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Abstract This letter demonstrates the potential of novel cryptic proteins resulting from TAR DNA-binding protein 43 (TDP-43) dysfunction as markers of TDP-43 pathology in neurodegenerative diseases.

Abstract Background Inclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence of Alzheimer’s disease (AD). Approximately, 30–70% AD cases present TDP-43 proteinopathy (AD-TDP), and a greater disease severity compared to AD patients without TDP-43 pathology. However, it remains unclear to what extent TDP-43 dysfunction is involved in AD pathogenesis. Methods To investigate whether TDP-43 dysfunction is a prominent feature in AD-TDP cases, we evaluated whether non-conserved cryptic exons, which serve as a marker of TDP-43 dysfunction in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), accumulate in AD-TDP brains. We assessed a cohort of 192 post-mortem brains from three different brain regions: amygdala, hippocampus, and frontal cortex. Following RNA and protein extraction, qRT-PCR and immunoassays were performed to quantify the accumulation of cryptic RNA targets and phosphorylated TDP-43 pathology, respectively. Results We detected the accumulation of misspliced cryptic or skiptic RNAs of STMN2, KCNQ2, UNC13A, CAMK2B, and SYT7 in the amygdala and hippocampus of AD-TDP cases. The topographic distribution of cryptic RNA accumulation mimicked that of phosphorylated TDP-43, regardless of TDP-43 subtype classification. Further, cryptic RNAs efficiently discriminated AD-TDP cases from controls. Conclusions Overall, our results indicate that cryptic RNAs may represent an intriguing new therapeutic and diagnostic target in AD, and that methods aimed at detecting and measuring these species in patient biofluids could be used as a reliable tool to assess TDP-43 pathology in AD. Our work also raises the possibility that TDP-43 dysfunction and related changes in cryptic splicing could represent a common molecular mechanism shared between AD-TDP and FTLD-TDP.

Treatments for neurodegenerative disease, including Frontotemporal dementia (FTD) and Amyotrophic lateral sclerosis (ALS), remain rather limited, underscoring the need for greater mechanistic insight and disease-relevant models. Our ability to develop novel disease models of genetic risk factors, disease modifiers, and other FTD/ALS-relevant targets is impeded by the significant amount of time and capital required to develop conventional knockout and transgenic mice. To overcome these limitations, we have generated a novel CRISPRi interference (CRISPRi) knockin mouse. CRISPRi uses a catalytically dead form of Cas9, fused to a transcriptional repressor to knockdown protein expression, following the introduction of single guide RNA against the gene of interest. To validate the utility of this model we have selected the TAR DNA binding protein (TDP-43) splicing target, stathmin-2 (STMN2). STMN2 RNA is downregulated in FTD/ALS due to loss of TDP-43 activity and STMN2 loss is suggested to play a role in ALS pathogenesis. The involvement of STMN2 loss of function in FTD has yet to be determined. We find that STMN2 protein levels in familial FTD cases are significantly reduced compared to controls, supporting that STMN2 depletion may be involved in the pathogenesis of FTD. Here, we provide proof-of-concept that we can simultaneously knock down Stmn2 and express the expanded repeat in the Chromosome 9 open reading frame 72 (C9ORF72) gene, successfully replicating features of C9-associated pathology. Of interest, depletion of Stmn2 had no effect on expression or deposition of dipeptide repeat proteins (DPRs), but significantly decreased the number of phosphorylated Tdp-43 (pTdp-43) inclusions. We submit that our novel CRISPRi mouse provides a versatile and rapid method to silence gene expression in vivo and propose this model will be useful to understand gene function in isolation or in the context of other neurodegenerative disease models.

Summary: C9orf72 repeat expansions are the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Poly(GR) proteins are toxic to neurons by forming cytoplasmic inclusions that sequester RNA-binding proteins including stress granule (SG) proteins. However, little is known of the factors governing poly(GR) inclusion formation. Here, we show that poly(GR) infiltrates a finely tuned network of protein-RNA interactions underpinning SG formation. It interacts with G3BP1, the key driver of SG assembly and a protein we found is critical for poly(GR) inclusion formation. Moreover, we discovered that N6-methyladenosine (m6A)-modified mRNAs and m6A-binding YTHDF proteins not only co-localize with poly(GR) inclusions in brains of c9FTD/ALS mouse models and patients with c9FTD, they promote poly(GR) inclusion formation via the incorporation of RNA into the inclusions. Our findings thus suggest that interrupting interactions between poly(GR) and G3BP1 or YTHDF1 proteins or decreasing poly(GR) altogether represent promising therapeutic strategies to combat c9FTD/ALS pathogenesis.

Abstract Behavioral characteristics may also take part in the etiology of dental caries. Sedentary behavior, especially watching television, is associated with increased intake of foods high in fat or free sugar, which could influence the occurrence of dental caries. The aim of this study was to assess the mediating effect of eating pattern on the relationship between television exposure time and the presence of dental caries in children. A cross-sectional study was conducted with a representative sample of 580 parent-child dyads with children aged 7 to 8 years in 20 public schools in Pelotas, Brazil. Parents or legal guardians were interviewed and provided information on demographic/socioeconomic data, children’s daily television exposure time, and answered the Biological Rhythms Interview for Assessment in Neuropsychiatry for Kids (BRIAN-K-eating pattern domain). Caries was evaluated through clinical examination. The mediating effect of eating pattern on the relationship between television exposure and presence of dental caries was estimated using the parametric g-formula. Prevalence of dental caries was 63%, and 22% of children watched TV 4 or more hours per day. Television exposure had no direct effect on the dental caries experience [odds ratio (OR): 1.05 (95% confidence interval (95%CI): 0.92–1.19)]. Nevertheless, difficulty maintaining regular eating pattern mediated the natural indirect effect of television exposure time (≥ 4 hours/day) on dental caries experience [OR: 1.07 (95%CI): 1.01–1.14)]. The results of this study confirm the indirect pathway between television viewing and dental caries and the role of disordered eating patterns in this association.

