Inflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders

JAMA Psychiatry, Journal Year: 2022, Volume and Issue: 79(5), P. 498 - 498

Published: March 30, 2022

Importance

Previous in vitro and postmortem research suggests that inflammation may lead to structural brain changes via activation of microglia and/or astrocytic dysfunction a range neuropsychiatric disorders.

Objective

To investigate the relationship between structures vivo explore transcriptome-driven functional basis with relevance mental illness.

Design, Setting, Participants

This study used multistage linked analyses, including mendelian randomization (MR), gene expression correlation, connectivity analyses. A total 20 688 participants UK Biobank, which includes clinical, genomic, neuroimaging data, 6 brains from neurotypical individuals Allen Human Brain Atlas (AHBA), RNA microarray data. Data were extracted February 2021 analyzed March October 2021.

Exposures

Genetic variants regulating levels activity circulating interleukin 1 (IL-1), IL-2, IL-6, C-reactive protein (CRP), brain-derived neurotrophic factor (BDNF) as exposures MR

Main Outcomes Measures

imaging measures, gray matter volume (GMV) cortical thickness (CT), outcomes. Associations considered significant at multiple testing–corrected threshold ofP < 1.1 × 10⁻⁴. Differential AHBA data was modeled regions mapped areas analyses; genes tested for biological disease overrepresentation annotation databases protein-protein interaction networks.

Results

Of Biobank sample, 10 828 (52.3%) female, mean (SD) age 55.5 (7.5) years. In genetically predicted IL-6 associated GMV middle temporal cortex (zscore, 5.76;P = 8.39 10⁻⁹), inferior (z score, 3.38;P 7.20 10⁻⁵), fusiform 4.70;P 2.60 10⁻⁷), frontal −3.59;P 3.30 10⁻⁵) together CT superior region −5.11;P 3.22 10⁻⁷). No associations found IL-1, CRP, or BDNF after correction comparison. 5 (83%) male, 42.5 (13.4) Brain-wide coexpression analysis showed highly interconnected network preferentially expressed gyrus (MTG), further formed connected (enrichment test expected vs observed given prevalence degree interactions STRING database: 43 nodes/30 edges 8 expected; node degree, 1.4; genome-wide significance,P 4.54 10⁻⁹). MTG differentially functionally enriched processes schizophrenia, autism spectrum disorder, epilepsy.

Conclusions Relevance

this study, determined structure potentially affects implicated developmental disorders, schizophrenia autism.

Language: Английский

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Towards a youth mental health paradigm: a perspective and roadmap

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(8), P. 3171 - 3181

Published: Aug. 1, 2023

Abstract Most mental disorders have a typical onset between 12 and 25 years of age, highlighting the importance this period for pathogenesis, diagnosis, treatment ill-health. This perspective addresses interactions risk protective factors brain development as key pillars accounting emergence psychopathology in youth. Moreover, we propose that novel approaches towards early diagnosis interventions are required reflect evolution emerging psychopathology, service models, knowledge exchange science practitioners. Taken together, transformative intervention paradigm research clinical care could significantly enhance health young people initiate shift prevention severe disorders.

Language: Английский

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The synaptic hypothesis of schizophrenia version III: a master mechanism

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(5), P. 1843 - 1856

Published: April 11, 2023

Abstract The synaptic hypothesis of schizophrenia has been highly influential. However, new approaches mean there a step-change in the evidence available, and some tenets earlier versions are not supported by recent findings. Here, we review normal development from structural functional imaging post-mortem studies that this is abnormal people at risk with schizophrenia. We then consider mechanism could underlie changes update hypothesis. Genome-wide association have identified number variants converging on pathways regulating elimination, formation plasticity, including complement factors microglial-mediated pruning. Induced pluripotent stem cell demonstrated patient-derived neurons show pre- post-synaptic deficits, signalling alterations, elevated, complement-dependent elimination structures compared to control-derived lines. Preclinical data environmental linked schizophrenia, such as stress immune activation, can lead synapse loss. Longitudinal MRI patients, prodrome, divergent trajectories grey matter volume cortical thickness controls, PET shows vivo for lower density patients Based evidence, propose version III This multi-hit model, whereby genetic and/or render synapses vulnerable excessive glia-mediated triggered during later neurodevelopment. loss disrupts pyramidal neuron function cortex contribute negative cognitive symptoms disinhibits projections mesostriatal regions dopamine overactivity psychosis. It accounts typical onset adolescence/early adulthood, its major factors, symptoms, identifies potential synaptic, microglial targets treatment.

