Age-related brain structural alterations as an intermediate phenotype of psychosis

Dukart, Juergen; Smieskova, Renata; Harrisberger, Fabienne; Lenz, Claudia; Schmidt, André; Walter, Anna; Huber, Christian G.; Riecher-Rössler, Anita; Simon, Andor E.; Lang, Undine E.; Fusar‐Poli, Paolo; Borgwardt, Stefan

doi:10.1503/jpn.160179

Cited by 34 publications

(23 citation statements)

References 67 publications

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“…Sixthly, due to the focus on the potential association between white matter volume and the polygenic schizophrenia-related risk score (PSRS) this study does not include a healthy control group but patients before and after the onset of psychosis. Finally, although there is a significant difference in age between the groups, we showed in previous study of grey matter volume and cortical thickness a similar pattern of structural alterations in ARMS and FEP [51]. However, this will not exclude the possibility that ARMS-NT patients will develop to ARMS-T or even FEP patients during the time-course.…”

Section: Discussioncontrasting

confidence: 65%

Impact on the Onset of Psychosis of a Polygenic Schizophrenia-Related Risk Score and Changes in White Matter Volume

Harrisberger

Smieskova

Egli

et al. 2018

Cell Physiol Biochem

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Background: Reductions in the volume of brain white matter are a common feature in schizophrenia and bipolar disorder while the association between white matter and polygenic schizophrenia-related risk is unclear. To look at the intermediate state between health and the full-blown disorder, we investigated this aspect in groups of patients before and after the onset of psychosis. Methods: On a 3 Tesla scanner, total and regional white matter volumes were investigated by structural magnetic resonance imaging (MRI) in the following groups: 37 at-risk mental state patients (ARMS), including 30 with no transition to psychosis (ARMS-NT) and 7 with a transition to psychosis (ARMS-T) pooled with 25 first episode psychosis (FEP) patients. These T₁-weighted images were automatically processed with the FreeSurfer software and compared with an odds-ratio-weighted polygenic schizophrenia-related risk score (PSRS) based on the publicly available top white matter single-nucleotide polymorphisms. Results: We found no association, only a trend, between PSRS and white matter volume over all groups (β = 0.24, p = 0.07, 95% confidence interval = [-0.02 – 0.49]). However, a higher PSRS was significantly associated with a higher probability of being assigned to the ARMS-T + FEP group rather than to the ARMS-NT group (β = 0.70, p = 0.02, 95% confidence interval = [0.14 – 1.33]); there was no such association with white matter volume. Additionally, a positive association was found between PSRS and the Brief Psychiatric Rating Scale (BPRS) total score for the pooled ARMS-NT/ARMS-T+FEP sample and for the ARMS-T + FEP group also, but none for the ARMS-NT group only. Conclusion: These findings suggest that at-risk mental state patients with a transition and first-episode psychosis patients have a higher genetic risk for schizophrenia than at-risk mental state patients with no transition to psychosis; this risk was associated with psychopathological symptoms. Further analyses may allow polygenic schizophrenia-related risk scores to be used as biomarkers to predict psychosis.

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Section: Discussioncontrasting

confidence: 65%

Impact on the Onset of Psychosis of a Polygenic Schizophrenia-Related Risk Score and Changes in White Matter Volume

Harrisberger

Smieskova

Egli

et al. 2018

Cell Physiol Biochem

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“…Different patterns of atrophy in the frontal cortex, cingulate cortex, parahippocampal gyri, the basal ganglia, and the thalamus has been reported from multiple groups in the past (Buchy, Makowski, Malla, Joober, & Lepage, 2018; Calvo, Delvecchio, Altamura, Soares, & Brambilla, 2019; Castro‐de‐Araujo & Kanaan, 2017; Kuang et al, 2017; Makowski et al, 2019; Nakamura et al, 2007; Schubert, Clark, & Baune, 2015; Tordesillas‐Gutierrez et al, 2018). The inverse trend (gray matter increase) has also been reported (Dukart et al, 2017). Data in resting state functional MRI (rs‐fMRI) that compare FEP patients with healthy controls (HC) are also controversial, varying from no differences between groups to regional or diffuse differences (Alonso‐Solis et al, 2012; Argyelan et al, 2015; Bang et al, 2018; Choe et al, 2018; Ganella et al, 2018; Gohel et al, 2018; Huang et al, 2020; Tang et al, 2019).…”