The study aimed to assess whether sleep quality is associated with global functioning and cognition in subjects that recently converted to bipolar disorder (BD), subjects without mood episodes at follow-up and subjects with a recurrent depressive episode in a sample of depressed adults. Significantly worse scores were found in global functioning, sleep quality, and cognitive complaints in the BD and recurrent depression groups when compared to the group without mood episode at follow-up. The findings also showed a significant association between functioning and cognitive complaints with sleep quality in all groups. The cross-sectional design prevents the inference of the causal relationship between sleep quality and measures of cognition and functioning. The authors reinforce the need to follow-up in order to improve functional and cognitive outcomes, notably with patients with BD, who may suffer in addition to damage caused by sleep alterations, also with neuroprogression in the long term.

Abstract Introduction The Brazilian psychiatric reform has revolutionized the way that mental health care is provided all over the country, introducing the Psychosocial Care Centers (CAPS) and encouraging care at liberty. The CAPS have been assigned many objectives, such as prevention of hospitalizations and intervention in crises or suicide. This paper aims to describe the correlation between the implementation of CAPS and the rates of psychiatric hospitalizations and suicides from 2008 to 2018. Methods This study has an ecological time series design and included residents of the city of Porto Alegre, RS, Brazil, who were hospitalized through the Sistema Único de Saúde (SUS). The data were obtained from official databases (DATASUS, CNES, and IBGE) and indicators were calculated (CAPS coverage, hospitalization rate, and suicide rate). Associations between the indicators were tested using Pearson’s correlation coefficients. Results We found a negative correlation between provision of CAPS and psychiatric hospitalizations (r = -0.607 p = 0.048). Conclusion These results support the hypothesis that there is a negative correlation between implementation of the CAPS and psychiatric hospitalizations. This reinforces the importance of implementing policies related to improving psychiatric reform.

A major function of TAR DNA-binding protein-43 (TDP-43) is to repress the inclusion of cryptic exons during RNA splicing. One of these cryptic exons is in UNC13A, a genetic risk factor for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The accumulation of cryptic UNC13A in disease is heightened by the presence of a risk haplotype located within the cryptic exon itself. Here, we revealed that TDP-43 extreme N-terminus is important to repress UNC13A cryptic exon inclusion. Further, we found hnRNP L, hnRNP A1, and hnRNP A2B1 bind UNC13A RNA and repress cryptic exon inclusion, independently of TDP-43. Finally, higher levels of hnRNP L protein associate with lower burden of UNC13A cryptic RNA in ALS/FTD brains. Our findings suggest that while TDP-43 is the main repressor of UNC13A cryptic exon inclusion, other hnRNPs contribute to its regulation and may potentially function as disease modifiers.

Objective: To investigate the association between emotional and behavioural problems and dental fear/anxiety (DFA) in children aged four to 12 years treated at a clinic in southern Brazil. Material and Methods: In this cross-sectional study where mother-child dyads were interviewed, emotional and behavioural problems were investigated using the Strengths and Difficulties Questionnaire (SDQ) (considering five subscales). Children's DFA was evaluated through the Venham Picture Test. For each SDQ subscale, Poisson regression model was explored. Prevalence ratios (PR) were estimated, considering a significant level of p ≤ 0.05. Results: Overall, 128 children participated in this study. Most children were female (54.7%) and aged between 7 and 9 years (39.8%). The prevalence of emotional problems was 47.7% and behavioural problems were 46.1%. The prevalence of DFA was 18.8%. Children with emotional problems had a 2.3 higher prevalence of DFA (95%CI 1.06-5.04). In general, behavioural problems were not associated with DFA (95%CI 0.84-3.34) only when conduct problems were considered (2.20; 95%CI 1.02-4.70). Conclusion: Children aged between 4 and 12 years who present emotional and conduct problems tend to show higher DFA.

Abstract Objective: to assess the association between caregivers’ mental disorders and schoolchildren’s obesogenic eating behavior. Methods: cross-sectional study used a public school-based sample of children and their primary caregivers. Caregivers had to report depressive episodes or generalized anxiety disorder (GAD) during the Mini-International Neuropsychiatric Interview (MINI). Children’s obesogenic eating behavior were assessed using food responsiveness (FR) and emotional overeating (EOE) subscales of the Children’s Eating Behaviour Questionnaire (CEBQ). Bivariate analysis was conducted using the t-test, ANOVA, Pearson correlation, and adjusted linear regression model was used (including variables caregivers: sex, age, economic indicator, and schooling; schoolchildren: sex and nutritional status). Results: study includes 596 children-caregiver dyads (309 boys and 287 girls). Among caregivers, 24.7% had experienced current depressive episodes, 38.7% had past depressive episodes, and 17.2% had GAD. We observed, after adjusted analysis, that having a caregiver in a current depressive episode, increases schoolchildren’s obesogenic behavior of, for FR at 0.235 points (β=0.235; CI95%=0.022-0.449;) and EOE at 0.337 points (β=0.337; CI95%=0.162-0.512). Conclusion: caregivers’ current depressive episodes were associated with higher averages of obesogenic eating behavior (caregiver-reported), both in consuming palatable food without feeling hungry (FR) and in increasing food intake in response to negative emotions (EOE).

