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MAO-A catalyzes the oxidative degradation of monoamines and is thus implicated in sex-specific neuroplastic processes that influence gray matter (GM) density (GMD) and microstructure (GMM). Given the exact monitoring of plasma hormone levels and sex steroid intake, transgender individuals undergoing gender-affirming hormone therapy (GHT) represent a valuable cohort to potentially investigate sex steroid-induced changes of GM and concomitant MAO-A density. Here, we investigated the effects of GHT over a median time period of 4.5 months on GMD and GMM as well as MAO-A distribution volume. To this end, 20 cisgender women, 11 cisgender men, 20 transgender women and 10 transgender men underwent two MRI scans in a longitudinal design. PET scans using [ 11 C]harmine were performed before each MRI session in a subset of 35 individuals. GM changes determined by diffusion weighted imaging (DWI) metrics for GMM and voxel based morphometry (VBM) for GMD were estimated using repeated measures ANOVA. Regions showing significant changes of both GMM and GMD were used for the subsequent analysis of MAO-A density. These involved the fusiform gyrus, rolandic operculum, inferior occipital cortex, middle and anterior cingulum, bilateral insula, cerebellum and the lingual gyrus (post-hoc tests: p FWE+Bonferroni < 0.025). In terms of MAO-A distribution volume, no significant effects were found. Additionally, the sexual desire inventory (SDI) was applied to assess GHT-induced changes in sexual desire, showing an increase of SDI scores among transgender men. Changes in the GMD of the bilateral insula showed a moderate correlation to SDI scores (rho = - 0.62, p Bonferroni = 0.047). The present results are indicative of a reliable influence of gender-affirming hormone therapy on 1) GMD and GMM following an interregional pattern and 2) sexual desire specifically among transgender men., Competing Interests: Declaration of competing interest With relevance to this work there is no conflict of interest to declare. R. Lanzenberger received travel grants and/or conference speaker honoraria within the last three years from Bruker BioSpin MR, Heel, and support from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019. G.S. Kranz declares that he received conference speaker honorarium from Roche, AOP Orphan and Pfizer. P. Handschuh received authorship honoraria from MedMedia Verlag and a travel grant from Angelini Pharma. The other authors report no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: The human brain is characterized by interacting large-scale functional networks fueled by glucose metabolism. Since former studies could not sufficiently clarify how these functional connections shape glucose metabolism, we aimed to provide a neurophysiologically-based approach., Methods: 51 healthy volunteers underwent simultaneous PET/MRI to obtain BOLD functional connectivity and [ 18 F]FDG glucose metabolism. These multimodal imaging proxies of fMRI and PET were combined in a whole-brain extension of metabolic connectivity mapping. Specifically, functional connectivity of all brain regions were used as input to explain glucose metabolism of a given target region. This enabled the modeling of postsynaptic energy demands by incoming signals from distinct brain regions., Results: Functional connectivity input explained a substantial part of metabolic demands but with pronounced regional variations (34 - 76%). During cognitive task performance this multimodal association revealed a shift to higher network integration compared to resting state. In healthy aging, a dedifferentiation (decreased segregated/modular structure of the brain) of brain networks during rest was observed. Furthermore, by including data from mRNA maps, [ 11 C]UCB-J synaptic density and aerobic glycolysis (oxygen-to-glucose index from PET data), we show that whole-brain functional input reflects non-oxidative, on-demand metabolism of synaptic signaling. The metabolically-derived directionality of functional inputs further marked them as top-down predictions. In addition, the approach uncovered formerly hidden networks with superior efficiency through metabolically informed network partitioning., Conclusions: Applying multimodal imaging, we decipher a crucial part of the metabolic and neurophysiological basis of functional connections in the brain as interregional on-demand synaptic signaling fueled by anaerobic metabolism. The observed task- and age-related effects indicate promising future applications to characterize human brain function and clinical alterations., Competing Interests: Declaration of competing interest R. Lanzenberger received investigator-initiated research funding from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019. M. Hacker received consulting fees and/or honoraria from Bayer Healthcare BMS, Eli Lilly, EZAG, GE Healthcare, Ipsen, ITM, Janssen, Roche, and Siemens Healthineers. All other authors report no conflict of interest in relation to this study., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Changes in distribution of associated molecular targets have been reported across several neuropsychiatric disorders. However, the high-resolution topology of most proteins is unknown and simultaneous in vivo measurement