Neuropsychopharmacology Unit

San Giovanni al Natisone, Italy

Neuropsychopharmacology Unit

San Giovanni al Natisone, Italy

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Aas M.,University of Oslo | Haukvik U.K.,University of Oslo | Haukvik U.K.,Diakonhjemmet Hospital | Djurovic S.,University of Oslo | And 10 more authors.
Journal of Psychiatric Research | Year: 2014

Objective: Here we investigated a two hit gene environment model in relation to functional genomic factors (BDNF mRNA), and volume of hippocampal subfields in schizophrenia spectrum and bipolar disorders, focusing on both an environmental (childhood trauma) and genetic risk factor (BDNF val66met). Method: A total of 323 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited. A history of childhood trauma was obtained using the Childhood Trauma Questionnaire. BDNF DNA and RNA were analyzed using standardized procedures. A subsample of n=108 underwent MRI scanning, and the FreeSurfer was used to obtain measures of hippocampal subfield. All MRI data were corrected for age and gender, with post-hoc analysis correcting for ICV. Results: A history of childhood trauma or being a met carrier of the BDNF val66met was associated with significantly reduced BDNF mRNA level. Additive effects were observed between a history of childhood trauma and BDNF val66met, in the direction of met carriers with high levels of childhood trauma having the lowest BDNF mRNA levels. Lastly, met carriers reporting high levels of childhood trauma (specifically sexual or physical abuse) had significantly reduced hippocampal subfield volumes CA2/3 and CA4 dentate gyrus. Conclusion: The current findings demonstrate that the reduced BDNF mRNA levels found in psychosis may be associated with both a history of childhood trauma and BDNF val66met variants. Further, our study supports a two hit model including a history of childhood trauma as well as genetic vulnerability (met carriers of the BDNF val66met) behind reduced volume of hippocampal subfields in psychosis. This was specifically found for areas important for neurogenesis, the CA2/3and the CA4 DG. © 2014 Elsevier Ltd. All rights reserved.

Magri C.,University of Brescia | Traversa M.,University of Brescia | Faraone S.V.,SUNY Upstate Medical University | Cattaneo A.,Neuropsychopharmacology Unit | And 4 more authors.
Psychiatric Genetics | Year: 2015

Objectives Evidence has supported a role for rare copy number variants in the etiology of attention-deficit hyperactivity disorder (ADHD), in particular, the region 15q13, which is also a hot spot for several neuropsychiatric disorders. This region spans several genes, but their role and the biological implications remain unclear. Methods We carried out, for the first time, an analysis of the 15q13 region in an Italian cohort of 117 ADHD patients and 77 controls using the MLPA method, confirmed by a genome single-nucleotide polymorphism array. In addition, we probed for downstream effects of the 15q13 deletions on gene expression by carrying out a transcriptomic analysis in blood. Results We found 15q13 deletions in two ADHD patients and identified 129 genes as significantly dysregulated in the blood of the two ADHD patients carrying 15q13 deletions compared with ADHD patients without 15q13 deletions. As expected, genes in the deleted region (KLF13, MTMR10) were downregulated in the two patients with deletions. Moreover, a pathway analysis identified apoptosis, oxidation reduction, and immune response as the mechanisms that were altered most significantly in the ADHD patients with 15q13 deletions. Interestingly, we showed that deletions in KLF13 and CHRNA7 influenced the expression of genes belonging to the same immune/inflammatory and oxidative stress signaling pathways. Conclusion Our findings are consistent with the presence of 15q13 deletions in Italian ADHD patients. More interestingly, we show that pathways related to immune/inflammatory response and oxidative stress signaling are affected by the deletion of KFL13 and CHRNA7. Because the phenotypic effects of 15q13 are pleiotropic, our findings suggest that there are shared biologic pathways among multiple neuropsychiatric conditions. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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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