Logo: to the web site of Uppsala University

Suicide remains a critical global public health issue, accounting for nearly one million deaths annually and imposing profound societal and economic burdens. Despite its urgency, the lack of diagnostic and predictive biomarkers continues to hinder the development of effective prevention and treatment strategies. This study presents a comprehensive meta-analysis that integrates publicly available postmortem brain transcriptomic datasets and a domestic cohort, encompassing 16 cohorts. The transcriptomic data, sourced from the Gene Expression Omnibus repository, were generated using various techniques, including traditional RNA sequencing, microarray methods, and single-cell RNA sequencing. Differential expression analyses were performed across multiple brain regions, with meta-analyses stratified by cortical regions, the dorsolateral prefrontal cortex (DLPFC), and combined. We further analyzed whether covariates may affect the identified genes. Three meta-analytic approaches were employed, complemented by pathway and cell-set enrichment analyses. The unadjusted meta-analysis consistently identified several genes with altered expression, including upregulated P2RY12, CX3CR1, and GPR34, and downregulated SOX9 and PMP2, all at nominal significance. Additionally, multiple genes encoding long non-coding RNAs (lncRNAs) exhibited nominally altered expression in suicide, including RP5-837J1.4, AC159540.14, DNM1P47, AC004158.2, EEF1A1P30, and RP11-339B21.8. Several alternative strategies to run meta-analysis were performed and moderators were investigated. Cell-type-specific expression deconvolution and meta-analysis identified several genes overlapping with bulk expression meta-analysis, and genes were attributed to neuronal lineages. These findings highlight plausible molecular targets for future validation studies, suggesting the involvement of microglia (P2RY12 and CX3CR1), astrocytes (SOX9), immune responses (GPR34), myelin regulation (PMP2), and epigenetic modulation via lncRNAs. This research advances the understanding of the molecular architecture of suicide and provides a foundation for future studies focused on targeted prevention and therapeutic interventions.

Psychiatric and neurological diseases present substantial challenges in healthcare, affecting millions of individuals worldwide. Conditions such as depression, trigeminal neuralgia (TN), and narcolepsy have a profound impact on the quality of life for both patients and their families. The complex nature of these conditions necessitates the development of innovative diagnostic and treatment strategies. In recent years, the importance of biomarkers in understanding, diagnosing, and managing psychiatric and neurological diseases has emerged as a promising field of research. In the current thesis, five studies were conducted to identify candidate biomarkers in depression, TN, and narcolepsy. Study I validated depression-associated genetic variants in the UK Biobank (UKB) cohort, with transcriptome and DNA methylation analyses in independent datasets. Eight single nucleotide polymorphisms corresponding to six protein-coding genes (TNXB, NCAM1, LTBP3, BTN3A2, DAG1, FHIT) were strongly linked to depression. Study II analyzed 92 proteins in cerebrospinal fluid and serum from TN patients, compared with multiple sclerosis patients and controls. Several proteins, including SFRP1, FKBP5, and TBCB, were elevated in TN, suggesting their relevance in disease mechanisms. Study III examined protein levels in adolescents assessed for depression in the domestic Psychiatric Health in Adolescent Study (PSY cohort) in Sweden, with transcriptome validation in independent cohorts. Key findings highlighted protein and transcriptomic differences, particularly in PPP3R1, implicating the calcineurin pathway and prefrontal cortex in depression. Study IV explored genetic evidence in the UKB to validate the role of 17 proteins from previous studies in TN. Novel associations were identified with C8B (complement system) and MFGE8 (neuroinflammation regulation), highlighting their roles in TN pathology. Finally, Study V assessed protein biomarkers in narcolepsy using Swedish and Finnish cohorts, with transcriptome validation in an independent dataset. The identified candidate proteins were indicative of neural development involving survival, growth, and differentiation (UNC5C, VWC2, GFR-alpha-1, ADAM23), oxidative stress (HAGH), immune response (CLEC10A), and cell cycle regulation (ILKAP). Collectively, these studies identify potential biomarkers across these conditions, offering insights into their underlying mechanisms. The findings expand our understanding of psychiatric and neurological health and may inform future research and therapeutic strategies.

Introduction Depression is a major global burden with unclear pathophysiology and poor treatment outcomes. Diagnosis of depression continues to rely primarily on behavioral rather than biological methods. Investigating tools that might aid in diagnosing and treating early-onset depression is essential for improving the prognosis of the disease course. While there is increasing evidence of possible biomarkers in adult depression, studies investigating this subject in adolescents are lacking.Methods In the current study, we analyzed protein levels in 461 adolescents assessed for depression using the Development and Well-Being Assessment (DAWBA) questionnaire as part of the domestic Psychiatric Health in Adolescent Study conducted in Uppsala, Sweden. We used the Proseek Multiplex Neuro Exploratory panel with Proximity Extension Assay technology provided by Olink Bioscience, followed by transcriptome analyses for the genes corresponding to the significant proteins, using four publicly available cohorts.Results We identified a total of seven proteins showing different levels between DAWBA risk groups at nominal significance, including RBKS, CRADD, ASGR1, HMOX2, PPP3R1, CD63, and PMVK. Transcriptomic analyses for these genes showed nominally significant replication of PPP3R1 in two of four cohorts including whole blood and prefrontal cortex, while ASGR1 and CD63 were replicated in only one cohort.Discussion Our study on adolescent depression revealed protein-level and transcriptomic differences, particularly in PPP3R1, pointing to the involvement of the calcineurin pathway in depression. Our findings regarding PPP3R1 also support the role of the prefrontal cortex in depression and reinforce the significance of investigating prefrontal cortex-related mechanisms in depression.

