Neuroinflammation and white matter pathology in schizophrenia: systematic review.

SCHRES-05886; No of Pages 11 Schizophrenia Research xxx (2014) xxx–xxx

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Review

Neuroinflammation and white matter pathology in schizophrenia: systematic review Souhel Najjar a,⁎,1, Daniel M. Pearlman a,b,1 a b

Neuroinflammation Research Group, Epilepsy Center Division, Department of Neurology, NYU School of Medicine, New York, New York, United States The Dartmouth Institute of Health Policy and Clinical Practice, Audrey and Theodor Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States

a r t i c l e

i n f o

Article history: Received 15 January 2014 Received in revised form 30 March 2014 Accepted 3 April 2014 Available online xxxx Keywords: White matter Neuroinflammation Schizophrenia Neuropathology Systematic review

a b s t r a c t Background: Neuroinflammation and white matter pathology have each been independently associated with schizophrenia, and experimental studies have revealed mechanisms by which the two can interact in vitro, but whether these abnormalities simultaneously co-occur in people with schizophrenia remains unclear. Method: We searched MEDLINE, EMBASE, PsycINFO and Web of Science from inception through 12 January 2014 for studies reporting human data on the relationship between microglial or astroglial activation, or cytokines and white matter pathology in schizophrenia. Results: Fifteen studies totaling 792 subjects (350 with schizophrenia, 346 controls, 49 with bipolar disorder, 37 with major depressive disorder and 10 with Alzheimer's disease) met all eligibility criteria. Five neuropathological and two neuroimaging studies collectively yielded consistent evidence of an association between schizophrenia and microglial activation, particularly in white rather than gray matter regions. Ultrastructural analysis revealed activated microglia near dystrophic and apoptotic oligodendroglia, demyelinating and dysmyelinating axons and swollen and vacuolated astroglia in subjects with schizophrenia but not controls. Two neuroimaging studies found an association between carrier status for a functional single nucleotide polymorphism in the interleukin-1β gene and abnormal white as well as gray matter volumes in schizophrenia but not controls. A neuropathological study found that orbitofrontal white matter neuronal density was increased in schizophrenia cases exhibiting high transcription levels of pro-inflammatory cytokines relative to those exhibiting low transcription levels and to controls. Schizophrenia was associated with decreased astroglial density specifically in subgenual cingulate white matter and anterior corpus callosum, but not other gray or white matter areas. Astrogliosis was consistently absent. Data on astroglial gene expression, mRNA expression and protein concentration were inconsistent. Conclusion: Neuroinflammation is associated with white matter pathology in people with schizophrenia, and may contribute to structural and functional disconnectivity, even at the first episode of psychosis. © 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction Schizophrenia is a severe neuropsychiatric disorder that represents the 18th leading cause of years lived with disability globally (Whiteford et al., 2013) and has an estimated point prevalence of 0.5% to 1.0% (Tandon et al., 2008). Functional and structural disconnectivity are among the most reproducible neurophysiological abnormalities associated with schizophrenia (Burns et al., 2003; Whalley et al., 2005; Liang et al., 2006; Begre and Koenig, 2008; Konrad and Winterer, 2008;

⁎ Corresponding author at: Epilepsy Center Division, Department of Neurology, NYU School of Medicine, 223 East 34th Street New York, NY 10016, United States. Tel.: + 1 646 558 0807; fax: + 1 646 385 7166. E-mail address: [email protected] (S. Najjar). 1 S.N. and D.M.P. contributed equally to this work.

Hoptman et al., 2010; Qiu et al., 2010; Whitford et al., 2011; Shi et al., 2012a,b; Curčić-Blake et al., 2013; Rane et al., 2013; Straube et al., 2013; Tepest et al., 2013) (recently reviewed by Schmitt et al. (2011)). Structural connectivity refers to macroscopic neuroanatomical dynamics, and is commonly measured by diffusion-tensor imaging (DTI) tractography, volumetric magnetic resonance imaging (MRI) and magnetization-transfer imaging. Functional connectivity refers to the temporal correlation between neuronal activity in two or more neuroanatomically distinct regions, and is commonly measured by functional MRI (Greicius et al., 2009; Honey et al., 2009). There are several recent systematic reviews on the evidence for structural disconnectivity in schizophrenia (Di et al., 2009; Bora et al., 2011; Olabi et al., 2011; Patel et al., 2011; De Peri et al., 2012; Kuswanto et al., 2012; Haijma et al., 2013; Samartzis et al., 2014; Yao et al., 2013). In the most inclusive of these, which focused on DTI studies, the authors found consistent evidence of white matter pathology affecting frontal, fronto-temporal and

http://dx.doi.org/10.1016/j.schres.2014.04.041 0920-9964/© 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Please cite this article as: Najjar, S., Pearlman, D.M., Neuroinflammation and white matter pathology in schizophrenia: systematic review, Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.04.041

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S. Najjar, D.M. Pearlman / Schizophrenia Research xxx (2014) xxx–xxx

fronto-limbic connections of the superior longitudinal fasciculus, cingulum bundle, uncinate fasciculus and corpus callosum (Samartzis et al., 2014), which they and others have provided evidence to suggest, are changes that may be evident during first-episode presentations of schizophrenia (Downhill et al., 2000; Bachmann et al., 2003; Innocenti et al., 2003; Li et al., 2014; Reis Marques et al., 2014; Samartzis et al., 2014). White matter pathology of oligodendroglia and myelinated fibers is thought to represent the neurobiological basis of structural and functional disconnectivity in schizophrenia (Davis et al., 2003). Oligodendroglial pathology documented in schizophrenia includes morphological abnormalities in prefrontal cortex (Uranova et al., 2001, 2011) and reduced cellular density, particularly in the prefrontal cortex, anterior cingulate cortex and hippocampus (Uranova et al., 2002; Davis et al., 2003; Hof et al., 2003; Uranova, 2004; Uranova et al., 2004; Vostrikov et al., 2004; Helldin et al., 2007; Mitelman et al., 2007a,b; Friedman et al., 2008a,b; Borgwardt et al., 2009a,b; Williams et al., 2013, 2014). Microarray messenger RNA (mRNA) expression studies and single-cell gene quantitative real-time polymerase chain reaction (PCR) studies have documented reduced expression of several oligodendroglial- and myelin-associated proteins in schizophrenia, such as 2′, 3′-cyclic nucleotide 3′-phosphodiesterase (CNP), myelin basic protein, myelinassociated glycoprotein (MAG), myelin and lymphocyte protein, gelsolin, transferrin and ErbB3 (Hakak et al., 2001; Davis et al., 2003; Flynn et al., 2003; Tkachev et al., 2003). A single nucleotide polymorphism in the Olig2 gene that is necessary for maturation of oligodendroglial lineage has been associated with reduced white matter fractional anisotropy (FA) in schizophrenia (Prata et al., 2012). Progressive white matter volume loss has also been documented in schizophrenia (Olabi et al., 2011; Haijma et al., 2013), and positively correlates with the severity of negative symptoms, impulsivity and aggression (Sanfilipo et al., 2000; Wible et al., 2001a,b; Hoptman et al., 2002; Wolkin et al., 2003; Uranova et al., 2011). In certain neurodevelopmental disorders, like periventricular leukomalacia, an insult to the developing brain results in neuroinflammation-mediated injury to oligodendroglial progenitor cells, which in turn leads to white matter pathology and disconnectivity abnormalities resembling those found in schizophrenia (Rousset et al., 2006; Leviton and Gressens, 2007). A separate line of investigation documents a robust association between neuroinflammation and schizophrenia (Bayer et al., 1999; Radewicz et al., 2000; Wierzba-Bobrowicz et al., 2005; Steiner et al., 2006; Steiner et al., 2008; van Berckel et al., 2008; Doorduin et al., 2009; Monji et al., 2009; Miller et al., 2011; Van Berckel et al., 2011; Van Der Doef et al., 2011; Fillman et al., 2013; Miller et al., 2013b) (recently reviewed by our group (Najjar et al., 2013)). Neuroinflammation is characterized by a complex cascade involving microglial activation, upregulated cytokine signaling, and/or astroglial loss and activation that persist beyond a transient neuroprotective phase normally down-regulated by feedback mechanisms, thereby establishing a progressive pathological state that promotes further neuronal injury (Streit et al., 2004; Najjar et al., 2013). Neuroinflammatory mechanisms implicated in schizophrenia, include glial (astroglial loss and activation, microglial activation and priming), immunologic (cytokines, chemokines, prostaglandins) and oxidative (reactive oxygen and nitrogen species) aberrations. These mechanisms are thought to result in glutamatergic (hypofunction) and dopaminergic (limbic hyperfunction, frontal hypofunction) dysregulation by various putative pathways, such as increasing astroglial synthesis of kynurenic acid (an N-methyl-D-aspartate receptor and α-7nicotinic acetylcholine receptor antagonist) and S100β, and upregulating excitatory amino acid transporter expression (Najjar et al., 2013). Only recently, however, as evidence supporting the importance of neuroinflammation in the pathophysiology of schizophrenia has accumulated over the last decade, have researchers begun directly investigating how neuroinflammation might link neurodevelopmental abnormalities to progressive white matter pathology/disconnectivity in schizophrenia (Chew et al., 2013; Monji et al., 2013). To date, there has been no systematic attempt to synthesize and analyze data to this

