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1.
J Affect Disord ; 260: 24-25, 2019 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-31493634

RESUMO

It is important to integrate findings converging from different perspectives to better contextualize hippocampal subfield changes induced by childhood trauma (CT). Here we integrate Malhi's et al. model on this issue. Understanding the complex neurobiological mechanisms underpinning CT could address the multifaceted nature of resilience to traumatic life experiences that may cause different effects in health and disease.

2.
PLoS One ; 14(7): e0218111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31283791

RESUMO

Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.

3.
Metabolomics ; 15(5): 74, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053995

RESUMO

INTRODUCTION: Current markers of Parkinson's disease (PD) fail to detect the early progression of disease state. Conversely, current omics techniques allow the investigation of hundreds of molecules potentially altered by disease conditions. Based on evidence previously collected by our group in a mouse model of PD, we speculated that a particular set of circulating lipids might be significantly altered by the pathology. OBJECTIVES: The aim of current study was to evaluate the potential of a particular set of N-acyl-phosphatidylethanolamines (NAPEs) as potential non-invasive plasma markers of ongoing neurodegeneration from Parkinson's disease in human subjects. METHODS: A panel of seven NAPEs were quantified by LC-MS/MS in the plasma of 587 individuals (healthy controls, n = 319; Parkinson's disease, n = 268); Random Forest classification and statistical modeling was applied to compare Parkinson's disease versus controls. All p-values obtained in different tests were corrected for multiplicity by controlling the false discovery rate (FDR). RESULTS: The results indicate that this panel of NAPEs is able to distinguish female PD patients from the corresponding healthy controls. Further to this, the observed downregulation of these NAPEs is in line with the results in plasma of a mouse model of Parkinson's (6-OHDA). CONCLUSIONS: In the current study we have shown the downregulation of NAPEs in plasma of PD patients and we thus speculate that these lipids might serve as candidate biomarkers for PD. We also suggest a molecular mechanism, explaining our findings, which involves gut microbiota.

4.
J Affect Disord ; 253: 35-43, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31022627

RESUMO

BACKGROUND: Alterations in hippocampal structure and function are present in bipolar disorder (BD). Childhood trauma is associated with risk for BD, and the several subfields of the hippocampus are differentially sensitive to the effects of stressors of the sort associated with risk for BD. The current study therefore sought to test the hypothesis that childhood trauma may be differentially associated with abnormal hippocampal subfield volumes in BD. METHODS: 104 participants with BD type I (BD-I, n = 56) or BD type II (BD-II, n = 48) and 81 healthy controls (HC) underwent high-resolution structural magnetic resonance neuroimaging. Hippocampal subfield volumes were determined using FreeSurfer. Childhood trauma was assessed with the Childhood Trauma Questionnaire (CTQ). RESULTS: There were significant effects of diagnosis on intracranial volume corrected hippocampal subfield volumes bilaterally as well as a significant interaction between diagnosis and childhood trauma. Hippocampal volumes did not differ between the BD-I and BD-II subgroups but hippocampal volumes were smaller in both groups when compared to HC. There was a significant effect of childhood trauma on bilateral presubiculum volume as well as significant interactions between diagnosis and childhood trauma on bilateral CA1, presubiculum and subiculum volumes, the direction of which differed between individuals with BD (larger) and HC (smaller). LIMITATIONS: Recall bias may influence the reliability of the retrospective assessment of childhood trauma experiences. CONCLUSIONS: Childhood trauma demonstrates differential effects on hippocampal subfield volumes of BD and HC, particularly in hippocampal subfields involved in emotion regulation.

5.
Ann Clin Transl Neurol ; 6(3): 456-465, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30911569

RESUMO

Objective: Genome-wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age-specific genetic risk for AD. The aim of this study was to quantify the age-specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS. Methods: Quantification of individual differences in age-specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age-specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P-value thresholds for disease association. Results: Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10-12) was observed for PRS based upon genome-wide significant SNPs (P ≤ 5 × 10-8). The strength of association was weaker with less stringent SNP selection thresholds. Interpretation: Both PRS and PHS can be used to predict an age-specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10-3, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10-3, the age-specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study).

