| 1. |
- Schijven, Dick, et al.
(författare)
-
Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium
- 2023
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 120:14
-
Tidskriftsartikel (refereegranskat)abstract
- Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
|
|
| 2. |
- Alnaes, Dag, et al.
(författare)
-
Brain Heterogeneity in Schizophrenia and Its Association With Polygenic Risk
- 2019
-
Ingår i: JAMA psychiatry. - : AMER MEDICAL ASSOC. - 2168-6238 .- 2168-622X. ; 76:7, s. 739-748
-
Tidskriftsartikel (refereegranskat)abstract
- ImportanceBetween-individual variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients with schizophrenia. However, group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature. ObjectivesTo compare brain structural variability between individuals with schizophrenia and healthy controls and to test whether respective variability reflects the polygenic risk score (PRS) for schizophrenia in an independent sample of healthy controls. Design, Setting, and ParticipantsThis case-control and polygenic risk analysis compared MRI-derived cortical thickness and subcortical volumes between healthy controls and patients with schizophrenia across 16 cohorts and tested for associations between PRS and MRI features in a control cohort from the UK Biobank. Data were collected from October 27, 2004, through April 12, 2018, and analyzed from December 3, 2017, through August 1, 2018. Main Outcomes and MeasuresMean and dispersion parameters were estimated using double generalized linear models. Vertex-wise analysis was used to assess cortical thickness, and regions-of-interest analyses were used to assess total cortical volume, total surface area, and white matter, subcortical, and hippocampal subfield volumes. Follow-up analyses included within-sample analysis, test of robustness of the PRS threshold, population covariates, outlier removal, and control for image quality. ResultsA comparison of 1151 patients with schizophrenia (mean [SD] age,33.8[10.6] years; 68.6% male [n=790] and 31.4% female [n=361]) with 2010 healthy controls (mean [SD] age,32.6[10.4] years; 56.0% male [n=1126] and 44.0% female [n=884]) revealed higher heterogeneity in schizophrenia for cortical thickness and area (t = 3.34), cortical (t=3.24) and ventricle (t range, 3.15-5.78) volumes, and hippocampal subfields (t range, 2.32-3.55). In the UK Biobank sample of 12 490 participants (mean [SD] age,55.9 [7.5] years; 48.2% male [n=6025] and 51.8% female [n=6465]), higher PRS was associated with thinner frontal and temporal cortices and smaller left CA2/3 (t=-3.00) but was not significantly associated with dispersion. Conclusions and RelevanceThis study suggests that schizophrenia is associated with substantial brain structural heterogeneity beyond the mean differences. These findings may reflect higher sensitivity to environmental and genetic perturbations in patients, supporting the heterogeneous nature of schizophrenia. A higher PRS was associated with thinner frontotemporal cortices and smaller hippocampal subfield volume, but not heterogeneity. This finding suggests that brain variability in schizophrenia results from interactions between environmental and genetic factors that are not captured by the PRS. Factors contributing to heterogeneity in frontotemporal cortices and hippocampus are key to furthering our understanding of how genetic and environmental factors shape brain biology in schizophrenia.
|
|
| 3. |
- Becklén, Meneca, et al.
(författare)
-
Plasma bilirubin levels are reduced in first-episode psychosis patients and associates to working memory and duration of untreated psychosis.
- 2021
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a severe mental disorder and one of its characteristics is cognitive impairments. Findings regarding levels of the heme metabolite and plasma antioxidant bilirubin in schizophrenia are inconclusive. However, a recently published study indicate that low levels of bilirubin may be implicated in the memory impairments seen in the disorder. The aim of this cross-sectional study was to investigate the levels of bilirubin in individuals with a first-episode psychosis (FEP) and to examine if bilirubin levels were associated to cognitive impairments, symptoms and duration of untreated psychosis (DUP). Bilirubin levels were reduced in 39 individuals with FEP compared with 20 HC (median [IQR]: 11.0 [9.0-13.0] µM vs. 15.0 [11.5-18.5] µM). In individuals with FEP, bilirubin levels were also positively correlated to two working memory tests (r = 0.40 and r = 0.32) and inversely correlated to DUP (r = - 0.36). Findings were not influenced by confounding factors. The results confirm the antioxidant deficit previously seen in schizophrenia, but also indicate that these changes may be related to DUP. The study also confirms that bilirubin may be implicated in the cognitive deficits that accompanies the disorder, here for the first time presented in individuals with FEP.