effect. As such, and given the variety of sub-disciplines contributing to this work, both the nature and quality of this evidence viewed in aggregate as well as the relative reproducibility of its composite findings individually, remain unclear. Here, we aimed to characterize the extant literature relating neuroinflammation to white matter pathology in schizophrenia by performing a systematic review of human data derived from neuropathological and neuroimaging studies. 2. Material and methods 2.1. Search strategy We performed a systematic electronic search for records indexed within MEDLINE, EMBASE, PsycINFO or Web of Science from inception through 12 January 2014 to identify potentially eligible studies; see Table S1 in the Supplementary Appendix for a copy of our full-length search strategy. We sought both published (peer-reviewed journal articles) and unpublished (meeting abstracts) data sources. We supplemented these electronic searches by manually reviewing the reference lists of eligible studies. 2.2. Study selection After removing duplicates from the set of records retrieved by these searches, we selected studies for inclusion based on the following eligibility criteria: (a) neuropathological or neuroimaging studies that provided data on both (b) neuroinflammation and (c) white matter pathology (d) in individuals with schizophrenia. Regarding the neuroinflammation criterion, we focused our analysis on studies providing data on microglia, cytokines and/or astroglia, because abnormalities involving these cells and signaling molecules represent the central elements of neuroinflammation (Streit et al., 2004). To avoid introducing bias in comparisons of gray and white matter pathology across different populations, disease states and other potential confounders, we excluded studies that reported data on neuroinflammation-related outcomes in gray but not white matter. 2.3. Data extraction and synthesis We extracted data onto a standardized and piloted data collection form maintained on an electronic spreadsheet (available from the authors by request). For characteristics of included studies and subjects, we extracted data on citation information, eligibility criteria, publication type, study type, age and sex of subjects and duration of illness. We extracted data on all outcome measures related to neuroinflammation in white and gray matter in individuals with schizophrenia and comparison groups. We extracted data on neuroinflammation-related outcomes for a given Brodmann Area or next most-specific neuroanatomical region provided. We preserved any existing distinctions regarding white versus gray matter, left versus right hemispheres and males versus females. We summarized comparisons between schizophrenia versus control subjects on continuous and categorical outcome measures as the mean difference with 95% confidence intervals (CIs) and odds ratios with 95% CIs, respectively, using the RevMan statistical software package (Review Manager version 5.2, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). 3. Results 3.1. Search results Fig. 1 summarizes the results of the search strategy and study selection processes. Fifteen studies described across 18 reports (14 journal articles and four meeting abstracts) met all eligibility criteria (see Table 1). Three studies were described across two reports each: (a) (Fillman et al., 2013; Fung et al., 2014), (b) (Beasley and Hercher,



747

Total records identified by systematic electronic database searches 137 196 69 345

396

MEDLINE (1946–W3 Nov 2013) EMBASE (1974–10 Jan 2014) PsycINFO (1808–W1 Jan 2014) Web of Science (1990–12 Jan 2014)

Unique records screened after removing duplicate records

350 Records excluded after screening titles and abstracts

46 Full-texts assessed for eligibility

31 Studies excluded with reasons 24 6 1

15

Not neuroinflammation Not white matter Missing outcome data

Studies (18 records) included for qualitative synthesis in the systematic review

Fig. 1. Study flow diagram.

2011, 2013) and (c) (Williams et al., 2014; Williams et al., 2013). There were 792 total subjects (see Table S2 in the Supplementary Appendix), including 350 subjects with schizophrenia (mean ± standard deviation: age, 48 ± 18 years; male sex, 66% ± 27%; duration of illness, 16 ± 10 years) and 346 controls (mean ± standard deviation: age, 46 ± 16 years; male sex, 65% ± 19%). The remaining subjects consisted of 49 with bipolar disorder, 37 with major depressive disorder and 10 with Alzheimer's disease. 3.2. Microglia Five neuropathological studies and two neuroimaging studies (222 subjects) yielded data on microglial activation in white matter brain tissue in schizophrenia (see Table 2). One neuropathological study assessed microglial density in the dorsolateral prefrontal gray and white matter and found a significantly increased density of major histocompatibility class II (MHC-II) human leukocyte antigen (HLA)-DR-immunoreactive dorsolateral prefrontal white matter microglia in subjects with schizophrenia compared with controls (Fillman et al., 2013). Another neuropathological study assessed dorsolateral prefrontal, superior temporal, and anterior cingulate gray and white matter. HLA-immunoreactive dorsolateral prefrontal and superior temporal gray and white matter microglial density was significantly increased in those with schizophrenia; this pattern approached statistical significance in anterior cingulate gray and white matter (Radewicz et al., 2000). Both of these studies found increased HLAimmunoreactive microglia l density in white relative to gray matter among those with schizophrenia. A third study reported no significant difference in the density of ionized calcium-binding adapter

