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ICOSR 2015—Neuroinflammation, White Matter, and Schizophrenia

19 Apr 2015

As part of our ongoing coverage of the 2015 International Congress on Schizophrenia Research (ICOSR), held March 29 through April 1 in Colorado Springs, we bring you session summaries from some of the participants in the Young Investigator program. We are, as always, grateful for the gracious assistance of conference directors Carol Tamminga and Chuck Schulz, as well as meeting staff Cristan Tamminga and Dorothy Denton. For this report, we thank Joshua Chiappelli of the University of Maryland.

April 20, 2015. Accumulating evidence suggests a potential role for inflammation in the pathophysiology of schizophrenia. This has stimulated inquiry into how inflammation affects the structure and functioning of the central nervous system, and how these effects can be measured. A symposium on March 29, 2015, the first day of the 15th International Congress on Schizophrenia Research, was organized around this theme.

Ofer Pasternak of Harvard Medical School in Boston, Massachusetts, described how advances in diffusion-weighted imaging (DWI) can reveal the impact of inflammation on white matter. Popular DWI techniques such as diffusion tensor imaging (DTI) have excellent sensitivity to changes in white matter microstructure but suffer from a lack of specificity, as measures such as fractional anisotropy (FA) can be affected by numerous mechanisms. A form of DWI known as free-water analysis can distinguish between water diffusing freely in extracellular space and water diffusing in close proximity to boundaries such as cell membranes. Since neuroinflammation is associated with increased permeability of the blood-brain barrier, leading to excessive water content of neural tissue, free-water analysis can be added to DTI to help distinguish between changes in white matter FA caused by additional water content in the extracellular space and changes caused by differences within white matter tracts. Using this methodology, Pasternak and colleagues have found that in the early course of schizophrenia, changes in FA appear to be primarily due to an increase in extracellular space (Pasternak et al., 2012), whereas in chronic schizophrenia, reduced FA appears to be due to changes in diffusion within the white matter tracts (Pasternak et al., 2015). These data suggest that white matter changes in the early course of illness may be due to neuroinflammation, while subsequent white matter deficits are caused by a neurodegenerative process.

PET ligands for translocator protein 18 kDa (TSPO), a microglial marker increased in conditions of active inflammation, show promise for allowing measurement of neuroinflammation in vivo. Rene Kahn of the University of Utrecht in the Netherlands presented data indicating higher TSPO binding in early-course schizophrenia patients than in controls. Furthermore, TSPO binding was positively correlated with peripheral levels of C-reactive protein in schizophrenia patients. Increased mRNA expression of TSPO was also found in postmortem samples of gray matter from older patients with schizophrenia. These effects were more pronounced in the temporal lobe than in the frontal lobe, suggesting regional differences in vulnerability to inflammation.

Previous studies with PET ligands for TSPO have revealed that some individuals show abnormally low binding, an effect that was found to be linked to a functional polymorphism in the gene for TSPO. Aristotle Voineskos of the Centre for Addiction and Mental Health in Toronto, Canada, presented data examining how this functional variant may be related to brain structure. TSPO genotype did not appear to be associated with white matter microstructure as measured with DTI, but did show an influence over age-related changes in cortical thickness. Although TSPO genotype was not associated with schizophrenia, this genetic variant may be an important contributor to differential vulnerability to the neurobiological effects of inflammation.

Souhel Najjar of the New York University School of Medicine in New York City presented a review of recent findings regarding neuroinflammation in schizophrenia, with a focus on how abnormalities in glial cells may be related to white matter abnormalities (Najjar and Pearlman, 2015). Evidence from neuropathological studies includes findings of increased HLA-immunoreactive microglial density in white matter relative to gray matter, activated microglia near apoptotic oligodendrocytes and demyelinating axons, and increased numbers of interstitial neurons in white matter in schizophrenia. Studies examining relative density of astrocytes and oligodendrocytes have yielded mixed results; however, there is no evidence of astrogliosis in schizophrenia, in contrast to other neuroinflammatory disorders such as multiple sclerosis or Alzheimer's disease. Consistent with the neuropathological evidence, studies have found increased levels of cytokines and S100B, and lower levels of myelin basic protein, BDNF, and GFAP in the blood of schizophrenia patients. Genetic studies have provided further evidence implicating glial abnormalities in schizophrenia, as the disorder was associated with SNPs in astroglia- and oligodendroglia-related genes.

In concluding remarks and a discussion moderated by Marek Kubicki and Martha Shenton, both of Harvard, the participants in this symposium identified several important themes for future research on neuroinflammation in schizophrenia, including the need to examine factors contributing to differential vulnerability to neuroinflammation; to understand specific mechanisms driving the neuroinflammatory cascade; and the need to recognize that neuroinflammation can be a healing process in reaction to another pathological process, and may or may not be inherently pathological. Interventions that alter neuroinflammation may have potential in preventing neurodegeneration and transforming the course of illness.—Joshua Chiappelli.