miR-9-5p is Downregulated in Serum Extracellular Vesicles of Patients Treated with Biperiden After Traumatic Brain Injury.

Traumatic brain injury (TBI) is a prevalent and debilitating condition, which often leads to the development of post-traumatic epilepsy (PTE), a condition that yet lacks preventive strategies. Biperiden, an anticholinergic drug, is a promising candidate that has shown efficacy in murine models of PTE. MicroRNAs (miRNAs), small regulatory RNAs, can help in understanding the biological basis of PTE and act as TBI- and PTE-relevant biomarkers that can be detected peripherally, as they are present in extracellular vesicles (EVs) that cross the blood-brain barrier. This study aimed to investigate miRNAs in serum EVs from patients with TBI, and their association with biperiden treatment and PTE. Blood samples of 37 TBI patients were collected 10 days after trauma and treatment initiation in a double-blind clinical trial. A total of 18 patients received biperiden, with three subjects developing PTE, and 19 received placebo, with two developing PTE. Serum EVs were characterized by size distribution and protein profiling, followed by high-throughput sequencing of the EV miRNome. Differential expression analysis revealed no significant differences in miRNA expression between TBI patients with and without PTE. Interestingly, miR-9-5p displayed decreased expression in biperiden-treated patients compared to the placebo group. This miRNA regulates genes enriched in stress response pathways, including axonogenesis and neuronal death, relevant to both PTE and TBI. These findings indicate that biperiden may alter miR-9-5p expression in serum EVs, which may play a role in TBI resolution.

Interaction between PTSD-PRS and trauma affects PTSD likelihood in women victims of sexual assault.

OBJECTIVE: Post-traumatic stress disorder (PTSD) is triggered by traumatic events, but genetic vulnerability and a history of childhood trauma are additional factors that may increase the risk of PTSD. Thus, our study focused on exploring the interaction between genetic susceptibility, as assessed by polygenic risk score (PRS), and traumatic events. METHODS: We evaluated 68 women with PTSD who had been sexually assaulted and 63 healthy controls without a history of sexual assault. DNA was genotyped using the Infinium Global Screening Array (Illumina), and PRS analysis was performed using PRSice. Furthermore, logistic regression models were employed to examine the interaction between childhood trauma, traumatic life events, and PTSD-PRS and how they contribute to the risk of developing PTSD. RESULTS: We found a significant association between PRS, childhood trauma (p = 0.03; OR = 1.241), and PTSD. Additionally, an interaction was observed between PRS, traumatic life events, and childhood trauma, particularly relating to physical and emotional neglect (p = 0.028; OR = 1.010). When examining neglect separately, we found a modest association between emotional neglect and PTSD (p = 0.014; OR = 1.086). CONCLUSIONS: Our findings highlight the importance of considering genetic vulnerability and traumatic experiences in understanding the etiology of PTSD.

A Systematic Review of LINE-1 Methylation Profile in Psychiatric Disorders.

Introduction: Long interspersed nuclear elements (LINEs) are endogenous retrotransposable elements. A few studies have linked the methylation pattern of LINE-1 to different mental disorders (e.g., post-traumatic stress disorder [PTSD], autism spectrum disorder [ASD], panic disorder [PD]). We sought to unify the existing knowledge in the field and provide a better understanding of the association between mental disorders and LINE-1 methylation. Methods: A systematic review was executed with 12 eligible articles according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: For psychotic disorders, PTSD, ASD, and PD, lower LINE-1 methylation levels were detected, whereas for mood disorders, the findings are controversial. The studies were conducted with subjects aged 18-80 years. Peripheral blood samples were utilized in 7/12 articles. Conclusion: Although most studies have shown that LINE-1 hypomethylation was associated with mental disorders, there were still some divergences (i.e., hypermethylation associated with mental disorders). These studies suggest that LINE-1 methylation may be an important factor related to the development of mental disorders and highlight the need to better comprehend the biological mechanisms underlying the role of LINE-1 in mental disorders pathophysiology.

Hyperarousal Symptom Severity in Women with Posttraumatic Stress Disorder Might Be Associated with LINE-1 Hypomethylation in Childhood Sexual Abuse Victims.

