Imaging microstructure with diffusion and susceptibility MR: neuronal density correlation in Disrupted‐in‐Schizophrenia‐1 mutant mice

Abstract

Purpose To probe cerebral microstructural abnormalities and assess changes of neuronal density in Disrupted‐in‐Schizophrenia‐1 (DISC1) mice using non‐Gaussian diffusion and quantitative susceptibility mapping (QSM). Materials and Methods Brain specimens of transgenic DISC1 mice (n = 8) and control mice (n = 7) were scanned. Metrics of neurite orientation dispersion and density imaging (NODDI) and diffusion kurtosis imaging (DKI), as well as QSM, were acquired. Cell counting was performed on Nissl‐stained sections. Group differences of imaging metrics and cell density were assessed. Pearson correlations between imaging metrics and cell densities were also examined. Results Significant increases of neuronal density were observed in the hippocampus of DISC1 mice. DKI metrics such as mean kurtosis exhibited significant group differences in the caudate putamen (P = 0.015), cerebral cortex (P = 0.021), and hippocampus (P = 0.011). However, DKI metrics did not correlate with cell density. In contrast, significant positive correlation between density of neurons and the neurite density index of NODDI in the hippocampus was observed (r = 0.783, P = 0.007). Significant correlation between density of neurons and susceptibility (r = 0.657, P = 0.039), as well as between density of neuroglia and susceptibility (r = 0.750, P = 0.013), was also observed in the hippocampus. Conclusion The imaging metrics derived from DKI were not sensitive specifically to cell density, while NODDI could provide diffusion metrics sensitive to density of neurons. The magnetic susceptibility values derived from the QSM method can serve as a sensitive biomarker for quantifying neuronal density.

Grey and white matter microstructure is associated with polygenic risk for schizophrenia

“…The intra-cellular compartment refers to the space bound by neurites and allows for the measurement of their density (NDI) and their spatial orientation (ODI) [ 57 , 58 ]. In vivo estimates of NDI have been biologically validated by ex vivo, histological estimates of neurite density in mice [ 59 ], and correlated with cortical myelination in humans [ 58 ].…”

Brain iron assessment in patients with First-episode schizophrenia using quantitative susceptibility mapping

“…In a related autopsy study, Williams et al examined the cytoarchitecture of dopaminergic neurons in the SN, and they observed increased nuclear and nucleolar size and decreased astrocyte density in schizophrenia compared to matched controls ( Williams et al, 2014 ). An animal model study demonstrated that there exist strong positive correlations between QSM value and the density of neurons plus neuroglia cells ( Gong et al, 2020 ). We suggested that the increased volumes and decreased QSM values of bilateral SN in the first-episode schizophrenia patients may be associated with the decreased density of ferritin-containing cells.…”

Grey and white matter micro-structure is associated with polygenic risk for schizophrenia

“…The intra-cellular compartment refers to the space bound by neurites and allows for the measurement of their density (by the neurite density index) and their spatial orientation (by the orientation dispersion index) [47, 48]. In vivo estimates of NDI have been biologically validated by ex vivo , histological estimates of neuronal neurite density in mice [49]. In humans, NDI was strongly positively correlated with cortical myelination and negatively correlated with cortical thickness, suggesting that high NDI might be indicative of density of myelinated axons in the cortex [48].…”

“…The intra-cellular compartment refers to the space bound by neurites and allows for the measurement of their density (NDI) and their spatial orientation (ODI) [53, 54]. In vivo estimates of NDI have been biologically validated by ex vivo , histological estimates of neurite density in mice [55], and correlated with cortical myelination in humans [54].…”