S168. THE ASSOCIATION BETWEEN MMP-9 AND CHOROID PLEXUS VOLUME IN SCHIZOPHRENIA
Authors: Seethaler Magdalena , Seitz Johanna , Makris Nikos , Rushmore Jarrett , Ik Kevin Cho Kang , Rizzoni Elizabeth , Heller Carina , Pasternak Ofer , Westin Carl-Frederik , Adam Szczepankiewicz Filip , Losak Jan , Ustohal Libor , Tomandl Josef , Vojtisek Lubomir , Kudlicka Petr , Wilson Woo Tsung-Ung , Kasparek Tomas , Kikinis Zora , Kubicki Marek 
Published: May 2020

Abstract

Background
Schizophrenia (SCZ) is a severe and chronic brain disorder that affects about 1% of the world population. It is among the most burdensome illnesses with a serious impact on patients, their families and society.
To this day, a lot remains unknown about the neuropathological cause and etiology of SCZ.
The prominent two-hit theory postulates that early neurodevelopmental abnormalities interact with a later “second hit” which occurs around symptom onset. Recent research points towards the role of inflammation in pathophysiology of schizophrenia.
Matrix metalloproteinase-9 (MMP-9) was recently suggested as a potential key player in both first and second “hit” in the pathology of SCZ. It is considered to not only regulate brain development and synaptic plasticity, but to also mediate neuroinflammation. A point of interest for interaction with neuroinflammatory pathways is the Choroid Plexus (ChP). MMP-9 has been reported to be upregulated in ChP in SCZ. Since ChP regulates CSF production and permeability of the blood-CSF-barrier, MMP-9 upregulation in ChP might lead to its enlargement, as well as enlargement of the lateral ventricles and increased extracellular water volume, all found previously in SCZ. We investigate, for the first time, the relationship between MMP-9 blood plasma concentration and volume of ChP in patients with SCZ compared to healthy controls (HC).

Methods
We included 66 subjects (25 female = 38%, 41 male = 62%, mean age 32.59 +/- 9.14 years); 32 were patients with SCZ, 34 were HC.
ELISA analysis was performed to measure MMP-9 blood concentrations in patients and HC.
A whole brain, high-resolution three-dimensional T1-weighted magnetization prepared rapid gradient echo (MPRAGE) sequence scan was used to collect 240 sagittal slices, field of view = 224 x 224 mm2, 1 mm3 isotropic voxel, TR = 2.3 s, TE = 2.33 ms, flip angle = 8° on a 3T Siemens Magnetom Prisma.
Structural T1 images underwent visual quality control, were realigned and parcellated into 176 gray and white matter regions using FreeSurfer software.
Preliminary analyses were conducted comparing 1) MMP-9 levels between groups and 2) relating MMP-9 levels to ChP volume utilizing regression analyses.

Results
Patients with SCZ showed a strong upregulation of MMP-9 compared to HC (patients: 120 ± 60 ng/ml; HC: 60 ± 40 ng/ml; p &lt; 0.0001). Furthermore, linear regression analyses - corrected for age and sex - demonstrated a positive association between concentration of MMP-9 and ChP volumes (left: R2 = .095, p &lt; .01; right: R2 = .084, p &lt; .02).

Discussion
To our knowledge, our study is the first to present preliminary evidence of an association between brain structure and MMP-9 peripheral upregulation in SCZ.
Advanced evaluation of MMP-9 might enhance our understanding of illness cause, enable outcome predictions and paint the way for more individualized psychopharmacotherapy, as MMP-9 might serve as potential pharmacological target.
However, further analyses are needed to validate our findings using as neuroanatomically precise methods as possible and to develop MMP-9 biomarkers that would capture central, as opposed to peripheral levels of MMP-9.