Introduction: Sexual assault and a history of childhood sexual abuse (CSA) are related to posttraumatic stress disorder (PTSD) development. Long interspersed nuclear elements (LINE-1) are transposable elements, and their methylation is used to infer DNA global methylation. DNA methylation can be affected by trauma exposition which in turn would be associated with PTSD. Thus, we investigated if the LINE-1 methylation pattern is related to PTSD symptoms in females with a history of CSA. Methods: This is a case-control study that examined, at baseline (W1), 64 women victims of sexual assault diagnosed with PTSD and 31 patients with PTSD who completed the 1-year follow-up (W2). Participants were categorized into two groups according to the presence of CSA (PTSDCSA+: NW1 = 19, NW2 = 10; PTSDCSA-: NW1 = 45, NW2 = 21). PTSD symptoms (re-experiencing, avoidance, hyperarousal, alterations in cognition/mood) were assessed using the Clinician-Administered PTSD Scale, and the history of CSA was assessed by the Childhood Trauma Questionnaire. LINE-1 methylation was measured in three sites (CpG1, CpG2, CpG3) located in the 5'UTR region using bisulfite conversion followed by pyrosequencing. Linear regression models were performed to test the relation between LINE-1 CpG sites methylation and PTSD symptoms. Results: We found a negative association between CpG2 methylation and hyperarousal symptoms among those in the PTSDCSA+ group in W1 (adjusted p = 0.003) compared to the PTSDCSA- group (p > 0.05). Still, no association was observed between other PTSD symptoms and other CpG sites. Further, in the longitudinal analysis, LINE-1 hypomethylation was no longer observed in PTSD participants exposed to CSA. Conclusion: Our findings suggest that LINE-1 methylation may help understand the relationship between trauma and PTSD. However, more studies are needed to investigate LINE-1 as an epigenetic marker of psychiatric disorders.

Lifetime cannabis use and childhood trauma associated with CNR1 genetic variants increase the risk of psychosis: findings from the STREAM study.

OBJECTIVES: Gene-environment interactions increase the risk of psychosis. The objective of this study was to investigate gene-gene and gene-environment interactions in psychosis, including single nucleotide variants (SNVs) of dopamine-2 receptor (D2R), N-methyl-d-aspartate receptor (NMDAR), and cannabinoid receptor type 1 (CB1R), lifetime cannabis use, and childhood trauma. METHODS: Twenty-three SNVs of genes encoding D2R (DRD2: rs1799978, rs7131056, rs6275), NMDAR (GRIN1: rs4880213, rs11146020; GRIN2A: rs1420040, rs11866328; GRIN2B: rs890, rs2098469, rs7298664), and CB1R (CNR1: rs806380, rs806379, rs1049353, rs6454674, rs1535255, rs2023239, rs12720071, rs6928499, rs806374, rs7766029, rs806378, rs10485170, rs9450898) were genotyped in 143 first-episode psychosis patients (FEPp) and 286 community-based controls by Illumina HumanCoreExome-24 BeadChip. Gene-gene and gene-environment associations were assessed using nonparametric Multifactor Dimensionality Reduction software. RESULTS: Single-locus analyses among the 23 SNVs for psychosis and gene-gene interactions were not significant (p > 0.05 for all comparisons); however, both environmental risk factors showed an association with psychosis (p < 0.001). Moreover, gene-environment interactions were significant for an SNV in CNR1 and cannabis use. The best-performing model was the combination of CNR1 rs12720071 and lifetime cannabis use (p < 0.001), suggesting an increased risk of psychosis. CONCLUSION: Our study supports the hypothesis of gene-environment interactions for psychosis involving T-allele carriers of CNR1 SNVs, childhood trauma, and cannabis use.