Background

The role of environmental factors in neurological disorders constitutes a topic of increasing importance. Teaching in European universities should expand and update this field gaining future health professionals including adjacent disciplines.

Aim

To describe recent efforts to create courses that cover crucial interdisciplinary content that we believe should be included in modern education, and to adapt modern pedagogic strategies.

Methods

In collaboration with RISE (Rencontres Internationales Santé Environnement), elective courses focused on Environmental Health and Medicine (EHM) were developed, in France, Sweden, and Turkey. The courses combined classic teaching methods and new pedagogic and digital solutions to create environment-related health awareness and facilitate future interprofessional collaboration in this field.

Results

UPRISE is an innovative elective course introduced in 2020 in Sweden's Uppsala University with the participation of lecturers from several countries and aim to recruit students from different universities. A total of 45, mainly female students (68%), participated in the course. In Strasbourg, France, a novel course on environmental medicine was held in 2019–2023 and examined 90 students, of which more than half were female. Nine graduate nurse students in Turkey attended ten seminar series focused on EHM. Overall, students expressed satisfaction with the courses.

Conclusions

This European project for courses in higher education arising from RISE was met with appreciation and challenges from academic institutions.

However, due to considerable efforts to introduce the EHM concept, a unique compulsory course for all medical students in the second year of training started in 2023 in all French medical faculties. In 2023, UPRISE was integrated into ENLIGHT, the European University Network to promote equitable quality of Life, sustainability, and Global engagement through Higher education Transformation.

BACKGROUND: Trigeminal neuralgia (TN) is a severe facial pain condition often associated with a neurovascular conflict. However, neuroinflammation has also been implicated in TN, as it frequently co-occurs with multiple sclerosis (MS).

METHODS: We analysed protein expression levels of TN patients compared to MS patients and controls. Proximity Extension Assay technology was used to analyse the levels of 92 proteins with the Multiplex Neuro-Exploratory panel provided by SciLifeLab, Uppsala, Sweden. Serum and CSF samples were collected from TN patients before (n = 33 and n = 27, respectively) and after (n = 28 and n = 8, respectively) microvascular decompression surgery. Additionally, we included samples from MS patients (n = 20) and controls (n = 20) for comparison.

RESULTS: In both serum and CSF, several proteins were found increased in TN patients compared to either MS patients, controls, or both, including EIF4B, PTPN1, EREG, TBCB, PMVK, FKBP5, CD63, CRADD, BST2, CD302, CRIP2, CCL27, PPP3R1, WWP2, KLB, PLA2G10, TDGF1, SMOC1, RBKS, LTBP3, CLSTN1, NXPH1, SFRP1, HMOX2, and GGT5. The overall expression of the 92 proteins in postoperative TN samples seems to shift towards the levels of MS patients and controls in both serum and CSF, as compared to preoperative samples. Interestingly, there was no difference in protein levels between MS patients and controls.

CONCLUSIONS: We conclude that TN patients showed increased serum and CSF levels of specific proteins and that successful surgery normalizes these protein levels, highlighting its potential as an effective treatment. However, the similarity between MS and controls challenges the idea of shared pathophysiology with TN, suggesting distinct underlying mechanisms in these conditions.

SIGNIFICANCE: This study advances our understanding of trigeminal neuralgia (TN) and its association with multiple sclerosis (MS). By analysing 92 protein biomarkers, we identified distinctive molecular profiles in TN patients, shedding light on potential pathophysiological mechanisms. The observation that successful surgery normalizes many protein levels suggests a promising avenue for TN treatment. Furthermore, the contrasting protein patterns between TN and MS challenge prevailing assumptions of similarity between the two conditions and point to distinct pathophysiological mechanisms.

Increased knowledge about sex differences is important for development of individualized treatments against many diseases as well as understanding behavioral and pathological differences. This review summarizes sex chromosome effects on gene expression, epigenetics, and hormones in relation to the brain. We explore neuroanatomy, neurochemistry, cognition, and brain pathology aiming to explain the current state of the art. While some domains exhibit strong differences, others reveal subtle differences whose overall significance warrants clarification. We hope that the current review increases awareness and serves as a basis for the planning of future studies that consider both sexes equally regarding similarities and differences.

Trigeminal neuralgia (TN) is a severe facial pain disease of uncertain pathophysiology and unclear genetic background. Although recent research has reported a more important role of genetic factors in TN pathogenesis, few candidate genes have been proposed to date. The present study aimed to identify independent genetic variants in the protein-coding genes associated with TN. We focused on genes previously linked to TN based on the results of four proteomic studies conducted by our research team. The goal was to validate these findings on the genetic level to enhance our understanding of the role of genetics in TN. The study is based on the participants from UK Biobank cohort. Following quality control, 175 independent single nucleotide polymorphisms (SNPs) in 17 genes were selected. The study sample comprised of diagnosed TN cases (N = 555) and randomly matched controls (N = 6245) based on specific criteria. Two SNPs corresponding to C8B rs706484 [odds ratio (OR) (95% confidence interval (CI)): 1.357 (1.158–1.590); p: 0.00016] and MFG-E8 rs2015495 [OR (95% CI): 1.313 (1.134–1.521); p: 0.00028] showed significant positive association with TN, indicating a positive effect of the SNP alleles on gene expression and disease risk. Interestingly, both SNPs are Expression Quantitative Trait Loci (eQTLs), and are associated with changes in the expression activity of their corresponding gene. Our findings suggest novel genetic associations between C8B, a key component of the complement system, and MFG-E8, which plays a role in regulating neuroinflammation, in relation to TN. The identified genetic variations may help explain why some individuals develop TN while others do not, indicating a potential genetic predisposition to the condition.