Abstract Introduction Bipolar disorder (BD) has a high heritability rate. Current studies have been dedicated to identifying prodromes of BD in the offspring of parents with BD (BO) and the sleep patterns of these individuals have been considered important factors. Objective To describe changes in sleep parameters among offspring of parents with BD when compared to offspring of controls and to identify if changes in parameters and quality of sleep predict the onset of BD among these individuals. Methods PubMed, PsycINFO, and Embase were systematically searched with no year or language restrictions, up to August 18, 2020. We searched for a combination of the following search items (“sleep*”) AND (“bipolar disorder*” OR “mania” OR “hypomania” OR “bipolar depression”) AND (“ultra-high risk” OR “high risk” OR “offspring” OR “first degree relatives”). Results A total of 10 studies were included in the systematic review and 4 studies were included in the meta-analysis. Our meta-analysis showed that the BO had greater daytime sleepiness as compared to the offspring of control parents. The systematic review indicated that shorter sleep duration, sleep disorders, and other related features can differentiate the two groups. Finally, some sleep patterns such as decreased sleep, difficulty falling asleep, and overall sleep problems might be predictors for the development of BD. Conclusion Results from the meta-analysis indicated that BO had greater daytime sleepiness. Qualitative results showed that the offspring of parents with BD have an increased likelihood of experiencing an adverse sleep pattern.

Background: The identification of predictors of recurrence and persistence of depressive episodes in major depressive disorder (MDD) can be important to inform clinicians and collaborate to clinical decisions. Objective: The aim of the present study is to predict recurrent or persistent depressive episodes, in addition to predicting severe recurrent or persistent depressive episodes using a machine learning method. Methods: This is a prospective cohort study with three years of follow-up. Individuals diagnosed with MDD in the first phase of the study (2012–2015) were evaluated in the second phase (2012–2015). The sociodemographic, clinical, comorbid disorders and substance use variables were used as predictors in all predictive models. Initially, the first model predicted recurrence/persistence, including subjects of any severity of depression level. The second model predicted recurrence/persistence depression as the first model, although it was trained with severely depressed subjects and those without indicative for depression. The third model predicted severe depression among depressed patients. Results: Area under the curve (AUC) values ranged from 0.65 to 0.81, and accuracies ranged from 62% to 71%. Psychiatric comorbidities, substance abuse/dependence, and family medical history were important features in all three models. Limitation: The time between baseline and the second phase of the study was approximately three years, making it difficult to detect depressive symptoms during this time frame. Also, age at depression onset and number of episodes were not included in the model due to the large number of missing data. Conclusions: In conclusion, this study adds new information that can help health professionals both in their clinical practice and in public services.

Studies suggest that personality disorders can predict mood disorders. The present study aims to assess whether personality traits in individuals with major depressive disorder (MDD) can predict the conversion to bipolar disorder (BD). This was a prospective cohort study conducted in two waves. In the first wave, 585 subjects were diagnosed with MDD; in the second wave, all of them were reevaluated in a three-year follow-up. Personality traits were evaluated, in the first phase, using the Millon Clinical Multiaxial Inventory (MCMI). MDD and BD diagnosis was performed by trained psychologists using a clinical structured interview based on diagnostics criteria of DSM IV, the Mini International Neuropsychiatric Interview, Plus version (MINI-PLUS). During the second wave, 468 individuals were reevaluated. Diagnostic conversion rate from MDD to BD was 12.4%. Higher mean scores in Antissocial, Borderline personality traits and in the sum of all Cluster B disorders were found among individuals who had converted to BD. In addition, individuals who converted to BD had lowest scores in obsessive-compulsive personality traits. Our findings suggest that Cluster B personality disorders can be considered as predictors of diagnostics conversion from MDD to BD. Also, it seems that obsessive-compulsive traits were lower among those individuals who have converted to BD.

In this report, we aim to assess the interaction of bipolar disorder and major depressive disorder with the evolution of social roles, economic classification, and substance misuse in emerging adults. This is a longitudinal population-based study (n = 231 at baseline), in which participants were reassessed at a mean of 5 years after baseline. A structured clinical interview was used to diagnose the participants with bipolar disorder and major depression; a control group without mood disorders was included. Men with mood disorders were less likely to be married in the beginning of the study and less likely to work in the follow-up. Women with major depression were less likely to study and more likely to be in a lower economic class at the beginning of the study. In comparison, women with bipolar disorder were less likely to live with their parents and more likely to live with their children in the first wave of the study. Substance misuse was more likely in people with mood disorders, especially in men, and women with bipolar disorder had the highest likelihood in the follow-up. Albeit longitudinal analyses were limited by a possibly insufficient sample size and mediating mechanisms for change, such as stigma, were not explored, the study suggests sex-related specificities regarding the change in social roles and substance use in people with mood disorders. Emerging adults, especially those with mood disorders, are in a period of change and instability and at a greater risk for substance use and abuse.

Objective: To evaluate the impact of defense mechanisms at baseline on depressive symptoms after brief psychotherapies and after 6-months of follow-up among depressed patients with and without cluster B personality disorders (PDs). Methods: This quasi-experimental study nested within a randomized clinical trial included a clinical sample of adults (18-60 years) diagnosed with major depressive disorder using the Mini-International Neuropsychiatric Interview. The Millon Clinical Multiaxial Inventory-III was applied to assess PD, the Defense Style Questionnaire 40 was used to analyze defense mechanisms, and the Beck Depression Inventory was used to measure the severity of depressive symptoms. Adjusted analysis was performed by linear regression. Results: The final sample consisted of 177 patients diagnosed with major depressive disorder, of whom 39.5% had cluster B PDs. Immature defenses at baseline significantly predicted the persistence of depressive symptoms at post-intervention and at 6-months of follow-up only in patients with PDs. Conclusion: In depressed patients with cluster B PDs, immature defenses predicted a poor response to brief therapies. The assessment of immature defenses at baseline can help identify patients at greater risk of poor therapeutic results and enable more appropriate treatment choices.