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molecule 1 protein (IBA1)-immunoreactive prefrontal white matter microglia among subjects with schizophrenia relative to controls (Beasley and Hercher, 2013). A fourth study found HLA-DR-immunoreactive prefrontal gray and white matter microglial activation in 3 of 14 subjects with schizophrenia (1 with microgliosis), 4 of 8 subjects with Alzheimer's disease (4 with microgliosis), 1 of 13 subjects with affective disorder (1 with microgliosis), and 0 of 13 controls. All three subjects with schizophrenia and microglial activation had late-onset schizophrenia at 40, 46, and 50 years of age. Microglial density was not quantified in this study (Bayer et al., 1999). Ultrastructural analyses from an electron microscopy study revealed activated microglia that contained myelin membranous debris located between myelin sheath lamellae and adjacent to swollen and vacuolated astroglia, in prefrontal white matter specimens of subjects with schizophrenia but not in those of controls (Uranova et al., 2011). Microglial-like cells were also detected between myelin sheath lamellae in gray matter sections. Oligodendroglia were either dystrophic (cytoplasmic swelling and vacuolation) in gray and white matter, or apoptotic/necrotic (nuclear chromatin clumping, pyknotic nuclei, and lysis of organelle membranes) in gray matter alone. Several patterns myelinated fiber abnormalities were also identified. These were characterized either by demyelination (focal lysis and disrupted compaction of myelin sheath lamellae often with formation of concentric lamellar bodies), dysmyelination or axonal degeneration. One positron emission tomography study evaluated the binding potential of (R)-N-11C-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide ((R)-11C-PK11195), which is a peripheral benzodiazepine receptor ligand somewhat specific for microglial activation. Whole-brain gray and white matter binding potentials were 30% and 20% higher, respectively, in those with schizophrenia compared with controls. Binding potential was also significantly increased in hippocampal combined gray and white matter among those with schizophrenia (Doorduin et al., 2009). Another neuroimaging study used a novel DTI approach that distinguishes between extracellular freewater volume—indicative of neuroinflammation (Wang et al., 2011), and tissue-specific fractional anisotropy (FAT)—reflecting axonal degeneration (Pasternak et al., 2009), the sum of which is equal to the value of FA as measured by conventional DTI studies. Among those with schizophrenia, extracellular free-water volume was significantly increased throughout gray and white matter, whereas FAT was significantly decreased specifically in the superior longitudinal fasciculus bilaterally, the right inferior frontal occipital fasciculus, and the intersection of callosal fibers with the right superior corona radiata (Pasternak et al., 2012). 3.3. Cytokines Two neuropathological studies and three neuroimaging studies (349 subjects) yielded data on the relationship between cytokines and white matter pathology (see Table 3). One study found a significant positive correlation between microglial density and interleukin-1β (IL-1β) mRNA expression in the dorsolateral prefrontal white – but not gray – matter among schizophrenia subjects (Fillman et al., 2013). In a follow-up analysis, the density of neuronal nuclear antigen (NeuN)-immunoreactive orbitofrontal white matter neurons was almost 50% higher in schizophrenia subjects with high transcription levels of interleukin (IL)-6, IL-8, IL-1β, and serpin peptidase inhibitor, clade A (α-1 antiproteinase, antitrypsin) and member 3 (SERPINA3) (henceforth “high-inflammation subgroup”) compared with controls. Significant differences were also observed in the density of NeuN-immunoreactive dorsolateral prefrontal white matter neurons (18.9% higher in the high-inflammation subgroup compared with controls), and the density of NeuN-immunoreactive orbitofrontal, but not dorsolateral prefrontal, white matter neurons (14.9% higher in the low-inflammation subgroup compared with controls, and 25.0% higher in the highinflammation subgroup compared with the low-inflammation subgroup). The density of glutamic acid decarboxylase 65/67 kDa


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Table 1 Included studies reporting on the relationship between neuroinflammation and white matter pathology in individuals with schizophrenia.

Microglia Fillman et al., 2013 Beasley and Hercher, 2013 Radewicz et al., 2000 Uranova et al., 2011 Bayer et al., 1999 Doorduin et al., 2009 Pasternak et al., 2012 Cytokines Fung et al., 2014 Fillman et al., 2013 Maitra et al., 2009 Meisenzahl et al., 2001 Prasad et al., 2013 Astroglia Williams et al., 2013, 2014 Williams et al., 2013 Beasley and Hercher, 2011 Radewicz et al., 2000 Falkai et al., 1999 Uranova et al., 2011 Katsel et al., 2011 Beasley et al., 2009 Barley et al., 2009

SCZ CTR PMID

Methods

Gray matter

White matter

Main outcome measures

37 20 8 12 14 7 18

37 20 10 12 13 8 20

22869038 23821786 10749103 22937264 10477118 19837763 23197727

Histology Histology Histology Histology Histology PET DTIFW b

BA46 PFC BA9, 22, 24 BA10 (layer V) Hipp, PFC Whole-brain d Whole-brain

BA46 PFC BA9, 22, 24 BA10 Hipp, PF Whole-brain d Whole-brain

Microglial density (HLA-DR) Microglial density (IBA-1) Microglial density (HLA-DR) Microglial, oligodendroglial, myelin sheath ultrastructure (electron microscopy) Activation (HLA-DR) Activation (11C-(R)-PK11195 binding potential) Volume (extracellular free-water), tissue-specific fractional anisotropy (FAT) c

37 37 61 44 39

37 37 54 48 29

23830667 22869038 19760350 11481169 23821786

Histology Histology MRI MRI DTI

– BA46 Whole-brain Whole-brain Whole-brain

BA11, 46 BA46 Whole-brain Whole-brain Whole-brain

Neuronal density (NeuN, GAD65/67), by mRNA: IL-6, IL-8, IL-1β, SERPINA3 mRNA: IL-6, IL-8, IL-1β, and SERPINA3 Gray and white matter volume, by IL-1β functional SNP allele 2 risk carriers Gray and white matter volume, by IL-1β functional SNP allele 2 risk carriers Fractional anisotropy, mean diffusivity, by IL-6 and C-reactive protein

10 10 20 8 33 12 18 15 14

20 20 20 10 26 12 21 13 13

22660922 24374936 21513031 10749103 10194775 22937264 21270770 19272755 19447584

Histology Histology Histology Histology Histology Histology Histology Histology Histology

BA25 BA25 – BA9, 22, 24 BA28, 48 BA10 BA24 – Thal, putamen

BA25, CC BA25 Superficial PF BA9, 22, 24 BA6, 3rd V, IH BA10 BA24 Internal capsule Internal capsule

Astroglial density (GFAP), oligodendroglial density Astroglial density (fibrillary vs. gemistocytic) Astroglial density (GFAP), oligodendroglial density Astroglial density (GFAP) Astroglial density (GFAP) Astroglial, oligodendroglial, myelin sheath ultrastructure (electron microscopy) mRNA: DIO, AQP4, ALDH1L1, S100β, GFAP, VIM, THBS4, GS, EAAT-2, GL GFAP protein concentration Astroglial (ALDH1L1, GFAP) and oligodendroglial gene expression a