Lifetime cannabis use and childhood trauma increase risk of psychosis in carriers of CNR1 genetic variants: findings from the STREAM study

Objectives: Gene-environment interactions increase the risk of psychosis. The objective of this study was to investigate gene-gene and gene-environment interactions in psychosis, including single nucleotide variants (SNVs) of dopamine-2 receptor (D2R), N-methyl-d-aspartate receptor (NMDAR), and cannabinoid receptor type 1 (CB1R), lifetime cannabis use, and childhood trauma. Methods: Twenty-three SNVs of genes encoding D2R (DRD2: rs1799978, rs7131056, rs6275), NMDAR (GRIN1: rs4880213, rs11146020; GRIN2A: rs1420040, rs11866328; GRIN2B: rs890, rs2098469, rs7298664), and CB1R (CNR1: rs806380, rs806379, rs1049353, rs6454674, rs1535255, rs2023239, rs12720071, rs6928499, rs806374, rs7766029, rs806378, rs10485170, rs9450898) were genotyped in 143 first-episode psychosis patients (FEPp) and 286 community-based controls by Illumina HumanCoreExome-24 BeadChip. Gene-gene and gene-environment associations were assessed using nonparametric Multifactor Dimensionality Reduction software. Results: Single-locus analyses among the 23 SNVs for psychosis and gene-gene interactions were not significant (p > 0.05 for all comparisons); however, both environmental risk factors showed an association with psychosis (p < 0.001). Moreover, gene-environment interactions were significant for an SNV in CNR1 and cannabis use. The best-performing model was the combination of CNR1 rs12720071 and lifetime cannabis use (p < 0.001), suggesting an increased risk of psychosis. Conclusion: Our study supports the hypothesis of gene-environment interactions for psychosis involving T-allele carriers of CNR1 SNVs, childhood trauma, and cannabis use.

Shorter Telomeres Related to Posttraumatic Stress Disorder Re-experiencing Symptoms in Sexually Assaulted Civilian Women.

Telomeres are short tandem repeats of "TTAGGG" that protect the chromosome ends from deterioration or fusion of chromosomes. Their repeat length shortens with cell division acting as a biomarker of cellular aging. Traumatic stress events during adulthood or childhood have been associated with posttraumatic stress disorder (PTSD) and short leukocyte telomere length (LTL). This study investigated whether LTL was associated with PTSD in a Brazilian sample of sexually assaulted civilian women at two time points: baseline and 1-year follow-up. At baseline, we assessed 64 women with PTSD following sexual assault (cases) and 60 women with no previous history of sexual trauma or mental disorders (healthy controls - HC). At follow-up visit, 13 persistent PTSD cases, 11 HCs, and 11 PTSD remitters patients were evaluated. PTSD diagnosis and severity were assessed using Mini International Neuropsychiatric Interview (Diagnostic and Statistical Manual of Mental Disorders III/IV criteria) and Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), respectively. LTL was measured using multiplex real-time polymerase chain reaction (PCR). In the baseline analysis, we observed that LTL was associated with re-experiencing symptoms (B = -0.16; confidence interval (CI) 95% = -0.027--0.005; Bonferroni-adjusted p-value = 0.02), but no association was observed between other PTSD symptoms and LTL. In the longitudinal analysis, telomere shortening was no longer observed in patients with PTSD and PTSD remitters. In conclusion, our findings indicate that shorter baseline LTL is associated with early stage of PTSD re-experiencing symptoms in recently sexually assaulted women.

Systems-Level Analysis of Genetic Variants Reveals Functional and Spatiotemporal Context in Treatment-resistant Schizophrenia.

Treatment-resistant schizophrenia (TRS) occurs in one-third of the patients, but the molecular determinants of poor antipsychotic response remain unclear. We compared genetic data of patients with TRS (n = 63) with non-TRS (n = 111) by polygenic risk scores (PRS) calculated by PRSice software using PGC2_SCZ (Psychiatric Genomics Consortium - Schizophrenia) data. TRS criteria followed the International Psychopharmacology Algorithm Project SCZ algorithm. Statistical clustering and functional enrichment analyses of genes harboring TRS-linked variants were performed. Individuals on the top three deciles of schizophrenia PRS distribution exhibited higher odds of being refractory to antipsychotics than those on the bottom three deciles. Clusters of interacting variant-harboring genes were identified among the association signals. They are upregulated in the dorsolateral prefrontal, orbitofrontal, temporal, and inferior parietal areas during adolescence and early adulthood. Similar gene modules were found using transcriptional data from the same brain regions in individuals with schizophrenia. Genes were enriched among markers of cortical interneurons and somatosensory pyramidal cells. Finally, the enrichment of the clustered genes in drug-response expression signatures revealed compounds that could be employed to identify novel antipsychotic targets. In conclusion, we identified variant-harboring genes that may predispose SCZ patients to poor antipsychotic response and found statistically enriched clusters which provided functional and spatiotemporal context for TRS, suggesting that genotypic variation may converge to biological alterations at the interplay between actin dynamics and synaptic organization.

