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Investigating the biomechanical properties of the aging mouse brain using an elastographic atlas1Department of Radiology, Charité - Universitätsmedizin Berlin, Berlin, Germany, 2Institute for Medical Immunology, Charité – Universitätsmedizin Berlin, Berlin, Germany, 3Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Berlin, Germany, 4Institute of Medical Informatics, Charité – Universitätsmedizin Berlin, Berlin, Germany
Synopsis
Keywords: Biology, Models, Methods, Aging, elastography
Motivation: The biomechanical signature of the aging brain and its correlation with the underlying microstructure, is poorly understood.
Goal(s): To systematically analyze the global and regional biomechanical properties of the brain during aging.
Approach: We investigated the in vivo biomechanical progression of the female mouse brain over an age range of 6 to 18 months using multifrequency MR elastography.
Results: Highly resolved elastographic atlases of the mouse brain at different ages were generated. Global and regional analysis revealed softening and reduced viscosity as dominating patters of biomechanical changes related to the structural variations of the aging brain.
Impact: This study demonstrated the use of MR elastography to track the biomechanical changes in the brains of aging healthy mice. Our study revealed softening and increased viscosity as biomechanical signature of the aging brain.
Introduction
The viscoelastic properties of brain tissue offer a biophysical signature sensitive to the intricate composition and organization of the nervous system [1,2]. MR elastography (MRE) [3] can quantify the cerebral biomechanical properties in vivo and assess the structural changes that occur in both physiological and pathological processes [4,5,6]. However, the biomechanical signature of the aging brain in relationship with the underlying microstructure remains understudied. The aim of this study is twofold: first, to generate an in vivo elastographic atlas of the mouse brain covering the lifespan from mature adults to elderly; and second, to systematically analyze the global and regional cerebral biomechanical properties, which can later be correlated with histopathological data.Methods
Cross-sectional In vivo MRI and MRE were conducted on 29 female wild-type C57BL/6 mice (Janvier, Le Genest Saint Isle, Cedex, France) aged 6 (n=9), 12 (n=10), and 18 (n=10) months, ranging from mature adults to old age. At every age point, MRE was performed on a 7T small-animal scanner (Bruker, Biospec, Ettlingen, Germany) equipped with a mouse volume coil, using 5 harmonic frequencies (1000,1100,1200,1300 and 1400 Hz). The vibration was generated by a piezoceramic actuator and transferred to the head via a head holder [7]. 3D wavefields were acquired at 8 wave dynamics by a single-shot spin-echo-EPI sequence with flow-compensated motion encoding gradients. Total acquisition time for 7 coronal slices of 0.18×0.18×0.8 mm resolution was 9 mins. MRE data were processed by k-MDEV-inversion [8], yielding maps of shear wave speed (SWS) and penetration rate (PR) (both in m/s) which represent stiffness and inverse viscosity, respectively. All MRE parameter maps were registered to the Allen mouse brain atlas via their corresponding anatomical T2w images. ROIs prescribed by the atlas were used for analysis. For statistical analysis, Kruskal Wallis test with post hoc pairwise comparison was used.Results
In vivo biomechanical brain atlases were generated for three age groups by averaging data from 29 mice. The atlases contain detailed anatomical structures and are illustrated in Fig. 1. It is evident that the entire brain experiences a decrease in stiffness and an increase in viscosity (increased PR) as it ages. Based on group analysis (Fig. 2), it was observed that the whole brain underwent significantly softened over time (p=0.023) with increased viscosity (p=0.004). Both white matter (p=0.002) and gray matter (p=0.045) exhibited age-related brain softening; however, PR remained unchanged over time for these two regions. Additionally, we have included the striatum, another grey matter structure which are relevant to aging. Striatum displayed aging-related increased in both SWS (p=0.045) and PR (p=0.001). All pairwise comparisons indicated that age-related differences were most pronounced between 6 and 12 months across all aforementioned areas. Results pertaining to the group analysis were summarized in Table 1.Discussion
Our initial findings indicated that the overall brain underwent biomechanical degradation as it aged, resulting in a more fluid-like behavior with reduced rigidity and increased viscosity, consistent with the literature [9,10]. This observation was also made in the white matter throughout the brain and may be linked to myeline degradation and the consequent loss of fiber integrity associated with aging [11]. Global gray matter showed significant viscosity changes, possibly due to age-related alterations in cerebral blood flow (CBF) and vascular permeability [12]. The impact of blood flow on biomechanical properties may be more prominent in gray matter than in white matter, given that CBF is nearly double in gray matter [13]. The striatum, a key component for motor function that deteriorates with age, also exhibited fluid-like properties in old age, which could be linked to structural loss and age-related shrinkage [14].Conclusion
In summary, our study provided preliminary in vivo elastographic atlases of the female mouse brain with detailed anatomical structures over aging. The global brain softened with increased viscosity during aging, indicating a progressive degradation of brain tissue to a more fluid-like state. The biomechanical changes in the cerebral subregions need to be further investigated and verified by histopathological analysis.Acknowledgements
The work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – GRK2260, CRC1540.References
[1] Munder, T, Pfeffer, A, Schreyer, S, Guo, J, Braun, J, Sack, I, Steiner, B, Klein, C: MR elastography detection of early viscoelastic response of the murine hippocampus to amyloid beta accumulation and neuronal cell loss due to Alzheimer's disease.J Magn Reson Imaging,47: 105-114, 2018.
