eRapport

Brain signature and early risk in youth with early-onset psychosis using new imaging methods, biomarkers, birth cohorts and national registries.

Prosjekt
Prosjektnummer
2020020
Ansvarlig person
Ingrid Agartz
Institusjon
Diakonhjemmet Sykehus AS
Prosjektkategori
Åpen prosjektstøtte
Helsekategori
Mental Health
Forskningsaktivitet
1. Underpinning, 2. Aetiology
Rapporter
2023 - sluttrapport
Adolescent early onset psychosis (EOP) is a rare and heterogeneous psychosis disorder, encompassing schizophrenia and affective psychosis spectrum. Symptoms emerge before 18 years of age. The mechanisms for how early life risk factors lead to psychosis and abnormal brain development are unknown as is the link between brain maturation and psychosis emergence. Neuroimaging studies of these co-occurring processes are important. Obstetric complications often describe the pre- and perinatal environment of offspring who later develop EOP. We used prospective data from the Medical Birth Registry of Norway, and clinical cohorts of patients with schizophrenia and bipolar disorder and healthy controls with brain imaging, genomic, and epigenomic data. Birth asphyxia was related to a higher genomic risk score for schizophrenia in patients, particularly the placental genomic risk score for schizophrenia (PlacGRS; based on placental gene expression), which was negatively associated with neonatal head size at birth. The findings suggest that exposure to birth asphyxia co-occurs with a higher genomic risk schizophrenia development. Genes that drive this interaction might be involved in abnormal cellular responses to hypoxic stress. We found differentially expressed placental and schizophrenia risk-associated genes in the caudate of patients (unpublished data) suggesting that genetic risk factors for schizophrenia might lead to alteration in brain development via placenta. An opposite epigenetic response to birth asphyxia found in patients across 4 DNA regions important for brain function and may contribute to a shared molecular risk mechanism for schizophrenia and bipolar disorder. Using advanced MRI methodology, we can determine relevant brain phenotypes for EOP development, in the absence of major confounders such as illness duration, pharmacological treatment exposure, and substance use. A barrier to this goal is the small to modest sample size of previous EOP studies and the heterogeneity of analytical methods. The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium increases statistical power by using standardized protocols for image processing, quality control, statistical analyses, and multi-site imaging data harmonization, and by pooling data from cohorts, worldwide. The project manager Ingrid Agartz and postdoctoral researcher Claudia Barth successfully lead the ENIGMA Early Onset Psychosis (EOP) Working Group (https://enigma.ini.usc.edu/ongoing/enigma-eop-working-group/). EOP pathophysiology is investigated by pooling datasets and using standardized processing protocols from currently 14 participating sites, spanning three continents, and including approximately 453 adolescents with EOP and 491 healthy adolescents, the largest EOP sample to date. So far, the effort resulted in three publications from our group (Gurholt et al. 2020, Barth et al. 2022, Si et al. 2024), including research on subcortical and cortical brain morphology as well as white matter microstructure. We demonstrated widespread brain structural alterations in adolescents with EOP relative to healthy adolescents, which were partly modulated by sex, age at onset, and medication. Ongoing projects are investigations of cortical deficits, including regional gray matter thickness, surface area, volume and local gyrification index, and patterns of structural brain alteration in EOP in relation to deficit patterns in other mental illnesses. With adult patients from the TOP-project we reported significantly smaller volumes in several thalamic nuclei in schizophrenia and more limited findings in bipolar disorders. Having more negative symptoms was associated with smaller pulvinar volumes. Neuron-specific enolase is an isoenzyme of the enzyme enolase occurring at a late event in neural differentiation, thus making it a specific neuronal marker and a useful index of neural maturation. This marker is lowered in both EOP and adult psychosis patients. Brain structure in adolescents with early-onset psychosis may show some unique features that are different from what is found in individuals with a more typical onset of psychosis in adulthood. The effects of antipsychotic medications on the brain at an early age need further consideration. Our findings further emphasize that the pre- and perinatal period as is an important area for treatment and prevention of severe mental illness. The pre- and perinatal period might be a time to improve clinical interventions that counteract birth asphyxia and promote care that enhances placental health and protects the early infant brain. Ingrid Agartz also spearheaded, together with Runar E. Smelror, an academic book on EOP, titled “Adolescent Psychosis – Clinical and Scientific Perspectives”, published by Elsevier Inc, USA, 2023. This book contains 13 chapters covering the main aspects of adolescent psychosis disorders. It will be useful in the diagnosis and treatment of psychosis disorders in the young and constitutes a bank of knowledge of adolescent psychosis for the researcher as well as the clinician and the interested individual.