The impact of neighborhood context on telomere length: A systematic review.

A growing body of research demonstrates the association between neighborhood context and health. The underlying biological mechanisms of this association are not fully understood. We conducted a systematic review of studies that investigated the association between neighborhood context and telomere length (TL), a DNA-protein complex that shortens after cell division. Short TL is linked to age-related diseases and may be impacted by chronic stress. Nineteen eligible articles identified through PubMed and Scopus met inclusion criteria. Results demonstrated inconsistent support for the relationship between neighborhood disadvantage and short TL. However, findings across several studies provide evidence for an inverse association between perceived neighborhood problems and TL, suggesting that TL may be an important factor in understanding health vulnerabilities associated specifically with negative perceptions of the neighborhood context.

BDNF in antipsychotic naive first episode psychosis: Effects of risperidone and the immune-inflammatory response system.

Brain-derived neurotrophic factor (BDNF) and the immune-inflammatory response system (IRS) have been implicated in the pathophysiology of schizophrenia. However, no research examined the associations between BDNF and immune activation both before and after treatment in antipsychotic-naïve first episode psychosis (AN-FEP). This study aims to examine serum BDNF levels and their association with IRS and the compensatory immune-regulatory reflex system (CIRS) in AN-FEP before and after risperidone treatment. We included 31 AN-FEP and 22 healthy controls. AN-FEP showed reduced levels of BDNF as compared to controls, and BDNF levels normalized after treatment with risperidone. BDNF levels were inversely correlated with a greater IRS response. Higher levels of IRS/CIRS biomarkers were associated with lower levels of BDNF including M1 macrophage, T-helper (Th)-1, Th-2, and Th-17, and T-regulatory (Treg) cell responses. Our findings indicate that AN-FEP is characterized by decreased levels of BDNF, which are normalized after treatment with risperidone. BDNF levels were inversely associated with activated immune-inflammatory pathways. The findings support the hypothesis that, increased IRS is linked to neurotoxicity, and that a decrease in BDNF may be part of the IRS/CIRS responses in FEP and, thus, be involved in the development of psychosis.

Telomere shortening in late-life depression: A potential marker of depression severity.

OBJECTIVES: Telomeres are structures at the extremity of chromosomes that prevents genomic instability, and its shortening seems to be a hallmark of cellular aging. Past studies have shown contradictory results of telomere length (TL) in major depression, and are a few studies in late-life depression (LLD). This explores the association between TL as a molecular marker of aging and diagnosis of LLD, the severity of depressive symptoms, and cognitive performance in older adults. METHODS/DESIGN: We included 78 older adults (45 with LLD and 33 nondepressed controls, according to DSM-V criteria), aged 60-90 years. TL was measured in leukocytes by a quantitative polymerase chain reaction, determining the relative ratio (T/S) between the telomere region copy number (T) and a single copy gene (S), using a relative standard curve. RESULTS: TL was significantly shorter in the LLD compared with control participants (p = .039). Comparing groups through the severity of depressive symptoms, we found a negative correlation with the severity of depressive symptoms (Hamilton Depression Rating Scale-21, r = -0.325, p = .004) and medical burden (r = -0.271, p = .038). There was no significant correlation between TL and cognitive performance (Mattis Dementia Rating Scale, r = 0.152, p = .21). CONCLUSIONS: We found that older adults with LLD have shorter telomere than healthy controls, especially those with a more severe depressive episode. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age-associated adverse outcomes linked to depression.

Klotho genetic variants mediate the association between obstructive sleep apnea and short telomere length.

