Abstract
BackgroundDiffusion tensor imaging (DTI) studies in schizophrenia consistently show global reductions in fractional anisotropy (FA), a putative marker of white matter integrity. Because magnetic resonance spectroscopy (MRS) studies permit for the non-invasive measurements of neurometabolites, such as N-acetylaspartate (NAA), a marker of neuronal integrity, and glutamate, which can be neurotoxic when over-released, this technique provides further understanding of the relationship between white matter microstructure and neuronal function.MethodsTwenty-nine schizophrenia patients and twenty controls participated in this 3T imaging study where we used DTI and tract-based spatial statistics (TBSS) to assess white matter integrity of the cingulum bundle and MRS to quantify NAA and glutamate in the anterior cingulate cortex (ACC) and hippocampus, i.e. in cortico-limbic regions connected by the cingulum bundle.ResultsWe found FA reductions with overlapping radial diffusivity (RD) elevations in patients in multiple tracts, suggesting white matter abnormalities in schizophrenia are driven by loss of myelin integrity. In controls, but not in patients, high hippocampal NAA levels were significantly associated with low RD in the hippocampal part of the cingulum, and low ACC glutamate levels were significantly associated with high FA in the hippocampus part of the cingulum.DiscussionIn conclusion, we demonstrate the potential utility of a multi-modal neuroimaging approach to help further our understanding of the relationship between white matter microstructure and neurochemistry in distinct cortical regions connected by white matter tracts.
Highlights
Recent neuroimaging studies have shown altered brain connectivity in patients with schizophrenia, associated with disturbed myelination in different fiber tracts and disruptions of white matter (WM) integrity, including prefrontal WM
Proteomic studies in postmortem brain by Daniel Martins-de-Souza have suggested a schizophrenia-related energy metabolism dysfunction in oligodendrocytes. These findings have been followed up using oligodendroglia cell lines and induced pluripotent stem cell-derived cerebral organoids, supporting the notion that alterations in glycolysis in oligodendrocytes are pivotal to the overall energy dysfunction in schizophrenia brains
Twenty-nine schizophrenia patients and twenty controls participated in this 3T imaging study where we used Diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS) to assess white matter integrity of the cingulum bundle and magnetic resonance spectroscopy (MRS) to quantify NAA and glutamate in the anterior cingulate cortex (ACC) and hippocampus, i.e. in cortico-limbic regions connected by the cingulum bundle
Summary
We present human post-mortem and in-vivo imaging studies on the pivotal role of oligedondrocyte loss and dysfunction with consecutive impairments of brain connectivity in schizophrenia. Natalya Uranova will show morphometric data on ultrastructural alterations of oligodendrocytes, myelin damage and degeneration and disturbed oligodendrocyte-axon interactions in post-mortem prefrontal white matter in schizophrenia. Adrienne Lahti will report diffusion tensor imaging data suggesting impaired axonal and myelin integrity. Proteomic studies in postmortem brain by Daniel Martins-de-Souza have suggested a schizophrenia-related energy metabolism dysfunction in oligodendrocytes. These findings have been followed up using oligodendroglia cell lines and induced pluripotent stem cell-derived cerebral organoids, supporting the notion that alterations in glycolysis in oligodendrocytes are pivotal to the overall energy dysfunction in schizophrenia brains. Enhancing oligodendrocyte generation and myelin repair by FDA-approved compounds, like quetiapine (an APD) or clemastine (a histamine antagonist) successfully reversed the above phenotype
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