Biology subjects

Rujescu, D.

Publications and source records attributed to Rujescu, D..

6 recordsLinked to original sources

bioRxiv2026

Cellular and mitochondrial correlates of regional glucose metabolism in the human cortex

Regional differences in human brain glucose metabolism reflect local energy demands, but their cellular and mitochondrial determinants remain unclear. We combined [18F]FDG positron emission tomography in healthy human participants with estimates of cellular composition and mitochondrial density to unravel (sub)cellular correlates of heterogeneity in brain glucose metabolism. By correcting for RNA content and differential gene expression due to postmortem sampling, we addressed methodological shortcomings in multimodal neuroimaging integration. We introduce transcriptionally derived cytoarchitectonic maps of the human cortex that are consistent with histological findings, providing a biologically grounded framework for relating in vivo neuroimaging signals. Accordingly, mitochondrial distribution showed strong association with the intrinsic energy requirements at resting state. In contrast, relations between metabolism and neuronal composition were driven by sensory input and mitochondria-sparse thin-axon neurons, suggesting that stimulation-induced energy demand is met rather by neuronal processes that are independent of mitochondrial abundance to maintain efficient information processing.

neuroscience↗

bioRxiv2026

Network-specific metabolic cost of functional connectivity in the human brain

Despite decades of extensive research, the complex architecture underlying human brain signaling remains incompletely understood. Previous work investigating the relationship between brain glucose metabolism and functional connectivity (FC) employed whole-brain analysis, without accounting for network interactions, dependencies or hierarchies. Here, we assess network-specific differences in the relationship between FC and metabolic demand, using [18F]FDG PET/MR data from three independent datasets. The metabolic cost of FC, i.e., the change in glucose demand associated with corresponding changes in FC, was modeled at rest, during cognitive task performance and in Alzheimer's disease (AD). Our findings reveal network-specific differences in metabolic cost, with the default mode (DM), somatomotor (SM) and fronto-temporal networks accounting for highest, intermediate and lowest metabolic demands, respectively. Similarly, time-resolved variability of FC demonstrated highest costs for states with DM network involvement and lowest for SM network participation. This relationship was reversed in participants with AD, who exhibited decreased demands in the DM network and increased costs in the SM network. Cognitive performance consistently revealed cost reductions in the DM and SM networks, as well as increases in task relevant networks. Together, these results highlight the flexibility of functional network architecture associated with cognitive demands and neuropathology, and shed light on the complex interplay between glucose metabolism and network interactions.

neuroscience↗

bioRxiv2026

Differential upregulation of metabolic demands and functional integration of the default mode network during stress

Psychosocial stress engages coordinated physiological and neural responses that enable adaptation to environmental challenges. However, maladaptive stress and reduced resilience are major risk factors for psychiatric and neurodegenerative disorders. As the brains metabolic response to stress remains largely unexplored, we used simultaneous [18F]FDG PET/MRI during performance of the Montreal Imaging Stress Task to assess cerebral glucose metabolism, BOLD activation and functional connectivity. On top of activation in relation to cognitive processing, psychosocial stress specifically recruits the posterior cingulate cortex (PCC) with increased glucose metabolism and attenuated BOLD deactivations. This was accompanied by reduced PCC integration within the default mode network and increased influence onto frontoparietal and dorsal attention networks. Moreover, individuals exhibiting an endocrine stress response showed lower resilience scores, failed to downregulate anterior cingulate cortex (ACC) metabolism during stress, and displayed an inverse relationship between ACC glucose metabolism and anterior insula functional connectivity. Together, these results demonstrate that acute psychosocial stress induces coordinated alterations in brain metabolism and large-scale network organization. Our findings show that metabolic imaging provides complementary information, revealing stress-related brain responses not captured by hemodynamics alone, thereby providing a multimodal framework for understanding human stress processing and individual vulnerability to stress-related psychiatric disorders.