The core features of obstructive sleep apnea (OSA) can potentially contribute to the acceleration of telomere shortening mechanisms. Other factor associated with telomeres is Klotho gene as it can negatively regulates telomerase activity. Noteworthy, KLOTHO protein level has recently been associated with OSA. In this sense, it was plausible to hypothesize that OSA would be associated with short telomere length and those with OSA plus risk single nucleotide polymorphisms (SNPs) in Klotho gene would present even shorter telomere length. As part of the EPISONO cohort, 1042 individuals answered questionnaires, underwent polysomnography and had blood collected for DNA extraction. OSA was defined according to AHI≥ 15 events/hour. Leukocyte telomere length (LTL) was measured through real-time polymerase chain reaction (qPCR) and Klotho SNPs were genotyped by array. Mediation analyses considered the presence of SNPs in Klotho gene and how this interaction can affect OSA and its consequence in telomere length. All the analyses were corrected for multiple comparisons. LTL was significantly shorter in OSA compared to controls in a severity-dependent manner (B = 0.055; CI = 0.007-0.102; p = 0.02). Among the 43 Klotho SNPs analyzed, we observed that 4 SNPs (rs525014, rs7982726, rs685417 and rs9563124) significantly mediated the association between OSA and short LTL. Klotho gene opens a new venue in OSA research since it can contribute in the increase of knowledge of the mechanisms involved in the consequences of short telomeres in individuals with OSA.

Is treatment-resistant schizophrenia associated with distinct neurobiological callosal connectivity abnormalities?

BACKGROUND: Resistance to antipsychotic treatment affects up to 30% of patients with schizophrenia. Although the time course of development of treatment-resistant schizophrenia (TRS) varies from patient to patient, the reasons for these variations remain unknown. Growing evidence suggests brain dysconnectivity as a significant feature of schizophrenia. In this study, we compared fractional anisotropy (FA) of brain white matter between TRS and non-treatment-resistant schizophrenia (non-TRS) patients. Our central hypothesis was that TRS is associated with reduced FA values. METHODS: TRS was defined as the persistence of moderate to severe symptoms after adequate treatment with at least two antipsychotics from different classes. Diffusion-tensor brain MRI obtained images from 34 TRS participants and 51 non-TRS. Whole-brain analysis of FA and axial, radial, and mean diffusivity were performed using Tract-Based Spatial Statistics (TBSS) and FMRIB's Software Library (FSL), yielding a contrast between TRS and non-TRS patients, corrected for multiple comparisons using family-wise error (FWE) < 0.05. RESULTS: We found a significant reduction in FA in the splenium of corpus callosum (CC) in TRS when compared to non-TRS. The antipsychotic dose did not relate to the splenium CC. CONCLUSION: Our results suggest that the focal abnormality of CC may be a potential biomarker of TRS.

Posttraumatic Stress Disorder and Neuroprogression in Women Following Sexual Assault: Protocol for a Randomized Clinical Trial Evaluating Allostatic Load and Aging Process Acceleration.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a prevalent, chronic, and severe disorder related to traumatic events. Women are disproportionately affected by PTSD than men and are more at risk in the occurrence of sexual assault victimization. Estimates suggest that 50% of women develop PTSD following sexual assault and successful clinical management can be challenging. Growing evidence has implicated neural, immune, and endocrine alterations underpinning PTSD, but only few studies have assessed the evolution of acute PTSD in women. OBJECTIVE: This study aims to measure whether the onset of PTSD is associated with accelerated aging in women following sexual assault. We hypothesize that the increase of allostatic load caused by PTSD leads to neuroprogression. We will implement a randomized clinical trial to compare responses to treatment with either interpersonal psychotherapy adapted for PTSD (IPT-PTSD) or the selective serotonin reuptake inhibitor sertraline. METHODS: We will include women between 18 and 45 years of age, who experienced sexual assault from 1 to 6 months before the initial evaluation, and present with a Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnosis of PTSD. Baseline evaluation will comprise clinical and psychometric assessments, structural and functional magnetic resonance imaging, neuropsychological testing, polysomnography, evaluation of immune and endocrine parameters, and genetic analyses. Age-matched female healthy controls will be included and subjected to the same evaluation. Patients will be randomized for treatment in 1 of the 2 arms of the study for 14 weeks; follow-up will continue until 1 year after inclusion via treatment as usual. The researchers will collect clinical and laboratory data during periodic clinical assessments up to 1-year follow-up. RESULTS: Data collection started in early 2016 and will be completed by the end of the first semester of 2020. Analyses will be performed soon afterward, followed by the elaboration of several articles. Articles will be submitted in early 2021. This research project has obtained a grant from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2014/12559-5). CONCLUSIONS: We expect to provide insight into the consequences of recent sexual assault exposure in women by investigating the degree of neuroprogression developing from an early stage of PTSD. We also expect to provide important evidence on the efficacy of a non-exposure psychotherapy (IPT-PTSD) to mitigate PTSD symptoms in recently sexually assaulted women. Further, we aim to obtain evidence on how treatment outcomes are associated with neuroprogression measures. TRIAL REGISTRATION: Brazilian Clinical Trials Registry RBR-3z474z; http://www.ensaiosclinicos.gov.br/rg/RBR-3z474z/. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/19162.

