Saturated Fatty Acids and White Matter Microstructure in Individuals With At-risk Mental State

Daiki Sasabayashi^{1

2

3}, Hiroko Itoh^{2

3}, Kiyotaka Nemoto⁴, Yuko Higuchi^{2

3}, Yukiko Akasaki^{2

5}, Alana Wickham¹, Kang Ik K Cho¹, Ofer Pasternak^{1

6

7}, Dheshan Mohandass¹, Ryan Zurrin¹, Tashrif Billah¹, Suheyla Cetin-Karayumak¹, Haruko Kobayashi^{2

3}, Kazumi Sakamoto², Yoichiro Takayanagi^{2

8}, Noa Tsujii⁵, Shinsuke Koike^{9

10

11}, Yoji Hirano^{12

13}, Kyo Noguchi¹⁴, Tomiki Sumiyoshi^{15

16

17}, Michio Suzuki^{2

3}, Tsutomu Takahashi^{2

3}, Marek Kubicki^{1

6

7}

Affiliations

¹ Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
² Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan.
³ Research Center for Idling Brain Science, University of Toyama, Toyama, Japan.
⁴ Department of Psychiatry, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
⁵ Department of Child Mental Health and Development, Toyama University Hospital, Toyama, Japan.
⁶ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Arisawabashi Hospital, Toyama, Japan.
⁹ The University of Tokyo Institute for Diversity and Adaptation of Human Mind, Tokyo, Japan.
¹⁰ Center for Evolutionary Cognitive Sciences, Graduate School of Art and Sciences, The University of Tokyo, Tokyo, Japan.
¹¹ International Research Center for Neurointelligence, The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo, Japan.
¹² Department of Psychiatry, Faculty of Medicine, Division of Clinical Neuroscience, University of Miyazaki, Miyazaki, Japan.
¹³ Institute of Industrial Science, The University of Tokyo, Tokyo, Japan.
¹⁴ Department of Radiology, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan.
¹⁵ Department of Preventive Intervention for Psychiatric Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
¹⁶ Department of Psychiatry, National Center of Neurology and Psychiatry Hospital, Tokyo, Japan.
¹⁷ Japan Health Research Promotion Bureau, Tokyo, Japan.

PMID: 40556544
DOI: 10.1093/schbul/sbaf089

Saturated Fatty Acids and White Matter Microstructure in Individuals With At-risk Mental State

Daiki Sasabayashi et al. Schizophr Bull. 2025.

. 2025 Jun 25:sbaf089.

doi: 10.1093/schbul/sbaf089. Online ahead of print.

Authors

Affiliations

¹ Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
² Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan.
³ Research Center for Idling Brain Science, University of Toyama, Toyama, Japan.
⁴ Department of Psychiatry, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
⁵ Department of Child Mental Health and Development, Toyama University Hospital, Toyama, Japan.
⁶ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Arisawabashi Hospital, Toyama, Japan.
⁹ The University of Tokyo Institute for Diversity and Adaptation of Human Mind, Tokyo, Japan.
¹⁰ Center for Evolutionary Cognitive Sciences, Graduate School of Art and Sciences, The University of Tokyo, Tokyo, Japan.
¹¹ International Research Center for Neurointelligence, The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo, Japan.
¹² Department of Psychiatry, Faculty of Medicine, Division of Clinical Neuroscience, University of Miyazaki, Miyazaki, Japan.
¹³ Institute of Industrial Science, The University of Tokyo, Tokyo, Japan.
¹⁴ Department of Radiology, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan.
¹⁵ Department of Preventive Intervention for Psychiatric Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
¹⁶ Department of Psychiatry, National Center of Neurology and Psychiatry Hospital, Tokyo, Japan.
¹⁷ Japan Health Research Promotion Bureau, Tokyo, Japan.

PMID: 40556544
DOI: 10.1093/schbul/sbaf089

Abstract

Background and hypothesis: Excessive saturated or deficient unsaturated fatty acids and white matter microstructural abnormalities are observed before the psychosis onset. Whereas fatty acids variations are implicated in white matter pathology, conventional Diffusion Tensor Imaging has limitations in disentangling their biological relevance. Free-water imaging provides improved biological specificity to white matter microstructure, such as fractional volume of free-water (FW) and tissue-specific fractional anisotropy (FAt). This study aims to investigate the associations between altered proportion of saturated or unsaturated fatty acids and free-water imaging parameters in prodromal psychosis.

Study design: We applied free-water imaging and Tract-Based Spatial Statistics to compare FAt and FW between 78 individuals with at-risk mental state (ARMS) and 129 healthy controls. In a subsample with available blood samples (n = 53 and n = 42, respectively), relationships between fatty acid composition of erythrocyte membrane and FAt or FW were examined alongside clinical and cognitive variables.

Study results: Compared to the controls, individuals with ARMS exhibited higher relative concentrations of saturated fatty acids as well as lower FAt and higher FW in multiple association and projection fibers. In the ARMS group, elevated proportion of saturated fatty acids was associated with lower FAt and with positive symptoms and impaired verbal fluency.

Conclusions: The association of saturated fatty acids with FAt in ARMS suggests that fatty acids may influence disrupted white matter microstructure, such as impaired myelin maintenance prior to psychosis onset. Future studies should explore early interventions to mitigate white matter cellular deterioration by optimizing saturated fatty acid levels.

Keywords: at-risk mental state; diffusion imaging; free-water imaging; saturated fatty acid; tract-based spatial statistics.

© The Author(s) 2025. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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Saturated Fatty Acids and White Matter Microstructure in Individuals With At-risk Mental State

Affiliations

Saturated Fatty Acids and White Matter Microstructure in Individuals With At-risk Mental State

Authors

Affiliations

Abstract

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