6.
Transl Psychiatry ; 9(1): 55, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30705288

RESUMO

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/etnologia , Doença de Alzheimer/genética , Glicoproteínas de Membrana/genética , Fosfolipase C gama/genética , Receptores Imunológicos/genética , Grupo com Ancestrais do Continente Africano/genética , Idoso , Idoso de 80 Anos ou mais , Argentina/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Índios Norte-Americanos/genética , Masculino , Pessoa de Meia-Idade
7.
Aging (Albany NY) ; 11(1): 73-88, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30620722

RESUMO

Circulating ceramide levels are abnormally elevated in age-dependent pathologies such as cardiovascular diseases, obesity and Alzheimer's disease. Nevertheless, the potential impact of age on plasma ceramide levels has not yet been systematically examined. In the present study, we quantified a focused panel of plasma ceramides and dihydroceramides in a cohort of 164 subjects (84 women) 19 to 80 years of age. After adjusting for potential confounders, multivariable linear regression analysis revealed a positive association between age and ceramide (d18:1/24:0) (ß (SE) = 5.67 (2.38); p = .0198) and ceramide (d18:1/24:1) (ß (SE) = 2.88 (.61); p < .0001) in women, and between age and ceramide (d18:1/24:1) in men (ß (SE) = 1.86 (.77); p = .0179). In women of all ages, but not men, plasma ceramide (d18:1/24:1) was negatively correlated with plasma estradiol (r = -0.294; p = .007). Finally, in vitro experiments in human cancer cells expressing estrogen receptors showed that incubation with estradiol (10 nM, 24 h) significantly decreased ceramide accumulation. Together, the results suggest that aging is associated with an increase in circulating ceramide levels, which in post-menopausal women is at least partially associated with lower estradiol levels.

8.
Neuropsychobiology ; 77(1): 8-12, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30110694

RESUMO

BACKGROUND/OBJECTIVES: This study aims to investigate the role of apolipoprotein E (APOE) e4 influencing the age at onset (AAO) of Alzheimer's disease (AD). In AD, the AAO of dementia varies from 40 to 90 years. Usually, AD patients who develop symptoms before the age of 65 are considered as early-onset AD (EOAD). However, considering the heterogeneity of the AD onset, the definition of late-onset AD (LOAD) cannot rely on an arbitrary cut-off. Thus, we aim to validate the anticipation effect of the APOE e4 allele in LOAD. Methods/Overview: Firstly, the optimal number of AAO subgroups was determined using MCLUST for 3 AD samples from Italy, Brazil, and from the ADNI consortium. MCLUST selects the best-fitting model based on the Bayesian information criterion (BIC), and the ideal cut-off for separating early onset from late onset in each sample. Then, when the AAO was modeled for each sample, the finite mixture model (FMM) analysis was used to analyze the effect of the APOE e4 in determining the risk for anticipated onset in LOAD. For the Brazilian sample, the ancestry was incorporated as a covariate. The FMM results from the 3 samples were meta-analyzed using METAL. RESULTS: We performed the AAO analysis on the APOE e4 in 474 Italian patients enrolled at the IRCCS Santa Lucia Foundation in Italy, 135 AD from the Outpatients Reference Center for Geriatrics from the Federal University of Minas Gerais in Brazil, and 376 from the ADNI consortium. Using this distribution model, we found that the specific LOAD cut-off was ≥64 for the Italian sample, ≥67 for the ADNI sample, and ≥74 for the Brazilian sample. The APOE e4 showed a significant anticipatory effect specific for LOAD in all 3 samples. The METAL analysis for the anticipatory e4 effect was genome-wide significant when analyzing the LOAD effect size under the fixed model (beta = -8.1; p < 0.0001). However, when analyzing EOAD there was no genome-wide significant anticipation effect (beta = 1.9244; p = 0.0219). CONCLUSIONS: This study showed that the mixture analysis can refine the ideal cut-off for defining LOAD as a homogeneous genetic entity. We also validated the e4 allele anticipatory effect only in LOAD. In summary, the tool developed in this study is a sophisticated statistical pipeline to analyze the AAO in genome-wide association studies of AD, to find new molecular targets as a new line of translational research to foster drug discovery.


