leukocytes and suggest that these peripheral cells might play an active role in the mechanisms of action of antidepressants. Copyright © 2009 CINP.


Paternico D.,LENITEM Laboratory of Epidemiology | Galluzzi S.,LENITEM Laboratory of Epidemiology | Drago V.,LENITEM Laboratory of Epidemiology | Bocchio-Chiavetto L.,Neuropsychopharmacology Unit | And 5 more authors.
Alzheimer's and Dementia | Year: 2012

Background: Low amyloid β42 (Aβ42) and high total tau and phosphorylated tau (p-tau) concentrations in the cerebrospinal fluid (CSF) are biomarkers of Alzheimer's disease (AD), reflecting brain deposition of amyloid plaques and tangles. Age and apolipoprotein E allele E4 are two strong risk factors for AD, but few data are still available on their effect on CSF markers in normal aging. Objective: To study the effect of age on CSF Aβ42, total tau, and p-tau levels in a well-characterized group of cognitively normal subjects. Methods: CSF Aβ42 levels of 81 subjects (27% female, 53 ± 15.3 years, range: 21-88) were determined with sandwich enzyme-linked immunosorbent assay; of these, total tau and p-tau levels were measured in 61 (75%) and 42 (52%) cases, respectively. A linear regression analysis between age and CSF markers was carried out on the whole sample and separately in apolipoprotein E allele ε4 carriers and noncarriers. Results: The median levels of all markers were significantly different between young (<65 years) and old (≥65 years) subjects (Aβ42: P =.03; tau: P =.02; p-tau: P =.002; tau/Aβ 42: P =.004; p-tau/Aβ42: P =.03). The association of marker levels with age was confirmed in linear regression models, where a positive relationship with age was observed for total tau (B = 2.3; 95% confidence interval [CI]: 0.89 to 3.7; P =.002), p-tau (B = 0.5; 95% CI: 0.1 to 0.9; P =.02), and tau/Aβ42 ratio (B = 0.006; 95% CI: 0.002 to 0.01; P =.002). No subjects showed abnormal tau, whereas 19% showed abnormal CSF Aβ42 concentrations. Conclusion: In cognitively normal subjects, the concentrations of CSF biomarkers of AD are associated with age. Further longitudinal studies could clarify whether Aβ42 low levels represent a preclinical AD biomarker. © 2012 The Alzheimer's Association. All rights reserved.


Zanardini R.,Neuropsychopharmacology Unit | Fontana A.,Alcohol dependence Rehabilitation Unit | Pagano R.,Alcohol dependence Rehabilitation Unit | Mazzaro E.,Alcohol dependence Rehabilitation Unit | And 5 more authors.
Alcoholism: Clinical and Experimental Research | Year: 2011

Background: Alcohol dependence is a chronic relapsing disorder characterized by repetitive alcohol drinking patterns and a loss of control over alcohol consumption. Recent studies have hypothesized that dysregulations in brain neurotrophic support regulated by neurotrophins may be involved in the vulnerability to dependence and in the brain damage caused by chronic alcohol consumption. The neurotrophin brain-derived neurotrophic factor (BDNF) plays a pivotal role in neurodevelopment and in the maintenance of adult brain homeostasis through the regulation of neurogenesis and neuronal plasticity. The role of BDNF and its signaling in the mechanisms of alcohol dependence has been well documented in studies of animal models, but a few studies have been conducted in human peripheral tissues. On the basis of this rationale, we compared BDNF levels in both serum and plasma in alcohol-dependent patients and healthy volunteers. Methods: Thirty-seven patients with a principal diagnosis of alcohol dependence were recruited. In parallel, a control group of 37 unrelated volunteers matched for gender and age was enrolled. Serum and plasma BDNF levels were measured by ELISA. Results: A significant reduction in BDNF serum levels was observed in the patient group compared to healthy subjects (p=0.028). On the contrary, no difference in BDNF plasma levels was evident between patients and controls. Conclusions: In conclusion, our data show an alteration of BDNF peripheral content in patients with alcohol dependence, suggesting the involvement of this neurotrophin in this psychopathology. © 2011 by the Research Society on Alcoholism.

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