The extent of diffusion MRI markers of neuroinflammation and white matter deterioration in chronic schizophrenia

Abstract

In a previous study we have demonstrated, using a novel diffusion MRI analysis called free-water imaging, that the early stages of schizophrenia are more likely associated with a neuroinflammatory response and less so with a white matter deterioration or a demyelination process. What is not known is how neuroinflammation and white matter deterioration change along the progression of the disorder. In this study we apply the free-water measures on a population of 29 chronic schizophrenia subjects and compare them with 25 matching controls. Our aim was to compare the extent of free-water imaging abnormalities in chronic subjects with the ones previously obtained for subjects at their first psychotic episode. We find that chronic subjects showed a limited extent of abnormal increase in the volume of the extracellular space, suggesting a less extensive neuroinflammatory response relative to patients at the onset of schizophrenia. At the same time, the chronic schizophrenia subjects had greater extent of reduced fractional anisotropy compared to the previous study, suggesting increased white matter deterioration along the progression of the disease. Our findings substantiate the role of neuroinflammation in the earlier stages of the disorder, and the effect of neurodegeneration that is worsening in the chronic phase.

Introduction

The development of diffusion MRI, and its most common analysis method, diffusion tensor imaging (DTI) (Basser et al., 1994), have made it possible to study imaging correlates of white matter pathologies in schizophrenia. Many DTI studies have found decreased fractional anisotropy (FA), and some have found increased mean diffusivity (MD) in different populations of schizophrenia subjects (see Fitzsimmons et al. (2013) for a recent review.) Despite non-specificity of the FA and MD measures, the DTI findings are often considered evidence of a white matter pathology that is likely related to demyelination (Kubicki et al., 2007). Myelin related deficiencies were also inferred from histopathological studies (Uranova et al., 2011), and genetics studies (Davis et al., 2003). An alternative interpretation of the DTI results associates the abnormalities with a neuroinflammatory response, further supported by increased cytokine levels, microglial activation measured with PET, genetic association, and upregulation of inflammatory pathways (see Najjar and Pearlman (2014), for a recent review of neuroinflammation related findings in schizophrenia.)

There is a reciprocal causative relation between neuroinflammation and degeneration, with prolonged inflammatory response that can lead to deterioration, and, on the other hand, inflammation that may be triggered by cellular deterioration (Streit, 2006). Distinguishing between neuroinflammation and deterioration is therefore important to understand the etiology of schizophrenia, and to better target potential treatments. Recently, free-water imaging (Pasternak et al., 2009) was proposed as an analysis method of diffusion MRI that can differentiate the contribution of water molecules diffusing freely in the extracellular space from the contribution of water molecules that diffuse close to tissue membranes. Therefore free-water imaging can help to differentiate between neuroinflammation that is expected to affect the water content in the extracellular space, and white matter deterioration that is expected to affect the tissue itself.

In our previous free-water imaging study, patients diagnosed with schizophrenia were scanned following their first psychotic episode (FE) (Pasternak et al., 2012). It was found that a regular DTI analysis comparing the FE group with matched controls shows a widespread global decrease in FA and overlapping increase in MD. However, applying the free-water imaging analysis revealed that the majority of differences between these groups could be explained as an increase in the extracellular space, and that anisotropy differences in the tissue were only limited to focal areas in the frontal lobe. This disambiguation of the source of differences between the groups led to a conclusion that the early stages of schizophrenia are more likely associated with a neuroinflammatory response and less so with a white matter deterioration or a demyelination process.

What is not known is how neuroinflammation and white matter deterioration change along the progression of the disorder. If schizophrenia has a neurodegenerative component, an increased extent of deterioration is expected as the disease progresses. Furthermore, it is not known whether neuroinflammation also plays a role in the chronic stages of schizophrenia. To address these questions, in this study we apply the free-water imaging method on a cohort of chronic schizophrenia (CHR) patients, and compare the extents of deterioration and neuroinflammation with the ones previously obtained for FE patients.