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Greater extracellular free-water in first-episode psychosis predicts better neurocognitive functioning

Molecular Psychiatry volume 23, pages 701–707 (2018)Cite this article

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Abstract

Free Water Imaging is a novel diffusion magnetic resonance (MR) imaging method that is able to separate changes affecting the extracellular space from those that reflect changes in neuronal cells and processes. A previous Free Water Imaging study in schizophrenia identified significantly greater extracellular water volume in the early stages of the disorder; however, its clinical and functional sequelae have not yet been investigated. Here, we applied Free Water Imaging to a larger cohort of 63 first-episode patients with psychosis and 70 healthy matched controls to better understand the functional significance of greater extracellular water. We used diffusion MR imaging data and the Tract-Based Spatial Statistics analytic pipeline to first analyze fractional anisotropy (FA), the most commonly employed metric for assessing white matter. This comparison was then followed by Free Water Imaging analysis, where two parameters, the fractional volume of extracellular free-water (FW) and cellular tissue FA (FA-t), were estimated and compared across the entire white matter skeleton between groups, and correlated with cognitive measures at baseline and following 12 weeks of antipsychotic treatment. Our results indicated lower FA across the whole brain in patients compared with healthy controls that overlap with significant increases in FW, with only limited decreases in FA-t. In addition, higher FW correlated with better neurocognitive functioning following 12 weeks of antipsychotic treatment. We believe this is the first study to suggest that an extracellular water increase during the first-episode of psychosis, which may be indicative of an acute neuroinflammatory process, and/or cerebral edema may predict better functional outcome.

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Acknowledgements

This work was supported in part by grants from the National Institutes of Mental Health to Dr. Lyall (5T32MH016259-35), Dr. Kubicki (R01AG042512 and R01MH102377), Dr. Pasternak (R01MH108574, R01MH074794, P41EB015902 and R01AG042512, R01MH102377), Dr. Szeszko (R01 MH076995), Dr. Robinson (R01 MH060004) and Dr. Gallego (K23 MH100264), the NSLIJ Research Institute General Clinical Research Center (M01 RR018535), an Advanced Center for Intervention and Services Research (P30 MH090590), a Center for Intervention Development and Applied Research (P50 MH080173) and NARSAD Young Investigator grants (to Dr. Szeszko and Dr. Pasternak).

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Author notes

  1. M Kubicki and P R Szeszko: Denotes Shared Authorship.

Authors and Affiliations

  1. Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    A E Lyall, O Pasternak, D Newell & M Kubicki

  2. Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    A E Lyall, M Fava & M Kubicki

  3. Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    O Pasternak & M Kubicki

  4. Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA

    D G Robinson, J W Trampush & A K Malhotra

  5. Psychiatry Research, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA

    D G Robinson, J W Trampush & A K Malhotra

  6. Departments of Psychiatry and Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, NY, USA

    D G Robinson, J W Trampush & A K Malhotra

  7. Department of Psychiatry, Weill Cornell Medical College, White Plains, NY, USA

    J A Gallego

  8. Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA

    K H Karlsgodt

  9. James J. Peters VA Medical Center, Bronx, NY, USA

    P R Szeszko

  10. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    P R Szeszko

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  1. A E Lyall
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Correspondence to A E Lyall.

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For a complete list of Dr. Fava’s disclosures, please see http://mghcme.org/faculty/faculty-detail/maurizio_fava#disclosure. Dr. Malhotra has been a consultant for Genomind, Forum Pharmaceuticals and Takeda Pharmaceuticals. The other authors declare no conflict of interest.

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Lyall, A., Pasternak, O., Robinson, D. et al. Greater extracellular free-water in first-episode psychosis predicts better neurocognitive functioning. Mol Psychiatry 23, 701–707 (2018). https://doi.org/10.1038/mp.2017.43

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