Assuntos
Alelos , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Predisposição Genética para Doença , Genoma Humano/genética , Idade de Início , Idoso , Teorema de Bayes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Modelos Estatísticos , Projetos Piloto , Fatores de Risco
9.
Front Aging Neurosci ; 10: 285, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30455639

RESUMO

Alzheimer's disease (AD) is a fatal dementing neurodegenerative disease, currently lacking an efficacious disease-modifying therapy. In the last years, there has been some interest in the use of homotaurine as a potential therapeutic compound for AD, but more work is still needed to prove its efficacy as disease modifier in dementia. Since inflammation is believed to play a key role in AD development, we sought to investigate here the in vivo homotaurine effect on inflammatory response in patients at the earliest stages of AD, i.e., suffering from amnestic mild cognitive impairment (aMCI). Thus, the present study aims to evaluate the effects of homotaurine supplementation on cytokine serum levels and memory performances in MCI patients. Neuropsychological, clinical and cytokine assessment was performed at baseline (T0) and after 1 year (T12) of homotaurine supplementation in 20 patients categorized as carriers (n = 9) or no carriers (n = 11) of the ε4 allele of the apolipoprotein E (APOE) gene, the strongest genetic risk factor for AD. The serum levels of the pro-inflammatory mediators Interleukin (IL) 1ß, Tumor necrosis factor-alpha (TNFα), IL-6 and IL-18, contextually with the anti-inflammatory molecules IL-18 binding protein (IL-18BP) and Transforming growth factor-beta (TGFß), were analyzed to explore significant differences in the inflammatory status between T0 and T12 in the two APOE variant carrier groups. No significant differences over time were observed in patients as for most cytokines, except for IL-18. Following homotaurine supplementation, patients carrying the APOEε4 allele showed a significant decrease in IL-18 (both in its total and IL-18BP unbound forms), in turn associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI may have a positive consequence on episodic memory loss due, at least in part, to homotaurine anti-inflammatory effects. This study strongly suggests that future research should focus on exploring the mechanisms by which homotaurine controls brain inflammation during AD progression.

10.
Neuroimmunomodulation ; 25(3): 129-137, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30326484

RESUMO

OBJECTIVE: Interaction between the nervous and immune systems may influence emotions, ultimately affecting human health. Cytokines may play a role in developing emotional dysregulation as in alexithymia, a personality construct characterized by the subclinical inability to identify and describe emotions, often associated with several psychiatric and psychosomatic disorders. The proinflammatory cytokine IL-18, with a recognized role in brain functions, may influence serotonin metabolism and appears to be associated with alexithymia. Healthy individuals carrying the long allele (L) of the serotonin transporter gene polymorphic region (5-HTTLPR), and thus having lower concentrations of serotonin in the synaptic cleft, show a greater tendency toward alexithymia, with some gender differences. To explore a potential physiological interaction between IL-18, serotonin neurotransmission, and alexithymia, we investigated whether IL-18 serum levels and 5-HTTLPR are linked to alexithymic traits in healthy subjects. METHODS: We measured IL-18 serum levels in 115 Italian-Caucasian healthy subjects genotyped for 5-HTTLPR allele variants, divided by gender and assessed for alexithymia scores using the 20-item Toronto Alexithymia Scale. RESULTS: IL-18 levels are significantly more elevated in individuals with the LL genotype (n = 25) than in carriers of the short allele (n = 90, p = 0.0073). Specifically, in LL males (n = 11), i.e., the group with the most relevant increase in IL-18, cytokine values positively correlated with difficulty identifying feelings, which is a component of alexithymia (r = 0.634, p = 0.036). CONCLUSIONS: These results indicate a possible novel interaction between IL-18 and the serotoninergic system to mediate emotional unawareness, suggesting putative biological predictors of emotional dysregulation, which in turn can act as a risk factor for a variety of medical conditions in susceptible subjects.