Dr Wortinger ended a one-year visit to the Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, MD, USA in the summer of 2023. At the Lieber institute, she has advanced her research by acquiring new methods and investigated placental gene expression in postmortem brain tissue of patients with schizophrenia (SZ) and healthy controls. Based on our previous work where we found a more robust interaction between placental genomic risk scores for SZ (PlacGRS; an index of genomic risk for SZ based on gene expression in placenta) and birth asphyxia on case-control status and PlacGRS was negatively correlated with neonatal head size at birth in those who experienced birth asphyxia. We searched for the expression of placental genes associated with risk for SZ in the dorsal lateral prefrontal cortex (DLPFC), hippocampal and caudate regions of the brain. We found 27 differentially expressed placental and SZ risk-associated genes in the caudate of 167 patients with SZ compared to 236 healthy controls (unpublished data). The expression of SZ risk genes both in placenta and brain support the possibility that genetic variation contributes to risk for SZ through pleiotropic effects in different organs. Our findings suggest that genetic risk factors for SZ might lead to alteration in brain development via the placenta.

2022
We characterized brain white matter tracts using MR diffusion-weighted MR in hitherto largest study of adolescent psychosis. Placental genetic risk is associated with head size at birth in individuals with a history of birth asphyxia, with implications for disease vulnerability. CMV infection may be important to cognitive performance in psychosis.In 2022, the project manager Ingrid Agartz and the postdoctoral researcher Claudia Barth successfully led the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Early Onset Psychosis (EOP) Working Group as Chair and Co-Chair, respectively (https://enigma.ini.usc.edu/ongoing/enigma-eop-working-group/). This effort resulted in one publication in 2022, in Molecular Psychiatry. We found widespread lower fractional anisotropy, an indirect measure of brain white matter microstructure, in adolescents with EOP compared to healthy adolescent controls, with the largest effect sizes in the superior longitudinal fasciculus, posterior corona radiata and superior fronto-occipital fasciculus. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP sample to date (n = 321), our findings suggest a profile of widespread white microstructure alterations in adolescents with EOP, most prominently in male individuals with early onset schizophrenia and individuals with a shorter duration of illness. The results of this study were disseminated via Twitter (@molpsychiatry) and via the Nature Portfolio Health Community. The ENIGMA EOP Working Group was also coordinating other projects, which are ongoing. Researcher Laura Wortinger, investigated the role of the placenta in fetal brain development, as pregnancy and birth complications can be signs of placental dysfunction. Using national birth registry data from the Medical Birth Registry of Norway and the NORMENT TOP and Youth-TOP psychosis samples, she calculated polygenic risk scores (PRS) from the latest genome-wide association study in schizophrenia and differentiated placental PRS (PlacPRS) from non-placental PRS. We found that PlacPRS in individuals with a history of birth asphyxia was associated with a higher likelihood of being a patient with schizophrenia. Higher PlacPRS for schizophrenia was also associated with having a lower head circumference in those with birth asphyxia. This relationship was specific to males and was also found with their adult intracranial volumes (intracranial volume is a proxy for head size). The findings suggest that placental pathophysiology and birth asphyxia may affect early and late trajectories of brain development, particularly in males with a higher vulnerability to schizophrenia. This knowledge might lead to new strategies of treatment and prevention in schizophrenia. The study is available as a preprint at Research Square [https://doi.org/10.21203/rs.3.rs-1626382/v1]. We report that cytomegalovirus seropositive adolescent patients with non-affective psychos (CMV+) (mean IQ 91) had significantly lower full-scale IQ than CMV seronegative (CMV-) patients (mean IQ 110). Further, CMV+ patients had both lower performance and lower verbal IQ relative to CMV- patients. The effect sizes were larger compared to previous studies in adults with psychotic disorders indicating that adolescent patients might be particularly susceptible to a negative impact of CMV infection.

With a mobility grant from Helse Sør-Øst, Laura started a one-year visit in the fall of 2022 to the Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, MD, USA. At the Lieber institute, she is advancing her research by acquiring new methods and investigating placental gene expression in postmortem brain tissue of patients with SZ and healthy controls.

