Elena Stekolshchikova’s research while affiliated with Skolkovo Institute of Science and Technology and other places

Although lipid biology may play a key role in the pathophysiology of mental health disorders such as schizophrenia (SCZ) and bipolar disorder (BD), the nature of this interplay and how it could shape phenotypic presentation, including cognitive performance is still incompletely understood. To address this question, we analyzed the association of plasma level of different lipid species with cognitive performance in the transdiagnostic PsyCourse Study. Plasma lipidomic profiles of 623 individuals (188 SCZ, 243 BD, 192 healthy controls) belonging to the PsyCourse Study were assessed using liquid chromatography and untargeted mass spectrometry. The association between 364 annotated lipid species from 16 lipid classes and six cognitive tests was evaluated. Likewise, the association of polygenic risk scores (PRS) for SCZ, BD, executive function (EF), and educational attainment (EA) with lipid plasma levels were also investigated. In the regression analysis, three lipid species belonging to phosphatidylethanolamine plasmalogen and one belonging to ceramide class showed significant negative association with Digit-Symbol test scores. Lipid class-based enrichment analysis in LipidR replicated the significance of the phosphatidylethanolamines class for the Digit-Symbol test, which evaluates the processing speed in cognitive tasks. Polygenic load for SCZ, BD, EF, or EA was not associated with lipid levels. Our findings suggest a link between lipids and cognitive performance independent of mental health disorders. Still, independent replication is warranted to better understand if phosphatidylethanolamines could represent an actionable pharmacologic target to tackle cognitive dysfunction, an important unmet clinical need that affects long-term functional outcomes in individuals with severe mental health disorders.

Understanding the molecular basis of the structural organization of the human brain may shed light on its functional mechanism. We present spatial lipidomics analysis of human brain sections containing neocortical gray matter and two white matter regions representing two axonal tracks: the cingulum bundle and the corpus callosum. Using matrix‐assisted laser desorption/ionization mass spectrometry imaging (MALDI‐MSI) we identify lipid composition differences not only between gray and white matter but also between two axonal tracks. Results, obtained with the MALDI‐MSI method, correlated with ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) analysis of these brain regions, with Spearman's correlation coefficient equal to 0.48 (the cingulum bundle vs. gray matter), 0.47 (the corpus callosum vs. gray matter), 0.33 (the cingulum bundle vs. the corpos callosum) on 75 lipids annotated in both experiments. Using UPLC‐MS/MS analysis, we further identified specific lipid classes that distinguished the two white matter regions (CL, PG, LPE), while gray and white matter comparison yielded well‐established differences in lipid composition between myelin‐rich and myelin poor regions (CL, DG, Cholesterol). Our findings highlight the significance of in‐depth molecular analysis of brain regions and enhance our comprehension of the brain's molecular composition. image

Numerous brain imaging studies have reported white matter alterations in schizophrenia, but the lipidome analysis of the corresponding tissue remains incomplete. In this study, we investigated the lipidome composition of six subcortical white matter regions corresponding to major axonal tracks in both control subjects and schizophrenia patients. All six regions exhibited a consistent pattern of quantitative lipidome alterations in schizophrenia, involving myelin-forming and mitochondria associated lipid classes. While alteration levels of myelin-forming lipids, particularly sphingolipids, aligned with the extent of the myelin changes reported in structural brain imaging studies, a significant decrease of mitochondria in the white matter, indicated by the lipidome alterations, was not previously investigated. To verify this effect, we performed lipidome analysis in a larger set of individuals and in the mitochondria-enriched membrane fraction, as well as directly quantified mitochondrial content. Our results suggest a substantial reduction of the mitochondrial quotient accompanied by the imbalance in myelin lipids in schizophrenia white matter.

Background Anxiety and depression significantly contribute to the overall burden of mental disorders, with depression being one of the leading causes of disability. Despite this, no biochemical test has been implemented for the diagnosis of these mental disorders, while recent studies have highlighted lipids as potential biomarkers. Methods Using a streamlined high-throughput lipidome analysis method, direct-infusion mass spectrometry, we evaluated blood plasma lipid levels in 604 individuals from a general urban population and analysed their association with self-reported anxiety and depression symptoms. We also assessed lipidome profiles in 32 patients with clinical depression, matched to 21 healthy controls. Findings We found a significant correlation between lipid abundances and the severity of self-reported depression symptoms. Moreover, lipid alterations detected in high scoring volunteers mirrored the lipidome profiles identified in patients with clinical depression included in our study. Based on these findings, we developed a lipid-based predictive model distinguishing individuals reporting severe depressive symptoms from non-depressed subjects with high accuracy. Interpretation This study demonstrates the possibility of generalizing lipid alterations from a clinical cohort to the general population and underscores the potential of lipid-based biomarkers in assessing depressive states. Funding This study was sponsored by the Moscow Center for Innovative Technologies in Healthcare, №2707-2, №2102-11.

