DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

CENC Researchers Blaze a Trail to New Insights in Mild Traumatic Brain Injury

Posted January 20, 2017
David Cifu, M.D., Virginia Commonwealth University (VCU), Department of Veterans Affairs

David Cifu, M.D., Virginia Commonwealth University (VCU), Department of Veterans Affairs

David Cifu, M.D., Virginia Commonwealth University (VCU), Department of Veterans Affairs
Photo provided courtesy of Dr. David Cifu

The Chronic Effects of Neurotrauma Consortium (CENC) was established through joint DoD and VA funding under the directorship of Dr. David Cifu (VCU). Associate directors, COL Sidney Hinds (US Army Medical Research and Materiel Command) and Dr. Rick Williams (RTI International), also assist in directing consortium efforts. The DoD funds were provided under an award to VCU from the fiscal year 2012 Psychological Health and Traumatic Brain Injury Research Program CENC Funding Opportunity. The consortium seeks to solidify a foundation for comprehensive knowledge of the basic science of mild traumatic brain injury (mTBI), determine the long-term effects of mTBI on brain function and neurodegeneration as well as susceptibility to mTBI in Service members and Veterans, and identify effective mTBI treatment strategies.

This massive research initiative draws from experts at government, academic, and private research facilities and medical centers across the nation, incorporating eleven Department of Veterans Affairs (VA) TBI and polytrauma centers as well as several Department of Defense and academic research centers. The coordinating center at VCU serves as a centralized hub to oversee and facilitate activities at VCU and other institutions, including core facilities for neuroimaging (Baylor College of Medicine), neuropathology (VA Boston), biomarkers (Uniformed Services University of the Health Sciences), and biostatistics, data management, and study management (RTI). VCU also oversees the consortium’s major research initiatives, which currently encompass one basic science and nine clinical research projects ranging from the neurological effects of Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) combat in Service members and Veterans to the visual sensory impairments and progression following mTBI.

The consortium’s early efforts have proved fruitful, yielding advancements in several research initiatives that were recently highlighted in a special issue of the journal Brain Injury. Articles in the issue provided findings from CENC investigators, information on novel study methodologies, and updates on CENC clinical studies currently underway. Results reported included inflammatory changes in optic nerves after repeated TBI1, abnormalities observed in the brain vasculature in a mouse model of repetitive mTBI2, and how post-traumatic stress disorder can compromise the detection of brain white matter integrity in military Veterans with mTBI3. The issue also featured an update describing study participant characteristics for the CENC Observational Study on Late Neurological Effects of OEF/OIF/OND, which was designed to assess the long-term physical and mental health of former combatants who have experienced mTBI4.

Notably, the CENC special issue of Brain Injury contains an article investigating the mechanism of progressive pathological chronic traumatic encephalopathy (CTE), a condition characterized by neurodegeneration and dementia resulting from repetitive head injury5. In this article, Dr. Ann McKee’s research group at Boston University Medical School conducted analyses on brain samples to examine changes in tau proteins, which are commonly found in the central nervous system and have been shown in previous CTE and Alzheimer’s disease studies to form deposits in the brain over time, in progressive pathological CTE in athletes and Veterans. They found that a certain type of neuron in the forebrain, the cholinergic basal forebrain (CBF) cortical projection neuron, develops changes in tau immunoreactive pathology that may be involved in the accumulation of “tangles” of this protein in the brain during the pathological stages of disease. The researchers believe tau tangles in CBF neurons may contribute to cognitive impairments in individuals with CTE and hypothesized that therapeutic interventions targeting tau may be effective in treating this disease.

Additional recent publications by CENC investigators catalogue advances made in the potential diagnostic advances and mechanistic underpinnings of neurotrauma. Findings published in The Journal of the American Medical Association Neurology revealed that military personnel who experience multiple TBIs have elevated blood concentrations of tau proteins6. In a complementary CENC study that appeared in The Journal of Neuropathy & Experimental Neurology, investigators established a mouse model for mTBI and found that repetitive mTBI causes reduced cerebral blood flow, axonal injury, gliosis, and increased T-tau and tau oligomers in the brain gray matter7.

