Cognitive and functional deficits are associated with white matter abnormalities in two independent cohorts of patients with schizophrenia

Yamada, Shinichi; Takahashi, Shun; Malchow, Berend; Papazova, Irina; Stöcklein, Sophia; Ertl‐Wagner, Birgit; Papazov, Boris; Kumpf, Ulrike; Wobrock, Thomas; Keller-Varady, Katriona; Hasan, Alkomiet; Falkai, Peter; Wagner, Elias; Raabe, Florian; Keeser, Daniel

doi:10.1007/s00406-021-01363-8

Cited by 14 publications

(6 citation statements)

References 57 publications

(64 reference statements)

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“…Signi cant contributing voxels were located in regions that have been previously associated with these scores. In previous studies on schizophrenia and ROD, the FA of the temporal part and the temporolombic GM was positively correlated with GAF score, in consistance with ndings in Cluster 6, which includes 17 ROP and 14 ROD patients at baseline 28,74 . Reduction of GM in fusiform and temporal lobe were associated with PANSS scores in schizophrenia 75 , as we observed in Cluster 3 which includes mainly ROP patients.…”

Section: Discussionsupporting

confidence: 71%

Brain texture as a marker of transdiagnostic clinical profiles in patients with recent-onset psychosis and depression

Κορδά¹,

Andreou

Ruef

et al. 2023

Preprint

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Prediction models of brain texture changes in recent-onset psychosis (ROP) and recent-onset depression (ROD) have lately been proposed. The validation of these models transdiagnostically at the individual level and the investigation of the variability in clinical profiles are still missing. Established prevention and treatment approaches focus on specific diagnoses and do not address the heterogeneity and manifold potential outcomes of patients. We aimed to investigate the utility of brain texture changes for a) identification of the psychopathological state (ROP and ROD) and b) the association of individualized brain texture maps with clinical symptom severity and outcome profiles. We developed transdiagnostic models based on structural MRI data on 116 patients with ROD, 122 patients with ROP, and 197 healthy controls (HC) from the Personalised pROgNostic tools for early psychosIs mAnagement (PRONIA) study by applying explainable artificial intelligence and clustering analysis. We investigated the contrast texture feature as the key feature for the identification of a general psychopathological state. The discrimination power of the trained prediction model was > 72% and validated in a second independent age and sex-matched sample of 137 ROP, 94 ROD, and 159 HC. Clustering analysis was implemented to map the texture brain changes produced from an explainable artificial intelligence algorithm, in a group fashion. The explained individualized brain contrast map grouped into 8 homogeneous clusters. In each group, we investigated the association between the explained brain contrast texture map and clinical symptom severity as well as outcome profiles. Different patterns in the explained brain contrast texture map showed unique associations of brain alterations with clinical symptom severity and clinical outcomes, i.e., age, positive, negative and depressive symptoms, and functionality. In some clusters, the mean explained brain contrast texture map values and/or brain contrast texture voxels significantly contribute to the classification decision significantly predicted PANSS scores, functionality and change in functionality over time. In conclusion, we created homogeneous clusters which statistically significant predict the clinical severity and outcome profile.

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Section: Discussionsupporting

confidence: 71%

Brain texture as a marker of transdiagnostic clinical profiles in patients with recent-onset psychosis and depression

Κορδά¹,

Andreou

Ruef

et al. 2023

Preprint

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“…Diffusion tensor imaging (DTI) studies found deficits in myelination and reduced fractional anisotropy as a marker of myelination in the hippocampus and fornix of patients with schizophrenia [ 40 , 41 ]; these changes were associated with cognitive deficits [ 42 ]. White matter fractional anisotropy values were significantly lower in patients with schizophrenia and cognitive deficits than in those with high cognitive performance [ 43 ]. A DTI study found a relationship between variants of genes related to oligodendrocytes, e.g., myelin-associated glycoprotein, and the integrity of white matter tracts and cognition in patients with schizophrenia [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Decreased Oligodendrocyte Number in Hippocampal Subfield CA4 in Schizophrenia: A Replication Study

