Introduction

Traumatic brain Injury (TBI) is a risk factor for earlier onset of Alzheimer’s disease (AD)¹, and the more severe the injury, the greater the risk of developing AD². Given the prevalence of AD in modern society, the possibility that TBI may predispose individuals to develop AD has significant social and economic implications. Therefore, it is important to understand how TBI triggers accelerated AD progression. In this study, we explored how neurotrauma accelerated white matter degeneration in a transgenic mouse model of AD using high-resolution ex vivo diffusion MRI.

Methods

3xTg-AD mice (Jackson Laboratory, ME) were bred and maintained at Boston University. Unanesthetized mice were pretreated with a non-sedating dose of the analgesic buprenorphine (0.2mg/kg, i.p.) prior to TBI. 3xTg-AD mice were subjected to left-lateral closed-head impact injury (Figure 1) at 10-12 weeks of age as described in our previous work³. At six months post-TBI, mice were sacrificed using transcardial perfusion. The harvested brains were submerged in 10% formalin for 24 hours and then stored in Gadavist-doped PBS (1:400 dilution) until MRI. MRI data were acquired using a 9.4T Bruker scanner (Bruker BioSpec 94/20) and a 2-element transmit/receive MRI cryoprobe. Key parameters are TR=300ms, TE=27.7ms, b=3000 s/mm² (64 directions) and 5000 s/mm² (96 directions), FOV=13.92x10.20x7.20mm³, Matrix=232x170x120, resolution=60 μm³. Diffusion MRI was analyzed in DSI Studio (http://dsistudio.labsolver.org). Age, gender-matched 3xTg-AD mice without TBI were used as controls.

Results

Figure 2 shows the representative quantitative anisotropy (QA) maps obtained from a mouse with TBI. At 6 months post TBI, decreased QA values were observed in the brain regions ipsilateral to the injury (arrows) compared to the corresponding contralateral regions. Figure 3 shows the representative QA maps of the regions around the hippocampus in mice with and without TBI. Compared to the control mouse, the mouse with neurotrauma showed decreased QA values in the corpus callosum and bilateral hippocampus, especially in the CA1 subregion.

Discussion

Our results demonstrated that ultra-high resolution diffusion MRI can capture subtle alterations of white matter integrity in different brain sub-regions. Using this technique, we were able to detect trauma-accelerated white matter degeneration in a mouse model of Alzheimer’s disease.

Conclusion

Neurotrauma accelerates white matter deterioration, which may contribute to the worsening of Alzheimer’s disease.

Acknowledgements

No acknowledgement found.

References

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2. Johnson VE, Stewart W, Smith DH. Traumatic brain injury and amyloid-beta pathology: a link to Alzheimer's disease? Nat Rev Neurosci. 2010;11(5):361-70. doi: 10.1038/nrn2808. PubMed PMID: 20216546; PMCID: PMC3979339.
3. Tagge CA, Fisher AM, Minaeva OV, et al. Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model. Brain. 2018;141:422-58. doi: 10.1093/brain/awx350. PubMed PMID: WOS:000424217900019.