Radiomic features of the hippocampal based on magnetic resonance imaging in the menopausal mouse model linked to neuronal damage and cognitive deficits

Abstract

Estrogen deficiency in the early postmenopausal phase is associated with an increased long-term risk of cognitive decline or dementia. Non-invasive characterization of the pathological features of the pathological hallmarks in the brain associated with postmenopausal women (PMW) could enhance patient management and the development of therapeutic strategies. Radiomics is a means to quantify the radiographic phenotype of a diseased tissue via the high-throughput extraction and mining of quantitative features from images acquired from modalities such as CT and magnetic resonance imaging (MRI). This study set out to explore the correlation between radiomics features based on MRI and pathological features of the hippocampus and cognitive function in the PMW mouse model. Ovariectomized (OVX) mice were used as PWM models. MRI scans were performed two months after surgery. The brain's hippocampal region was manually annotated, and the radiomic features were extracted with PyRadiomics. Chemiluminescence was used to evaluate the peripheral blood estrogen level of mice, and the Morris water maze test was used to evaluate the cognitive ability of mice. Nissl staining and immunofluorescence were used to quantify neuronal damage and COX1 expression in brain sections of mice. The OVX mice exhibited marked cognitive decline, brain neuronal damage, and increased expression of mitochondrial complex IV subunit COX1, which are pathological phenomena commonly observed in the brains of AD patients, and these phenotypes were significantly correlated with radiomics features (p < 0.05, |r|>0.5), including Original_firstorder_Interquartile Range, Original_glcm_Difference Average, Original_glcm_Difference Average and Wavelet-LHH_glszm_Small Area Emphasis. Meanwhile, the above radiomics features were significantly different between the sham-operated and OVX groups (p < 0.01) and were associated with decreased serum estrogen levels (p < 0.05, |r|>0.5). This initial study indicates that the above radiomics features may have a role in the assessment of the pathology of brain damage caused by estrogen deficiency using routinely acquired structural MR images.

Keywords: Cognitive decline; Estrogen deficiency; MRI; Ovariectomized mouse; Radiomics features.

Fig. 1

Ovariectomy (OVX) caused estrogen deficiency and cognitive impairment in mice. (A) Image of female C57/BL6 mice after sham surgery or OVX. Body weights (B) and cerebral index (C) of mice in each group at 2 months postoperatively. Data represent the mean ± standard error of the mean. ns: no statistical significance. In each group at least 10 mice were tested. (D) Serum estrogen levels in the two study groups after ovariectomy or sham operations. (E) Escape latency in the positioning navigation experiment for each group. (F) Percentage of total time spent in the target quadrant during the probe trials in each group. (G) The number of times that the mice crossed the platform in each group in the probe trials. (H) Escape time to target each group in the probe trials. Data represent the mean ± standard error of the mean. Student’s t-test: *p < 0.05, **p < 0.01 and ***p < 0.001. ns: no statistical significance. In each group, at least 10 mice were tested

Fig. 2

Ovariectomy caused neuronal injury in the hippocampus of mice. (A) Photomicrographs of H&E–stained hippocampus sections for each group of mice (bar = 50 μm). (B) Identification of neuronal survival by Nissl staining in the hippocampus (bar = 20 μm). (C) The quantity of healthy neuronal cells in each visual field with densely stained Nissl bodies. Data represent the mean ± standard error of the mean. Student’s t-test: ***p < 0.001. ns: no statistical significance. In each group, at least 10 mice were tested

Fig. 3

Ovariectomy increased COX-1 expression in the hippocampus of mice brains. (A) Typical images of neuronal cells (NeuN labeled) and COX-1 were co-located by immunofluorescence. Bar = 50 μm. (B) The mean fluorescence intensity of COX-1 was determined, and the levels of COX-1 intensity were expressed as a relative change in comparison with the OVX group, which was set to 100%. Data represent the mean ± standard error of the mean. Student’s t-test: ***p < 0.001. ns: no statistical significance. In each group, at least 10 mice were tested

Fig. 4

In the brain of OVX mice, radiomics features including Original_firstorder_Interquartile Range, Original_glcm_Difference Average, Original_glcm_Difference Average, and Wavelet-LHH_glszm_Small Area Emphasis, were associated with the peripheral blood estrogen levels, cognitive performance, the extent of neuronal damage, and the expression of COX1. (A) Mouse brain MR images: coronal and axial slices. Region of interest (ROIs) in the hippocampus was manually drawn to be analyzed with texture analysis methods. (B-E) Correlation curve fitting diagram (n = 31) of the radiometrics features with the peripheral blood estrogen (E2) levels (pmol/L) escape latency (s) of mice in the hidden-platform test of the Morris water maze (markers for cognitive performance), dark neurons number (biomarkers for neuronal damage), and the expression of COX1 (markers of disordered energy metabolism). The Pearson correlation and Spearman rank correlation test were used for the correlations