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Decreased basal ganglia and thalamic iron in early psychotic spectrum disorders are associated with increased psychotic and schizotypal symptoms

Abstract

Iron deficits have been reported as a risk factor for psychotic spectrum disorders (PSD). However, examinations of brain iron in PSD remain limited. The current study employed quantitative MRI to examine iron content in several iron-rich subcortical structures in 49 young adult individuals with PSD (15 schizophrenia, 17 schizoaffective disorder, and 17 bipolar disorder with psychotic features) compared with 35 age-matched healthy controls (HC). A parametric approach based on a two-pool magnetization transfer model was applied to estimate longitudinal relaxation rate (R1), which reflects both iron and myelin, and macromolecular proton fraction (MPF), which is specific to myelin. To describe iron content, a synthetic effective transverse relaxation rate (R2*) was modeled using a linear fitting of R1 and MPF. PSD patients compared to HC showed significantly reduced R1 and synthetic R2* across examined regions including the pallidum, ventral diencephalon, thalamus, and putamen areas. This finding was primarily driven by decreases in the subgroup with schizophrenia, followed by schizoaffective disorder. No significant group differences were noted for MPF between PSD and HC while for regional volume, significant reductions in patients were only observed in bilateral caudate, suggesting that R1 and synthetic R2* reductions in schizophrenia and schizoaffective patients likely reflect iron deficits that either occur independently or precede structural and myelin changes. Subcortical R1 and synthetic R2* were also found to be inversely related to positive symptoms within the PSD group and to schizotypal traits across the whole sample. These findings that decreased iron in subcortical regions are associated with PSD risk and symptomatology suggest that brain iron deficiencies may play a role in PSD pathology and warrant further study.

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Fig. 1: T1w MPRAGE image and R1, MPF and R2* parametric maps of an example HC participant.
Fig. 2: HC and PSD group differences in quantitative MRI measures.
Fig. 3: HC and PSD diagnostic subgroup differences in quantitative MRI measures.
Fig. 4: Partial plots of the relationship between synthetic R2* in left thalamus and the SIS, SANS, and SAPS scores.

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Acknowledgements

This work was supported by the National Institutes of Health (R01MH108962 to ML and R01EB027087 to AS) and the Radiology Department at the NYU Grossman School of Medicine. We acknowledge our participants for their contribution. We thank Research Match and NAMI for supporting our recruitment efforts.

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The study was conceptualized by YVS and ML. Imaging data acquisition and processing was performed by YVS, FM, and ML. PS and AS provided expertise in MRI pulse sequence and quantitative parametric mapping. Recruitment of participants and clinical assessment were conducted with the help of HB and DCG. RA participated in statistical analysis and interpretation of results. YVS drafted the original manuscript with the help of ML. All authors were involved with manuscript review and editing.

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Correspondence to Yu Veronica Sui.

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Sui, Y.V., McKenna, F., Bertisch, H. et al. Decreased basal ganglia and thalamic iron in early psychotic spectrum disorders are associated with increased psychotic and schizotypal symptoms. Mol Psychiatry 27, 5144–5153 (2022). https://doi.org/10.1038/s41380-022-01740-2

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