Other current accomplishments from the consortium are derived from the neuroimaging core facilities and include the development of a new analytical technique (also featured in the CENC special issue of Brain Injury) to examine white matter hyperintensities, areas appearing bright white on magnetic resonance imaging (MRI) scanners, on fluid attenuate inversion recovery MRI sequences8, and the incorporation of new strategies to examine diffusion and volumetric MRI data.

In addition to core research efforts initiated by CENC funding, the consortium seeks to build upon previous DoD-funded studies and encourages cross-collaborative efforts with other government agencies to bolster and provide for the future continuity of research efforts supported by the consortium. CENC investigator Dr. Christine MacDonald (University of Washington) builds upon work she originally performed in the lab of Dr. David Brody (Washington University) through two Congressionally Directed Medical Research Programs (CDMRP) Psychological Health and Traumatic Brain Injury FY07 and FY09 research awards. These awards funded her prospective analyses to assess MRI and clinical outcome measures at early time points up to 12 months after injury for active military personnel who experienced TBI in either concussive blast or non-blast settings. In a project currently funded through the consortium, Dr. MacDonald builds on these previous studies to examine this same cohort at three to five years after injury. Her findings suggest that Service members who experienced blast concussion during combat display lasting mental health symptoms (e.g., hypervigilance and hyperarousal under posttraumatic stress disorder) and abnormal microstructural changes in the brain architecture. A predictive model constructed from longitudinal analyses of patient imaging data from acute through long-term periods after TBI occurrence suggests the progressive worsening of symptom severity beyond one year post-injury. Dr. MacDonald’s insightful results have led to a newly awarded NIH grant to conduct longitudinal studies to continue her examination of long-term advanced MRI imaging data and clinical outcomes of military personnel who sustained concussive TBIs during deployment. These studies will complement and expand her prospectively acquired consortium research results.

As of October 2016, the consortium has produced 29 peer-reviewed publications, 29 poster and 18 oral presentations or invited talks at national or international meetings, and 5 abstracts. The consortium director, Dr. Cifu, has given five lectures on the management of combat-associated concussions at national and international meetings as well as a CENC update for Grand Rounds at the Prince Sultan Military Medical City in Saudi Arabia. Dr. Cifu was also interviewed about topics related to concussion by National Public Radio (NPR) host John Fogle, and spoke at the VCU Health and Virginia PBS and NPR collaborative Community Idea Stations Science Matters event, “Dissecting Science: Your Amazing Brain.” This event featured an informal scientific exploration of different aspects of brain function, immunology, and disease. More information on CENC publications, presentations, and other public releases can be found at https://cenc.rti.org.

Works cited:

(1) Tzekov R, Pifer J, Myers A, et al. 2016. Inflammatory changes in optic nerve after close-head repeated traumatic brain injury. CENC Special Issue of Brain Inj 30(12):1428-1435.

(2) Lynch CE, Crynen G, Ferguson S, et al. 2016. Chronic cerebrovascular abnormalities in a mouse model of repetitive mild traumatic brain injury. CENC Special Issue of Brain Inj 30(12):1414-1427.

(3) Davenport ND, Lamberty GJ, Nelson NW, et al. 2016. PTSD confounds detection of compromised cerebral white matter integrity in military veterans reporting a history of mild traumatic brain injury. CENC Special Issue of Brain Inj 30(12):1491-1500.

(4) Walker WC, Carne W, Franke LM, et al. 2016. The Chronic Effects of Neurotrauma Consortium (CENC) observational study: Description of study and characteristics of early participants. CENC Special Issue of Brain Inj 30(12):1469-1480.

(5) Mufson EJ, Perez SE, Muhammad N, et al. 2016. Progression of tau pathology within cholinergic nucleus basalis neurons in chronic traumatic encephalopathy: A Chronic Effects of Neurotrauma Consortium Study. CENC Special Issue of Brain Inj 30(12):1399-1413.

(6) Olivera A, Lejbman N, Jeromin A, et al. 2015. Peripheral total tau in military personnel who sustain traumatic brain injuries during deployment. JAMA Neurol 72(10):1109-1116.

(7) Ojo JO, Mouzon B, Algamal M, et al. 2016. Chronic repetitive mild traumatic brain injury results in reduced cerebral blood flow, axonal injury, gliosis, and increased T-tau and tau oligomers. J Neuropathol Exp Neurol 75(7):636-655.