ABSTRACT. Schizophrenia and common mental disorders are noteworthy social and economic concern worldwide. Epidemiologic studies on the impact of specific mental disorders in emerging countries are scarce. Objectives: We aimed to characterize the demographic, social, and economic burden of schizophrenia and common mental disorders patients in the health system in Brazil. Methods: Data on these conditions in Brazil between 2008 and 2019 were collected through the website of the Departamento de Informática do Sistema Único de Saúde (Information Technology Department of the Unified Health System - DATASUS) maintained by the Brazilian Ministry of Health. Mean annual hospital admissions were 154,009.67, and cumulative incidence of 77.44 admissions per 100,000 inhabitants. Results: Average annual hospital expenses were US$ 67,216,056.04, with an average admission cost of US$ 432.58. The most affected age groups were older adults albeit younger individuals showed a trend towards increase of occurrences in recent years. There were a higher number of admissions in men compared to women. Conclusions: We consider the results obtained important to assist in evaluating and guiding public policies regarding the prevention and treatment in health systems.

Abstract Introduction Childhood trauma has been suggested to be involved in susceptibility to bipolar disorder (BP). However, it remains unclear whether the occurrence of childhood trauma is differently distributed in subthreshold bipolar disorder (SBP). Objective To assess childhood trauma in young adults with SBP, as compared to young adults with BP and population controls (PC). Method This was a cross-sectional, population-based study. The Mini International Neuropsychiatric Interview (MINI) was used to define the groups with BP (subjects with a lifetime or current manic episode or lifetime or current hypomania with a history of a depressive episode), SBP (subjects with a history of hypomanic episode without lifetime or current depressive episode), and subjects without mood disorders (PC). Childhood trauma was assessed using de Childhood Trauma Questionnaire (CTQ). We investigated differences regarding childhood trauma across the three groups (BP, SBP and PC). Result Except for sexual abuse, all subtypes of childhood trauma remained associated with the BP group as compared to PC. Additionally, when we compared SBP and BP, significant differences were found only for emotional abuse. No significant differences were found in relation to childhood trauma between the SBP and PC groups after adjusting for confounding factors. Conclusion These findings suggest that investigating childhood trauma, with a particular focus on emotional abuse, could be considered a preventive measure and potentially improve the prognosis.

This study aimed to assess the association between maternal diagnosis of Bipolar Disorder (BD) and the biological rhythms of their offspring, and describe the synchronization of biological rhythms among mothers and their offspring. This study included 59 mothers with a diagnosis of BD and 59 mothers who have not been diagnosed with BD at the first stage of the study, as well as their offspring aged 9–11 years. The mothers' biological rhythms were assessed using the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN) and the offspring's biological rhythms were evaluated using the same assessment tool in the kids' version. The offspring of mothers with BD showed a significantly higher disruption of overall biological rhythm when compared to the offspring of mothers without BD. The mothers with BD and their offspring showed a higher disruption of biological rhythms in all the BRIAN/BRIAN-k domains when compared to the mothers without BD and their offspring. Additionally, we identified a positive correlation between the disruption of biological rhythms in mothers and the disruption of biological rhythms in their offspring. It is likely that they synced their own rhythm with the disrupted rhythm of their mothers.

Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited cerebellar ataxia caused by the expansion of a polyglutamine (polyQ) repeat in the gene encoding ATXN3. The polyQ expansion induces protein inclusion formation in the neurons of patients and results in neuronal degeneration in the cerebellum and other brain regions. We used adeno-associated virus (AAV) technology to develop a new mouse model of SCA3 that recapitulates several features of the human disease, including locomotor defects, cerebellar-specific neuronal loss, polyQ-expanded ATXN3 inclusions, and TDP-43 pathology. We also found that neurofilament light is elevated in the cerebrospinal fluid (CSF) of the SCA3 animals, and the expanded polyQ-ATXN3 protein can be detected in the plasma. Interestingly, the levels of polyQ-ATXN3 in plasma correlated with measures of cerebellar degeneration and locomotor deficits in 6-month-old SCA3 mice, supporting the hypothesis that this factor could act as a biomarker for SCA3.

The aberrant translation of a repeat expansion in chromosome 9 open reading frame 72 (C9orf72), the most common cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), results in the accumulation of toxic dipeptide repeat (DPR) proteins in the central nervous system We have found that, among the sense DPR proteins, HDAC6 specifically interacts with the poly (GA) and co-localizes with inclusions in both patient tissue and a mouse model of this disease (c9FTD/ALS). Overexpression of HDAC6 increased poly (GA) levels in cultured cells independently of HDAC6 deacetylase activity, suggesting that HDAC6 can modulate poly (GA) pathology through a mechanism that depends upon their physical interaction. Moreover, decreasing HDAC6 expression by stereotaxic injection of antisense oligonucleotides significantly reduced the number of poly (GA) inclusions in c9FTD/ALS mice. These findings suggest that pharmacologically reducing HDAC6 levels could be of therapeutic value in c9FTD/ALS.

Abstract Background The human genome contains “dark” gene regions that cannot be adequately assembled or aligned using standard short-read sequencing technologies, preventing researchers from identifying mutations within these gene regions that may be relevant to human disease. Here, we identify regions with few mappable reads that we call dark by depth, and others that have ambiguous alignment, called camouflaged. We assess how well long-read or linked-read technologies resolve these regions. Results Based on standard whole-genome Illumina sequencing data, we identify 36,794 dark regions in 6054 gene bodies from pathways important to human health, development, and reproduction. Of these gene bodies, 8.7% are completely dark and 35.2% are ≥ 5% dark. We identify dark regions that are present in protein-coding exons across 748 genes. Linked-read or long-read sequencing technologies from 10x Genomics, PacBio, and Oxford Nanopore Technologies reduce dark protein-coding regions to approximately 50.5%, 35.6%, and 9.6%, respectively. We present an algorithm to resolve most camouflaged regions and apply it to the Alzheimer’s Disease Sequencing Project. We rescue a rare ten-nucleotide frameshift deletion in CR1, a top Alzheimer’s disease gene, found in disease cases but not in controls. Conclusions While we could not formally assess the association of the CR1 frameshift mutation with Alzheimer’s disease due to insufficient sample-size, we believe it merits investigating in a larger cohort. There remain thousands of potentially important genomic regions overlooked by short-read sequencing that are largely resolved by long-read technologies.