Language: Английский

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Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes

Neuropsychopharmacology, Journal Year: 2022, Volume and Issue: 48(1), P. 151 - 167

Published: Sept. 2, 2022

Abstract Over the last five decades, a large body of evidence has accrued for structural and metabolic brain alterations in schizophrenia. Here we provide an overview these findings, focusing on measures that have traditionally been thought to reflect synaptic spine density or activity are relevant understanding if there is lower disorder. We conducted literature searches identify meta-analyses other studies patients with chronic first-episode schizophrenia, people at high genetic clinical risk psychosis. identified 18 including over 50,000 subjects total, covering: MRI gyrification index, grey matter volume, cortical thickness, neurite orientation dispersion imaging, PET imaging regional glucose metabolism magnetic resonance spectroscopy N-acetylaspartate. also review preclinical relationship between ex vivo protein 2A (SV2A). These show schizophrenia associated volumes accelerated loss time, abnormal patterns, SV2A levels markers comparison controls (effect sizes from ~ −0.11 −1.0). Key regions affected include frontal, anterior cingulate temporal cortices hippocampi. several limitations interpretation findings terms alterations. Nevertheless, taken post-mortem they suggest some regions. However, gaps evidence, particular whether generalise cohorts.

Language: Английский

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The schizophrenia syndrome, circa 2024: What we know and how that informs its nature

Schizophrenia Research, Journal Year: 2023, Volume and Issue: 264, P. 1 - 28

Published: Dec. 12, 2023

Language: Английский

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Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(6), P. 1869 - 1881

Published: Feb. 9, 2024

Abstract Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying layout. We tested large-scale structural in schizophrenia relate to normative and functional connectome architecture, systematically evaluated robustness generalizability of network-level alterations. Leveraging anatomical MRI scans from 2439 adults 2867 healthy controls 26 ENIGMA sites data Human Connectome Project ( n = 207), we against two susceptibility models: (i) hub vulnerability, which examines associations between regional centrality magnitude disease-related alterations; (ii) epicenter mapping, identifies regions whose typical connectivity profile most closely resembles morphological To assess specificity, contextualized influence site, disease stages, individual clinical factors compared that found affective disorders. Our findings show schizophrenia-related cortical thinning spatially associated hubs, suggesting highly interconnected are more vulnerable Predominantly temporo-paralimbic frontal emerged as epicenters profiles linked schizophrenia’s alteration patterns. Findings were robust across sites, related symptoms. Moreover, transdiagnostic comparisons revealed overlapping bipolar, but not major depressive disorder, suggestive pathophysiological continuity within schizophrenia-bipolar-spectrum. In sum, over course follow brain emphasizing marked temporo-frontal at both level group individual. Subtle variations stages suggest interacting pathological processes, while patient-specific symptoms support additional inter-individual variability vulnerability schizophrenia. work outlines potential pathways better understand macroscale inter-

Language: Английский

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The MR neuroimaging protocol for the Accelerating Medicines Partnership® Schizophrenia Program

Schizophrenia, Journal Year: 2025, Volume and Issue: 11(1)