2021
In this project, we investigate a large array of MRI brain phenotypes in 12-18 years old adolescents with early-onset psychosis disorders. We use in-house clinical cohorts, and collaborating samples for large-scale analyses. We investigate how brain morphology and function are related with risk factors leading up to psychosis development in youth.There is a large knowledge gap for the adolescent early-onset psychosis affective and non-affective disorders (EOP) and bipolar disorders at all levels of understanding. Patient samples studied in adolescence (<19 years of age) have been too limited to reliably answering relevant research questions and psychosis disorders suffer problematic heterogeneity. To overcome this problem we have developed well-characterized clinical samples studied over time and coordinate international networks to achieve a sufficient numbers of participants. We use advanced MR methodology (e.g. brain structure and connectivity, myelin mapping) to characterize brain phenotypes and combine with psychosis risk markers i.e. obstetric complications (OCs) from the Norwegian Medical Birth Registry (MBRN) and polygenetic risk to systematize among clinical diversity and find the relevant subgroups. We show that in 500 adult schizophrenia and bipolar spectrum patients, 30% had severe OCs, of which birth asphyxia was most frequent (≥ 44%). Asphyxia was associated with smaller intracranial volume (ICV), lower global brain volumes and total surface area on MRI scans. A subset of the patients and healthy controls underwent diffusion-weighted imaging (DWI). The posterior limb of the internal capsule showed a significant diagnostic group × birth asphyxia interaction, reflecting a stronger association between birth asphyxia and compromised integrity of white matter microstructure among patients relative to controls. The results suggest a greater susceptibility to hypoxia in severe mental illness, which could lead to impeded brain development. We evaluated asphyxia for ICV and intelligence quotient (IQ) assessment and found indication that the positive correlation between ICV and IQ was stronger in patients with schizophrenia who experienced asphyxia, particularly for verbal intellectual abilities. ICV and verbal intellectual abilities may be clinically relevant markers that can be added to the prediction tools for schizophrenia risk evaluation. Cognitive performance was examined in 71 EOP patients relative to the healthy adolescent standardized scores for the MATRICS Consensus Cognitive Battery as we previously established. On a group level, the EOP patients performed worse than the reference group in all domains, most notably for speed of processing. The oldest age group showed largest impairments. This study provides a cognitive performance profile in EOP, stratified by age and sex, relative to adolescent standardized scores. We used resting state fMRI to compare the within-network functional connectivity in the default mode brain network (DMN) in the brain between 68 EOP patients and 95 controls. We found significantly weaker within-network DMN connectivity in patients, in widespread cortical brain areas. Affective psychosis patients deviated the most. Lithium and anticonvulsants but not antipsychotic medicine use predicted lower DMN connectivity scores. The Tau protein is necessary for microtubule cytoskeleton, which provides structural integrity throughout development. The plasma tau levels in EOP are low. A switch from non-neuronal enolase to neuron-specific enolase (NSE) occurs during neuronal maturation. NSE concentrations measured by enzyme immunoassay are lower in both adults (1000 patients and 900 controls) and adolescents (100 EOP patients and controls). The clinical importance of these neuronal biomarkers to EOP is yet to be determined.

NEI

2020
In this project, we investigate a large array of MRI brain phenotypes in 12-18 years old adolescents with early-onset psychosis disorders. We use in-house clinical cohorts, and collaborating samples for large-scale analyses. We investigate how brain morphology and function are related with risk factors leading up to psychosis development in youth.There is a large knowledge gap for the adolescent early-onset psychosis affective and non-affective disorders (EOP) and bipolar disorders at all levels of understanding. Patient samples studied in adolescence have been too limited to reliably answering relevant research questions and the psychosis disorders suffer problematic heterogeneity. To overcome this problem we have developed well-characterized clinical samples studied over time and coordinate a large international network to achieve a sufficient numbers of participants. We use advanced MR methodology (e.g. brain structure and connectivity, myelin mapping, free-water imaging) to characterize brain phenotypes and combine with psychosis risk markers such as early life and birth complications from the Norwegian Medical Birth Registry and polygenetic risk to systematize among clinical diversity and find the relevant subgroups. Using 3T diffusion weighted imaging we investigated differences in white matter microstructure and the impact of antipsychotic medication status in medicated and unmedicated the EOP patients relative to healthy controls. We calculated case-control differences in diffusion metrics and investigated association with antipsychotic medication. Fractional anisotropy (FA) is an indirect measure of co-linearity of fibers, and we found lower FA in the left genu of the corpus callosum, the left anterior corona radiata and the right superior longitudinal fasciculus in EOP patients relative to healthy controls. Mean FA in the left anterior corona radiata was showed higher FA values in medicated compared to unmedicated EOP patients. The present study is the first to link antipsychotic medication status to altered regional FA in the left anterior corona radiata, a region hypothesized to contribute to the etiology of psychosis. Since we used a limited sample, there is a need for replications for firm conclusions about putatively enhancing effects of antipsychotic medication on white matter microstructure in adolescent-onset psychosis. From multi-site collaboration, coordinated by us (ENIGMA-EOP; http://enigma.ini.usc.edu), we present new brain structure findings in the hitherto largest international sample of adolescent EOP patients from 11 international clinical EOP cohorts. This mega-analysis of 296 EOP patients (early-onset schizophrenia, n=183; affective psychosis, n=72; other psychosis, n=41) and 360 healthy controls showed significantly smaller intracranial volume (ICV) and hippocampus and larger caudate and lateral ventricles in patients. We find a similar profile of volumetric brain structure alterations as in adult psychosis with some notable exceptions; the relatively small ICV and large caudate volumes (Gurholt et al., 2020). The ICV showed the strongest effect size (Cohen’s d=-0.36), driven by EOS patients, but evidenced in all subgroups and was greater than found in large-scale ENIGMA consortium studies of adult patients with schizophrenia and bipolar disorder.