LINE-1 hypomethylation is associated with poor risperidone response in a first episode of psychosis cohort.

Aim: We investigated the DNA methylation profile over LINE-1 in antipsychotic-naive, first-episode psychosis-patients (n = 69) before and after 2 months of risperidone treatment and in healthy controls (n = 62). Materials & methods: Patients were evaluated using standardized scales and classified as responders and nonresponders. DNA from blood was bisulfite converted and LINE-1 fragments were amplified and pyrosequencing was performed. Results: Lower LINE-1 methylation was observed in antipsychotic-naive first-episode psychosis patients than in healthy controls. Lower DNA methylation levels before treatment were associated with poor risperidone responses. A positive correlation was observed between LINE-1 methylation levels and positive symptoms response. Conclusion: Our study brings new insight regarding how epigenomic studies and clinical correlation studies can supplement psychosis treatment.

A systematic review on the effects of social discrimination on telomere length.

Discrimination is unfair treatment against a certain group based on race, age, gender, sexual orientation, or other social identities. Discrimination is pervasive in society, elevates psychosocial stress, and is associated with negative mental and physical health outcomes. However, more research is needed to understand the biological mechanisms underlying discrimination-related health disparities. Telomere science may contribute to elucidate some of these aspects. Telomeres are protein-DNA complexes that shorten after cell division and are valuable markers of cellular aging. Short telomeres have been associated with the onset of age-related diseases. Evidence shows that chronic psychological stress may accelerate telomere shortening. Since discrimination can lead to psychological strain with cumulative impact on general health, we hypothesized that groups that report more discrimination show reduced telomere length (TL) as a consequence of psychosocial stress elevation. Through a systematic review of the literature we found 12 articles that met our criteria. Eligible studies measured racial, gender, unfair policing, and multiple forms of discrimination in association with TL. Our review showed mixed results, suggesting that there is weak evidence of a main association between discrimination and TL. However, discrimination may interact with several variables (such as depressive symptoms, acculturation, higher socioeconomic status, internalization of negative racial bias, and not discussing discrimination experiences with others) and contribute to shorten telomeres. Discrimination is a complex social construct composed of a vast sum of experiences, impressions, and contexts that in combination with other sources of stress may have an impact on TL. Telomeres may be a plausible pathway to investigate health discrepancies in discriminated groups in society, but more evidence is needed to investigate the potential harm of discrimination on cells.

Gene expression changes associated with trajectories of psychopathology in a longitudinal cohort of children and adolescents.

We aimed to identify blood gene expression patterns associated to psychopathological trajectories retrieved from a large community, focusing on the emergence and remission of general psychiatric symptoms. Hundred and three individuals from the Brazilian High-Risk Cohort Study (BHRCS) for mental disorders were classified in four groups according to Child Behavior Checklist (CBCL) total score at the baseline (w0) and after 3 years (w1): low-high (L-H) (N = 27), high-low (H-L) (N = 12), high-high (H-H) (N = 34) and low-low (L-L) groups (N = 30). Blood gene expression profile was measured using Illumina HT-12 Beadchips, and paired analyses comparing w0 and w1 were performed for each group. Results: 98 transcripts were differentially expressed comparing w0 and w1 in the L-H, 33 in the H-L, 177 in the H-H and 273 in the L-L. Of these, 66 transcripts were differentially expressed exclusively in the L-H; and 6 only in the H-L. Cross-Lagged Panel Models analyses revealed that RPRD2 gene expression at w1 might be influenced by the CBCL score at w0. Moreover, COX5B, SEC62, and NDUFA2 were validated with another technique and were also differentially regulated in postmortem brain of subjects with mental disorders, indicating that they might be important not only to specific disorders, but also to general psychopathology and symptoms trajectories. Whereas genes related to metabolic pathways seem to be associated with the emergence of psychiatric symptoms, mitochondrial inner membrane genes might be important over the course of normal development. These results suggest that changes in gene expression can be detected in blood in different psychopathological trajectories.