Abstract Tauopathies are neurodegenerative disorders characterized by aggregation of microtubule associated tau protein in neurons and glia. They are clinically and pathologically heterogeneous depending on the isoform of tau protein that accumulates (three or four 31-to-32-amino-acid repeats [3R or 4R] in the microtubule binding domain), as well as the cellular and neuroanatomical distribution of tau pathology. Growing evidence suggests that distinct tau conformers may contribute to the characteristic features of various tauopathies. Globular glial tauopathy (GGT) is a rare 4R tauopathy with globular cytoplasmic inclusions within neurons and glial cells. Given the unique cellular distribution and morphology of tau pathology in GGT, we sought to determine if tau species in GGT had distinctive biological properties. To address this question, we performed seeding analyses with postmortem brain tissues using a commercial tau biosensor cell line. We found that brain lysates from GGT cases had significantly higher seeding competency than other tauopathies, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer’s disease (AD). The robust seeding activity of GGT brain lysates was independent of phosphorylated tau burden and diminished upon removal of tau from samples, suggesting that seeding properties were indeed mediated by tau in the lysates. In addition, cellular inclusions in the tau biosensor cell line induced by GGT had a distinct, globular morphology that was markedly different from inclusions induced by other tauopathies, further highlighting the unique nature of tau species in GGT. Characterization of different tau species in GGT showed that detergent-insoluble, fibril-like tau contained the highest seeding activity, as reflected in its ability to increase tau aggregation in primary glial cultures. Taken together, our data suggest that unique seeding properties differentiate GGT-tau from other tauopathies, which provides new insight into pathogenic heterogeneity of primary neurodegenerative tauopathies.

Abstract Background A G4C2 hexanucleotide repeat expansion in the noncoding region of C9orf72 is the major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). Putative disease mechanisms underlying c9FTD/ALS include toxicity from sense G4C2 and antisense G2C4 repeat-containing RNA, and from dipeptide repeat (DPR) proteins unconventionally translated from these RNA products. Methods Intracerebroventricular injections with adeno-associated virus (AAV) encoding 2 or 149 G4C2 repeats were performed on postnatal day 0, followed by assessment of behavioral and neuropathological phenotypes. Results Relative to control mice, gliosis and neurodegeneration accompanied by cognitive and motor deficits were observed in (G4C2)149 mice by 6 months of age. Recapitulating key pathological hallmarks, we also demonstrate that sense and antisense RNA foci, inclusions of poly(GA), poly(GP), poly(GR), poly(PR), and poly(PA) DPR proteins, and inclusions of endogenous phosphorylated TDP-43 (pTDP-43) developed in (G4C2)149 mice but not control (G4C2)2 mice. Notably, proteins that play a role in the regulation of stress granules – RNA-protein assemblies that form in response to translational inhibition and that have been implicated in c9FTD/ALS pathogenesis – were mislocalized in (G4C2)149 mice as early as 3 months of age. Specifically, we observed the abnormal deposition of stress granule components within inclusions immunopositive for poly(GR) and pTDP-43, as well as evidence of nucleocytoplasmic transport defects. Conclusions Our in vivo model of c9FTD/ALS is the first to robustly recapitulate hallmark features derived from both sense and antisense C9orf72 repeat-associated transcripts complete with neurodegeneration and behavioral impairments. More importantly, the early appearance of persistent pathological stress granules prior to significant pTDP-43 deposition implicates an aberrant stress granule response as a key disease mechanism driving TDP-43 proteinopathy in c9FTD/ALS.

Abstract Pathogenic mutations in the tau gene (microtubule associated protein tau, MAPT) are linked to the onset of tauopathy, but the A152T variant is unique in acting as a risk factor for a range of disorders including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB). In order to provide insight into the mechanism by which A152T modulates disease risk, we developed a novel mouse model utilizing somatic brain transgenesis with adeno-associated virus (AAV) to drive tau expression in vivo, and validated the model by confirming the distinct biochemical features of A152T tau in postmortem brain tissue from human carriers. Specifically, TauA152T-AAV mice exhibited increased tau phosphorylation that unlike animals expressing the pathogenic P301L mutation remained localized to the soluble fraction. To investigate the possibility that the A152T variant might alter the phosphorylation state of tau on T152 or the neighboring T153 residue, we generated a novel antibody that revealed significant accumulation of soluble tau species that were hyperphosphorylated on T153 (pT153) in TauA152T-AAV mice, which were absent the soluble fraction of TauP301L-AAV mice. Providing new insight into the role of A152T in modifying risk of tauopathy, as well as validating the TauA152T-AAV model, we demonstrate that the presence of soluble pT153-positive tau species in human postmortem brain tissue differentiates A152T carriers from noncarriers, independent of disease classification. These results implicate both phosphorylation of T153 and an altered solubility profile in the mechanism by which A152T modulates disease risk.