Schmitt

Tatsch

Vollhardt

et al. 2022

Cells

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Hippocampus-related cognitive deficits in working and verbal memory are frequent in schizophrenia, and hippocampal volume loss, particularly in the cornu ammonis (CA) subregions, was shown by magnetic resonance imaging studies. However, the underlying cellular alterations remain elusive. By using unbiased design-based stereology, we reported a reduction in oligodendrocyte number in CA4 in schizophrenia and of granular neurons in the dentate gyrus (DG). Here, we aimed to replicate these findings in an independent sample. We used a stereological approach to investigate the numbers and densities of neurons, oligodendrocytes, and astrocytes in CA4 and of granular neurons in the DG of left and right hemispheres in 11 brains from men with schizophrenia and 11 brains from age- and sex-matched healthy controls. In schizophrenia, a decreased number and density of oligodendrocytes was detected in the left and right CA4, whereas mean volumes of CA4 and the DG and the numbers and density of neurons, astrocytes, and granular neurons were not different in patients and controls, even after adjustment of variables because of positive correlations with postmortem interval and age. Our results replicate the previously described decrease in oligodendrocytes bilaterally in CA4 in schizophrenia and point to a deficit in oligodendrocyte maturation or a loss of mature oligodendrocytes. These changes result in impaired myelination and neuronal decoupling, both of which are linked to altered functional connectivity and subsequent cognitive dysfunction in schizophrenia.

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“… 25 White matter abnormalities are widespread, 24 but findings suggest that FA reductions are particularly pronounced in the white matter of the left frontal and temporal lobes, 26 as well as in frontolimbic and frontotemporal circuitries. 27 , 28 Notably, white matter microstructural abnormalities are more pronounced in individuals with lower cognitive performance, 29 , 30 are associated with the level of functioning, 30 and indicate a deficit subtype of SZ. 31 …”

Section: Introductionmentioning

confidence: 99%

Disturbed Oligodendroglial Maturation Causes Cognitive Dysfunction in Schizophrenia: A New Hypothesis

Falkai

Rossner

Raabe

et al. 2023

Schizophrenia Bulletin

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Background and Hypothesis Cognitive impairment is a hallmark of schizophrenia, but no effective treatment is available to date. The underlying pathophysiology includes disconnectivity between hippocampal and prefrontal brain regions. Supporting evidence comes from diffusion-weighted imaging studies that suggest abnormal organization of frontotemporal white matter pathways in schizophrenia. Study Design Here, we hypothesize that in schizophrenia, deficient maturation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes substantially contributes to abnormal frontotemporal macro- and micro-connectivity and subsequent cognitive deficits. Study Results Our postmortem studies indicate a reduced oligodendrocyte number in the cornu ammonis 4 (CA4) subregion of the hippocampus, and others have reported the same histopathological finding in the dorsolateral prefrontal cortex. Our series of studies on aerobic exercise training showed a volume increase in the hippocampus, specifically in the CA4 region, and improved cognition in individuals with schizophrenia. The cognitive effects were subsequently confirmed by meta-analyses. Cell-specific schizophrenia polygenic risk scores showed that exercise-induced CA4 volume increase significantly correlates with OPCs. From animal models, it is evident that early life stress and oligodendrocyte-related gene variants lead to schizophrenia-related behavior, cognitive deficits, impaired oligodendrocyte maturation, and reduced myelin thickness. Conclusions Based on these findings, we propose that pro-myelinating drugs (e.g., the histamine blocker clemastine) combined with aerobic exercise training may foster the regeneration of myelin plasticity as a basis for restoring frontotemporal connectivity and cognition in schizophrenia.

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Cognitive and functional deficits are associated with white matter abnormalities in two independent cohorts of patients with schizophrenia

Cited by 14 publications

References 57 publications

Brain texture as a marker of transdiagnostic clinical profiles in patients with recent-onset psychosis and depression

Brain texture as a marker of transdiagnostic clinical profiles in patients with recent-onset psychosis and depression

Decreased Oligodendrocyte Number in Hippocampal Subfield CA4 in Schizophrenia: A Replication Study

Disturbed Oligodendroglial Maturation Causes Cognitive Dysfunction in Schizophrenia: A New Hypothesis

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