11.
J Neuropsychiatry Clin Neurosci ; : appineuropsych17120351, 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30282513

RESUMO

The habenula is a small midbrain structure that is important for brain signaling and learning from negative events. Thus, the habenula is strongly connected to both the reward system and motor regions. Increasing evidence suggests a role for the habenula in the etiology of psychiatric disorders, including mood and substance use disorders. However, no studies to date have investigated habenular resting-state functional connectivity (rsFC) in suicide-related behaviors (SB). The authors enrolled 123 individuals with major depressive disorder (MDD) or bipolar disorder and a history of suicide-related behaviors (SB+), 74 individuals with MDD or bipolar disorder and a history of suicidal ideation but no history of SB (SB-), and 75 healthy control subjects (HC). A seed-based approach was used to identify regions showing different rsFC with the habenula followed by region of interest to region of interest post hoc comparisons. Compared with both the SB- and HC groups, the SB+ group showed higher connectivity between the left habenula and the left parahippocampal gyrus, the right amygdala, and the right precentral and postcentral gyri. Patients with mood disorders displayed higher rsFC between the left habenula and left middle temporal gyrus, the left angular gyrus, and the left posterior cingulate cortex, as well as lower rsFC between the right habenula and the left thalamus, when compared with HCs. These findings suggest that the habenula is involved in the neural circuitry of suicide. The higher habenular rsFC found in the SB+ group may mediate a dysfunction in the mechanism that links the habenula with motor activity and contextual associative processing.

12.
Front Comput Neurosci ; 12: 75, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30254581

RESUMO

The dynamics of the environment where we live in and the interaction with it, predicting events, provided strong evolutionary pressures for the brain functioning to process temporal information and generate timed responses. As a result, the human brain is able to process temporal information and generate temporal patterns. Despite the clear importance of temporal processing to cognition, learning, communication and sensory, motor and emotional processing, the basal mechanisms of how animals differentiate simple intervals or provide timed responses are still under debate. The lesson we learned from the last decade of research in neuroscience is that functional and structural brain connectivity matter. Specifically, it has been accepted that the organization of the brain in interacting segregated networks enables its function. In this paper we delineate the route to a promising approach for investigating timing mechanisms. We illustrate how novel insight into timing mechanisms can come by investigating brain functioning as a multi-layer dynamical network whose clustered dynamics is bound to report the presence of metastable states. We anticipate that metastable dynamics underlie the real-time coordination necessary for the brain's dynamic functioning associated to time perception. This new point of view will help further clarifying mechanisms of neuropsychiatric disorders.

13.
Nat Commun ; 9(1): 3560, 2018 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158661

RESUMO

In the original version of this Article, references in the Methods section incorrectly referred to references in the Supplementary References section. The relevant references (now numbered 20, 27, 42, 47, 69-80) have been removed from the Supplementary References section of the Supplementary Information file and added to the References section of the main manuscript, in both the PDF and HTML versions of the Article.

14.
Brain Behav ; 8(10): e01094, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30160376

RESUMO

BACKGROUND: Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder. It is well established that different motor subtypes of PD evolve with different clinical courses and prognoses. The complete psychiatric profile underlying these different phenotypes since the very early stage of the disease is debated. AIMS OF THE STUDY: We aimed at investigating the psychiatric profile of the three motor subtypes of PD (akinetic-rigid, tremor-dominant, and mixed) in de novo drug-naïve patients with PD. METHODS: Sixty-eight patients with PD, divided into 39 akinetic-rigid (AR), seven mixed (MIX), and 22 tremor-dominant (TD) patients underwent a complete assessment of psychiatric, cognitive, and motor symptoms. RESULTS: No significant differences were found among groups. CONCLUSIONS: Our results suggest that a differentiation of the psychiatric symptoms associated with specific motor subtypes of PD is not detectable in de novo drug-naïve patients. Previous evidence that emerges later along the disease progression may be a consequence of the dopaminergic and nondopaminergic damage increase.

