Traumatic Brain Injury and Secondary Neurodegenerative Disease
Abstract
1. Introduction
2. Mechanisms of Neurodegeneration after TBI
3. Imaging
4. Cognitive and Behavioral Manifestations
5. Therapeutic Targets
5.1. Oxidative Stress
5.2. Cell-Based Therapies
5.3. Aggregation-Prone Proteins
5.4. Neuroinflammation
Therapeutic Target | Outcomes & Mechanism of Action | References |
---|---|---|
Oxidative Stress | ||
PEG-SOD | Catalyzes the degradation of superoxide radicals; combined with PEG molecules to increase in vivo half-life | [64] |
Polyphenols & Flavonoids | Water-soluble antioxidants; directly react with ROS in addition to stimulating the Nrf2-ARE pathway | [65,66,67,68] |
Mitoquinone | Acts as a renewable antioxidant to reduce mitochondrial ROS | [70] |
Cell-based Therapies | ||
Neural stem cells | Improves motor recovery and cognition by replacing neurons lost to neurodegeneration | [73,74,75] |
Mesenchymal stromal stem cells | Reduces proinflammatory mediators and improved functional recovery. IL-10 overexpression alters microglial polarization in favor of anti-inflammatory processes | [76,77] |
Aggregation-prone Proteins | ||
Tau | Preventing pathologic accumulation via immunization against phosphorylated tau improves neurocognitive outcomes | [84,85,86] |
Amyloid-beta protein | Aβ may be targeted through enhanced clearance (immunization), decreased production (α-secretase overexpression), or decreased aggregation (Aβ binding molecules). | [87,88,89,90] |
Neuroinflammation | ||
Minocycline | Attenuates microglial activation and improves functional outcomes | [92,93,94] |
Doxycycline | Decreases MMP-9 activity and preserves blood-brain-barrier integrity | [95] |
Hydroxychloroquine/chloroquine | Attenuates microglial activation and preserves blood-brain-barrier integrity | [96,97] |
PPAR agonists | Attenuates microglial activation and mitochondrial dysfunction, decreases TBI lesion sizes | [98,99,100] |
Cannabinoid 2 receptor agonist | Prevents neuronal degeneration and preserves blood-brain-barrier integrity | [101] |
Inflammasomes | Decreases pro-inflammatory mediators such as caspase-1, IL-18, & IL-1β. Can also reduce pyroptotic cell death by inhibiting gasdermin D cleavage. | [102,103,104] |
Interferon-beta | Attenuates neuroinflammation, decreases lesion volume, and improves long-term functional outcomes | [105] |
6. Conclusions and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Neurotrauma-Related Disease | Key Behavioral Features | References |
---|---|---|
Chronic traumatic encephalopathy | Paranoia, mood swings, apathy, impulsivity, depression, and suicidality | [70,71,72] |
Unclassified dementia | Anxiety, apathy, and possibly agitation/disinhibition | [73,74,75,76] |
Parkinson’s disease | Motivational decline and slowed thinking | [3,77,78] |
Alzheimer’s disease | Depression, cognitive impairment, memory loss | [79,80] |
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Dodd, W.S.; Panther, E.J.; Pierre, K.; Hernandez, J.S.; Patel, D.; Lucke-Wold, B. Traumatic Brain Injury and Secondary Neurodegenerative Disease. Trauma Care 2022, 2, 510-522. https://doi.org/10.3390/traumacare2040042
Dodd WS, Panther EJ, Pierre K, Hernandez JS, Patel D, Lucke-Wold B. Traumatic Brain Injury and Secondary Neurodegenerative Disease. Trauma Care. 2022; 2(4):510-522. https://doi.org/10.3390/traumacare2040042
Chicago/Turabian StyleDodd, William S., Eric J. Panther, Kevin Pierre, Jairo S. Hernandez, Devan Patel, and Brandon Lucke-Wold. 2022. "Traumatic Brain Injury and Secondary Neurodegenerative Disease" Trauma Care 2, no. 4: 510-522. https://doi.org/10.3390/traumacare2040042
APA StyleDodd, W. S., Panther, E. J., Pierre, K., Hernandez, J. S., Patel, D., & Lucke-Wold, B. (2022). Traumatic Brain Injury and Secondary Neurodegenerative Disease. Trauma Care, 2(4), 510-522. https://doi.org/10.3390/traumacare2040042