neuroscience↗

bioRxiv2020

Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

BACKGROUNDSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODSWe conducted the largest to date genome-wide genotype-by-sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH. RESULTSAcross disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815; p=3.2x10-8), that interacts with sodium/potassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence (p<1x10-6) for cross-disorder GxS interaction (rs7302529, p=1.6x10-7; rs73033497, p=8.8x10-7; rs7914279, p=6.4x10-7) implicating various functions. Gene-based analyses identified GxS interaction across disorders (p=8.97x10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282; p=1.5x10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509; p=1.1x10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDR<0.05). CONCLUSIONSIn the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.

genetics↗

bioRxiv2017

Genome-wide Association Study of Clinical Features in the Schizophrenia Psychiatric Genomics Consortium: Confirmation of Polygenic Effect on Negative Symptoms

Schizophrenia is a clinically heterogeneous disorder. Proposed revisions in DSM - 5 included dimensional measurement of different symptom domains. We sought to identify common genetic variants influencing these dimensions, and confirm a previous association between polygenic risk of schizophrenia and the severity of negative symptoms. The Psychiatric Genomics Consortium study of schizophrenia comprised 8,432 cases of European ancestry with available clinical phenotype data. Symptoms averaged over the course of illness were assessed using the OPCRIT, PANSS, LDPS, SCAN, SCID, and CASH. Factor analyses of each constituent PGC study identified positive, negative, manic, and depressive symptom dimensions. We examined the relationship between the resultant symptom dimensions and aggregate polygenic risk scores indexing risk of schizophrenia. We performed genome - wide association study (GWAS) of each quantitative traits using linear regression and adjusting for significant effects of sex and ancestry. The negative symptom factor was significantly associated with polygene risk scores for schizophrenia, confirming a previous, suggestive finding by our group in a smaller sample, though explaining only a small fraction of the variance. In subsequent GWAS, we observed the strongest evidence of association for the positive and negative symptom factors, with SNPs in RFX8 on 2q11.2 (P = 6.27x10-8) and upstream of WDR72 / UNC13C on 15q21.3 (P = 7.59x10-8), respectively. We report evidence of association of novel modifier loci for schizophrenia, though no single locus attained established genome - wide significance criteria. As this may have been due to insufficient statistical power, follow - up in additional samples is warranted. Importantly, we replicated our previous finding that polygenic risk explains at least some of the variance in negative symptoms, a core illness dimension.

genetics↗

bioRxiv2017

Placental gene expression mediates the interaction between obstetrical history and genetic risk for schizophrenia

Defining the environmental context in which genes enhance susceptibility can provide insight into the pathogenesis of complex disorders, like schizophrenia. Here we show that the intrauterine and perinatal environment modulates the association of schizophrenia with genomic risk, as measured with polygenic risk scores (PRS) based primarily on GWAS significant variants. Genomic risk interacts with intrauterine and perinatal complications (Early Life Complications, ELCs) in each of three independent samples from USA, Italy and Germany (overall n= 1693, p= 6e-05). In each sample, the liability of schizophrenia explained by PRS is nominally more than five times greater in the presence of a history of ELCs compared with its absence. In each sample, patients with positive ELC histories have higher PRS than patients without ELCs, which is further confirmed in two additional patient samples from Germany and Japan (overall n=2038, p= 1e-04). The gene set based on the schizophrenia loci interacting with ELCs is highly expressed in multiple placental compartments and dynamically regulated in placenta from complicated in comparison with normal pregnancies. The same genes are differentially up-regulated in placentae from male compared with female offspring. The interaction between genomic risk and ELCs is mainly driven by GWAS significant loci enriched for genes highly expressed in the various placenta samples. Molecular pathway analyses based on the genes not driving this interaction reflect previous analyses about schizophrenia risk-genes, while genes highly and differentially expressed in placentae implicate an orthogonal biology involving cellular stress. These results suggest that the most significant genetic variants detected by current schizophrenia GWAS contribute to risk in part by converging on a developmental trajectory sensitive to events affecting placentation, which may underlie the male preponderance of schizophrenia and offer new insights into primary prevention.

genetics↗