Traumatic brain injury: a risk factor for neurodegenerative diseases

Gupta, Rajaneesh; Sen, Nilkantha

doi:10.1515/revneuro-2015-0017

Cited by 118 publications

(72 citation statements)

References 67 publications

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“…More importantly, they illustrated the utility of an antibody treatment directed against cis P-tau in preventing TBI-induced pathology (Kondo et al, 2015). The occurrence of these GOs and pathways and the work of Kondo, in large part support the claims of Barnes, Danshevar, Gupta and Sen and co-workers of a TBI-induced increased risk of developing neurodegenerative diseases later in life (Barnes et al, 2014; Danshevar et al, 2015; Gupta and Sen 2015). …”

Section: Discussionsupporting

confidence: 62%

“…Clinical cases of TBI in the civilian world are predominantly categorized as ‘mild’ and concussive in nature, requiring a visit to a hospital emergency department followed by discharge (Korley et al, 2015). In addition to the immediate health related effects of TBI on patients, recent epidemiological studies suggest that there is an association between diverse forms of concussive TBI and the subsequent development of neurodegenerative dementia-related illness in later life (Barnes et al, 2014; Danshevar et al, 2015; Gupta and Sen 2015). …”

Section: Introductionmentioning

confidence: 99%

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Mild traumatic brain injury-induced hippocampal gene expressions: The identification of target cellular processes for drug development

Tweedie

Rachmany

Kim

et al. 2016

Journal of Neuroscience Methods

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Background Neurological dysfunction after traumatic brain injury (TBI) poses short-term or long-lasting health issues for family members and health care providers. Presently there are no approved medicines to treat TBI. Epidemiological evidence suggests that TBI may cause neurodegenerative disease later in life. In an effort to illuminate target cellular processes for drug development, we examined the effects of a mild TBI on hippocampal gene expression in mouse. Methods mTBI was induced in a closed head, weight drop-system in mice (ICR). Animals were anesthetized and subjected to mTBI (30 g). Fourteen days after injury the ipsilateral hippocampus was utilized for cDNA gene array studies. mTBI animals were compared with sham-operated animals. Genes regulated by TBI were identified to define TBI-induced physiological/pathological processes. mTBI regulated genes were divided into functional groupings to provide gene ontologies. Genes were further divided to identify molecular/cellular pathways regulated by mTBI. Results Numerous genes were regulated after a single mTBI event that mapped to many ontologies and molecular pathways related to inflammation and neurological physiology/pathology, including neurodegenerative disease. Conclusions These data illustrate diverse transcriptional changes in hippocampal tissues triggered by a single mild injury. The systematic analysis of individual genes that lead to the identification of functional categories, such as gene ontologies and then molecular pathways, illustrate target processes of relevance to TBI pathology. These processes may be further dissected to identify key factors that can be evaluated at the protein level to highlight possible treatments for TBI in human disease and potential biomarkers of neurodegenerative processes.

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Mild traumatic brain injury-induced hippocampal gene expressions: The identification of target cellular processes for drug development

Tweedie

Rachmany

Kim

et al. 2016

Journal of Neuroscience Methods

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“…TBI has been identified as a major risk factor for CTE and AD, which are characterized by abnormally phosphorylated tau aggregates in neurons and glia of multiple brain regions [28, 29]. For example, one in three NFL players are expected to experience cognitive problems in their lifetime.…”

Section: Tau In Traumatic Brain Injury and Chronic Traumatic Encephalmentioning

confidence: 99%

Function and regulation of tau conformations in the development and treatment of traumatic brain injury and neurodegeneration