Generalized Anxiety Disorder (GAD) presents a high prevalence in the population, leading to distress and disability. Immune system alterations have been associated with anxiety-related behaviors in rodents and GAD patients. CD300f immune receptors are highly expressed in microglia and participate not only in the modulation of immune responses but also in pruning and reshaping synapses. It was recently demonstrated that CD300f might be influential in the pathogenesis of depression in a sex-dependent manner. Here, we evaluated the role of CD300f immune receptor in anxiety, using CD300f knockout mice (CD300f−/−) and patients with GAD. We observed that male CD300f−/− mice had numerous behavioral changes associated with a low-anxiety phenotype, including increased open field central locomotion and rearing behaviors, more exploration in the open arms of the elevated plus-maze test, and decreased latency to eat in the novelty suppressed feeding test. In a cross-sectional population-based study, including 1111 subjects, we evaluated a common single-nucleotide polymorphism rs2034310 (C/T) in the cytoplasmatic tail of CD300f gene in individuals with GAD. Notably, we observed that the T allele of the rs2034310 polymorphism conferred protection against GAD in men, even after adjusting for confounding variables. Overall, our data demonstrate that CD300f immune receptors are involved in the modulation of pathological anxiety behaviors in a sex-dependent manner. The biological basis of these sex differences is still poorly understood, but it may provide significant clues regarding the neuropathophysiological mechanisms of GAD and can pave the way for future specific pharmacological interventions.

Background: It has been reported that patients with bipolar disorder (BD) present changes in peripheral levels of the inflammatory cytokine CCL11, particularly at latestages. The aim of this study is to evaluate CCL11 levels in a population-based sample of drug-naive young adults. Methods: This is a cross-sectional study nested to a large population-based study. 29 drug-naive young adults with BD and 29 controls selected from this cohort were matched for sex, age, and years of education. The diagnosis of psychiatric disorders was performed using the Mini International Neuropsychiatric Interview PLUS. Serum levels of CCL11 were measured using sandwich-ELISA. Independent samples T-test was used to assess differences between groups regarding CCL11 levels. Multivariate linear regression analyses were used to evaluate the effect of independent factors on CCL11 levels. Results: There were no demographic differences between individuals with BD and controls. No significant differences were found regarding CCL11 levels between groups. The final multivariate model showed that the variables that remained independently associated with higher CCL11 levels were male sex (B:41.41 [CI95%: 15.66 - 67.15], p = 0.002) and tobacco use (B:22.71 [CI95%: 1.28 - 44.15], p = 0.038). Conclusions: The present study suggests that there is a possible influence of sex and tobacco use on CCL11 levels, as male sex and smoking status were associated with higher CCL11 levels in our sample. It also suggests that peripheral levels of CCL11 may not be involved in the pathophysiology of BD at early stages of the disorder.

Summary: A G4C2 hexanucleotide repeat expansion in an intron of C9orf72 is the most common cause of frontal temporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). A remarkably similar intronic TG3C2 repeat expansion is associated with spinocerebellar ataxia 36 (SCA36). Both expansions are widely expressed, form RNA foci, and can undergo repeat-associated non-ATG (RAN) translation to form similar dipeptide repeat proteins (DPRs). Yet, these diseases result in the degeneration of distinct subsets of neurons. We show that the expression of these repeat expansions in mice is sufficient to recapitulate the unique features of each disease, including this selective neuronal vulnerability. Furthermore, only the G4C2 repeat induces the formation of aberrant stress granules and pTDP-43 inclusions. Overall, our results demonstrate that the pathomechanisms responsible for each disease are intrinsic to the individual repeat sequence, highlighting the importance of sequence-specific RNA-mediated toxicity in each disorder.

Abstract Background Many neurodegenerative diseases are caused by nucleotide repeat expansions, but most expansions, like the C9orf72 ‘GGGGCC’ (G4C2) repeat that causes approximately 5–7% of all amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases, are too long to sequence using short-read sequencing technologies. It is unclear whether long-read sequencing technologies can traverse these long, challenging repeat expansions. Here, we demonstrate that two long-read sequencing technologies, Pacific Biosciences’ (PacBio) and Oxford Nanopore Technologies’ (ONT), can sequence through disease-causing repeats cloned into plasmids, including the FTD/ALS-causing G4C2 repeat expansion. We also report the first long-read sequencing data characterizing the C9orf72 G4C2 repeat expansion at the nucleotide level in two symptomatic expansion carriers using PacBio whole-genome sequencing and a no-amplification (No-Amp) targeted approach based on CRISPR/Cas9. Results Both the PacBio and ONT platforms successfully sequenced through the repeat expansions in plasmids. Throughput on the MinION was a challenge for whole-genome sequencing; we were unable to attain reads covering the human C9orf72 repeat expansion using 15 flow cells. We obtained 8× coverage across the C9orf72 locus using the PacBio Sequel, accurately reporting the unexpanded allele at eight repeats, and reading through the entire expansion with 1324 repeats (7941 nucleotides). Using the No-Amp targeted approach, we attained > 800× coverage and were able to identify the unexpanded allele, closely estimate expansion size, and assess nucleotide content in a single experiment. We estimate the individual’s repeat region was > 99% G4C2 content, though we cannot rule out small interruptions. Conclusions Our findings indicate that long-read sequencing is well suited to characterizing known repeat expansions, and for discovering new disease-causing, disease-modifying, or risk-modifying repeat expansions that have gone undetected with conventional short-read sequencing. The PacBio No-Amp targeted approach may have future potential in clinical and genetic counseling environments. Larger and deeper long-read sequencing studies in C9orf72 expansion carriers will be important to determine heterogeneity and whether the repeats are interrupted by non-G4C2 content, potentially mitigating or modifying disease course or age of onset, as interruptions are known to do in other repeat-expansion disorders. These results have broad implications across all diseases where the genetic etiology remains unclear.

