http://bura.brunel.ac.uk/handle/2438/8614 Fri, 01 May 2026 01:26:47 GMT 2026-05-01T01:26:47Z http://bura.brunel.ac.uk/handle/2438/33232 Title: Multiscale characterization of cortical signatures in positive and negative schizotypy: a worldwide ENIGMA study Authors: Kirschner, M; Hodzic-Santor, B; Kennedy, L; Hansen, JY; Antoniades, M; Nenadić, I; Kircher, T; Krug, A; Meller, T; Dannlowski, U; Grotegerd, D; Flinkenflügel, K; Meinert, S; Borgers, T; Goltermann, J; Hahn, T; Böhnlein, J; Leehr, EJ; Barkhau, C; Fornito, A; Arnatkeviciute, A; Bellgrove, MA; Tiego, J; DeRosse, P; Green, M; Quidé, Y; Pantelis, C; Chan, RCK; Wang, Y; Ettinger, U; Debbané, M; Derome, M; Gaser, C; Besteher, B; Diederen, K; Spencer, TJ; Houenou, J; Pomarol-Clotet, E; Salvador, R; Rössler, W; Smigielski, L; Kumari, V; Premkumar, P; Park, HRP; Wiebels, K; Jansen, I; Gilleen, J; Allen, P; Marsman, J-B; Lebedeva, I; Tomyshev, A; Fett, A-K; Sommer, I; Koops, S; Grant, P; Ferrari, A; Wan, B; Bègue, I; Hernaus, D; Jalbrzikowski, M; Paquola, C; Larivière, S; Bernhardt, B; Valk, SL; Misic, B; van Erp, TGM; Turner, JA; Thompson, PM; Aleman, A; Dagher, A; Kaiser, S; Modinos, G Abstract: Positive and negative schizotypy reflect distinct patterns of subclinical traits in the general population associated with neurodevelopmental and schizophrenia-spectrum pathologies. Yet, a comprehensive characterization of the unique and shared neuroanatomical signatures of these schizotypy dimensions is lacking. Leveraging 3D brain MRI data from 2730 unmedicated healthy individuals, we identified neuroanatomical profiles of positive and negative schizotypy and systematically compared them with disorder-specific, microarchitectural, neurotransmitter-level, and connectome measures. Positive and negative schizotypy were associated with distinct cortical signatures, of predominantly thinner frontal and thicker paralimbic cortical areas, respectively. These cortical signatures of positive and negative schizotypy were differentially linked to brain-wide cortical patterns of schizophrenia-spectrum (clinical high-risk for psychosis, schizophrenia) and neurodevelopmental conditions (ADHD, autism spectrum disorder and 22q11.2 deletion syndrome). Additionally, the positive and negative schizotypy-related cortical profiles mapped onto different local attributes of gene expression, cortical myelination, D1, and histamine receptor distributions. Network models further showed that positive and negative schizotypy cortical signatures were spatially associated with cortical hubs, suggesting that highly interconnected regions are more vulnerable to the morphological differences associated with both schizotypy dimensions. Finally, predominantly sensorimotor-to-association and paralimbic areas emerged as epicenters with connectivity profiles significantly linked to the schizotypy-related cortical patterns. Collectively, this study identified cortical signatures of positive and negative schizotypy traits that are embedded along multiple scales of cortical organization and neuropsychiatric pathologies. Our work yields novel insights into how neurobiology and brain architecture may guide neuroanatomical vulnerability and resilience to psychopathology in the general population. Description: Data availability: All meta-analytic data reported in the manuscript are included in the article and its supplementary information files. Summary statistics of the case-control meta-analyses from the ENIGMA Working Groups are available from the ENIGMA Toolbox (https://enigma-toolbox.readthedocs.io/en/latest/). Preprocessed normative cortico-cortical, subcortico-cortical, and subcortico-subcortical functional and structural connectivity data are available from the ENIGMA Toolbox (https://enigma-toolbox.readthedocs.io/en/latest/). Molecular, connectivity, and receptor datasets are available from https://github.com/netneurolab/hansen_crossdisorder_vulnerability.git and https://github.com/netneurolab/hansen_receptors.git. Additional information can be made available upon reasonable request to the authors.; Code availability: All software and analysis code used in this study are openly available. Image preprocessing pipelines are available through the ENIGMA consortium (https://github.com/ENIGMA-git). Statistical analyses were performed in R (version 