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The association of matrix metalloproteinase 9 (MMP9) with hippocampal volume in schizophrenia: a preliminary MRI study

Abstract

Matrix metalloproteinases 9 (MMP9) are enzymes involved in regulating neuroplasticity in the hippocampus. This, combined with evidence for disrupted hippocampal structure and function in schizophrenia, has prompted our current investigation into the relationship between MMP9 and hippocampal volumes in schizophrenia. 34 healthy individuals (mean age = 32.50, male = 21, female = 13) and 30 subjects with schizophrenia (mean age = 33.07, male = 19, female = 11) underwent a blood draw and T1-weighted magnetic resonance imaging. The hippocampus was automatically segmented utilizing FreeSurfer. MMP9 plasma levels were measured with ELISA. ANCOVAs were conducted to compare MMP9 plasma levels (corrected for age and sex) and hippocampal volumes between groups (corrected for age, sex, total intracranial volume). Spearman correlations were utilized to investigate the relationship between symptoms, medication, duration of illness, number of episodes, and MMP9 plasma levels in patients. Last, we explored the correlation between MMP9 levels and hippocampal volumes in patients and healthy individuals separately. Patients displayed higher MMP9 plasma levels than healthy individuals (F(1, 60) = 21.19, p < 0.0001). MMP9 levels correlated with negative symptoms in patients (R = 0.39, p = 0.035), but not with medication, duration of illness, or the number of episodes. Further, patients had smaller left (F(1,59) = 9.12, p = 0.0040) and right (F(1,59) = 6.49, p = 0.013) hippocampal volumes. Finally, left (R = −0.39, p = 0.034) and right (R = −0.37, p = 0.046) hippocampal volumes correlated negatively with MMP9 plasma levels in patients. We observe higher MMP9 plasma levels in SCZ, associated with lower hippocampal volumes, suggesting involvement of MMP9 in the pathology of SCZ. Future studies are needed to investigate how MMP9 influences the pathology of SCZ over the lifespan, whether the observed associations are specific for schizophrenia, and if a therapeutic modulation of MMP9 promotes neuroprotective effects in SCZ.

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Fig. 1: Group comparison of MMP9 values.
Fig. 2: Correlation of MMP9 levels and hippocampal volume.

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Acknowledgements

This work is part of the Ph.D. thesis of Carina Heller.

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JS-H Ph.D. MD: Substantial contributions to the design of the work, analysis, and interpretation of data; drafting the work; final approval of the version to be published; agreement to be accountable for all aspects of the work. MS MD: Substantial contributions to the analysis of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. NM Ph.D. MD: Substantial contributions to the analysis of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. JR Ph.D.: Substantial contributions to the analysis of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. K-IKC Ph.D.: Substantial contributions to the analysis of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. ER: Substantial contributions to the analysis of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. MV Ph.D.: Substantial contributions to the analysis of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. OSS MD: Substantial contributions to the analysis of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. CH: Substantial contributions to the analysis of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. OP Ph.D.: Substantial contributions to the analysis of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. FAS Ph.D.: Substantial contributions to the analysis of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. C-FW Ph.D.: Substantial contributions to the analysis of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. JL Ph.D. MD: Substantial contributions to the acquisition of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. LU Ph.D. MD: Substantial contributions to the acquisition of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. JT Ph.D. MD: Substantial contributions to the acquisition of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. LV Ph.D.: Substantial contributions to the acquisition of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. PKI: Substantial contributions to the acquisition of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. MJ: Substantial contributions to the acquisition of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. TWW Ph.D. MD: Substantial contributions to the design of the work, analysis, and interpretation of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. TK Ph.D. MD: Substantial contributions to the acquisition of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. ZK Ph.D.: Substantial contributions to the design of the work, analysis, and interpretation of data; revising the draft; final approval of the version to be published; agreement to be accountable for all aspects of the work. MK Ph.D. MD: Substantial contributions to the design of the work, analysis, and interpretation of data; drafting the work; final approval of the version to be published; agreement to be accountable for all aspects of the work

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Seitz-Holland, J., Seethaler, M., Makris, N. et al. The association of matrix metalloproteinase 9 (MMP9) with hippocampal volume in schizophrenia: a preliminary MRI study. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-00997-5

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