|
|
| 4. |
- Eren, Feride, et al.
(författare)
-
Immunological protein profiling of first-episode psychosis patients identifies CSF and blood biomarkers correlating with disease severity
- 2023
-
Ingår i: Brain, behavior, and immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 111, s. 376-385
-
Tidskriftsartikel (refereegranskat)abstract
- Background and HypothesisImmune activation is suggested to play an important role in psychosis. In this study, a large number of immune-related proteins were analyzed to obtain a more comprehensive picture of immune aberrations in schizophrenia.Study DesignNinety-two immune markers were analyzed by the Olink Protein Extension Assay (Inflammatory Panel) in plasma and cerebrospinal fluid (CSF) from 77 first-episode psychosis (FEP) patients (of which 43 later received the diagnosis of schizophrenia) and 56 healthy controls, all recruited from the Karolinska Schizophrenia Project (KaSP), Stockholm, Sweden.Study ResultsDifferential analysis showed that 12 of 92 inflammatory proteins were significantly higher in the plasma of FEP patients (n = 77) than in controls, and several proteins were positively correlated with disease severity. Patients from the same cohort diagnosed with schizophrenia (n = 43), showed significantly higher levels of 15 plasma proteins compared to controls whereas those not receiving this diagnosis showed no significant differences. The presently used OLINK inflammatory panel allowed the detection of only 47 CSF proteins of which only CD5 differed between patients and controls.ConclusionsThe levels of several peripheral immune markers, particularly those interfering with WNT/β-catenin signaling, were significantly higher in patients with FEP than in healthy controls and associated with illness severity.
|
|
| 5. |
- Gutman, Boris A, et al.
(författare)
-
A meta-analysis of deep brain structural shape and asymmetry abnormalities in 2,833 individuals with schizophrenia compared with 3,929 healthy volunteers via the ENIGMA Consortium
- 2022
-
Ingår i: Human Brain Mapping. - : John Wiley & Sons. - 1065-9471 .- 1097-0193. ; 43:1, s. 352-372
-
Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.
|
|
| 6. |
- Haroon, Humza, et al.
(författare)
-
Cerebrospinal fluid proteomic signatures are associated with symptom severity of first-episode psychosis
- 2024
-
Ingår i: Journal of Psychiatric Research. - : Elsevier. - 0022-3956 .- 1879-1379. ; 171, s. 306-315
-
Tidskriftsartikel (refereegranskat)abstract
- Apart from their diagnostic, monitoring, or prognostic utility in clinical settings, molecular biomarkers may be instrumental in understanding the pathophysiology of psychiatric disorders, including schizophrenia. Using untargeted metabolomics, we recently identified eight cerebrospinal fluid (CSF) metabolites unique to first-episode psychosis (FEP) subjects compared to healthy controls (HC). In this study, we sought to investigate the CSF proteomic signatures associated with FEP. We employed 16-plex tandem mass tag (TMT) mass spectrometry (MS) to examine the relative protein abundance in CSF samples of 15 individuals diagnosed with FEP and 15 age-and-sex-matched healthy controls (HC). Multiple linear regression model (MLRM) identified 16 differentially abundant CSF proteins between FEP and HC at p < 0.01. Among them, the two most significant CSF proteins were collagen alpha-2 (IV) chain (COL4A2: standard mean difference [SMD] = -1.12, p = 1.64 × 10-4) and neuron-derived neurotrophic factor (NDNF: SMD = -1.03, p = 4.52 × 10-4) both of which were down-regulated in FEP subjects compared to HC. We also identified several potential CSF proteins associated with the pathophysiology and the symptom profile and severity in FEP subjects, including COL4A2, NDNF, hornerin (HRNR), contactin-6 (CNTN6), voltage-dependent calcium channel subunit alpha-2/delta-3 (CACNA2D3), tropomyosin alpha-3 chain (TPM3 and TPM4). Moreover, several protein signatures were associated with cognitive performance. Although the results need replication, our exploratory study suggests that CSF protein signatures can be used to increase the understanding of the pathophysiology of psychosis.
