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J Neurosci DOI:10.1523/JNEUROSCI.2904-12.2012

Excessive extracellular volume reveals a neurodegenerative pattern in schizophrenia onset.

Publication TypeJournal Article
Year of Publication2012
AuthorsPasternak, O, Westin, C-F, Bouix, S, Seidman, LJ, Goldstein, JM, Woo, T-UW, Petryshen, TL, Mesholam-Gately, RI, McCarley, RW, Kikinis, R, Shenton, ME, Kubicki, M
JournalJ Neurosci
Date Published2012 Nov 28
KeywordsAdolescent, Adult, Brain, Brain Mapping, Diffusion Magnetic Resonance Imaging, Female, Humans, Male, Nerve Degeneration, Nerve Fibers, Myelinated, Psychotic Disorders, Schizophrenia

Diffusion MRI has been successful in identifying the existence of white matter abnormalities in schizophrenia in vivo. However, the role of these abnormalities in the etiology of schizophrenia is not well understood. Accumulating evidence from imaging, histological, genetic, and immunochemical studies support the involvement of axonal degeneration and neuroinflammation--ubiquitous components of neurodegenerative disorders--as the underlying pathologies of these abnormalities. Nevertheless, the current imaging modalities cannot distinguish neuroinflammation from axonal degeneration, and therefore provide little specificity with respect to the pathophysiology progression and whether it is related to a neurodegenerative process. Free-water imaging is a new methodology that is sensitive to water molecules diffusing in the extracellular space. Excessive extracellular volume is a surrogate biomarker for neuroinflammation and can be separated out to reveal abnormalities such as axonal degeneration that affect diffusion characteristics in the tissue. We applied free-water imaging on diffusion MRI data acquired from schizophrenia-diagnosed human subjects with a first psychotic episode. We found a significant increase in the extracellular volume in both white and gray matter. In contrast, significant signs of axonal degeneration were limited to focal areas in the frontal lobe white matter. Our findings demonstrate that neuroinflammation is more prominent than axonal degeneration in the early stage of schizophrenia, revealing a pattern shared by many neurodegenerative disorders, in which prolonged inflammation leads to axonal degeneration. These findings promote anti-inflammatory treatment for early diagnosed schizophrenia patients.


Alternate JournalJ. Neurosci.
PubMed ID23197727
PubMed Central IDPMC3549332
Grant ListR01-MH074794 / MH / NIMH NIH HHS / United States
R01 MH050740 / MH / NIMH NIH HHS / United States
P50 MH080272 / MH / NIMH NIH HHS / United States
R01-MH082918 / MH / NIMH NIH HHS / United States
M01 RR001032 / RR / NCRR NIH HHS / United States
R01 MH082918 / MH / NIMH NIH HHS / United States
P50-MH080272 / MH / NIMH NIH HHS / United States
M01-RR01032 / RR / NCRR NIH HHS / United States
P41 RR013218 / RR / NCRR NIH HHS / United States
R01 MH074794 / MH / NIMH NIH HHS / United States
P41-RR013218 / RR / NCRR NIH HHS / United States
R01-MH050740 / MH / NIMH NIH HHS / United States