Linking Traumatic Brain Injury to Chronic Traumatic Encephalopathy: Identification of Potential Mechanisms Leading to Neurofibrillary Tangle Development

Journal of neurotrauma (Impact Factor: 3.71). 02/2014; 31(13). DOI: 10.1089/neu.2013.3303
Source: PubMed


Significant attention has recently been drawn to the potential link between head trauma and the development of neurodegenerative disease, namely chronic traumatic encephalopathy (CTE). The acute neurotrauma associated with sports related concussions in athletes and blast induced traumatic brain injury in soldiers elevates the risk for future development of chronic neurodegenerative diseases such as CTE. CTE is a progressive disease distinguished by characteristic tau neurofibrillary tangles (NFTs) and occasionally transactive response DNA binding protein 43 (TDP43) oligomers; both of which have a predilection for perivascular and subcortical areas near reactive astrocytes and microglia. The disease is currently only diagnosed post-mortem by neuropathologic identification of NFTs. A recent workshop sponsored by National Institute of Neurological Disorders and Stroke emphasized the need for pre-mortem diagnosis to better understand disease pathophysiology and to develop targeted treatments. In order to accomplish this objective, it is necessary to discover the mechanistic link between acute neurotrauma and the development of chronic neurodegenerative and neuropsychiatric disorders such as CTE. In this review we briefly summarize what is currently known about CTE development and pathophysiology, and subsequently discuss injury-induced pathways that warrant further investigation. Understanding the mechanistic link between acute brain injury and chronic neurodegeneration will facilitate the development of appropriate diagnostic and therapeutic options for CTE and other related disorders. Key Words: Chronic Traumatic Encephalopathy, Neurofibrillary Tau Tangles.

Download full-text


Available from: Brandon Lucke-Wold, Feb 19, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent wars in Iraq and Afghanistan have accounted for an estimated 270,000 blast exposures among military personnel. Blast traumatic brain injury (TBI) is the 'signature injury' of modern warfare. Blood brain barrier (BBB) disruption following blast TBI can lead to long-term and diffuse neuroinflammation. In this study, we investigate for the first time the role of bryostatin-1, a specific protein kinase C (PKC) modulator, in ameliorating BBB breakdown. Thirty seven Sprague-Dawley rats were used for this study. We utilized a clinically relevant and validated blast model to expose animals to moderate blast exposure. Groups included: control, single blast exposure, and single blast exposure + bryostatin-1. Bryostatin-1 was administered i.p. 2.5 mg/kg after blast exposure. Evan's blue, immunohistochemistry, and western blot analysis were performed to assess injury. Evan's blue binds to albumin and is a marker for BBB disruption. The single blast exposure caused an increase in permeability compared to control (t = 4.808, p < 0.05), and a reduction back toward control levels when bryostatin-1 was administered (t = 5.113, p < 0.01). Three important PKC isozymes, PKCα, PKCδ, and PKCε, were co-localized primarily with endothelial cells but not astrocytes. Bryostatin-1 administration reduced toxic PKCα levels back toward control levels (t = 4.559, p < 0.01) and increased the neuroprotective isozyme PKCε (t = 6.102, p < 0.01). Bryostatin-1 caused a significant increase in the tight junction proteins VE-cadherin, ZO-1, and occludin through modulation of PKC activity. Bryostatin-1 ultimately decreased BBB breakdown potentially due to modulation of PKC isozymes. Future work will examine the role of bryostatin-1 in preventing chronic neurodegeneration following repetitive neurotrauma.
    Full-text · Article · Oct 2014 · Molecular Neurobiology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Scientific knowledge of omega-3 fatty acids (FAs) has grown in the last decade to a greater understanding of their mechanisms of action and their potential therapeutic effects. Omega-3 FAs have shown therapeutic potential with respect to hyperlipidemia, depression, attention-deficit hyperactivity disorder, and mild cognitive impairment. Laboratory evidence and clinical interest have grown such that omega-3 FAs have now assumed a role in concussion management. This has coincided with recent research that has also helped to increase the scientific understanding of cerebral concussion; although concussion or mild traumatic brain injury was assumed to be a malfunctioning brain without anatomical damage, we now know that there is the potential for damage and dysfunction at the cellular and microstructural levels. Specifically, with concussion abnormal metabolism of glucose may occur and intracellular mitochondrial dysfunction can persist for several days. In this article, we discuss the role of omega-3 FAs, particularly docosahexaenoic acid, in concussion management.
    Preview · Article · Nov 2014 · Military medicine
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The concept that frontotemporal dementia (FTD) is a purely cortical dementia has largely been refuted by the recognition of its close association with motor neuron disease, and the identification of transactive response DNA-binding protein 43 (TDP-43) as a major pathological substrate underlying both diseases. Genetic findings have transformed this field and revealed connections between disorders that were previous thought clinically unrelated. The discovery that the C9ORF72 locus is responsible for the majority of hereditary FTD, amyotrophic lateral sclerosis (ALS), and FTD–ALS cases and the understanding that repeat-containing RNA plays a crucial role in pathogenesis of both disorders has paved the way for the development of potential biomarkers and therapeutic targets for these devastating diseases. In this review, we summarize the historical aspects leading up to our current understanding of the genetic, clinical, and neuropathological overlap between FTD and ALS, and include brief discussions on chronic traumatic encephalopathy (CTE), given its association with TDP-43 pathology, its associated increased dementia risk, and reports of ALS in CTE patients. In addition, we describe other genetic associations between dementia and neuromuscular disease, such as inclusion body myositis with Paget's disease and FTD.
    Full-text · Article · Dec 2014 · Annals of the New York Academy of Sciences
Show more