Excessive Extracellular Volume Reveals a Neurodegenerative Pattern in Schizophrenia Onset

Harvard University, Cambridge, Massachusetts, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2012; 32(48):17365-17372. DOI: 10.1523/JNEUROSCI.2904-12.2012
Source: PubMed


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.

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    • "As previously reported, these inflammatory processes could be reflected in retinal structures. Using a novel free-water neuroimaging method, Pasternak et al. (2012) have suggested that neuroinflammation, accompanied by excessive extracellular volume , is more prominent than axonal degeneration in patients with a first psychotic episode. Therefore, due to these putative neuroinflammatory processes, it would be conceivable to find an increased volume of nervous tissue in patients with a recent psychotic episode, such as those in the RIE subsample of our study. "
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    ABSTRACT: Optical coherence tomography (OCT) has been recently used to investigate neuropsychiatric disorders. We aimed to study retinal OCT measures of patients with schizophrenia with respect to healthy controls, and to evaluate possible differences between recent illness episode (RIE) and non-recent illness episode (NRIE) patients. Thirty schizophrenia patients were classified as RIE (n=10) or NRIE (n=20), and compared with 30 matched controls. Statistical analyses included linear mixed-effects models to study the association between OCT measures and group membership. Multivariate models were used to control for potential confounders. In the adjusted linear mixed-effects regression model, patients had a significantly thinner retinal nerve fiber layer (RNFL) in overall measurements, and in the nasal, superior and inferior quadrants. Macular inner ring thickness and macular volume were also significantly smaller in patients than controls. Compared with controls, in the adjusted model only NRIE (but not RIE) patients had significantly reduced RNFL overall measures, superior RNFL, nasal RNFL, macular volume, and macular inner ring thickness. No significant correlation was found between illness duration and retinal measurements after controlling for age. In conclusion, retinal parameters observed using OCT in schizophrenia patients could be related to clinical status and merit attention as potential state biomarkers of the disorder. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    07/2015; 229(1-2). DOI:10.1016/j.psychres.2015.07.028
    • "Recently, schizophrenia has increasingly been associated with progressive neurodegeneration, and one of the predominant underlying mechanisms appears to be immuno-inflammatory processes (Durrenberger et al. 2014; Pasternak et al. 2012; Pérez-Neri et al. 2006). Further to this, animal studies have established beneficial roles of T cells in cognition and behaviour ; for example, T cell replenishment restored cognitive impairment caused by systemic immune deficiency (Brynskikh et al. 2008; Kipnis et al. 2004; Wolf et al. 2009; Ziv et al. 2006). "
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    ABSTRACT: Schizophrenia is a severe and highly complex neurodevelopmental disorder with an unknown etiopathology. Recently, immunopathogenesis has emerged as one of the most compelling etiological models of schizophrenia. Over the past few years considerable research has been devoted to the role of innate immune responses in schizophrenia. The findings of such studies have helped to conceptualize schizophrenia as a chronic low-grade inflammatory disorder. Although the contribution of adaptive immune responses has also been emphasized, however, the precise role of T cells in the underlying neurobiological pathways of schizophrenia is yet to be ascertained comprehensively. T cells have the ability to infiltrate brain and mediate neuro-immune cross-talk. Conversely, the central nervous system and the neurotransmitters are capable of regulating the immune system. Neurotransmitter like dopamine, implicated widely in schizophrenia risk and progression can modulate the proliferation, trafficking and functions of T cells. Within brain, T cells activate microglia, induce production of pro-inflammatory cytokines as well as reactive oxygen species and subsequently lead to neuroinflammation. Importantly, such processes contribute to neuronal injury/death and are gradually being implicated as mediators of neuroprogressive changes in schizophrenia. Antipsychotic drugs, commonly used to treat schizophrenia are also known to affect adaptive immune system; interfere with the differentiation and functions of T cells. This understanding suggests a pivotal role of T cells in the etiology, course and treatment of schizophrenia and forms the basis of this review.
    Journal of Neuroimmune Pharmacology 07/2015; DOI:10.1007/s11481-015-9626-9 · 4.11 Impact Factor
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    • "Extracellular free-water volume is an emerging marker that is likely related to neuroinflammation, and enhances current diffusion MRI measures. Figure modified with permission from Pasternak et al. (2012b). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) "
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    ABSTRACT: In recent years evidence has accumulated to suggest that neuroinflammation might be an early pathology of schizophrenia that later leads to neurodegeneration, yet the exact role in the etiology, as well as the source of neuroinflammation, are still not known. The hypothesis of neuroinflammation involvement in schizophrenia is quickly gaining popularity, and thus it is imperative that we have reliable and reproducible tools and measures that are both sensitive, and, most importantly, specific to neuroinflammation. The development and use of appropriate human in vivo imaging methods can help in our understanding of the location and extent of neuroinflammation in different stages of the disorder, its natural time-course, and its relation to neurodegeneration. Thus far, there is little in vivo evidence derived from neuroimaging methods. This is likely the case because the methods that are specific and sensitive to neuroinflammation are relatively new or only just being developed. This paper provides a methodological review of both existing and emerging positron emission tomography and magnetic resonance imaging techniques that identify and characterize neuroinflammation. We describe \how these methods have been used in schizophrenia research. We also outline the shortcomings of existing methods, and we highlight promising future techniques that will likely improve state-of-the-art neuroimaging as a more refined approach for investigating neuroinflammation in schizophrenia. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 06/2015; DOI:10.1016/j.schres.2015.05.034 · 3.92 Impact Factor
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