ADAM12, A disintegrin and metalloprotease; AQP4, aquaporin-4; ALDH1L1, aldehyde dehydrogenase 1 family member L1; BA, Brodmann area; BA6, premotor cortex and supplementary motor area; BA9, dorsolateral prefrontal cortex; BA11, orbitofrontal cortex; BA22, superior temporal gyrus; BA28, entorhinal cortex; BA24, anterior cingulate; BA25, subgenual cingulate; BA48, subiculum; CC, corpus callosum; CTR, control; DIO, diodinase type II; EAAT2, excitatory amino-acid transporter 2; EM, electron microscopy; FA, fractional anisotropy; FAT, fractional anisotropy in tissue; FW, free-water; GAD, glutamic acid decarboxylase; GL, glutaminase; GFAP, glial fibrillary acidic protein; GS, glutamine synthase; Hipp, hippocampus; HLA-DR, human leukocyte antigen DR; IH, inferior horn; IL, interleukin; PMID, PubMed Identifier; PET, positron emission tomography; PF, prefrontal region; PFC, prefrontal cortex; (R)-[11C]-PK11195, isoquinoline (R)-N-11C-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)-isoquinoline-3-carboxamide; SCZ, schizophrenia; Thal, thalami; THBS4, thrombospondin; VIM, vimentin; 3rd V, 3rd ventricle subventricular zone. a NG2, PDGFRα, SOX11, SOX10, OLIG2, FYN, TF CNP, GALC, GTX, MAG, MAL, MOG, MOBP and PLP1. b Diffusion-tensor imaging with free-water extracellular fluid volume measurement as a marker neuroinflammation (see Pasternak et al., 2012). c Fractional anisotropy in tissue equal to [conventional] fractional anisotropy less free-water extracellular fluid volume. d Gray and white matter; frontal, occipital, temporal and parietal cortices; basal ganglia, thalamus, hippocampus, midbrain, cerebellum and pons.

(GAD65/67)-immunoreactive orbitofrontal, but not dorsolateral prefrontal, white matter neurons was also significantly higher in both high-inflammation and low-inflammation subgroups compared with controls; however, there was no statistically significant difference between the high-inflammation and low-inflammation subgroups. Among the high-inflammation subgroup, a significant negative correlation was also observed between the densities of NeuN-immunoreactive white matter neurons and GAD67-immunoreactive gray matter neurons in the dorsolateral prefrontal region (Fung et al., 2014). Two studies assessed gray and white matter volumes of schizophrenia and control participants in relation to carrier status for a functional single nucleotide polymorphism in the IL-1β gene, which involves a C–T transposition at position −511. Participants were genotyped to establish whether they were allele 2 (A2) carriers (genotype T/T or C/T) or A1 non-carriers (genotype C/C). In the first study, A2 carrier subjects with schizophrenia had significantly decreased total white matter, frontal gray matter, and temporal gray matter volumes compared with A2 carrier controls (Meisenzahl et al., 2001). The second study found significantly increased volumes of frontal white – but not gray – matter, occipital white matter, bilateral arcuate fasciculi and left inferior temporal gray matter in the A2 carrier schizophrenia subjects compared with A1 non-carrier schizophrenia subjects. Gray matter volumes in the right lateral prefrontal cortex, thalamus, insula and right medial temporal lobe were significantly lower among schizophrenia subjects compared with controls. Gray and white matter volumes did not differ significantly between A2 versus A1 controls in any regions (Maitra et al., 2009). A conventional DTI study found significantly decreased FA in the superior longitudinal, arcuate and uncinate fasciculi and forceps minor among those with schizophrenia compared with controls. A significant positive correlation was also observed between serum concentrations of IL-6,

but not C-reactive protein, and FA in the forceps minor among those with schizophrenia (Prasad et al., 2013). 3.4. Astroglia Eight neuropathological studies (230 subjects) yielded data on the relationship between astroglial pathology and white matter (see Table 4). One study measured astroglial density in the subgenual cingulate gray and white matter (the base, located at the depth of the sulcus— and the crown), as well as the anterior corpus callosum. Astroglial density was significantly decreased in subgenual cingulate gray matter (specifically in layer I), both at the crown and the base of subgenual cingulate white matter, and in anterior corpus callosum among those with schizophrenia compared with controls (Williams et al., 2014). In a follow-up analysis that was limited to the subgenual cingulate white matter, the number of fibrillary astroglia was significantly decreased at the base – but not the crown – among those with schizophrenia (Williams et al., 2013a). Three additional studies reported that astroglial density in white matter sections of the premotor area, the third ventricle and the inferior horn subventricular zones, the dorsolateral prefrontal, superior temporal, and anterior cingulate cortices, and internal capsule did not differ significantly between subjects with schizophrenia compared to controls. These three studies also found no significant differences in astroglial density in gray matter sections of subiculum, entorhinal cortex, dorsolateral prefrontal cortex, superior temporal gyrus, anterior cingulate cortex, thalamus, or putamen (Falkai et al., 1999; Radewicz et al., 2000; Beasley and Hercher, 2011). Of these, two studies also evaluated oligodendroglial density—one in the subgenual cingulate gray and white matter as well as the anterior corpus callosum (Williams et al., 2014), and the other in the superficial prefrontal white matter



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Table 2 Association between microglial and white matter pathology in individuals with schizophrenia compared with controls.

Whole-brain Doorduin et al., 2009 (w.m.) Doorduin et al., 2009 (g.m.) Left hemisphere Pasternak et al., 2012 (w.m.) Pasternak et al., 2012 (g.m.) Right hemisphere Pasternak et al., 2012 (w.m.) Pasternak et al., 2012 (g.m.) Prefrontal Fillman et al., 2013 (w.m.) Fillman et al., 2013 (g.m.) Beasley and Hercher, 2013 (w.m.) Beasley and Hercher, 2013 (g.m.) Radewicz et al., 2000 (w.m.) c Radewicz et al., 2000 (g.m.) Bayer et al., 1999 (both) Hippocampus Doorduin et al., 2009 (both) Superior temporal Radewicz et al., 2000 (g.m.) c Radewicz et al., 2000 (g.m.) Anterior cingulate Radewicz et al., 2000 (w.m.)c Radewicz et al., 2000 (g.m.) d

Effect size (95% CI)a

P valueb

(0.51) (0.41)

0.45 0.45

(−0.18 to 1.08) (−0.10 to 1.00)

n/s n/s

0.1031 0.1826

(NR) (NR)

0.0115 0.0165

(NR) (NR)

b.02 b.02

(NR) (NR)

0.1042 0.1885

(NR) (NR)

0.0112 0.0136

(NR) (NR)

b.02 b.03

113 50 NR NR NR 115 3

(4) (NR) (NR) (NR) (NR) (9) (21)

103 49 NR NR NR 89 0

(4) (NR) (NR) (NR) (NR) (5) (0)

10 – – – N26 26 13

(8 to 12) – – – – (19 to 33) (1 to 267)

b.03 n/s n/s n/s b.05 b.05 .n/s

2.07

(0.42)

1.37

(0.30)

0.70

(0.33 to 1.07)

.004

Density, mean (s.e.m.), cells mm Density, mean (s.e.m.), cells mm−2

N139 139

(NR) (6)

NR 88

(NR) (5)