[2] Millward, JM, Guo, J, Berndt, D, Braun, J, Sack, I, Infante-Duarte, C: Tissue structure and inflammatory processes shape viscoelastic properties of the mouse brain. Nmr Biomed,28: 831-839, 2015.
[3] R. Muthupillai, R.L. Ehman, Magnetic resonance elastography, Nat. Med. 2 (5) (1996) 601–603.
[4] S Wang, C A. Guertler, R J. Okamoto, C L. Johnson, M D.J. McGarry, P V. Bayly, Mechanical stiffness and anisotropy measured by MRE during brain development in the minipig, NeuroImage, Volume 277, 2023.
[5] J.M. Millward, J. Guo, D. Berndt, J. Braun, I. Sack, C. Infante-Duarte, Tissue structure and inflammatory processes shape viscoelastic properties of the mouse brain, NMR Biomed. 28 (7) (2015) 831–839.
[6] C. Klein, E.G. Hain, J. Braun, K. Riek, S. Mueller, B. Steiner, I. Sack, Enhanced adult neurogenesis increases brain stiffness: in vivo magnetic resonance elastography in a mouse model of dopamine depletion, PLoS ONE 9 (3) (2014) e92582.
[7] G. Bertalan, J. Guo, H. Tzschatzsch, C. Klein, E. Barnhill, I. Sack, J. Braun, Fast tomoelastography of the mouse brain by multifrequency single-shot MR elastography, Magn. Reson. Med. 81 (4) (2019) 2676–2687.
[8] H. Tzschatzsch, J. Guo, F. Dittmann, S. Hirsch, E. Barnhill, K. Johrens, J. Braun, I. Sack, Tomoelastography by multifrequency wave number recovery from timeharmonic propagating shear waves, Med. Image Anal. 30 (2016) 1–10.
[9] I. Sack, B. Beierbach, J. Wuerfel, D. Klatt, U. Hamhaber, S. Papazoglou, P. Martus, J. Braun, The impact of aging and gender on brain viscoelasticity, Neuroimage 46 (3) (2009) 652–657.
[10] Arani, A., Murphy, M. C., Glaser, K. J., Manduca, A., Lake, D. S., Kruse, S. A., et al. (2015). Measuring the effects of aging and sex on regional brain stiffness with MR elastography in healthy older adults. Neuroimage 111, 59–64.
[11]Peters, A., Moss, M.B. and Sethares, C. (2000), Effects of aging on myelinated nerve fibers in monkey primary visual cortex. J. Comp. Neurol., 419: 364-376.
[12]J. G. Vaidya, S. Paradiso, L. L. Boles Ponto, L. M. McCormick, R. G. Robinson, Aging, grey matter, and blood flow in the anterior cingulate cortex, NeuroImage,2007;37(4)
[13]Carroll TJ, Horowitz S, Shin W et-al. Quantification of cerebral perfusion using the "bookend technique": an evaluation in CNS tumors. Magn Reson Imaging. 2008;26 (10)
[14]N. Raz, K. M. Rodrigue, K. M. Kennedy, D. Head, F. Gunning-Dixon, J. D. Acker, Differential Aging of the Human Striatum: Longitudinal Evidence, American Journal of Neuroradiology Oct 2003, 24 (9) 1849-1856;
Figures
Group mean and standard deviation (SD, in brackets) of shear wave speed (SWS in m/s) and penetration rate (PR in m/s)
Whole brain (WB), grey matter(GM), white matter(WM), striatum (Str)