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Greater Extracellular Free-Water in First-Episode Psychosis Predicts Better Neurocognitive Functioning

Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Nature Publishing Group
Publication Date:
Volume Number:
Issue Number:
Mol Psychiatry. 2018 Mar;23(3):701-7.
PubMed ID:
Appears in Collections:
P41 EB015902/EB/NIBIB NIH HHS/United States
R01 MH102377/MH/NIMH NIH HHS/United States
R01 MH060004/MH/NIMH NIH HHS/United States
M01 RR018535/RR/NCRR NIH HHS/United States
R01 MH076995/MH/NIMH NIH HHS/United States
P50 MH080173/MH/NIMH NIH HHS/United States
R01 MH074794/MH/NIMH NIH HHS/United States
P30 MH090590/MH/NIMH NIH HHS/United States
R01 MH108574/MH/NIMH NIH HHS/United States
K23 MH100264/MH/NIMH NIH HHS/United States
T32 MH016259/MH/NIMH NIH HHS/United States
R01 AG042512/AG/NIA NIH HHS/United States
Generated Citation:
Lyall A.E., Pasternak O., Robinson D.G., Newell D., Trampush J.W., Gallego J.A., Fava M., Malhotra A.K., Karlsgodt K.H., Kubicki M., Szeszko P.R. Greater Extracellular Free-Water in First-Episode Psychosis Predicts Better Neurocognitive Functioning. Mol Psychiatry. 2018 Mar;23(3):701-7. PMID: 28348381. PMCID: PMC5617750.
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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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