N51 51

(NR) (46 to 56)

b.01 b.01

Density, mean (s.e.m.), cells mm−2 Density, mean (s.e.m.), cells mm−2

NR NR

(NR) (NR)

NR NR

(NR) (NR)

N0 N0

– –

– .n/s

Microglia-related outcome

Schizophrenia

Control

11 11

2.18 1.99

(0.70) (0.64)

1.73 1.54

Free-water volume, mean Free-water volume, mean

0.1145 0.1991

(NR) (NR)

Free-water volume, mean Free-water volume, mean

0.1154 0.2021

Density, mean (s.d.), cells mm−2 Density, mean (s.d.), cells mm−2 Density, mean (s.d.), cells mm−2 Density, mean (s.d.), cells mm−2 Density, mean (s.e.m.), cells mm−2 Density, mean (s.e.m.), cells mm−2 Activation, n (%) 11

C-(R)-PK11195, mean (s.d.), BP C-(R)-PK11195, mean (s.d.), BP

C-(R)-PK11195, mean (s.d.), BP −2

BP, binding potential; (R)-[11C]-PK11195, isoquinoline (R)-N-11C-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)-isoquinoline-3-carboxamide; CI, confidence interval; g.m., gray matter; NR, not reported; n/s, not significant; s.d., standard deviation; s.e.m., standard error of the mean w.m., white matter. a Continuous data are mean difference (95% CI); categorical data are odds ratio (95% CI). b Extracted from original reports. c Values were inferred based on the following statement from the original report: “Although microglia were not quantified in the white matter, a qualitative comparison showed that more HLA-DR immunoreactivity was observed in white matter than in grey matter.” d Tissue fractional anisotropy was specifically decreased in the superior longitudinal fasciculus bilaterally, the right inferior frontal occipital fasciculus, and the intersection of callosal fibers with the right superior corona radiata. There were no significant between-group differences in tissue fractional anisotropy in any gray matter regions in the brain.

(Beasley and Hercher, 2011). Neither found a significant difference between schizophrenia cases and controls in any of the brain regions assessed (Beasley and Hercher, 2011; Williams et al., 2014). The previously mentioned electron microscopy study also found swollen and vacuolated astroglia containing membranous myelin debris in both gray and white matter of schizophrenia subjects but not controls (Uranova et al., 2011). One study compared the mRNA expression of nine astroglial markers (diodinase type II, aquaporin-4, S100β, glutaminase, excitatory amino acid transporter-2 [EAAT-2], thrombospondin, aldehyde dehydrogenase 1 family member L1 [ALDH1L1], glial fibrillary acid protein [GFAP] and vimentin) in post mortem specimens of anterior cingulate gray and white matter. Expression of each marker in the anterior cingulate white matter or cortical layers I–III was not significantly different among those with schizophrenia compared to controls. However, the expression of diodinase type II, aquaporin-4, S100β, glutaminase, EAAT-2, and thrombospondin – but not ALDH1L1, GFAP, or vimentin – was significantly increased in layers IV-VI among those with schizophrenia (Katsel et al., 2011). Another study used quantitative PCR to measure astroglial (GFAP and ALDH1L1) and oligodendroglial (proteoglycan 4, platelet-derived growth factor receptor α, sex-determining region Y [SRY]-box 11, SRY-box 10, oligodendrocyte lineage transcription factor 2, Fyn tyrosine kinase, transferrin, CNP, galactosylceramidase, NKX6 homeobox 2 transcription factor, myelin-associated glycoprotein, T-cell differentiation protein, myelin-oligodendrocyte glycoprotein, myelin-associated oligodendrocyte basic protein and proteolipid protein) gene expression in post mortem specimens of thalamus, putamen and corpus callosum. Expression of GFAP and ALDH1L1 was significantly increased in all the brain regions assessed among those with schizophrenia and major depressive disorder compared with those with bipolar disorder and controls. Expression of CNP, galactosylceramidase, myelin-associated glycoprotein and myelin-oligodendrocyte glycoprotein was significantly decreased in all regions assessed among those with schizophrenia compared with bipolar or major depressive

disorders and controls (Barley et al., 2009). Another study that evaluated GFAP protein concentration in the dorsal and ventral aspects of the anterior limb of the internal capsule, found no significant betweengroup differences between subjects with schizophrenia relative to controls (Beasley et al., 2009). 4. Discussion To our knowledge, this is the first systematic review on the relationship between neuroinflammation and white matter pathology in individuals with schizophrenia. There are several notable findings. First, neuropathological and neuroimaging studies provide consistent evidence of an association between schizophrenia and microglial activation and proliferation, particularly in the white matter. Neuropathological studies that reported data on microglial density in gray matter alone (not included in our review) have yielded mixed results (Arnold et al., 1998; Falke et al., 2000; Wierzba-Bobrowicz et al., 2005; Steiner et al., 2006, 2008; Busse et al., 2012). One free-water DTI study found an association between first-episode schizophrenia and widespread neuroinflammation and focally reduced FAT in frontal white matter. To our knowledge, this is the only study of its kind, either in gray or white matter. Second, pro-inflammatory cytokine genetic mutations and mRNA expression levels are associated with reduced white matter volume and increased white matter neuronal density, respectively. Third, astroglial density is decreased specifically in the subgenual cingulate gray and white matter, and anterior corpus callosum in schizophrenia. Studies not included in this review have also reported reduced astroglial density in anterior cingulate and dorsolateral prefrontal cortices, as well as hippocampus (Webster et al., 2001; Doyle and Deakin, 2002; Rajkowska et al., 2002; Stark et al., 2004; Steffek et al., 2008). Since astroglia regulate synaptic glutamate levels, these findings are consistent with glutamatergic dysfunction that is associated with schizophrenia (Najjar et al., 2013). Included studies provided inconsistent data on astroglial-marker gene and mRNA expression, and


6


Table 3 Association between cytokines and white matter pathology in individuals with schizophrenia compared with controls. Cytokine-related findings

P value

(IL-1β gene SNP) schizophrenia (A2) vs. controls (A1) (IL-1β gene SNP) controls (A2) vs. controls (A1)

.03 .25

(IL-1β gene SNP) schizophrenia (A2) vs. schizophrenia (A1)

b.001

(IL-1β gene SNP) schizophrenia (A2) vs. schizophrenia (A1) (IL-1β gene SNP) controls (A2) vs. controls (A1)

b.001 n/s

Neuronal density (NeuN) Neuronal density (NeuN) Neuronal density (NeuN) Neuronal density (GAD65/67) Neuronal density (GAD65/67)

(IL-6, IL-8, IL-1β, SERPINA3 mRNA) 43.7% schizophrenia (high) vs. controls (IL-6, IL-8, IL-1β, SERPINA3 mRNA) 14.9% schizophrenia (low) vs. controls (IL-6, IL-8, IL-1β, SERPINA3 mRNA) 25.0% schizophrenia (high) vs. schizophrenia (low) (IL-6, IL-8, IL-1β, SERPINA3 mRNA) schizophrenia (high) vs. controls (IL-6, IL-8, IL-1β, SERPINA3 mRNA) schizophrenia (low) vs. controls