Genetic risk for Alzheimer's disease and functional brain connectivity in children and adolescents.

Research suggested accumulation of tau proteins might lead to the degeneration of functional networks. Studies investigating the impact of genetic risk for Alzheimer's disease (AD) on early brain connections might shed light on mechanisms leading to AD development later in life. Here, we aim to investigate whether the polygenic risk score for Alzheimer's disease (AD-PRS) influences the connectivity among regions susceptible to tau pathology during childhood and adolescence. Participants were youth, aged 6-14 years, and recruited in Porto Alegre (discovery sample, n = 332) and São Paulo (replication sample, n = 304), Brazil. Subjects underwent genotyping and 6-min resting state funcional magnetic resonance imaging. Connections between the local maxima of tau pathology networks were used as dependent variables. The AD-PRS was associated with the connectivity between the right precuneus and the right superior temporal gyrus (discovery sample: ß = 0.180, padjusted = 0.036; replication sample: ß = 0.202, p = 0.031). This connectivity was also associated with inhibitory control (ß = 0.157, padjusted = 0.035) and moderated the association between the AD-PRS and both immediate and delayed recall. These findings suggest the AD-PRS may affect brain connectivity in youth, which might impact memory performance and inhibitory control in early life.

Ndel1 oligopeptidase activity as a potential biomarker of early stages of schizophrenia.

Our previous studies showed reduced Ndel1 enzyme activity in patients with chronic schizophrenia (SCZ), and only a subtle NDEL1 mRNA increases in antipsychotic-naïve first-episode psychosis (FEP) individuals compared to matched healthy controls (HC). Aiming to refine the evaluation of Ndel1 enzyme activity in early stages of psychosis, we compared 3 groups composed by (1) subjects at ultra-high-risk (UHR) for psychosis, (2) a cohort comprising antipsychotic-naïve FEP individuals (assessed in three moments, at baseline (FEP-0), and after 2 months (FEP-2 M) and one year (FEP-1Y) of treatment with risperidone), and (3) a HC group. There was no significant difference in Ndel1 enzyme activity between UHR and HC, but this activity was significantly lower in FEP compared to HC. Conversely, Ndel1 activity in HC groups was higher than in FEP even before (FEP-0) or after the treatment with risperidone (FEP-2 M and FEP-1Y), and with progressive decrease of Ndel1 activity and significant improvement of symptoms observed after this treatment. In addition, a positive correlation was observed for Ndel1 activity with clinical symptoms as assessed by PANSS, while a negative correlation was seen for GAF scores. Our results suggest that reductions in Ndel1 activity in FEP may be possibly related to responses to the illness, rather than to the pharmacological effects of antipsychotics, which might be acting essentially in the symptoms suppression. This hypothesis might be further evaluated in prospective long-term follow-up studies with a larger sample cohort.

DGCR2 influences cortical thickness through a mechanism independent of schizophrenia pathogenesis.

We investigated the role of DGCR2, a corticogenesis-related gene, on schizophrenia (SZ) and its subphenotypes, including brain morphology. A total of 221 SZ patients, 263 controls and 70 antipsychotic-naïve first episode of psychosis (FEP) were genotyped for 17 DGCR2 polymorphisms. While no association between DGCR2 polymorphisms and SZ was found, the missense variant rs2072123 was associated to left rostral anterior cingulate thickness, showing that DGCR2 seems not to be associated directly with the SZ but might be influencing the brain morphology. We also showed a DGCR2 downregulation in SZ patients when compared to controls and FEP.