Section: Introductionsupporting

confidence: 59%

MultimodalMRIassessment for first episode psychosis: A major change in the thalamus and an efficient stratification of a subgroup

Faria

Zhao

et al. 2020

Human Brain Mapping

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Multi‐institutional brain imaging studies have emerged to resolve conflicting results among individual studies. However, adjusting multiple variables at the technical and cohort levels is challenging. Therefore, it is important to explore approaches that provide meaningful results from relatively small samples at institutional levels. We studied 87 first episode psychosis (FEP) patients and 62 healthy subjects by combining supervised integrated factor analysis (SIFA) with a novel pipeline for automated structure‐based analysis, an efficient and comprehensive method for dimensional data reduction that our group recently established. We integrated multiple MRI features (volume, DTI indices, resting state fMRI—rsfMRI) in the whole brain of each participant in an unbiased manner. The automated structure‐based analysis showed widespread DTI abnormalities in FEP and rs‐fMRI differences between FEP and healthy subjects mostly centered in thalamus. The combination of multiple modalities with SIFA was more efficient than the use of single modalities to stratify a subgroup of FEP (individuals with schizophrenia or schizoaffective disorder) that had more robust deficits from the overall FEP group. The information from multiple MRI modalities and analytical methods highlighted the thalamus as significantly abnormal in FEP. This study serves as a proof‐of‐concept for the potential of this methodology to reveal disease underpins and to stratify populations into more homogeneous sub‐groups.

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“…This is also expected and consistent with previous evidence of reduced cingulate grey matter (Salvadore et al ., 2011; Rodriguez-Cano et al ., 2014; Schmaal et al ., 2017) in MDD. However, others have observed increased thickness of rostral ACC in MDD (Ancelin et al ., 2019) and of other cortical regions in SCZ (Dukart et al ., 2017), which does correspond to our findings among individuals at higher genetic risk of SCZ.…”

Section: Discussionsupporting

confidence: 92%

Stratifying major depressive disorder by polygenic risk for schizophrenia in relation to structural brain measures

et al. 2019

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BackgroundSubstantial clinical heterogeneity of major depressive disorder (MDD) suggests it may group together individuals with diverse aetiologies. Identifying distinct subtypes should lead to more effective diagnosis and treatment, while providing more useful targets for further research. Genetic and clinical overlap between MDD and schizophrenia (SCZ) suggests an MDD subtype may share underlying mechanisms with SCZ.MethodsThe present study investigated whether a neurobiologically distinct subtype of MDD could be identified by SCZ polygenic risk score (PRS). We explored interactive effects between SCZ PRS and MDD case/control status on a range of cortical, subcortical and white matter metrics among 2370 male and 2574 female UK Biobank participants.ResultsThere was a significant SCZ PRS by MDD interaction for rostral anterior cingulate cortex (RACC) thickness (β = 0.191, q = 0.043). This was driven by a positive association between SCZ PRS and RACC thickness among MDD cases (β = 0.098, p = 0.026), compared to a negative association among controls (β = −0.087, p = 0.002). MDD cases with low SCZ PRS showed thinner RACC, although the opposite difference for high-SCZ-PRS cases was not significant. There were nominal interactions for other brain metrics, but none remained significant after correcting for multiple comparisons.ConclusionsOur significant results indicate that MDD case-control differences in RACC thickness vary as a function of SCZ PRS. Although this was not the case for most other brain measures assessed, our specific findings still provide some further evidence that MDD in the presence of high genetic risk for SCZ is subtly neurobiologically distinct from MDD in general.

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Age-related brain structural alterations as an intermediate phenotype of psychosis

Cited by 34 publications

References 67 publications

Impact on the Onset of Psychosis of a Polygenic Schizophrenia-Related Risk Score and Changes in White Matter Volume

Impact on the Onset of Psychosis of a Polygenic Schizophrenia-Related Risk Score and Changes in White Matter Volume

MultimodalMRIassessment for first episode psychosis: A major change in the thalamus and an efficient stratification of a subgroup

Stratifying major depressive disorder by polygenic risk for schizophrenia in relation to structural brain measures

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