Dur to the corona situation there has been no site visit abroad during 2020.

Vitenskapelige artikler
Wortinger LA, Shadrin AA, Szabo A, Nerland S, Smelror RE, Jørgensen KN, Barth C, Andreou D, Thoresen M, Andreassen OA, Djurovic S, Ursini G, Agartz I

The impact of placental genomic risk for schizophrenia and birth asphyxia on brain development.

Transl Psychiatry 2023 Nov 08;13(1):343. Epub 2023 nov 8

PMID: 37938559

Barth C, Kelly S, Nerland S, Jahanshad N, Alloza C, Ambrogi S, Andreassen OA, Andreou D, Arango C, Baeza I, Banaj N, Bearden CE, Berk M, Bohman H, Castro-Fornieles J, Chye Y, Crespo-Facorro B, De la Serna E, Díaz-Caneja CM, Gurholt TP, Hegarty CE, James A, Janssen J, Johannessen C, Jönsson EG, Karlsgodt KH, Kochunov P, Lois NG, Lundberg M, Myhre AM, Pascual-Diaz S, Piras F, Smelror RE, Spalletta G, Stokkan TS, Sugranyes G, Suo C, Thomopoulos SI, Tordesillas-Gutiérrez D, Vecchio D, Wedervang-Resell K, Wortinger LA, Thompson PM, Agartz I

In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis.

Mol Psychiatry 2023 Mar;28(3):1159. Epub 2022 des 12

PMID: 36510004

Mørch-Johnsen L, Jørgensen KN, Barth C, Nerland S, Bringslid IK, Wortinger LA, Andreou D, Melle I, Andreassen OA, Agartz I

Thalamic nuclei volumes in schizophrenia and bipolar spectrum disorders - Associations with diagnosis and clinical characteristics.

Schizophr Res 2023 Jun;256():26. Epub 2023 apr 29

PMID: 37126979

Andreou D, Steen NE, Jørgensen KN, Smelror RE, Wedervang-Resell K, Nerland S, Westlye LT, Nærland T, Myhre AM, Joa I, Reitan SMK, Vaaler A, Morken G, Bøen E, Elvsåshagen T, Boye B, Malt UF, Aukrust P, Skrede S, Kroken RA, Johnsen E, Djurovic S, Andreassen OA, Ueland T, Agartz I

Lower circulating neuron-specific enolase concentrations in adults and adolescents with severe mental illness.

Psychol Med 2023 Mar;53(4):1479. Epub 2021 aug 11

PMID: 35387700

Nerland S, Stokkan TS, Jørgensen KN, Wortinger LA, Richard G, Beck D, Van der Meer D, Westlye LT, Andreassen OA, Agartz I, Barth C

A comparison of intracranial volume estimation methods and their cross-sectional and longitudinal associations with age.

Hum Brain Mapp 2022 Oct 15;43(15):4620. Epub 2022 jun 16

PMID: 35708198

Calkova T, Cervenka S, Yolken RH, Andreassen OA, Andreou D

Cytomegalovirus infection associated with lower IQ in adolescent patients with schizophrenia spectrum disorders: A preliminary report.