Abstract Introduction Posttraumatic stress disorder (PTSD) develops after exposure to a potentially traumatic event. Its clinical condition may lead to the development of risk behaviors, and its early detection is a relevant aspect to be considered. The aim of this study was to assess the association between childhood trauma and suicide risk in individuals with PTSD. Method This was a cross-sectional study conducted with individuals aged 18 to 60 years who were evaluated at a mental health research outpatient clinic. PTSD diagnosis and suicide risk identification were performed using specific modules of the Mini International Neuropsychiatric Interview (MINI-Plus). The Childhood Trauma Questionnaire (CTQ) was used to evaluate traumatic events in childhood. Results Of the 917 individuals evaluated, 55 were diagnosed with PTSD. The suicide risk prevalence in individuals with PTSD was 63.6%. Emotional neglect and emotional abuse scores tended to be higher in the suicide risk group (p

Repeat-associated non-AUG (RAN) translation contributes to the pathogenic mechanism of several microsatellite expansion diseases. Here the authors delineate the different steps involved in recruiting the ribosome to initiate G4C2 RAN translation to produce poly-Glycine Alanine, poly-Glycine Proline, and poly-Glycine Arginine repeats.

Summary: Dendritic mislocalization of microtubule associated protein tau is a hallmark of tauopathies, but the role of dendritic tau is unknown. We now report that tau interacts with the RNA-binding protein (RBP) TIA1 in brain tissue, and we present the brain-protein interactome network for TIA1. Analysis of the TIA1 interactome in brain tissue from wild-type (WT) and tau knockout mice demonstrates that tau is required for normal interactions of TIA1 with proteins linked to RNA metabolism, including ribosomal proteins and RBPs. Expression studies show that tau regulates the distribution of TIA1, and tau accelerates stress granule (SG) formation. Conversely, TIA1 knockdown or knockout inhibits tau misfolding and associated toxicity in cultured hippocampal neurons, while overexpressing TIA1 induces tau misfolding and stimulates neurodegeneration. Pharmacological interventions that prevent SG formation also inhibit tau pathophysiology. These studies suggest that the pathophysiology of tauopathy requires an intimate interaction with RNA-binding proteins. : Vanderweyde et al. show that the interaction of microtubule associated protein tau with the RNA binding protein (RBP) TIA1 regulates stress granule (SG) formation as well as misfolding and aggregation of tau. TIA1 knockdown prevents tau misfolding and tau-mediated toxicity, which points to RBPs as potential targets for therapy of tauopathies.

Objective: To identify the association of metabolic syndrome (MetS) and psychiatric disorders in young adults in southern Brazil. Methods: This population based cross-sectional study involved a total of 1,023 young adults between the ages of 21 and 32 years. Current episodes of psychiatric disorders were assessed using the Mini International Neuropsychiatric Interview – Plus version. MetS was evaluated using the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III). Results: Of the 1,023 participants, 24.3% were identified with MetS, 13.5% were diagnosed with anxiety disorders, 7.5% with current depression, 3.9% with bipolar disorders and 10.1% were at risk of suicide. MetS was associated with ethnicity (p = 0.022), excess weight (p < 0.001), current anxiety disorders (p < 0.001), current mood disorders (bipolar disorder in mood episode and current depression) (p < 0.001), and suicide risk (p < 0.001). Conclusions: MetS was associated with psychiatric disorders. Awareness of factors associated with MetS can help identify high-risk individuals and stimulate disease prevention and control programs, as well as lifestyle changes.

Objective: To correlate neurotrophic factors – brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and beta-nerve growth factor (beta-NGF) – and severity of depressive symptoms in patients diagnosed with major depressive disorder (MDD) undergoing cognitive-behavioral therapy (CBT). Methods: In this quasi-experimental study, participants were selected by convenience and received 16 sessions of CBT. The outcomes of interest were severity of depressive symptoms and changes in neurotrophic factor levels after CBT. The differences between variables before and after treatment (deltas) were analyzed. Results: Patients had significant changes in symptom severity after treatment. No significant associations were found between Beck Depression Inventory II (BDI-II) scores and any independent variable. No correlations were observed between BDNF or GDNF levels and BDI scores before or after treatment, although there was a trend toward significant differences in beta-NGF levels. Conclusion: BDNF, beta-NGF, and GDNF were not influenced by the effects of CBT on depressive symptoms.

Objective: To evaluate the association between abuse of and dependence on different psychoactive substances and the presence of anxiety disorders in a sample of young adults from a city in southern Brazil. Methods: Between 2007 and 2009, we carried out a cross-sectional, population-based study of individuals aged 18-24 years who lived in Pelotas, a city in southern Brazil. We evaluated anxiety disorders using the Mini International Neuropsychiatric Interview 5.0 (MINI), and use of psychoactive substances with the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST 2.0/0MS). We used Fisher’s exact test for univariate analysis, and Poisson regression models with robust variance for multivariable analysis. Results: The sample consisted of 1,560 young adults. The overall prevalence of abuse/dependence was 26.9% for alcohol, 24.9% for tobacco, and 7.3% for illicit substances. Individuals with agoraphobia had a 32% higher prevalence of tobacco abuse/dependence (prevalence ratio [PR] = 1.32 [95%CI 1.01-1.74]). Individuals with posttraumatic stress disorder (PTSD) or generalized anxiety disorder (GAD) had a 2.41-fold (95%CI 1.22-4.77) and 1.76-fold (95%CI 1.00-3.11) higher prevalence of illicit substance abuse/dependence, respectively. Conclusion: In this population-based sample, we found associations between GAD, PTSD, and increased prevalence of illicit substance abuse/dependence. In addition, individuals with agoraphobia seem to have increased tobacco abuse/dependence.

Objective: To evaluate the serum leptin levels in cannabis smokers. Methods: This was a cross-sectional population-based study of participants between the ages of 18 and 35 years. The data were collected through a self-administered questionnaire covering sociodemographic data and the use of psychoactive substances. Leptin levels were measured using a commercial ELISA kit. Results: Of the 911 participants, 6.7% were identified as cannabis smokers and had significantly lower leptin levels (p = 0.008). When stratified by gender, there was a significant decrease in leptin levels among male smokers (p = 0.039). Conclusion: Cannabis smoking was linked to leptin levels in men, suggesting that the response to biological signals may be different between men and women.

