Sexual Dimorphism in Extracellular Matrix Composition and Viscoelasticity of the Healthy and Inflamed Mouse Brain.

Magnetic resonance elastography (MRE) has revealed sexual dimorphism in brain stiffness in healthy individuals and multiple sclerosis (MS) patients. In an animal model of MS, named experimental autoimmune encephalomyelitis (EAE), we have previously shown that inflammation-induced brain softening was associated with alterations of the extracellular matrix (ECM). However, it remained unclear whether the brain ECM presents sex-specific properties that can be visualized by MRE. Therefore, here we aimed at quantifying sexual dimorphism in brain viscoelasticity in association with ECM changes in healthy and inflamed brains. Multifrequency MRE was applied to the midbrain of healthy and EAE mice of both sexes to quantitatively map regional stiffness. To define differences in brain ECM composition, the gene expression of the key basement membrane components laminin (Lama4, Lama5), collagen (Col4a1, Col1a1), and fibronectin (Fn1) were investigated by RT-qPCR. We showed that the healthy male cortex expressed less Lama4, Lama5, and Col4a1, but more Fn1 (all p < 0.05) than the healthy female cortex, which was associated with 9% softer properties (p = 0.044) in that region. At peak EAE cortical softening was similar in both sexes compared to healthy tissue, with an 8% difference remaining between males and females (p = 0.006). Cortical Lama4, Lama5 and Col4a1 expression increased 2 to 3-fold in EAE in both sexes while Fn1 decreased only in males (all p < 0.05). No significant sex differences in stiffness were detected in other brain regions. In conclusion, sexual dimorphism in the ECM composition of cortical tissue in the mouse brain is reflected by in vivo stiffness measured with MRE and should be considered in future studies by sex-specific reference values.

Changes in Liver Mechanical Properties and Water Diffusivity During Normal Pregnancy Are Driven by Cellular Hypertrophy.

During pregnancy, the body's hyperestrogenic state alters hepatic metabolism and synthesis. While biochemical changes related to liver function during normal pregnancy are well understood, pregnancy-associated alterations in biophysical properties of the liver remain elusive. In this study, we investigated 26 ex vivo fresh liver specimens harvested from pregnant and non-pregnant rats by diffusion-weighted imaging (DWI) and magnetic resonance elastography (MRE) in a 0.5-Tesla compact magnetic resonance imaging (MRI) scanner. Water diffusivity and viscoelastic parameters were compared with histological data and blood markers. We found livers from pregnant rats to have (i) significantly enlarged hepatocytes (26 ± 15%, p < 0.001), (ii) increased liver stiffness (12 ± 15%, p = 0.012), (iii) decreased viscosity (-23 ± 14%, p < 0.001), and (iv) increased water diffusivity (12 ± 11%, p < 0.001). In conclusion, increased stiffness and reduced viscosity of the liver during pregnancy are mainly attributable to hepatocyte enlargement. Hypertrophy of liver cells imposes fewer restrictions on intracellular water mobility, resulting in a higher hepatic water diffusion coefficient. Collectively, MRE and DWI have the potential to inform on structural liver changes associated with pregnancy in a clinical context.

The influence of body temperature on tissue stiffness, blood perfusion, and water diffusion in the mouse brain.

While hypothermia of the brain is used to reduce neuronal damage in patients with conditions such as traumatic brain injury or stroke, little is known about how temperature affects the biophysical properties of in vivo brain tissue. Therefore, we measured shear wave speed (SWS), apparent diffusion coefficient (ADC), and cerebral blood flow (CBF) in the mouse brain at different body temperatures to investigate the relationship between temperature and tissue stiffness, water diffusion, and blood perfusion in the living brain. Multifrequency magnetic resonance elastography (MRE), diffusion-weighted imaging (DWI), and arterial spin labeling (ASL) were performed in seven mice while increasing and recording body temperature from hypothermia (28-30 °C) to normothermia (36-38 °C). SWS, ADC, and CBF were analyzed in regions of whole brain, cortex, hippocampus, and diencephalon. Our results show that SWS decreases while ADC and CBF increase from hypothermia to normothermia (whole brain SWS: -6.2%, ADC: +34.0%, CBF: +80.2%; cortex SWS: -10.1%, ADC: +30.9%, CBF: +82.4%; all p > 0.05). We found a significant inverse correlation between SWS and both ADC and CBF in all analyzed regions except diencephalon (whole brain SWS-ADC: r = -0.8, p < 0.005; SWS-CBF: r = -0.84, p < 0.005; cortex SWS-ADC: r = -0.74, p < 0.05; SWS-CBF: r = -0.65, p < 0.05). These results show that in vivo brain stiffness is inversely correlated with temperature, extracellular water mobility, and microvascular blood flow. Regional differences indicate that cortical areas are more markedly affected by hypothermia than central regions such as diencephalon. Temperature should be considered as a confounder in elastographic measurements, especially in preclinical settings. STATEMENT OF SIGNIFICANCE: Hibernating mammals lower their body temperature and metabolic activity. A hypothermic state can also be induced for medical purposes to reduce the risk of neural damage in patients with neurological disease or injury. However, little is known how physical soft-tissue properties of the in-vivo brain such as water diffusion, blood perfusion or mechanical parameters correlate with each other when temperature changes. Our study demonstrates for the first time that those quantitative imaging markers are tightly linked to changes in body temperature. While water diffusion and blood perfusion are reduced during hypothermia, brain stiffness significantly increases, suggesting that multiparametric quantitative MRI should be used for the noninvasive assessment of brain metabolic activity.