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Featured ArticleArticles, Neurobiology of Disease

Excessive Extracellular Volume Reveals a Neurodegenerative Pattern in Schizophrenia Onset

Ofer Pasternak, Carl-Fredrik Westin, Sylvain Bouix, Larry J. Seidman, Jill M. Goldstein, Tsung-Ung W. Woo, Tracey L. Petryshen, Raquelle I. Mesholam-Gately, Robert W. McCarley, Ron Kikinis, Martha E. Shenton and Marek Kubicki
Journal of Neuroscience 28 November 2012, 32 (48) 17365-17372; DOI: https://doi.org/10.1523/JNEUROSCI.2904-12.2012
Ofer Pasternak
1Departments of Psychiatry,
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Carl-Fredrik Westin
2Radiology, and
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Sylvain Bouix
1Departments of Psychiatry,
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Larry J. Seidman
4Massachusetts Mental Health Center, Public Psychiatry Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,
6Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114,
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Jill M. Goldstein
1Departments of Psychiatry,
3Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115,
4Massachusetts Mental Health Center, Public Psychiatry Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,
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Tsung-Ung W. Woo
5Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478,
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Tracey L. Petryshen
6Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114,
7Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, Massachusetts 02142,
8Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02144, and
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Raquelle I. Mesholam-Gately
4Massachusetts Mental Health Center, Public Psychiatry Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,
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Robert W. McCarley
4Massachusetts Mental Health Center, Public Psychiatry Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,
9Department of Psychiatry, Veterans Affairs Boston Healthcare System, Brockton Division, Brockton, Massachusetts 02301
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Ron Kikinis
2Radiology, and
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Martha E. Shenton
1Departments of Psychiatry,
9Department of Psychiatry, Veterans Affairs Boston Healthcare System, Brockton Division, Brockton, Massachusetts 02301
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Marek Kubicki
1Departments of Psychiatry,
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  • Figure 1.
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    Figure 1.

    Abnormal DTI values in first-episode patients. Axial slices (bottom) and 3D rendering (top) demonstrate a global pattern for significant FA value decreases (red to yellow) and for significant MD value increases (blue to dark blue) throughout the white matter skeleton (green). The FA map is drawn on top of the MD map and on top of the skeleton.

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    Figure 2.

    Abnormal free-water values in first-episode patients. Axial slices (bottom) and 3D rendering (top) demonstrate a localized pattern for significant FAT value decreases (red to yellow) in fibers that pass through the frontal lobe. A global pattern for significant free-water value increases (blue to dark blue) is found throughout the white matter skeleton (green). The FAT map is drawn on top of the free-water map and on top of the skeleton.

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    Figure 3.

    Individual differences in FAT. Each first-episode patient had lower FAT values than age-matched controls when averaging within the area that showed significant voxelwise group differences in FAT. The clear separation between the two groups suggests that the FAT measure in this area (marked red to yellow in Fig. 2) is a strong biomarker for schizophrenia.

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    Figure 4.

    Global differences in free water. Free-water values in patients are globally significantly higher than free-water values in controls. The global pattern of increase is evident both in white and gray matter, in both hemispheres. Black lines represent the mean and the 95% confidence interval.

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    Table 1.

    Clinical and experimental parameters

    ControlsFirst episodet test
    Number of subjects2018
    Female54
    Male1514
    Age (years)24.05 ± 3.9921.61 ± 4.34t(36) = −1.88; p = 0.07
    Education (years)13.78 ± 2.5114.17 ± 1.65t(36) = 0.55; p = 0.59
    Motion (mm)0.70 ± 0.260.68 ± 0.26t(36) = −0.22; p = 0.83
    TE (ms)85.84 ± 1.3685.73 ± 1.28t(36) = −0.26; p = 0.80
    SNR (raw)12.06 ± 1.4712.12 ± 1.58t(36) = 0.12; p = 0.91
    SNR filtered13.05 ± 1.1413.22 ± 1.18t(36) = 0.46; p = 0.65
    CPZ (mg/d)472.24 ± 651.33
    Duration of illness (months)6.19 ± 4.27
    Duration of medication (months)4.04 ± 3.58
    Antipsychotic medication (typical/atypical/both/none)1/12/2/3
    • The t test column holds the t statistic (with degrees of freedom) and significance value, p, for an unpaired two-sample t test.

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    Table 2.

    Global gray and white matter ROIs

    Mean free waterDifferencet(df); p
    First episodeControls
    Left gray matter0.19910.18260.0165t(33) = 2.48; p = 0.0184
    Right gray matter0.20210.18850.0136t(33) = 2.23; p = 0.0331
    Left white matter0.11450.10310.0115t(33) = 2.54; p = 0.0161
    Right white matter0.11540.10420.0112t(33) = 2.55; p = 0.0155
    • t(df) is the t statistic and degrees of freedom; p is the significance value.

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The Journal of Neuroscience: 32 (48)
Journal of Neuroscience
Vol. 32, Issue 48
28 Nov 2012
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Excessive Extracellular Volume Reveals a Neurodegenerative Pattern in Schizophrenia Onset
Ofer Pasternak, Carl-Fredrik Westin, Sylvain Bouix, Larry J. Seidman, Jill M. Goldstein, Tsung-Ung W. Woo, Tracey L. Petryshen, Raquelle I. Mesholam-Gately, Robert W. McCarley, Ron Kikinis, Martha E. Shenton, Marek Kubicki
Journal of Neuroscience 28 November 2012, 32 (48) 17365-17372; DOI: 10.1523/JNEUROSCI.2904-12.2012

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Excessive Extracellular Volume Reveals a Neurodegenerative Pattern in Schizophrenia Onset
Ofer Pasternak, Carl-Fredrik Westin, Sylvain Bouix, Larry J. Seidman, Jill M. Goldstein, Tsung-Ung W. Woo, Tracey L. Petryshen, Raquelle I. Mesholam-Gately, Robert W. McCarley, Ron Kikinis, Martha E. Shenton, Marek Kubicki
Journal of Neuroscience 28 November 2012, 32 (48) 17365-17372; DOI: 10.1523/JNEUROSCI.2904-12.2012
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