.00000001 .00001 .0007 .007 .005

Microglial density Neuronal density (NeuN) Neuronal density (NeuN) Neuronal density (NeuN) Neuronal density (NeuN) Neuronal density (GAD65/67) Neuronal density (GAD65/67)

Correlation with IL-1β mRNA among schizophrenia, but not Controls Correlation with GAD67 gray matter neuron density among Schizophrenia (high) (r = −0.54) (IL-6, IL-8, IL-1β, SERPINA3 mRNA) 18.9% schizophrenia (high) vs. controls (IL-6, IL-8, IL-1β, SERPINA3 mRNA) schizophrenia (low) vs. controls (IL-6, IL-8, IL-1β, SERPINA3 mRNA) schizophrenia (high) vs. schizophrenia (low) (IL-6, IL-8, IL-1β, SERPINA3 mRNA) schizophrenia (high) vs. controls (IL-6, IL-8, IL-1β, SERPINA3 mRNA) schizophrenia (low) vs. controls

.04 .04 .06 n/s n/s n/s n/s

Outcome White matter Whole-brain Meisenzahl et al., 2001 Meisenzahl et al., 2001 Occipital Maitra et al., 2009 Prefrontal Maitra et al., 2009 Maitra et al., 2009 Orbitofrontal Fung et al., 2014 Fung et al., 2014 Fung et al., 2014 Fung et al., 2014 Fung et al., 2014 Dorsolateral prefrontal Fillman et al., 2013 Fung et al., 2014 Fung et al., 2014 Fung et al., 2014 Fung et al., 2014 Fung et al., 2014 Fung et al., 2014 Arcuate fasciculi Prasad et al., 2013 Prasad et al., 2013 S. Longitudinal fasciculus Prasad et al., 2013 Prasad et al., 2013 Forceps minor Prasad et al., 2013 Prasad et al., 2013 Uncinate fasciculus Prasad et al., 2013 Prasad et al., 2013 Gray matter Whole-brain Meisenzahl et al., 2001 Meisenzahl et al., 2001 Temporal cortex Meisenzahl et al., 2001 Meisenzahl et al., 2001 Meisenzahl et al., 2001 Maitra et al., 2009 Maitra et al., 2009 Thalamus, insula Maitra et al., 2009 Prefrontal cortex Meisenzahl et al., 2001 Meisenzahl et al., 2001 Maitra et al., 2009 Maitra et al., 2009

White matter volume White matter volume

–

White matter volume White matter volume White matter volume

–

– – – –

Fractional anisotropy Fractional anisotropy

–

Correlation between IL-6 or CRP among schizophrenia Schizophrenia vs. controls

n/s .001


–

Correlation in IL-6 or CRP among schizophrenia Schizophrenia vs. controls

n/s .001


Correlation with IL-6 among schizophrenia (r = 0.49), but not controls Schizophrenia vs. controls

.02 .03


Correlation with IL-6, but not CRP, among schizophrenia (r = 0.37) Schizophrenia vs. controls

.08 .04

– –

(IL-1β gene SNP) controls (A2) vs. controls (A1) (IL-1β gene SNP) schizophrenia (A2) vs. controls (A1)

n/s n/s

–

(IL-1β gene SNP) schizophrenia (A2) vs. controls (A1) (IL-1β gene SNP) schizophrenia (A2) vs. schizophrenia (A1) (IL-1β gene SNP) controls (A2) vs. controls (A1) (IL-1β gene SNP) schizophrenia (A2) vs. schizophrenia (A1) Schizophrenia vs. controls

.04 .001 n/s b.001 b.001

Schizophrenia vs. controls

b.001

(IL-1β gene SNP) schizophrenia (A2) vs. controls (A1) (IL-1β gene SNP) controls (A2) vs. controls (A1) (IL-1β gene SNP) controls (A2) vs. controls (A1) Schizophrenia vs. controls

b.02 n/s n/s b.001

Gray matter volume Gray matter volume Gray matter volume Gray matter volume Gray matter volume Gray matter volume Gray matter volume Gray matter volume Gray matter volume Gray matter volume Gray matter volume Gray matter volume

– –

significant decrease; , significant increase; −, no significant difference; A1, non-carrier (genotype C/C) for a functional single nucleotide polymorphism in the IL-1β gene that involves a C–T transposition at position −511; A2, carrier (genotype T/T or C/T) for a functional single nucleotide polymorphism in the IL-1β gene that involves a C–T transposition at position −511; CRP, C-reactive protein; DTI, diffusion-tensor imaging; GAD 65/67, glutamic acid decarboxylase 65 kDa and 67 kDa; MRI, magnetic resonance imaging; IL, interleukin; SERPINA3, serpin peptidase inhibitor, clade A (α-1 antiproteinase, antitrypsin), member 3; SNP, single nucleotide polymorphism.

protein concentration in schizophrenia. However, in contrast to neurodegenerative disorders, included studies yielded consistent evidence that astrogliosis is absent among individuals with schizophrenia. Fourth, neither of the two studies having evaluated oligodendroglial density in the subgenual cingulate gray and white matter, anterior corpus callosum and prefrontal superficial white matter found significant differences between subjects with schizophrenia and controls. Since the anterior cingulate cortex and anterior corpus callosum are critical for integrating limbic inputs and connecting prefrontal cortices, respectively, these findings suggest that factors in addition to oligodendroglial pathology contribute to the disconnectivity of these structures associated with schizophrenia. Other studies not included in this review have reported reduced

oligodendroglial density in the prefrontal region and superior frontal gyrus (Uranova et al., 2002; Davis et al., 2003; Hof et al., 2003; Uranova, 2004; Uranova et al., 2004; Vostrikov et al., 2004; Helldin et al., 2007; Williams et al., 2013, 2014), but not in the anterior cingulum bundle (Segal et al., 2009). These findings should be interpreted in light of several limitations. First, because the majority enrolled small numbers of patients and sought small effect sizes, it is possible that some studies were inadequately powered and therefore yielding Type II errors. Second, differences in immunohistochemical techniques, selection criteria for cases, predetermined anatomical regions of interests, and outcome measures across studies, may have introduced measurement, reporting and/or detection biases (Steiner et al., 2006; Schnieder and Dwork, 2011).



7

Table 4 Association between astroglial and white matter pathology in individuals with schizophrenia compared with controls.

