Fluid compartments influence elastography of the aging mouse brain

Abstract

Objective: Elastography of the brain has the potential to reveal subtle but clinically important changes in the structure and composition as a function of age, disease, and injury. 

Approach: In order to quantify the specific effects of aging on mouse brain elastography, and to determine the key factors influencing observed changes, we applied optical coherence tomography reverberant shear wave elastography at 2000 Hz to a group of wild-type healthy mice ranging from young to old age. 

Main Results: We found a strong trend towards increasing stiffness with age, with an approximately 30% increase in shear wave speed from 2 months to 30 months within this sampled group. Furthermore, this appears to be strongly correlated with decreasing measures of whole brain fluid content, so older brains have less water and are stiffer. Rheological models are applied, and the strong effect is captured by specific assignment of changes to the glymphatic compartment of the brain fluid structures along with a correlated change in the parenchymal stiffness. 

Significance: Short-term and longer-term changes in elastography measures may provide a sensitive biomarker of progressive and fine-scale changes in the glymphatic fluid channels and parenchymal components of the brain.

Brain elastography in aging relates to fluid/solid trendlines

“…The strongest correlation we found within our set of measurements was the inverse relationship between free water and shear modulus as depicted in figure 4. This negative correlation is most pronounced in the grey matter where greater amounts of extracellular matrix (or glymphatic) free water are associated with softer grey matter, which is consistent with our earlier results both theoretical and experimental (Ge et al 2022(Ge et al , 2023 as detailed in the following section. Moreover, our results suggest a positive relationship between NDI and MD with age and stiffness in grey matter, while FA exhibits a negative correlation with stiffness and age in white matter.…”

“…There is a profound difference in trendline between the aging effects we found in mouse studies (Ge et al 2022(Ge et al , 2023 and this human study. Earlier experiments found that the mouse brain cortical grey matter stiffens and becomes drier (lower W ) with age, whereas the human brain softens and has a higher water fraction W as a function of age.…”

“…As a final comparison, it should be noted that general composite models, for example those outlined by Christensen (1969) and Lakes (1999), are not able to capture the relationship between G and W shown in figure 5. This inability has previously been depicted in figure A.1 of Ge et al (2023) for the aging murine brain, and strongly implies that more specific models, such as the framework developed herein, are required to capture the behavior of the aging brain.…”

“…We derived the stress-strain behavior of the brain as a two-component model with a larger scale network representing the vascular and perivascular branching structures, down to the level of capillaries, and then including an additional version representing the smaller scale fluid channels within the interstitial spaces, in particular the glymphatic system. These parameters are conditioned by anatomical measures, including a key power law parameter a that captures the multiscale fractal nature of the fluid channels within the soft tissue parenchyma, discussed in more detail in Ge et al (2022Ge et al ( , 2023. The complex Young's modulus as a function of frequency is then derived by Laplace transform theory as the sum of components.…”

“…It is convenient to assume a baseline case of shear modulus G at a reference age or condition, then a modified shear modulus G G E 2 c = is observed in the elastic matrix, captured by the fractional factor of , E c and this modification can be can be derived through the transformation rules (Parker 2017a). Now summarizing and combining these influences for the brain model (Ge et al 2023), the leading terms in the equations for the complex modulus can be written approximately as:…”