Objective:To assess the relationship between crack cocaine use and dimensions of quality of life and social functioning in young adults.Methods:This was a cross-sectional, population-based study involving 1,560 participants in Pelotas, Brazil. Crack cocaine use and abuse were investigated using the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) inventory. Outcomes of interest were quality of life, religiosity, and social functioning in terms of education, occupational status, family structure, and medical treatment history.Results:Lifetime crack cocaine use was associated with poor quality of life, worse functioning, impaired academic performance, and lower religious involvement. A greater maternal presence and higher paternal absence were more also more pronounced in crack cocaine users, who were also more likely to seek psychological and psychiatric treatment than the general population.Conclusion:Quality of life was severely impacted by crack cocaine use, especially in terms of general and physical health. Social functioning also differed between the general population and crack users, who had lower educational attainment and religious involvement. Maternal presence, paternal absence, and mental health-seeking behaviors were also more frequent among crack cocaine users, although these individuals reported lower rates of treatment satisfaction. Crack cocaine users also had significant social impairment, so that interventions involving family management and a greater focus on general health, quality of life, and functioning may make crucial contributions to the recovery of this group.

Objectives To verify the prevalence of current posttraumatic stress disorder (PTSD) in young adults, the occurrence of comorbidities and its association with quality of life. Methods This is a cross-sectional population-based study. The targeted population consisted on individuals aged 18 to 24 years old, who lived in the urban area of Pelotas-RS, Brazil. Cluster sampling was applied. PTSD and its comorbidities were assessed using the Mini International Neuropsychiatric Interview (MINI 5.0), whereas quality of life was evaluated with the eight domains of the Medical Outcomes Survey Short-form General Health Survey (SF-36). Results A total of 1,762 young adults were selected. The prevalence of PTSD was 2.1% and current episode of depression was the most prevalent comorbidity (71.9%). The individuals with PTSD had lower scores in all domains of quality of life. Conclusion These findings indicate that PTSD is associated with other psychopathologies, especially depression, and it has a substantial impact over quality of life in a sample of young adults.

Objective: To evaluate the prevalence of alcohol abuse and/or dependence in a population-based sample of young adults and assess the prevalence of comorbid mood disorders, anxiety, and suicide risk in this population. Methods: This cross-sectional, population-based study enrolled 1,953 young adults aged 18-35 years. The CAGE questionnaire was used to screen for alcohol abuse and/or dependence, with CAGE scores ≥ 2 considered positive. Psychiatric disorders were investigated through the structured Mini International Neuropsychiatric Interview (MINI). Results: Alcohol abuse and/or dependence was identified in 187 (9.60%) individuals (5.10% among women and 15.20% among men). Alcohol abuse and/or dependence were more prevalent among men than women, as well as among those who used tobacco, illicit drugs or presented with anxiety disorder, mood disorder, and suicide risk. Conclusion: These findings suggest that alcohol abuse and/or dependence are consistently associated with a higher prevalence of psychiatric comorbidities, could be considered important predictors of other psychiatric disorders, and deserve greater public heath attention, pointing to the need for alcohol abuse prevention programs.

Objetivo Investigar as características psicométricas de uma versão traduzida da escala, propondo uma Versão Revisada que atenda aos critérios de adaptação transcultural para o contexto brasileiro. Métodos Este estudo incluiu 231 sujeitos – deprimidos (45,5%), bipolares (7,8%) e saudáveis (46,7%) – que participaram de uma pesquisa epidemiológica no sul do Brasil. A avaliação de transtornos mentais foi realizada por meio da Clinical Interview for DSM-IV (SCID) e uma versão traduzida da Escala de Avaliação de Depressão de Hamilton (HAM-D), que habitualmente vem sendo utilizada no país sem estudos de adaptação. Resultados Identificou-se o ponto de corte (9 pontos) para discriminar a presença ou não de sintomas de depressão pela análise da curva ROC, resultando em uma sensibilidade e especificidade de 90 e 91%, respectivamente. A validade interna foi investigada pela análise fatorial e consistência dos itens. Dos 17 itens originais, apenas o item que avalia a “consciência do transtorno” não apresentou carga fatorial satisfatória para avaliar depressão geral e foi eliminado; os 16 restantes agruparam-se em cinco dimensões, denominadas: Humor deprimido, Anorexia, Insônia, Somatização e Ansiedade, as quais, com exceção da última, mostraram homogeneidade nos seus construtos (coeficientes alfa entre 0,66 e 0,78). Na análise de conteúdo dos itens, cinco especialistas sugeriram alterações redacionais em sete itens. Conclusão O estudo determina um ponto de corte diferente do original e evidencia características psicométricas favoráveis para a utilização da escala no Brasil.

Objective:To investigate peripheral levels of interleukin-10 (IL-10) in patients with major depressive disorder (MDD) and bipolar disorder (BD) and evaluate the relationship between IL-10, age of disease onset, and duration of illness.Methods:Case-control study nested in a population-based cohort of 231 individuals (age 18-24 years) living in Pelotas, state of Rio Grande do Sul, Brazil. Participants were screened for psychopathology using the Mini-International Neuropsychiatric Interview (MINI) and the Structured Clinical Interview for DSM-IV (SCID-I). Serum IL-10 was measured using commercially available immunoassay kits.Results:Peripheral levels of IL-10 were not significantly different in individuals with MDD or BD as compared to controls. However, higher IL-10 levels were found in MDD patients with a later disease onset as compared with controls or early-onset patients. In addition, IL-10 levels correlated negatively with illness duration in the MDD group. In the BD group, age of onset and duration of illness did not correlate with IL-10 levels.Conclusion:Higher levels of IL-10 are correlated with late onset of MDD symptoms. Moreover, levels of this cytokine might decrease with disease progression, suggesting that an anti-inflammatory balance may be involved in the onset of depressive symptoms and disease progression in susceptible individuals.