@article{7a98bd3ada1945048bc431ffae97c505,
title = "Lower fractional anisotropy without evidence for neuro-inflammation in patients with early-phase schizophrenia spectrum disorders",
abstract = "Various lines of research suggest immune dysregulation as a potential therapeutic target for negative and cognitive symptoms in schizophrenia spectrum disorders (SSD). Immune dysregulation would lead to higher extracellular free-water (EFW) in cerebral white matter (WM), which may partially underlie the frequently reported lower fractional anisotropy (FA) in SSD. We aim to investigate differences in EFW concentrations – a presumed proxy for neuro-inflammation – between early-phase SSD patients (n = 55) and healthy controls (HC; n = 37), and to explore immunological and cognitive correlates. To increase specificity for EFW, we study several complementary magnetic resonance imaging contrasts that are sensitive to EFW. FA, mean diffusivity (MD), magnetization transfer ratio (MTR), myelin water fraction (MWF) and quantitative T1 and T2 were calculated from diffusion-weighted imaging (DWI), magnetization transfer imaging (MTI) and multicomponent driven equilibrium single-pulse observation of T1/T2 (mcDESPOT). For each measure, WM skeletons were constructed with tract-based spatial statistics. Multivariate SSD-HC comparisons with WM skeletons and their average values (i.e. global WM) were not statistically significant. In voxel-wise analyses, FA was significantly lower in SSD in the genu of the corpus callosum and in the left superior longitudinal fasciculus (p < 0.04). Global WM measures did not correlate with immunological markers (i.e. IL1-RA, IL-6, IL-8, IL-10 and CRP) or cognition in HC and SSD after corrections for multiple comparisons. We confirmed lower FA in early-phase SSD patients. However, non–FA measures did not provide additional evidence for immune dysregulation or for higher EFW as the primary mechanism underlying the reported lower FA values in SSD.",
keywords = "Free water, Inflammation, Magnetic resonance imaging, Psychotic disorders, Schizophrenia, White matter",
author = "Gangadin, {Shiral S.} and Mandl, {Ren{\'e} C.W.} and {de Witte}, {Lot D.} and {van Haren}, {Neeltje E.M.} and Schutte, {Maya J.L.} and Begemann, {Marieke J.H.} and Kahn, {Ren{\'e} S.} and Sommer, {Iris E.C.}",
note = "Funding Information: To improve specificity of DWI, recent studies adjusted the tensor modelling to derive a component more sensitive to EFW than FA. This method demonstrated group-level increases of EFW, especially in patients with early-phase SSD compared to healthy controls (HC) (Chang et al., 2021; Guo et al., 2020; Lyall et al., 2017; Pasternak et al., 2012). In chronically ill patients, EFW increases were not observed (Gurholt et al., 2020; Oestreich et al., 2017). The hypothesis that EFW increases are associated with immune dysregulation is supported by DWI studies that find significant correlations with clinical markers of inflammation (i.e. peripheral cytokines and glutathione levels in brain) (Di Biase et al., 2021; Lesh et al., 2019; Rodrigue et al., 2019). Recent preclinical studies also demonstrated increased EFW in WM after immune activation (i.e. maternal immune activation and interferon-γ overexpression) (Di Biase et al., 2020; Febo et al., 2020). Although this line of research is incipient, immune dysregulation – presumably reflected in EFW increases – is hypothesized to occur during the early phase of SSD, whereas WM tissue degeneration (i.e. atrophy or demyelination) might be more characteristic for the chronic phase (Gangadin et al., 2019; Pasternak et al., 2016).This work was supported by the Stanley Medical Research Institute (grant number: 12T-008) and the Dutch Research Council (NWO; grant number: 40-00812-98-12154). S.G. was supported by a Graduate School of Medical Sciences PhD scholarship from the University Medical Center Groningen (UMCG; Open Round 2018). The funding sources had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Funding Information: This work was supported by the Stanley Medical Research Institute (grant number: 12T-008 ) and the Dutch Research Council ( NWO ; grant number: 40-00812-98-12154 ). S.G. was supported by a Graduate School of Medical Sciences PhD scholarship from the University Medical Center Groningen (UMCG; Open Round 2018). The funding sources had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Funding Information: The authors thank all the participants of the study for their time and contribution. We thank the research assistants and interns for their support with the data collection. To this end, Jantina Brummelman, Sanne Schuite-Koops, Erna van {\textquoteleft}t Hag, Meike Bak, Margot Slot, Pascal Pas, Mascha Linszen, Sophie Heringa, Edwin van Dellen, Willemijn van der Veen, Lyliana Nasib and Bibi Navas Garcia, deserve a special mention. The following mental healthcare institutions were essential in our patient recruitment: UCP Groningen, Reinier van Arkel, Mentrum, UMC Utrecht, GGZ InGeest, GGZ Noord-Holland-Noord, Altrecht GGZ, GGZ Centraal. This work was supported by the Stanley Medical Research Institute (grant number: 12T-008) and the Dutch Research Council (NWO; grant number: 40-00812-98-12154). S.G. was supported by a Graduate School of Medical Sciences PhD scholarship from the University Medical Center Groningen (UMCG; Open Round 2018). Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2024",
month = feb,
doi = "10.1016/j.schres.2022.12.009",
language = "English",
volume = "264",
pages = "557--566",
journal = "Schizophrenia Research",
issn = "0920-9964",
publisher = "ELSEVIER SCIENCE BV",
}