White matter 3rd Ventricle subventricular zone Falkai et al., 1999 [M] L Falkai et al., 1999 [F] L Falkai et al., 1999 [M] R Falkai et al., 1999 [F] R Premotor Falkai et al., 1999 [M] L Falkai et al., 1999 [F] L Falkai et al., 1999 [M] R Falkai et al., 1999 [F] R Inferior horn subventricular zone Falkai et al., 1999 [M] L Falkai et al., 1999 [F] L Falkai et al., 1999 [M] R Falkai et al., 1999 [F] R Prefrontal or superior temporal Beasley and Hercher, 2011 Radewicz et al., 2000 Radewicz et al., 2000 Thalamus Barley et al., 2009 Corpus callosum Williams et al., 2013, 2014 Barley et al., 2009 Internal capsule Beasley et al., 2009 (dorsal) Beasley et al., 2009 (ventral) Barley et al., 2009 Subgenual cingulate Williams et al., 2013, 2014 base Williams et al., 2013, 2014 crown Anterior cingulate Radewicz et al., 2000 Katsel et al., 2011 (mRNA) Katsel et al., 2011 (mRNA) Gray matter Anterior cingulate Radewicz et al., 2000 Katsel et al., 2011 (mRNA) Katsel et al., 2011 (mRNA) c Prefrontal, superior temporal Radewicz et al., 2000 Radewicz et al., 2000 Subiculum Falkai et al., 1999 [M] L Falkai et al., 1999 [F] L Falkai et al., 1999 [M] R Falkai et al., 1999 [F] R Entorhinal Falkai et al., 1999 [M] L Falkai et al., 1999 [F] L Falkai et al., 1999 [M] R Falkai et al., 1999 [F] R

Astroglia-related outcome

Schizophrenia

Control

Effect size (95% CI)a

P value b

Density, mean (s.d.), cells cm−3 Density, mean (s.d.), cells cm−3 Density, mean (s.d.), cells cm−3 Density, mean (s.d.), cells cm−3

160.7 (98.7) 173.1 (91.5) 157.9 (78.8) 181.0 (104.6)

147.8 (91.5) 119.3 (84.5) 155.4 (92.9) 128.9 (101.5)

12.90 (−58.84 to 84.64) 53.80 (−7.87 to 115.47) 2.50 (−62.72 to 67.72) 52.10 (−20.40 to 125.60)

n/s n/s n/s n/s


68.9 (53.5) 47.9 (45.7) 67.3 (46.5) 42.6 (48.3)

101.2 (49.6) 75.0 (70.1) 96.3 (63.4) 59.5 (50.1)

−32.20 (−71.19 to 6.59) −27.10 (−70.39 to 16.19) −29.00 (−71.20 to 13.20) −16.90 (−51.73 to 17.93)

n/s n/s n/s n/s


106.8 (53.4) 138.5 (88.8) 123.2 (50.4) 135.4 (74.0)

172.9 (41.9) 115.4 (67.2) 163.6 (43.5) 121.4 (72.2)

−66.10 (−99.20 to −33.00) 23.10 (−36.10 to 82.24) −40.40 (−73.15 to −7.65) 14.00 (−41.16 to 69.16)

b.0001 n/s b.05 n/s

Density, mean (s.e.m.), cells mm−2 Density, mean (s.e.m.), cells mm−2 Density, mean (s.e.m.), cells mm−2

NR (NR) NR (NR) NR (NR)


–– –– ––

n/s n/s n/s

Gene expression: GFAP, ALDH1L1

NR (NR)

NR (NR)

––

b.05

Density, mean (s.d.), cells mm−2 Gene expression: GFAP, ALDH1L1

12.5 (11.1) NR (NR)

31.6 (4.9) NR (NR)

−19.10 (−26.44 to −11.76) ––

b.05 b.05

Protein concentration: GFAP Protein concentration: GFAP Gene expression: GFAP, ALDH1L1

0.282 (0.081) 0.288 (0.089) NR (NR)

0.294 (0.036) 0.307 (0.057) NR (NR)

−0.18 (−0.93 to 0.56) −0.24 (−0.99 to 0.50) ––

n/s n/s b.05

Density, mean (s.d.), cells mm−2 Density, mean (s.d.), cells mm−2

22.1 (3.0) 21.4 (4.2)

34.4 (4.0) 31.8 (3.1)

−12.30 (−15.10 to −9.50) −10.40 (−13.47 to −7.33)

b.00001 b.00001

Density, mean (s.d.), cells mm−2 GFAP, ALDH1L1, GFAP, VIM, GS DIO, AQP4, S100β, THBS4, EAAT2, GL



–– –– ––

n/s n/s n/s

Density, mean (s.e.m.), cells mm−2 GFAP, ALDH1L1, GFAP, VIM, GS DIO, AQP4, S100β, THBS4, EAAT2, GL



–– –– −26% to −37%

n/s n/s b.05

Density, mean (s.e.m.), cells mm−2 Density, mean (s.e.m.), cells mm−2

NR (NR) NR (NR)

NR (NR) NR (NR)

–– ––

n/s n/s


68.9 (60.9) 65.8 (42.4) 64.3 (57.9) 70.4 (33.1)

61.6 (36.1) 46.7 (21.8) 96.6 (94.6) 49.9 (14.1)

7.30 (−30.15 to 44.75) 19.10 (−3.35 to 41.55) −32.30 (−92.00 to 27.40) 20.50 (3.76 to 37.24)

n/s n/s n/s .05


66.1 (63.1) 51.3 (31.9) 60.4 (53.2) 48.9 (27.9)

53.1 (22.8) 48.6 (19.5) 69.5 (60.5) 44.2 (19.3)

13.00 (−22.30 to 48.30) 2.70 (−15.14 to 20.54) −9.10 (−49.77 to 31.57) 4.70 (−13.29 to 22.69)

n/s n/s n/s n/s

ALDH1L1, aldehyde dehydrogenase 1 family member L1; CI, confidence interval; GFAP, glial fibrillary acid protein; L, left; M, males; n/s, not significant; F, females; R, right; s.d., standard; s.e.m., standard error of the mean. a Effect sizes were calculate as unstandardized mean differences with the exception of the values for Beasley et al., 2009 which were standardized mean differences. b Values were extracted from the original reports. c Values for this row specifically refer to layers IV–VI, as there was no between-group difference in layers I–III for these genes.

Third, since microglial activation can be influenced by the severity of disease (Rogers et al., 1988; Mattiace et al., 1990) and attenuated by antipsychotics (Kato et al., 2011a,b), and the majority of subjects in neuropathological studies had chronic schizophrenia, neuroinflammatory changes may have been under-reported (Steiner et al., 2006; Fillman et al., 2013). Whether neuroinflammation is a cause or effect of white matter pathology in schizophrenia remains unclear. Several observations favor a causative role. While the initial white matter inflammatory response may be evoked by antecedent degenerative and destructive changes of white matter, several animal models of perinatal white matter injury have consistently showed that microglial activation-related

inflammatory changes (e.g., proinflammatory cytokines, inducible nitric oxide synthase, reactive oxygen species) are principally responsible for pre-oligodendroglial apoptotic death, leading to impairment of myelination and limitation of normal development of white matter (Haynes et al., 2003; Pang et al., 2003; Matute et al., 2007; Pang et al., 2010; Taylor et al., 2010). Our findings of microglial activation, increased neural IL-6 and IL-1β levels (particularly in white matter) and a negative correlation between serum IL-6 concentrations and FA values in the uncinate fasciculus among those with schizophrenia are consistent with this interpretation. The most recent meta-analysis of cytokine alterations in schizophrenia, reported increased IL-6 and IL-1β levels among those with schizophrenia (Miller et al., 2011). Experimental