et al. 2016

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One of the two common hallmark lesions of Alzheimer’s disease (AD) brains is neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein (p-tau). NFTs are also a defining feature of other neurodegenerative disorders and have recently been identified in the brains of patients suffering from chronic traumatic encephalopathy (CTE). However, NFTs are not normally observed in traumatic brain injury (TBI) until months or years after injury. This raises the question of whether NFTs are a cause or a consequence of long-term neurodegeneration following TBI. Two conformations of phosphorylated tau, cis p-tau and trans p-tau, which are regulated by the peptidyl-prolyl isomerase Pin1, have been previously identified. By generating a polyclonal and monoclonal antibody (Ab) pair capable of distinguishing between cis and trans isoforms of p-tau (cis p-tau and trans p-tau, respectively), cis p-tau was identified as a precursor of tau pathology and an early driver of neurodegeneration in AD, TBI and CTE. Histological studies shows the appearance of robust cis p-tau in the early stages of human mild cognitive impairment (MCI), AD and CTE brains, as well as after sport- and military-related TBI. Notably, cis p-tau appears within hours after closed head injury and long before other known pathogenic p-tau conformations including oligomers, pre-fibrillary tangles and NFTs. Importantly, cis p-tau monoclonal antibody treatment not only eliminates cis p-tau induction and tau pathology, but also restores many neuropathological and functional outcome in TBI mouse models. Thus, cis p-tau is an early driver of tau pathology in TBI and CTE and detection of cis p-tau in human bodily fluids could potentially provide new diagnostic and prognostic tools. Furthermore, humanization of the cis p-tau antibody could ultimately be developed as a new treatment for AD, TBI and CTE.

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“…Brain traumas range from mild to severe with the former being the case in the majority of occurrences (Sosin et al, 1996) and generally not displaying marked behavioral symptoms, while the latter occurs less often, but presents significant motor and/or cognitive dysfunction that can have perpetual adverse consequences on the quality of life (Binder, 1986; Millis et al, 2001). TBI can also increase the risk for other neurological disorders such as seizures (D'Ambrosio et al, 2004; D'Ambrosio and Perucca, 2004; Curia et al, 2011), Alzheimer’s disease (Sullivan et al, 1987; Schofield et al, 1997; Fleminger et al, 2003; Ikonomovic et al, 2004; DeKosky et al, 2007; Gupta and Sen, 2016; Scott et al, 2016) and Parkinson’s disease (Marras et al, 2014; Acosta et al, 2015; Tanner et al, 2015; Taylor et al, 2016), which further exacerbate neurologic dysfunction. Psychiatric comorbidities, such as major depression, generalized anxiety disorder, and post-traumatic stress disorder are also escalated after TBI (Rogers and Read, 2007; Ponsford et al, 2012; Na et al, 2014; Warren et al, 2015; Alway et al, 2016; Scholten et al, 2016) and further limit the successful integration of patients to society and the workforce.…”

Section: Introductionmentioning

confidence: 99%

Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

Kline

Leary

Radabaugh

et al. 2016

Progress in Neurobiology

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Traumatic brain injury (TBI) is a significant health care crisis that affects two million individuals in the United Sates alone and over ten million worldwide each year. While numerous monotherapies have been evaluated and shown to be beneficial at the bench, similar results have not translated to the clinic. One reason for the lack of successful translation may be due to the fact that TBI is a heterogeneous disease that affects multiple mechanisms, thus requiring a therapeutic approach that can act on complementary, rather than single, targets. Hence, the use of combination therapies (i.e., polytherapy) has emerged as a viable approach. Stringent criteria, such as verification of each individual treatment plus the combination, a focus on behavioral outcome, and post-injury vs. pre-injury treatments, were employed to determine which studies were appropriate for review. The selection process resulted in 37 papers that fit the specifications. The review, which is the first to comprehensively assess the effects of combination therapies on behavioral outcomes after TBI, encompasses five broad categories (inflammation, oxidative stress, neurotransmitter dysregulation, neurotrophins, and stem cells, with and without rehabilitative therapies). Overall, the findings suggest that combination therapies can be more beneficial than monotherapies as indicated by 46% of the studies exhibiting an additive or synergistic positive effect versus on 19% reporting a negative interaction. These encouraging findings serve as an impetus for continued combination studies after TBI and ultimately for the development of successful clinically relevant therapies.

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Traumatic brain injury: a risk factor for neurodegenerative diseases

Cited by 118 publications

References 67 publications

Mild traumatic brain injury-induced hippocampal gene expressions: The identification of target cellular processes for drug development

Mild traumatic brain injury-induced hippocampal gene expressions: The identification of target cellular processes for drug development

Function and regulation of tau conformations in the development and treatment of traumatic brain injury and neurodegeneration

Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

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