(8) Stone JR, Wilde EA, Taylor BA, et al. Supervised learning technique for the automated identification of white matter hyperintensities in traumatic brain injury. CENC Special Issue of Brain Inj 30(12):1458-1468.

Recent Consortium Publications:

Bigler ED. 2016. Systems biology, neuroimaging, neuropsychology, neuroconnectivity, and traumatic brain injury. Front Syst Neurosci 10:55.

Cifu DX, Carne WF and Eapen BC. 2016. Chronic traumatic encephalopathy (CTE). Medscape Drugs & Diseases. WebMD Inc. Published April 14, 2016. Accessed April 19, 2016.

Gardner RC, Burke JF, Nettiksimmons J, et al. 2015. Traumatic brain injury in later life increases risk for Parkinson disease. Ann Neurology 77(6):987-995.

Gattu R, Akin FW, Cacace AT, et al. 2016. Vestibular, balance, microvascular, and white matter neuroimaging characteristics of blast injuries: Four case reports. CENC Special Issue of Brain Inj 30(12):1501-1514.

Gilmore CS, Camchong J, Davenport ND, et al. 2016. Deficits in visual system functional connectivity after blast-related mild TBI are associated with injury severity and executive dysfunction. Brain Behav 6(5):e00454.

Jaramillo CA, Eapen BC, McGeary CA, et al. 2015. A cohort study examining headaches among veterans of Iraq and Afghanistan wars: Associations with traumatic brain injury, PTSD, and depression. Headache 56(3):528-539.

Jurick SM, Bangen K, Evangelista N, et al. 2016. Advanced neuroimaging to quantify myelin in vivo – application to TBI. CENC Special Issue of Brain Inj 30(12):1452-1457.

Peltz CB, Gardner RC, Kenney K, et al. 2016. Neurobehavioral characteristics of older veterans with remote traumatic brain injury. J Head Trauma Rehabil (Epub ahead of print).

Pugh MJ, Finley EP, Wang CP, et al. 2016. A retrospective cohort study of comorbidity trajectories associated with traumatic brain injury in veterans of the Iraq and Afghanistan wars. CENC Special Issue of Brain Inj 30(12):1481-1490.

Seal KH, Bertenthal B, Samulson K, et al. 2016. Association between mild traumatic brain injury and mental health problems with self-reported cognitive dysfunction in Iraq and Afghanistan veterans. J Rehabil Res Dev 53(2):185-198.

Tate DF, Gusman M, Kini J, et al. Susceptibility weighted imaging and white matter abnormalities in service members with persistent cognitive symptoms following mild traumatic brain injury. Military Medicine (in press).

Tate DF, Wilde EA, Bouix S, et al. 2015. Introduction to the brain imaging and behavior special: Mild traumatic brain injury among active duty service members and veterans. Brain Imaging Behav 9(3):367-402.

Uchendu US, Omalu BI, Cifu DX, et al. 2016. Repeated concussions: Time to spur action among vulnerable veterans. Am J Public Health 106(8):1366-1368.

Wilde EA, Bouix S, Tate DF, et al. 2015. Advanced neuroimaging applied to veterans and service personnel with traumatic brain injury: State of the art and potential benefits. Brain Imaging Behav 9(3):355-357.

Wilde EA, Bigler ED, Huff T, et al. 2016. Quantitative structural neuroimaging of mild traumatic brain injury in the Chronic Effects of Neurotrauma Consortium (CENC): Comparison of data across scanners. CENC Special Issue of Brain Inj 30(12):1442-1451.

Links:

Public and Technical Abstracts: Military and Veterans Rehabilitation and Recovery from Injury Network (MAVERICK): Chronic Effects of Neurotrauma Consortium (CENC)

http://www.tandfonline.com/toc/ibij20/30/12?nav=tocList

https://cenc.rti.org/

https://twitter.com/cenc_research

https://www.instagram.com/cenc_research/

https://www.facebook.com/cencconcussion/

http://ideastations.org/radio/news/vcu-researcher-pleased-films-focus-concussions

http://ideastations.org/dissecting-science

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Last updated Friday, January 20, 2017