15.
J Womens Health (Larchmt) ; 27(11): 1368-1377, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30085899

RESUMO

BACKGROUND: Alzheimer's disease (AD) is characterized by progressive cognitive decline, often associated with Behavioral and Psychological Symptoms of Dementia (BPSD). Acetylcholinesterase inhibitors (ChEi) may attenuate cognitive decline and mitigate BPSD. The EVOLUTION group found that the switch from oral ChEi to transdermal rivastigmine patch formulation resulted in improvement/stabilization in the frequency of clinically relevant BPSD, but gender-specific subgroup analyses were not reported. METHODS: Participants underwent Neuropsychiatric Inventory to assess the frequency and severity of neuropsychiatric symptoms at baseline and 3 and 6 months after the switch from oral ChEi to transdermal rivastigmine patch. A descriptive post hoc analysis was conducted to assess whether there were gender-based differences in BPSD profile during the 6 months after the switch. RESULTS: The entire sample consisted of 475 patients, 274 women and 201 men. Women were on average slightly older and with poorer cognitive performance (60.6% of the women had moderate-AD, defined as Mini-Mental State Examination [MMSE] score of 10-17, vs. 43.8% of men). In mild-AD patients (MMSE score 18-26), the frequency of BPSD did not change significantly over time and an association was found between gender and depression (odds ratio; OR [95% confidence interval; CI] female vs. male = 3.32 [1.44-7.67]), anxiety (2.42 [1.23-4.79]), apathy (2.25 [1.07-4.70]), nighttime behavior disturbances (3.97 [1.66-9.49]), and appetite/eating abnormalities (2.39 [1.10-5.18]). Moderate-AD female patients had euphoria more frequently than male patients (OR [95% CI] female vs. male = 3.67 [1.25-10.74]). The frequency of delusions, anxiety, and irritability decreased during the first 3 months after the switch, independently of gender. CONCLUSION: Mild-AD women tended to suffer more frequently from BPSD than men; in the 3 months after treatment switch, moderate-AD patients showed a decrease in delusions, anxiety, and irritability, with no significant differences between genders. Ad hoc studies to investigate this potential gender effect in AD could be well worthwhile.

16.
Schizophr Res Cogn ; 12: 42-49, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29928596

RESUMO

Timing disturbances have being proposed as a key component of schizophrenia pathogenesis. However, the contribution of cognitive impairment to such disorders has not been clarified. Here, we investigated duration estimation and predictive timing in 30 patients with DSM-5 diagnosis of schizophrenia (SZ) compared to 30 healthy controls (HC). Duration estimation was examined in a temporal and colour discrimination task, fully controlled for working memory (WM) and attention requirements, and by more traditional temporal production and temporal bisection tasks. Predictive timing was measured in a temporal and spatial orienting of attention task. Expectations about stimulus onset (temporal condition) or location (spatial condition) were induced by valid and invalid symbolic cues. Results showed that discrimination of temporal and colour stimulus attributes was equally impaired in SZ. This, taken with the positive correlation between temporal bisection performance and neuropsychological measures of WM, indicates that duration estimation impairments in SZ are underpinned by WM dysfunction. Conversely, we found dissociation in temporal and spatial predictive ability in SZ. Unlike controls, patients were selectively unperturbed by events appearing at an unexpected moment in time, though were perturbed by targets appearing at an unexpected location. Moreover, patients were able to generate temporal expectations more implicitly, as their performance was influenced by the predictive nature of the flow of time itself. Our findings shed new light on the debate over the specificity of timing distortions in SZ, providing evidence that predictive timing is a precise marker of SZ, more sensitive than duration estimation, serving as a valid heuristic for studying the pathophysiology of the disorder.

17.
Artigo em Inglês | MEDLINE | ID: mdl-29929763

RESUMO

Brain imaging is a non-invasive and in vivo direct estimation of detailed brain structure, regional brain functioning and estimation of molecular processes in the brain. The main objective of this review was to analyze functional and structural neuroimaging studies of individuals at risk for suicide. We reviewed articles published between 2005 and 2018, indexed in PubMed and Medline, assessing structural and functional alterations of the brain of individuals at high risk for suicide and at low risk for suicide. We reviewed functional and structural neuroimaging studies which included individuals with a history of suicidal ideation or attempt in major depressive disorder (MDD), bipolar disorder (BD), psychosis, and borderline personality disorder (BPD). We selected 45 papers that focused on suicidality in MDD, 17 papers on BD, 11 papers on psychosis, and 5 papers on BPD. The suicidal brain across psychiatric diagnoses seems to heavily involve dysfunction of the fronto-temporal network, primarily involving reductions of gray and white matter volumes in the pre-frontal cortex (PFC), anterior cingulate, and superior temporal gyrus. Nonetheless, there are several ways to define suicidal behaviour and ideation. Therefore, it still remains difficult to combine the evidence from imaging studies that used different definitions of suicidality.