J Psychiatr Res 2022 Jul;151():571. Epub 2022 mai 24

PMID: 35636034

Wortinger LA, Barth C, Nerland S, Jørgensen KN, Shadrin AA, Szabo A, Haukvik UK, Westlye LT, Andreassen OA, Thoresen M, Agartz I

Association of Birth Asphyxia With Regional White Matter Abnormalities Among Patients With Schizophrenia and Bipolar Disorders.

JAMA Netw Open 2021 12 01;4(12):e2139759. Epub 2021 des 1

PMID: 34928356

Hilland E, Johannessen C, Jonassen R, Alnæs D, Jørgensen KN, Barth C, Andreou D, Nerland S, Wortinger LA, Smelror RE, Wedervang-Resell K, Bohman H, Lundberg M, Westlye LT, Andreassen OA, Jönsson EG, Agartz I

Aberrant default mode connectivity in adolescents with early-onset psychosis: A resting state fMRI study.

Neuroimage Clin 2022;33():102881. Epub 2021 nov 12

PMID: 34883402

Andreou D, Jørgensen KN, Nerland S, Smelror RE, Wedervang-Resell K, Johannessen CH, Myhre AM, Andreassen OA, Blennow K, Zetterberg H, Agartz I

Lower plasma total tau in adolescent psychosis: Involvement of the orbitofrontal cortex.

J Psychiatr Res 2021 Dec;144():255-261. Epub 2021 okt 20

PMID: 34700214

Wortinger LA, Jørgensen KN, Barth C, Nerland S, Smelror RE, Vaskinn A, Ueland T, Andreassen OA, Agartz I

Significant association between intracranial volume and verbal intellectual abilities in patients with schizophrenia and a history of birth asphyxia.

Psychol Med 2021 Mar 10. Epub 2021 mar 10

PMID: 33750510

Barth C, Nerland S, de Lange AG, Wortinger LA, Hilland E, Andreassen OA, Jørgensen KN, Agartz I

In Vivo Amygdala Nuclei Volumes in Schizophrenia and Bipolar Disorders.

Schizophr Bull 2021 08 21;47(5):1431-1441.

PMID: 33479754

Andreou D, Jørgensen KN, Nerland S, Engen K, Yolken RH, Andreassen OA, Agartz I

Cytomegalovirus infection associated with smaller dentate gyrus in men with severe mental illness.

Brain Behav Immun 2021 08;96():54-62. Epub 2021 mai 16

PMID: 34010712

Gurholt TP, Lonning V, Nerland S, Jørgensen KN, Haukvik UK, Alloza C, Arango C, Barth C, Bearden CE, Berk M, Bohman H, Dandash O, Díaz-Caneja CM, Edbom CT, van Erp TGM, Fett AJ, Frangou S, Goldstein BI, Grigorian A, Jahanshad N, James AC, Janssen J, Johannessen C, Karlsgodt KH, Kempton MJ, Kochunov P, Krabbendam L, Kyriakopoulos M, Lundberg M, MacIntosh BJ, Rund BR, Smelror RE, Sultan A, Tamnes CK, Thomopoulos SI, Vajdi A, Wedervang-Resell K, Myhre AM, Andreassen OA, Thompson PM, Agartz I,

Intracranial and subcortical volumes in adolescents with early-onset psychosis: A multisite mega-analysis from the ENIGMA consortium.

Hum Brain Mapp 2022 Jan;43(1):373. Epub 2020 okt 5

PMID: 33017498

Barth C, Lonning V, Gurholt TP, Andreassen OA, Myhre AM, Agartz I

Exploring white matter microstructure and the impact of antipsychotics in adolescent-onset psychosis.

PLoS One 2020;15(5):e0233684. Epub 2020 mai 29

PMID: 32470000

Andreou D, Steen NE, Jørgensen KN, Smelror RE, Wedervang-Resell K, ..... Agartz I.

Lower circulating neuron-specific enolase concentrations in adults and adolescents with severe mental illness

2021; Psychological Medicine 1–10. https://doi.org/10.1017/ S0033291721003056

Deltagere
  • Dimitrios Andreou Forsker (annen finansiering)
  • Eva Hilland Postdoktorstipendiat (annen finansiering)
  • Kjetil Nordbø Jørgensen Forsker (annen finansiering)
  • Stener Nerland Doktorgradsstipendiat (annen finansiering)
  • Claudia Barth Postdoktorstipendiat (finansiert av denne bevilgning)
  • Laura A Wortinger Bakke Forsker (finansiert av denne bevilgning)
  • Ingrid Agartz Prosjektleder

eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT

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