Published: April 2, 2025

Abstract Neuroimaging with MRI has been a frequent component of studies individuals at clinical high risk (CHR) for developing psychosis, goals understanding potential brain regions and systems impacted in the CHR state identifying prognostic or predictive biomarkers that can enhance our ability to forecast outcomes. To date, most involving are likely not sufficiently powered generate robust generalizable neuroimaging results. Here, we describe prospective, advanced, modern protocol was implemented complex multi-site, multi-vendor environment, as part large-scale Accelerating Medicines Partnership® Schizophrenia Program (AMP® SCZ), including rationale various choices. This includes T1- T2-weighted structural scans, resting-state fMRI, diffusion-weighted imaging collected two time points, approximately 2 months apart. We also present preliminary variance analyses several measures, such signal- contrast-to-noise ratio (SNR/CNR) spatial smoothness, provide quantitative data on relative percentages participant, site, platform (i.e., scanner model) variance. Site-related is generally small (typically <10%). For SNR/CNR measures from fMRI participant largest (as desired; 40–76%). However, diffusion there substantial platform-related (>55%) due differences hardware capabilities different scanners. Also, smoothness large inherent, difficult control, between vendors their acquisitions reconstructions. These results illustrate some factors will need be considered AMP SCZ data, which cohort date. Watch Dr. Harms discuss this article https://vimeo.com/1059777228?share=copy#t=0 .

Language: Английский

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Cross disorder comparisons of brain structure in schizophrenia, bipolar disorder, major depressive disorder, and 22q11.2 deletion syndrome: A review of ENIGMA findings

Psychiatry and Clinical Neurosciences, Journal Year: 2022, Volume and Issue: 76(5), P. 140 - 161

Published: Feb. 4, 2022

This review compares the main brain abnormalities in schizophrenia (SZ), bipolar disorder (BD), major depressive (MDD), and 22q11.2 Deletion Syndrome (22q11DS) determined by ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) consortium investigations. We obtained ranked effect sizes for subcortical volumes, regional cortical thickness, surface area, diffusion tensor imaging abnormalities, comparing each of these disorders relative to healthy controls. In addition, studies report on significant associations between metrics disorder-related factors such as symptom severity treatments. Visual comparison size profiles shows that are generally same direction scale with (in order SZ > BD MDD). The 22q11DS, a rare genetic syndrome increases risk psychiatric disorders, appear be much larger than either complex disorders. is consistent idea effects compared common variants. Cortical thickness area 22q11DS psychosis without more similar those MDD; pattern not observed structures fractional anisotropy sizes. similarities measures across mimic shared variance reported based family structural phenotypes.

Language: Английский

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Neurodevelopmental disturbances in schizophrenia: evidence from genetic and environmental factors

Journal of Neural Transmission, Journal Year: 2022, Volume and Issue: 130(3), P. 195 - 205

Published: Nov. 12, 2022

Abstract Since more than 3 decades, schizophrenia (SZ) has been regarded as a neurodevelopmental disorder. The hypothesis proposes that SZ is associated with genetic and environmental risk factors, which influence connectivity in neuronal circuits during vulnerable developmental periods. We carried out non-systematic review of genetic/environmental factors increase light its hypothesis. also reviewed the potential impact SZ-related on grey white matter pathology brain function based magnetic resonance imaging post-mortem studies. Finally, we studies have used patient-derived models to gain knowledge role early stages. Taken together, these indicate variety may interact pre- or postnatal period and/or adolescence induce symptoms adulthood. These disturbances macro- microconnectivity regions involving prefrontal, temporal parietal cortices hippocampus. On molecular cellular level, disturbed synaptic plasticity, loss oligodendrocytes impaired myelination shown patients. cellular/histological phenotypes are related such obstetric complications, maternal infections childhood trauma identified recent genome-wide association contribute active processes interfering plasticity adult brain. Advances stem cell technologies providing promising mechanistic insights into how developing Further research needed understand timing different complex biological taking place result interplay between factors.

Language: Английский

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Network-Based Spreading of Gray Matter Changes Across Different Stages of Psychosis

JAMA Psychiatry, Journal Year: 2023, Volume and Issue: 80(12), P. 1246 - 1246

Published: Sept. 20, 2023

Psychotic illness is associated with anatomically distributed gray matter reductions that can worsen progression, but the mechanisms underlying specific spatial patterning of these changes unknown.

Language: Английский

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