8


models have shown that elevated levels of IL-1β or IL-6 can cause oligodendroglial death, myelin damage and axonal damage in vitro (di Penta et al., 2013), whereas administration of IL-1 receptor antagonist can improve myelination of injured white matter (Pang et al., 2003). One study included in our review reported an inverse relationship between IL-6 and brain-derived neurotropic factor (BDNF) levels among the subgroup of schizophrenia subjects exhibiting high mRNA expression of IL-6 and IL-1β (Fillman et al., 2013). Experimental models have shown an inverse relationship between IL-1β and BDNF levels (Barrientos et al., 2004) and that low BDNF concentrations can worsen white matter injury (Cui et al., 2013). In addition, our included study's finding of an association between first-episode schizophrenia and diffusely increased extracellular free-water volume with focally decreased FAT in frontal white matter, suggests that neuroinflammation precedes myelin breakdown and axonal degeneration in schizophrenia (Pasternak et al., 2012). Several additional neuroimaging studies not included in our review provide indirect evidence associating neuroinflammation with white matter pathology in schizophrenia (Pfefferbaum et al., 1999; DeLisi et al., 2006; Garver et al., 2008; Peters et al., 2010). Major risk factors for schizophrenia include a history of maternal and prenatal infections, prior hospitalization for severe infection, and autoimmune comorbidity (Yolken and Torrey, 1995; Gilvarry et al., 1996; Torrey et al., 1997; Buka et al., 2001; Brown et al., 2005; Eaton et al., 2006; Mortensen et al., 2007; Torrey et al., 2007; Buka et al., 2008; Brown and Derkits, 2010; Benros et al., 2011; Chen et al., 2012; Benros et al., 2014a,b)—all of which link elevated pro-inflammatory cytokines to the pathogenesis schizophrenia (as reviewed by Miller et al. (2013a) and Meyer (2013)). Prenatal exposure to inflammation or infection can injure developing oligodendroglia, resulting in prominent white matter pathology and motor, cognitive, and behavioral impairments (recently reviewed by Deng (2010))—all of which are associated with pre-psychosis and schizophrenia (Chew et al., 2013). A significant positive correlation has been observed between fetal exposure to elevated maternal serum IL-8 levels during second and third trimesters and increased ventricular cerebrospinal fluid volume, as well as decreased left entorhinal and posterior cingulate cortical volumes in schizophrenia (Ellman et al., 2010). These studies support the hypothesis that prenatal inflammation-induced microglial priming is involved in the pathophysiology of schizophrenia (Meyer, 2013). An increased density of interstitial white matter neurons, one of the more consistent pathological abnormalities found in schizophrenia (Anderson et al., 1996; Eastwood and Harrison, 2003; Kirkpatrick et al., 2003; Eastwood and Harrison, 2005; Connor et al., 2011; Yang et al., 2011) (recently reviewed by Connor et al. (2011)), further supports the hypothesis that neuroinflammation precedes white matter pathology in schizophrenia. One putative mechanism of increased white matter neuronal density in human disease involves entrapment of neurons migrating from the germinal matrix to the cortex due to inflammation-induced early white matter injury (Rousset et al., 2006; Leviton and Gressens, 2007). IL-6 has been shown to directly inhibit neuronal migration in vitro (Wei et al., 2011). Another putative mechanism involves inflammation-induced aberrant differentiation of glial cells into neurons (Leviton and Gressens, 2007; Connor et al., 2011). Cultured microglia have been shown to express neuronal markers following exposure to interferon-γ (Butovsky et al., 2007). Several findings from our review suggest that these mechanisms are relevant to schizophrenia. The density of NeuN-immunoreactive white matter neurons was (a) increased in the orbitofrontal region among those with schizophrenia; (b) increased in the orbitofrontal and dorsolateral prefrontal regions in high-inflammation versus lowinflammation schizophrenia subgroups; and (c) negatively correlated with GAD67-immunoreactive dorsolateral prefrontal gray matter neurons in the high-inflammation subgroup only. The latter finding is consistent with many neuropathological studies that have documented reduced expression of GAD67 in the dorsolateral prefrontal gray matter in individuals with schizophrenia (Guidotti et al., 2000; Hashimoto et al., 2008;

Thompson et al., 2009). However, the lack of a difference in the density of GAD67-immunoreactive orbitofrontal white matter neurons between high-inflammation versus low-inflammation subgroups suggests that factors in addition to inflammation, such as persistent cortical subplate remnants (Connor et al., 2011) may also play a role (Fung et al., 2014). In conclusion, neuroinflammation is associated with white matter pathology characterized by axonal degeneration, myelin breakdown, reduced density of astroglia and oligodendroglia in selected areas and increased density of white matter neurons among individuals with schizophrenia. Neuroinflammation may contribute to white matter structural and functional disconnectivity, even at the first episode of psychosis. Adequately powered neuropathological studies, weighted towards younger individuals who died shortly after first psychotic episodes, are needed to further explore the relationship between neuroinflammation and early white matter pathology in schizophrenia. Controlled longitudinal studies using free-water DTI analyses in individuals with first-episode schizophrenia before and after treatment with immune or anti-inflammatory therapies are also likely to be informative. Clinical trials evaluating the effect of early initiation of existing and novel immune and anti-inflammatory therapies on white matter pathology and disease progression in schizophrenia are warranted. Role of the funding source The authors declare none. Contributions S.N. and D.M.P. contributed equally to this work, to include the conception and design of the study, data collection, and analyses and interpretation of data. Both authors wrote the paper and subsequently revised it for important intellectual content. Both authors gave final approval of the version to be published. Conflicts of interest Both authors declare that there is nothing to disclose. Acknowledgements The authors declare none.

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Alterations in frontal white matter neurochemistry and microstructure in schizophrenia: implications for neuroinflammation.

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

White matter changes in early phase schizophrenia and cannabis use: an update and systematic review of diffusion tensor imaging studies.

Imaging neuroinflammation in gray and white matter in schizophrenia: an in-vivo PET study with [18F]-FEPPA.

Astrocytes in Oligodendrocyte Lineage Development and White Matter Pathology.

Accelerated white matter aging in schizophrenia: role of white matter blood perfusion.

Tryptophan Metabolism and White Matter Integrity in Schizophrenia.

White matter abnormalities in schizophrenia and schizotypal personality disorder.

Profiles of white matter tract pathology in frontotemporal dementia.

Association of GRM3 polymorphism with white matter integrity in schizophrenia.

White matter lesions and depression: a systematic review and meta-analysis.

Physical Activity and White Matter Hyperintensities: A Systematic Review of Quantitative Studies.

Clinical pain in schizophrenia: a systematic review.

Editorial: White blood cells matter in neonatal white-matter injury.

Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder.

White matter microstructure pathology in classic galactosemia revealed by neurite orientation dispersion and density imaging.

In vivo imaging of neuroinflammation in schizophrenia.

Performances of diffusion kurtosis imaging and diffusion tensor imaging in detecting white matter abnormality in schizophrenia.

White Matter Integrity in Genetic High-Risk Individuals and First-Episode Schizophrenia Patients: Similarities and Disassociations.

Brain white matter microstructure in deficit and non-deficit subtypes of schizophrenia.

White matter deficits in schizophrenia are global and don't progress with age.

Regional white matter abnormalities in drug-naive, first-episode schizophrenia patients and their healthy unaffected siblings.

ZNF804A genetic variation (rs1344706) affects brain grey but not white matter in schizophrenia and healthy subjects.

Effects of age on white matter integrity and negative symptoms in schizophrenia.