18.
Nat Commun ; 9(1): 2265, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29891954

RESUMO

Antipsychotics are the most widely used medications for the treatment of schizophrenia spectrum disorders. While such drugs generally ameliorate positive symptoms, clinical responses are highly variable in terms of negative symptoms and cognitive impairments. However, predictors of individual responses have been elusive. Here, we report a pharmacogenetic interaction related to a core cognitive dysfunction in patients with schizophrenia. We show that genetic variations reducing dysbindin-1 expression can identify individuals whose executive functions respond better to antipsychotic drugs, both in humans and in mice. Multilevel ex vivo and in vivo analyses in postmortem human brains and genetically modified mice demonstrate that such interaction between antipsychotics and dysbindin-1 is mediated by an imbalance between the short and long isoforms of dopamine D2 receptors, leading to enhanced presynaptic D2 function within the prefrontal cortex. These findings reveal one of the pharmacodynamic mechanisms underlying individual cognitive response to treatment in patients with schizophrenia, suggesting a potential approach for improving the use of antipsychotic drugs.

19.
Front Hum Neurosci ; 12: 212, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29881338

RESUMO

The ability to generate probabilistic expectancies regarding when and where sensory stimuli will occur, is critical to derive timely and accurate inferences about updating contexts. However, the existence of specialized neural networks for inferring predictive relationships between events is still debated. Using graph theoretical analysis applied to structural connectivity data, we tested the extent of brain connectivity properties associated with spatio-temporal predictive performance across 29 healthy subjects. Participants detected visual targets appearing at one out of three locations after one out of three intervals; expectations about stimulus location (spatial condition) or onset (temporal condition) were induced by valid or invalid symbolic cues. Connectivity matrices and centrality/segregation measures, expressing the relative importance of, and the local interactions among specific cerebral areas respect to the behavior under investigation, were calculated from whole-brain tractography and cortico-subcortical parcellation. Results: Response preparedness to cued stimuli relied on different structural connectivity networks for the temporal and spatial domains. Significant covariance was observed between centrality measures of regions within a subcortical-fronto-parietal-occipital network -comprising the left putamen, the right caudate nucleus, the left frontal operculum, the right inferior parietal cortex, the right paracentral lobule and the right superior occipital cortex-, and the ability to respond after a short cue-target delay suggesting that the local connectedness of such nodes plays a central role when the source of temporal expectation is explicit. When the potential for functional segregation was tested, we found highly clustered structural connectivity across the right superior, the left middle inferior frontal gyrus and the left caudate nucleus as related to explicit temporal orienting. Conversely, when the interaction between explicit and implicit temporal orienting processes was considered at the long interval, we found that explicit processes were related to centrality measures of the bilateral inferior parietal lobule. Degree centrality of the same region in the left hemisphere covaried with behavioral measures indexing the process of attentional re-orienting. These results represent a crucial step forward the ordinary predictive processing description, as we identified the patterns of connectivity characterizing the brain organization associated with the ability to generate and update temporal expectancies in case of contextual violations.

20.
Front Aging Neurosci ; 10: 92, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29755337

RESUMO

The risk for Alzheimer's disease (AD) is associated with the presence of the 𝜀4 allele of Apolipoprotein E (APOE) gene and, recently, with a novel genetic variant of the RNF219 gene. This study aimed at evaluating interactions between APOE-𝜀4 and RNF219/G variants in the modulation of behavioral and cognitive features of two cohorts of patients suffering from mild cognitive impairment (MCI) or AD. We enrolled a total of 173 female MCI or AD patients (83 MCI; 90 AD). Subjects were screened with a comprehensive set of neuropsychological evaluations and genotyped for the APOE and RNF219 polymorphic variants. Analysis of covariance was performed to assess the main and interaction effects of APOE and RNF219 genotypes on the cognitive and behavioral scores. The analysis revealed that the simultaneous presence of APOE-𝜀4 and RNF219/G variants results in significant effects on specific neuropsychiatric scores in MCI and AD patients. In MCI patients, RNF219 and APOE variants worked together to impact the levels of anxiety negatively. Similarly, in AD patients, the RNF219 variants were found to be associated with increased anxiety levels. Our data indicate a novel synergistic activity APOE and RNF219 in the modulation of behavioral traits of female MCI and AD patients.

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