|
|
| 7. |
- Koskuvi, Marja, et al.
(författare)
-
Lower complement C1q levels in first-episode psychosis and in schizophrenia
- 2024
-
Ingår i: Brain, Behavior, and Immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 117, s. 313-319
-
Tidskriftsartikel (refereegranskat)abstract
- Recent evidence has implicated complement component (C) 4A in excessive elimination of synapses in schizophrenia. C4A is believed to contribute to physiological synapse removal through signaling within the C1q initiated classical activation axis of the complement system. So far, a potential involvement of C1q in the pathophysiology of schizophrenia remains unclear. In this study, we first utilized large-scale gene expression datasets (n = 586 patients with schizophrenia and n = 986 controls) to observe lower C1QA mRNA expression in prefrontal cortex tissue of individuals with schizophrenia (P = 4.8x10-05), while C1QA seeded co-expression networks displayed no enrichment for schizophrenia risk variants beyond C4A. We then used targeted liquid chromatography-mass spectrometry (LS-MS) to measure cerebrospinal fluid (CSF) levels of C1qA in 113 individuals with first-episode psychosis (FEP), among which 66 individuals was later diagnosed with schizophrenia, and 87 healthy controls. CSF concentrations of C1qA were lower in individuals diagnosed with FEP (P = 0.0001), also after removing subjects with a short-term prescription of an antipsychotic agent (P = 0.0005). We conclude that C1q mRNA and protein levels are lower in schizophrenia and that further experimental studies are needed to understand the functional implications.
|
|
| 8. |
- Larsson, Cornelia, et al.
(författare)
-
Facial affect recognition in first-episode psychosis is impaired but not associated with psychotic symptoms.
- 2022
-
Ingår i: Heliyon. - : Elsevier. - 2405-8440. ; 8:9
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Social dysfunction is a key feature of psychotic disorders such as schizophrenia linked to disability. Less is known about social functioning in the early stages of the disorder and if there is an association to psychotic symptoms.Aims: Investigate if antipsychotic drug-naïve or briefly medicated individuals with first-episode psychosis (FEP), have impaired facial affect recognition (FAR) compared to control participants and if psychotic symptoms are associated with the FAR ability.Method: Individuals with FEP (n = 67) and control participants (n = 51) performed a computer-aided FAR task on basic emotions. Psychotic symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Group performances were compared using age and gender as covariates. The associations between FAR and performance on the subscales of PANSS were analyzed.Results: Compared to control participants, individuals with FEP were impaired in general FAR (Beta = -2.04 [95 % conf: -3.75/-1.62], p < 0.001) and FAR of negative emotions (Beta = -1.74 [95 % conf: -3.08/-1.22], p < 0.001), driven by difficulties in recognition of anger and disgust. In both groups, there was a pattern of mistaking negative emotions for other negative emotions. There were no significant group differences in FAR of happiness. No significant associations between FAR and psychotic symptoms were observed.Discussion: The results indicate that FAR, an underlying mechanism of social functioning is impaired early in the course of psychotic disorders. Current findings do not support the hypothesis that misinterpretation of facial expressions in individuals with FEP underlies or contributes to symptoms of psychosis.
|
|
| 9. |
- Lee, Maria, et al.