3.6.0), including partial correlation analyses using pcor.test and random-effects meta-analyses using the metafor package (rma function). Spatial correlation, hub, and epicenter analyses were conducted using the ENIGMA Toolbox (https://enigma-toolbox.readthedocs.io/en/latest/). Dominance analysis was performed with the domir package (version 1.2.0; 10.32614/CRAN.package.domir).; Supplementary information is available online at: https://www.nature.com/articles/s41380-026-03547-x#Sec24 . Sat, 18 Apr 2026 00:00:00 GMT http://bura.brunel.ac.uk/handle/2438/33232 2026-04-18T00:00:00Z http://bura.brunel.ac.uk/handle/2438/33221 Title: Rewiring lipid metabolism: A novel approach to overcome drug resistance in multiple myeloma Authors: Almarzouq, A; Kaci, FN; Lepore, A; Besse, A; Mohammad, A; Zhang, X; Driessen, C; Besse, L; Papa, S; Bubici, C Abstract: Despite significant therapeutic advancements in multiple myeloma (MM) treatment, which have improved patient outcomes and extended survival, most patients experience relapse or are non-responsive to therapy, leading to relapsed/refractory multiple myeloma (RRMM). The disease's complex progression, driven by intricate molecular mechanisms and genetic alterations, contributes to its resistance phenotype, underscoring an urgent need for innovative strategies to improve patient outcomes. Myeloma cells undergo extensive metabolic reprogramming to sustain rapid proliferation and survival. A key feature of this reprogramming is altered lipid metabolism, particularly the dysregulation of de novo fatty acid synthesis. Recent studies have identified de novo lipogenesis (DNL) as a critical metabolic vulnerability in MM. In our study, we characterized a novel de novo lipogenesis inhibitor (DNL-I) designed to target lipid metabolism in MM. DNL-I disrupts lipid homeostasis by selectively inhibiting de novo lipogenesis, the biosynthetic pathway responsible for endogenous fatty acid production. Our findings demonstrate that DNL-I potently induces apoptosis in both MM cells sensitive to standard therapies and those resistant to proteasome inhibitors (PI). The apoptotic effect was dose-dependent, with increasing concentrations of DNL-I correlating with enhanced cell death across multiple MM cell lines. Mechanistically, we found that DNL-I downregulates the expression of key enzymes involved in fatty acid synthesis, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), without altering the expression or activity of enzymes associated with fatty acid β-oxidation, such as carnitine palmitoyltransferase 1 (CPT1). This selective inhibition confirms that DNL-I specifically targets de novo lipogenesis, a pathway increasingly recognized as a vulnerability in cancer cells reliant on lipid availability for membrane biogenesis and signalling. Particularly, we conducted rescue experiments to validate the role of lipid depletion in DNL-I's mechanism of action. Supplementing MM cells with an exogenous lipid mixture containing arachidonic, linoleic, linolenic, myristic, oleic, palmitic, and stearic acids fully reversed DNL-I-induced apoptosis in both sensitive and PI-resistant MM cell lines. This reversal suggests that the cytotoxic effects of DNL-I stem directly from its disruption of lipid availability, which is essential for MM cell survival and proliferation. Notably, untargeted metabolomic analyses of DNL-I-treated MM cells revealed significant alterations in amino acid metabolism, the tricarboxylic acid (TCA) cycle, and sphingolipid metabolism, all of which are essential for MM cell survival. These findings highlight the therapeutic potential of targeting de novo lipogenesis in MM, particularly for overcoming resistance to proteasome inhibitors, and underscore the importance of lipid metabolism as a novel therapeutic target in this disease. Description: Authors note: CB and SP are co-senior authors and correspondence should be addressed to: s.papa@leeds.ac.uk or concetta.bubici@brunel.ac.uk .; At head ot abstract title: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational Mon, 03 Nov 2025 00:00:00 GMT http://bura.brunel.ac.uk/handle/2438/33221 2025-11-03T00:00:00Z http://bura.brunel.ac.uk/handle/2438/33209 Title: Synuclein Disorder‐Related Genetic Determinants of Mild Behavioural Impairment in a Pre‐Clinical Community Cohort