Evaluation of metronomic chemotherapy response using diffusion and dynamic contrast-enhanced MRI.

PURPOSE: To investigate the feasibility of using diffusion MRI (dMRI) and dynamic contrast-enhanced (DCE) MRI to evaluate the treatment response of metronomic chemotherapy (MCT) in the 4T1 mammary tumor model of locally advanced breast cancer. METHODS: Twelve Balb/c mice with metastatic breast cancer were divided into treated and untreated (control) groups. The treated group (n = 6) received five treatments of anti-metabolite agent 5-Fluorouracil (5FU) in the span of two weeks. dMRI and DCE-MRI were acquired for both treated and control groups before and after MCT. Immunohistochemically staining and measurements were performed after the post-MRI measurements for comparison. RESULTS: The control mice had significantly (p<0.005) larger tumors than the MCT treated mice. The DCE-MRI analysis showed a decrease in contrast enhancement for the control group, whereas the MCT mice had a more stable enhancement between the pre-chemo and post-chemo time points. This confirms the antiangiogenic effects of 5FU treatment. Comparing amplitude of enhancement revealed a significantly (p<0.05) higher enhancement in the MCT tumors than in the controls. Moreover, the MCT uptake rate was significantly (p<0.001) slower than the controls. dMRI analysis showed the MCT ADC values were significantly larger than the control group at the post-scan time point. CONCLUSION: dMRI and DCE-MRI can be used as potential biomarkers for assessing the treatment response of MCT. The MRI and pathology observations suggested that in addition to the cytotoxic effect of cell kills, the MCT with a cytotoxic drug, 5FU, induced changes in the tumor vasculature similar to the anti-angiogenic effect.

Quantifying myofiber integrity using diffusion MRI and random permeable barrier modeling in skeletal muscle growth and Duchenne muscular dystrophy model in mice.

PURPOSE: To measure the microstructural changes during skeletal muscle growth and progressive pathologies using the random permeable model with diffusion MRI, and compare findings to conventional imaging modalities such as three-point Dixon and T2 imaging. METHODS: In vivo and ex vivo DTI experiments with multiple diffusion times (20-700 ms) were completed on wild-type (n = 22) and muscle-dystrophic mdx mice (n = 8) at various developmental time points. The DTI data were analyzed with the random permeable model framework that provides estimates of the unrestricted diffusion coefficient (D0 ), membrane surface-to-volume ratio (S/V), and membrane permeability (κ). In addition, the MRI experiments included conventional measures, such as tissue fat fractions and T2 relaxation. RESULTS: During normal muscle growth between week 4 and week 13, the in vivo S/V, fractional anisotropy, and fat fraction correlated positively with age (ρ = 0.638, 0.664, and 0.686, respectively), whereas T2 correlated negatively (ρ = -0.847). In mdx mice, all DTI random permeable model parameters and fat fraction had significant positive correlation with age, whereas fractional anisotropy and T2 did not have significant correlation with age. Histological measurements of the perimeter-to-area ratio served as a proxy for the model-derived S/V in the cylindrical myofiber geometry, and had a significant correlation with the ex vivo S/V (r = 0.71) as well as the in vivo S/V (r = 0.56). CONCLUSION: The present study demonstrates that DTI at multiple diffusion times with the random permeable model analysis allows for noninvasively quantifying muscle fiber microstructural changes during both normal muscle growth and disease progression. Future studies can apply our technique to evaluate current and potential treatments to muscle myopathies.

In vivo quantification of demyelination and recovery using compartment-specific diffusion MRI metrics validated by electron microscopy.

There is a need for accurate quantitative non-invasive biomarkers to monitor myelin pathology in vivo and distinguish myelin changes from other pathological features including inflammation and axonal loss. Conventional MRI metrics such as T2, magnetization transfer ratio and radial diffusivity have proven sensitivity but not specificity. In highly coherent white matter bundles, compartment-specific white matter tract integrity (WMTI) metrics can be directly derived from the diffusion and kurtosis tensors: axonal water fraction, intra-axonal diffusivity, and extra-axonal radial and axial diffusivities. We evaluate the potential of WMTI to quantify demyelination by monitoring the effects of both acute (6weeks) and chronic (12weeks) cuprizone intoxication and subsequent recovery in the mouse corpus callosum, and compare its performance with that of conventional metrics (T2, magnetization transfer, and DTI parameters). The changes observed in vivo correlated with those obtained from quantitative electron microscopy image analysis. A 6-week intoxication produced a significant decrease in axonal water fraction (p<0.001), with only mild changes in extra-axonal radial diffusivity, consistent with patchy demyelination, while a 12-week intoxication caused a more marked decrease in extra-axonal radial diffusivity (p=0.0135), consistent with more severe demyelination and clearance of the extra-axonal space. Results thus revealed increased specificity of the axonal water fraction and extra-axonal radial diffusivity parameters to different degrees and patterns of demyelination. The specificities of these parameters were corroborated by their respective correlations with microstructural features: the axonal water fraction correlated significantly with the electron microscopy derived total axonal water fraction (ρ=0.66; p=0.0014) but not with the g-ratio, while the extra-axonal radial diffusivity correlated with the g-ratio (ρ=0.48; p=0.0342) but not with the electron microscopy derived axonal water fraction. These parameters represent promising candidates as clinically feasible biomarkers of demyelination and remyelination in the white matter.