(författare)
-
Cognitive Function and Variability in Antipsychotic Drug-Naive Patients With First-Episode Psychosis : A Systematic Review and Meta-Analysis.
- 2024
-
Ingår i: JAMA psychiatry. - 2168-6238.
-
Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: Cognitive impairment contributes significantly to clinical outcome and level of function in individuals with psychotic disorders. These impairments are present already at psychosis onset at a group level; however, the question of heterogeneity in cognitive function among patients has not been systematically investigated.OBJECTIVE: To provide an updated quantification of cognitive impairment at psychosis onset before patients receive potentially confounding antipsychotic treatment, and to investigate variability in cognitive function compared with healthy controls.DATA SOURCES: In this systematic review and meta-analysis, PubMed articles were searched up to September 15, 2022.STUDY SELECTION: Original studies reporting data on cognitive function in antipsychotic drug-naive patients with first-episode psychosis (FEP) were included.DATA EXTRACTION AND SYNTHESIS: Data were independently extracted by 2 researchers. Cognitive tasks were clustered according to 6 domains of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery and the domain of executive function. Random-effects model meta-analyses of mean differences and coefficient of variation ratios (CVRs) were performed, as well as meta-regressions, assessment of study quality, and publication bias.MAIN OUTCOMES AND MEASURES: The main outcome measure was Hedges g for mean differences in cognition and CVR for within-group variability.RESULTS: Fifty studies were included in the analysis with a total of 2625 individuals with FEP (mean [SD] age, 25.2 [3.6] years, 60% male; 40% female) and 2917 healthy controls (mean [SD] age, 26.0 [4.6]; 55% male; 45% female). In all cognitive domains, the FEP group displayed significant impairment compared with controls (speed of processing: Hedges g = -1.16; 95% CI, -1.35 to -0.98; verbal learning: Hedges g = -1.08; 95% CI, -1.28 to -0.88; visual learning: Hedges g = -1.05; 95% CI, -1.27 to -0.82; working memory: Hedges g = -1.04; 95% CI, -1.35 to -0.73; attention: Hedges g = -1.03; 95% CI, -1.24 to -0.82; reasoning/problem solving: Hedges g = -0.90; 95% CI, -1.12 to -0.68; executive function: Hedges g = -0.88; 95% CI, -1.07 to -0.69). Individuals with FEP also exhibited a larger variability across all domains (CVR range, 1.34-1.92).CONCLUSIONS AND RELEVANCE: Results of this systematic review and meta-analysis identified cognitive impairment in FEP before the initiation of antipsychotic treatment, with large effect sizes. The high variability within the FEP group suggests the need to identify those individuals with more severe cognitive problems who risk worse outcomes and could benefit the most from cognitive remediation.
|
|
| 10. |
- Lee, Maria, et al.
(författare)
-
No association between cortical dopamine D2 receptor availability and cognition in antipsychotic-naive first-episode psychosis
- 2021
-
Ingår i: NPJ SCHIZOPHRENIA. - : Springer Nature. - 2334-265X. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- Cognitive impairment is an important predictor of disability in schizophrenia. Dopamine neurotransmission in cortical brain regions has been suggested to be of importance for higher-order cognitive processes. The aim of this study was to examine the relationship between extrastriatal dopamine D2-R availability and cognitive function, using positron emission tomography and the high-affinity D2-R radioligand [C-11]FLB 457, in an antipsychotic-naive sample of 18 first-episode psychosis patients and 16 control subjects. We observed no significant associations between D2-R binding in the dorsolateral prefrontal cortex or hippocampus (beta = 0.013-0.074, partial r= -0.037-0.273, p = 0.131-0.841). Instead, using Bayesian statistics, we found moderate support for the null hypothesis of no relationship (BFH0:H1 = 3.3-8.2). Theoretically, our findings may suggest a lack of detrimental effects of D2-R antagonist drugs on cognition in schizophrenia patients, in line with clinical observations.
|
|