Lipids are the most abundant but poorly explored components of the human brain. Here, we present a lipidome map of the human brain comprising 75 regions, including 52 neocortical ones. The lipidome composition varies greatly among the brain regions, affecting 93% of the 419 analyzed lipids. These differences reflect the brain’s structural characteristics, such as myelin content (345 lipids) and cell type composition (353 lipids), but also functional traits: functional connectivity (76 lipids) and information processing hierarchy (60 lipids). Combining lipid composition and mRNA expression data further enhances functional connectivity association. Biochemically, lipids linked with structural and functional brain features display distinct lipid class distribution, unsaturation extent, and prevalence of omega-3 and omega-6 fatty acid residues. We verified our conclusions by parallel analysis of three adult macaque brains, targeted analysis of 216 lipids, mass spectrometry imaging, and lipidome assessment of sorted murine neurons.

Numerous brain imaging studies have reported white matter alterations in schizophrenia, but the lipidome analysis of the corresponding tissue remains incomplete. In this study, we investigated the lipidome composition of six subcortical white matter regions corresponding to major axonal tracks in both control subjects and schizophrenia patients. All six regions exhibited a consistent pattern of quantitative lipidome alterations in schizophrenia, affecting specific lipid classes. These alterations partly involved myelin-forming lipid classes, particularly sphingolipids, with the extent of alterations reflecting the myelin changes previously reported in structural brain imaging studies. The other part of the schizophrenia-associated alterations, which showed a significant decrease in the disorder, involved lipid classes abundant in mitochondria. A similar significant decrease was also observed in the mitochondria-enriched membrane fraction isolated from the white matter of individuals with schizophrenia. This suggests a substantial reduction in the number of mitochondria in subcortical white matter in schizophrenia, a hypothesis supported by quantitative mitochondria staining.

Importance: No clinically applicable diagnostic test exists for severe mental disorders. Lipids harbor potential as disease markers. Objective: To define a reproducible profile of lipid alterations in the blood plasma of patients with schizophrenia (SCZ) independent of demographic and environmental variables and to investigate its specificity in association with other psychiatric disorders, ie, major depressive disorder (MDD) and bipolar disorder (BPD). Design, setting, and participants: This was a multicohort case-control diagnostic analysis involving plasma samples from psychiatric patients and control individuals collected between July 17, 2009, and May 18, 2018. Study participants were recruited as consecutive and volunteer samples at multiple inpatient and outpatient mental health hospitals in Western Europe (Germany and Austria [DE-AT]), China (CN), and Russia (RU). Individuals with DSM-IV or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses of SCZ, MDD, BPD, or a first psychotic episode, as well as age- and sex-matched healthy controls without a mental health-related diagnosis were included in the study. Samples and data were analyzed from January 2018 to September 2020. Main outcomes and measures: Plasma lipidome composition was assessed using liquid chromatography coupled with untargeted mass spectrometry. Results: Blood lipid levels were assessed in 980 individuals (mean [SD] age, 36 [13] years; 510 male individuals [52%]) diagnosed with SCZ, BPD, MDD, or those with a first psychotic episode and in 572 controls (mean [SD] age, 34 [13] years; 323 male individuals [56%]). A total of 77 lipids were found to be significantly altered between those with SCZ (n = 436) and controls (n = 478) in all 3 sample cohorts. Alterations were consistent between cohorts (CN and RU: [Pearson correlation] r = 0.75; DE-AT and CN: r = 0.78; DE-AT and RU: r = 0.82; P < 10-38). A lipid-based predictive model separated patients with SCZ from controls with high diagnostic ability (area under the receiver operating characteristic curve = 0.86-0.95). Lipidome alterations in BPD and MDD, assessed in 184 and 256 individuals, respectively, were found to be similar to those of SCZ (BPD: r = 0.89; MDD: r = 0.92; P < 10-79). Assessment of detected alterations in individuals with a first psychotic episode, as well as patients with SCZ not receiving medication, demonstrated only limited association with medication restricted to particular lipids. Conclusions and relevance: In this study, SCZ was accompanied by a reproducible profile of plasma lipidome alterations, not associated with symptom severity, medication, and demographic and environmental variables, and largely shared with BPD and MDD. This lipid alteration signature may represent a trait marker of severe psychiatric disorders, indicating its potential to be transformed into a clinically applicable testing procedure.