Excessive extracellular volume reveals a neurodegenerative pattern in schizophrenia onset

Abstract

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.

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.

Figure 2.

Abnormal free-water values in first-episode patients. Axial slices (bottom) and 3D rendering (top) demonstrate a localized pattern for significant FA_T 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 FA_T map is drawn on top of the free-water map and on top of the skeleton.

Figure 3.

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

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.