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.

Diverging white matter trajectories in children after traumatic brain injury

“…Higher MD indicates poor WM organization, and increasing MD over time reflects a progressive loss of WM organization. This could be interpreted as progressive demyelination, but a neuroinflammatory response could also increase MD 22,23 and is a problematic secondary injury in TBI. 24 Excess tissue water due to inflammation can also register as an increase in MD.…”

Neurobiology of Schizophrenia Onset

“…This scenario may, at least in part, explain the previous postmortem findings of decreased dendritic spines and neuropil in subjects with schizophrenia (Garey et al 1998;Costa et al 2001;Lewis 1997, 2000;Selemon and Goldman-Rakic 1999). Of interest, consistent with this hypothesis, using a novel free-water imaging technique, it has recently been shown that the extracellular space in the cerebral cortex, of which ECM and PNNs are major components, was significantly decreased in first-episode schizophrenia patients (Pasternak et al 2012).…”

Complex regional pain syndrome: The matter of white matter?

“…However, more research is needed to study the role of central inflammaltion in CRPS and its relationship to DTI abnormalities. For example, neuroinflammation‐specific changes of extracellular volume are more likely to be identified with free‐water imaging which is sensitive to water diffusion in the extracellular space (Pasternak et al., 2012, 2015). …”