Authors: Sander‐Long, M; Creese, B; Corbett, A; Rosenzweig, I; Cummings, J; Ballard, C Abstract: Background: The GBA variant confers increased risk of synuclein disorders but it is unclear what impact it has in pre-clinical groups. This study aimed to identify early psychiatric and cognitive manifestations amongst pre-clinical GBA carriers in a community cohort. Method: This study used data from the PROTECT-UK cohort to compare 388 GBA carriers (N370S, E326K and T369M) without Parkinson's disease to age-matched controls. Neuropsychiatric symptoms (NPS) were measured with the Mild Behaviour Impairment Checklist, and cognition was measured using computerised neuropsychology. Results: Results: GBA carriers over 70 had significantly increased NPS compared with controls (z = 2.13, p = 0.03). There was no difference between carriers and non-carriers in younger individuals but a sub-group comparison in the overall cohort showed that NPS were more severe in quartile four (Q4) of carriers compared to Q4 of controls (z = 2.39, p = 0.017), indicating an increase in NPS in this sub-group across a broader age range. No differences in cognition were seen. Discussion: These findings suggest that NPS may be an early clinical manifestation of emerging synucleinopathy amongst individuals prior to diagnosis. Key Points: * This study examines neuropsychiatric symptoms in pre-clinical carriers of GBA variants * GBA carriers over 70 years old show significantly more pre-clinical neuropsychiatric symptoms, and carrier status is linked to severity of symptoms * Neuropsychiatric symptoms may be an early clinical manifestation of emerging synucleinopathy amongst pre-clinical carriers, raising the potential for early risk profiling based on genetic status Description: Data Availability Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.; Supporting Information is available online at: https://onlinelibrary.wiley.com/doi/full/10.1002/gps.70189#support-information-section . Thu, 19 Mar 2026 00:00:00 GMT http://bura.brunel.ac.uk/handle/2438/33209 2026-03-19T00:00:00Z http://bura.brunel.ac.uk/handle/2438/33208 Title: Neuropsychiatric symptoms and their impact on cognitive functioning in patients with Parkinson's disease: A systematic review of the literature Authors: Blasutto, B; Matrone, G; Creese, B; Fattapposta, F; Casagrande, M Abstract: Parkinson's disease (PD) is a progressive, neurodegenerative disorder that affects the dopaminergic system and is characterized by motor and nonmotor symptoms, which affect the quality of life. Among these, neuropsychiatric symptoms (NPS), such as depression, hallucinations, and apathy, are common and can accelerate cognitive decline. Although the association between some specific NPS (e.g., apathy) and cognitive functions has been investigated, no review has systematically examined the relationship between the whole of NPS and cognitive functions in PD patients without dementia. Therefore, the purpose of this study was to analyze the relationship between NPS taken together and cognitive impairment in patients with PD. According to the PRISMA-Statement, this systematic review critically examined the difference in cognitive performance between patients diagnosed with idiopathic PD with and without NPS. Results were classified according to the cognitive domain evaluated. Eleven studies met the eligibility criteria. The results showed that PD patients with NPS showed impaired performance on cognitive tasks compared with those without NPS, as well as in longitudinal studies. These results were also confirmed when the different domains were considered separately. Despite the limited number of included studies, the importance of assessing NPS in their totality rather than individual behavioral symptoms emerges. Clinical manifestations may vary among individuals and across different stages of the disease. Therefore, assessing the presence of these symptoms and the timing of their onset would be appropriate and may give the clinician important insights into the possible course and management of the disease. Description: Availability of data and materials: Data or materials for the manuscript are available upon request.; Code availability: Not applicable. Thu, 26 Mar 2026 00:00:00 GMT http://bura.brunel.ac.uk/handle/2438/33208 2026-03-26T00:00:00Z