in multi-receptor systems is complicated. To account for the missing proteomic information, messenger ribonucleic acid (mRNA) transcripts are typically used as a surrogate. Nonetheless, post-transcriptional and post-translational processes might cause the discrepancy between the final distribution of proteins and gene expression patterns. Therefore, this study aims to investigate ex vivo links between mRNA expression and corresponding receptor density in the human cerebral cortex. To this end, autoradiography data on the density of 15 different receptors in 38 brain regions were correlated with the expression patterns of 50 associated genes derived from microarray data (mA), RNA sequencing data (RNA-Seq) provided by the Allen Human Brain Atlas and predicted mRNA expression patterns (pred-mRNA). Spearman's rank correlation was used to evaluate the possible links between proteomic data and mRNA expression patterns. Correlations between mRNA and protein density varied greatly between targets: Positive associations were found for e.g. the serotonin 1A (pred-mRNA: r s  = 0.708; mA: r s  = 0.601) or kainate receptor (pred-mRNA: r s  = 0.655; mA: r s  = 0.601; RNA-Seq: r s  = 0.575) as well as a few negative associations e.g. γ-Aminobutyric acid (GABA) A receptor subunit α3 (pred-mRNA: r s  = -0.638; mA: r s  = -0.619) or subunit α5 (pred-mRNA: r s  = -0.565; mA: r s  = -0.563), while most of the other investigated target receptors showed low correlations. The high variability in the correspondence of mRNA expression and receptor spatial distribution warrants caution when inferring the topology of molecular targets in the brain from transcriptome data. This not only highlights the longstanding value of molecular imaging but also indicates a need for comprehensive proteomic studies., Competing Interests: Declaration of Competing Interest With relevance to this work, there is no conflict of interest to declare. R. Lanzenberger received travel grants and/or conference speaker honoraria within the last three years from Bruker BioSpin MR, Heel, and support from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019. Matej Murgaš, Paul Michenthaler, Murray B. Reed and Gregor Gryglewski have no conflicts of interest to declare., (Copyright © 2022. Published by Elsevier Inc.)

Open access post-mortem transcriptome atlases such as the Allen Human Brain Atlas (AHBA) can inform us about mRNA expression of numerous proteins of interest across the whole brain, while in vivo protein binding in the human brain can be quantified by means of neuroreceptor positron emission tomography (PET). By combining both modalities, the association between regional gene expression and receptor distribution in the living brain can be approximated. Here, we compare the characteristics of D 2 and D 3 dopamine receptor distribution by applying the dopamine D 2/3 receptor agonist radioligand [ 11 C]-(+)-PHNO and human gene expression data. Since [ 11 C]-(+)-PHNO has a higher affinity for D 3 compared to D 2 receptors, we hypothesized that there is a stronger relationship between D 2/3 non-displaceable binding potentials (BP ND ) and D 3 mRNA expression. To investigate the relationship between D 2/3 BP ND and mRNA expression of DRD2 and DRD3 we performed [ 11 C]-(+)-PHNO PET scans in 27 healthy subjects (12 females) and extracted gene expression data from the AHBA. We also calculated D 2 /D 3 mRNA expression ratios to imitate the mixed D 2/3 signal of [ 11 C]-(+)-PHNO. In accordance with our a priori hypothesis, a strong correlation between [ 11 C]-(+)-PHNO and DRD3 expression was found. However, there was no significant correlation with DRD2 expression. Calculated D 2 /D 3 mRNA expression ratios also showed a positive correlation with [ 11 C]-(+)-PHNO binding, reflecting the mixed D 2/3 signal of the radioligand. Our study supports the usefulness of combining gene expression data from open access brain atlases with in vivo imaging data in order to gain more detailed knowledge on neurotransmitter signaling., Competing Interests: Declaration of Competing Interest Without relevance to this work, Matthäus Willeit declares to having received speaker honoraria and consulting fees from Janssen-Cilag Pharma GmbH, Austria. Wolfgang Wadsak declares to having received speaker honoraria from GE Healthcare, research grants from Ipsen Pharma, Eckert-Ziegler AG, Scintomics and ITG. He is a part time employee of CBmed Ltd (Center for Biomarker Research in Medicine, Graz, Austria). Marcus Hacker received consulting fees and/or honoraria from Bayer Healthcare BMS, Eli Lilly, EZAG, GE Healthcare, Ipsen, ITM, Janssen, Roche, Siemens Healthineers. Rupert Lanzenberger received travel grants and/or conference speaker honoraria within the last three years from Bruker BioSpin MR, Heel, and support from Siemens Healthcare regarding clinical research using PET/MR. Siegfried Kasper received grants/research support, consulting fees and/or honoraria within the last three years from Angelini, AOP Orphan Pharmaceuticals AG, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd. and Takeda. Arkadiusz Komorowski, Ana Weidenauer, Martin Bauer, Ulrich Sauerzopf, Matej Murgaš, Markus Mitterhauser, and Nicole Praschak-Rieder have no conflicts of interest to declare., (Copyright © 2020. Published by Elsevier Inc.)