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Single episode of moderate to severe traumatic brain injury leads to chronic neurological deficits and Alzheimer’s-like pathological dementia

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Abstract

Traumatic brain injury (TBI) is one of the foremost causes of disability and mortality globally. While the scientific and medical emphasis is to save lives and avoid disability during acute period of injury, a severe health problem can manifest years after injury. For instance, TBI increases the risk of cognitive impairment in the elderly. Remote TBI history was reported to be a cause of the accelerated clinical trajectory of Alzheimer’s disease-related dementia (ADRD) resulting in earlier onset of cognitive impairment and increased AD-associated pathological markers like greater amyloid deposition and cortical thinning. It is not well understood whether a single TBI event may increase the risk of dementia. Moreover, the cellular signaling pathways remain elusive for the chronic effects of TBI on cognition. We have hypothesized that a single TBI induces sustained neuroinflammation and disrupts cellular communication in a way that results later in ADRD pathology. To test this, we induced TBI in young adult CD1 mice and assessed the behavioral outcomes after 11 months followed by pathological, histological, transcriptomic, and MRI assessment. On MRI scans, these mice showed significant loss of tissue, reduced CBF, and higher white matter injury compared to sham mice. We found these brains showed progressive atrophy, markers of ADRD, sustained astrogliosis, loss of neuronal plasticity, and growth factors even after 1-year post-TBI. Because of progressive neurodegeneration, these mice had motor deficits, showed cognitive impairments, and wandered randomly in open field. We, therefore, conclude that progressive pathology after adulthood TBI leads to neurodegenerative conditions such as ADRD and impairs neuronal functions.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the electron microscopy and histology core, and small animal imaging core at AU for histological and MRI assistance respectively.

Funding

Financial support for this project was provided by the awards from the Augusta University Research Institute MCGFD08343 and RIA00056 to KV, and partially by extramural funds NIA R01AG062655 to FD, and NINDS R01NS114560 to KV.

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Authors and Affiliations

  1. Brain Injury, Senescence, and Translational Neuroscience Lab, Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    Kumar Vaibhav, Mayuri Gulhane, Manish Kumar, Meenakshi Ahluwalia, Liam Goldman & Fernando L. Vale

  2. Transdisciplinary Research Initiative in Inflammaging and Brain Aging (TRIBA), Augusta University, Augusta, GA, USA

    Kumar Vaibhav

  3. Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA, USA

    Pankaj Ahluwalia, Meenakshi Ahluwalia, Ashis K. Mondal & Ravindra Kolhe

  4. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA

    Manish Kumar

  5. Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA

    Meenakshi Ahluwalia & Ali S. Arbab

  6. Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA

    Ashiq M. Rafiq, Jacob B. Miller & Ferenc Deak

  7. Center for Undergraduate Research Studies, Augusta University, Augusta, GA, USA

    Vibha Amble & Manuela G. Zabala

  8. The Graduate School, Augusta University, Augusta, GA, USA

    Jacob B. Miller

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  1. Kumar Vaibhav
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  2. Mayuri Gulhane
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  3. Pankaj Ahluwalia
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Contributions

KV conceptualized the project, designed the experiments, prepared the TBI model, and supervised the entire project. KV, AA, FLV, FD, RK, MA, MK, MG, and PA wrote the manuscript. AA, VA, and KV assisted with MRI experiments and analysis. MA, LG, MG, and KV assisted with mice behavior tests and analysis. FD, AMR, JBM, and KV assisted with synaptic plasticity experiments and analysis. MG, VA, MGZ, MA, and KV assisted with histology and immunohistochemistry experiments. MA, PKA, AKM, RK, and KV assisted with Nanostring transcriptomic experiments and initial analysis of data. MA and MK assisted with data interpretation. PKA did final transcriptomic analysis and prepared respective figures. All authors read, revised, and approved the manuscript for publication.

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Correspondence to Kumar Vaibhav.

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The authors declare that there is no financial conflict of interest. We also declare that one of the co-authors (FD) is an Associate Editor of Geroscience.

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Vaibhav, K., Gulhane, M., Ahluwalia, P. et al. Single episode of moderate to severe traumatic brain injury leads to chronic neurological deficits and Alzheimer’s-like pathological dementia. GeroScience (2024). https://doi.org/10.1007/s11357-024-01183-3

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