Mild traumatic brain injury (mTBI) caused by blast effects of explosive devices is the """"""""signature injury"""""""" of soldiers, Marines, and other service members in the current Iraq and Afghanistan conflicts. Repetitive mTBI characteristic of troops deployed to Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF), may have devastating personal, professional and domestic consequences. Impairment of memory and concentration, increased anxiety, irritability and mood instability, and sleep disturbance interfere with job and family relationships, producing substantial disability. In addition to these immediate consequences of mTBI, blast trauma damage to brain tissue and/or subsequent brain reparative effects may initiate processes leading to neurodegeneration and dementia. This proposal will apply advanced functional and structural neuroimaging and cerebrospinal fluid (CSF) biomarkers to address the following questions: 1) Are there objective neuroimaging and CSF biomarkers that: a) characterize the behavioral phenotype of blast-induced mTBI;and b) distinguish mTBI from combat trauma posttraumatic stress disorder (PTSD)? 2) Is there long-term cognitive impairment in repetitive blast mTBI and, if so, is cognitive impairment associated with CSF biomarkers of and genetic risk factors for neurodegenerative dementia? The term """"""""mTBI"""""""" here is used to denote a syndrome of persistent postconcussive symptoms ([PCS] cognitive, behavioral, and somatic) that continue to be expressed months and years after blast concussion events that produce mTBI. Our preliminary neuroimaging results demonstrate previously unrecognized structural and functional abnormalities independent of comorbid PTSD in OIF/OEF Veterans with mTBI and persistent PCS. Specific Objective 1: To characterize the clinical (neurocognitive, neurologic, behavioral) and structural/functional neuroimaging characteristics of blast trauma repetitive mild traumatic brain injury (mTBI) in OIF/OEF Veterans with PCS. Specific Objective 2: To determine if OIF/OEF Veterans with repetitive mTBI with persistent PCS express CSF biomarker changes associated with the onset and progression of neurodegenerative dementing disorders. Specific Objective 3: To determine the effects of genetic risk factors for neurodegeneration (apolipoprotein E [APOE] polymorphisms and microtubule associated protein tau [MAPT] subhaplotypes) on both clinical characteristics, and neuroimaging and CSF biomarkers in OIF/OEF Veterans with repetitive mTBI and persistent PCS. This proposal addresses the RR&D priority areas of Validation and Refinement of Diagnostic Imaging Technology and Innovative Approaches to Late or Long-Term Consequences of TBI. VHA faces a huge burden of providing primary medical, rehabilitative, mental health and long term care to this vulnerable population. Identification of objective neuroimaging and CSF biomarkers of mTBI and clarification of the long- term risks of neurodegenerative dementias in mTBI will: 1) improve diagnosis of mTBI, 2) provide targets for improving Veterans'health care;and 3) allow appropriate allocation of limited health care, compensation and pension, and social resources. Successful completion of the proposed research has a high likelihood of yielding both short-term and long-term clinical impacts. Within 24 months, the project will yield tools for objective biomarker diagnosis of mTBI. Within 4 years, results from the proposed project will form the evidence base for rational design of clinical trials to treat current symptoms of mTBI and to prevent progression to neurodegenerative dementing disorders.

Public Health Relevance

Repetitive mild traumatic brain injury (mTBI) caused by blast effects of explosive devices is the signature injury of soldiers, Marines, and other service members in the current Iraq and Afghanistan conflicts and may have devastating personal, professional and domestic consequences. The proposed project will use sophisticated brain imaging techniques and measurement of chemicals in spinal fluid (the fluid surrounding the brain) to identify objective markers of mTBI. These markers will help to improve the diagnosis of mTBI in Veterans of the Iraq and Afghanistan wars, improve Veterans'health care, and allow appropriate allocation of limited health care, compensation and pension, and social resources. A long-term goal is to determine the risks of repetitive blast trauma mTBI for progressing to such fatal dementing disorders as Alzheimer's disease or the mid-life dementia that has been found in professional boxers and football players.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01RX000521-02
Application #
8256521
Study Section
Brain Injury: TBI &Stroke (RRD1)
Project Start
2011-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
VA Puget Sound Healthcare System
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98108
Undurti, Arundhati; Colasurdo, Elizabeth A; Sikkema, Carl L et al. (2018) Chronic Hypopituitarism Associated with Increased Postconcussive Symptoms Is Prevalent after Blast-Induced Mild Traumatic Brain Injury. Front Neurol 9:72
Rau, Holly K; Hendrickson, Rebecca C; Roggenkamp, Hannah C et al. (2018) Fatigue - but not mTBI history, PTSD, or sleep quality - directly contributes to reduced prospective memory performance in Iraq and Afghanistan era Veterans. Clin Neuropsychol 32:1319-1336
Pagulayan, Kathleen F; Rau, Holly; Madathil, Renee et al. (2018) Retrospective and Prospective Memory Among OEF/OIF/OND Veterans With a Self-Reported History of Blast-Related mTBI. J Int Neuropsychol Soc 24:324-334
Agoston, Denes V; Shutes-David, Andrew; Peskind, Elaine R (2017) Biofluid biomarkers of traumatic brain injury. Brain Inj 31:1195-1203
Schindler, A G; Meabon, J S; Pagulayan, K F et al. (2017) Blast-related disinhibition and risk seeking in mice and combat Veterans: Potential role for dysfunctional phasic dopamine release. Neurobiol Dis 106:23-34
Meabon, James S; Huber, Bertrand R; Cross, Donna J et al. (2016) Repetitive blast exposure in mice and combat veterans causes persistent cerebellar dysfunction. Sci Transl Med 8:321ra6
Huber, B R; Meabon, J S; Hoffer, Z S et al. (2016) Blast exposure causes dynamic microglial/macrophage responses and microdomains of brain microvessel dysfunction. Neuroscience 319:206-20
Peskind, Elaine R; Kraemer, Brian; Zhang, Jing (2015) Biofluid Biomarkers of Mild Traumatic Brain Injury: Whither Plasma Tau. JAMA Neurol 72:1103-5
Petrie, Eric C; Cross, Donna J; Yarnykh, Vasily L et al. (2014) Neuroimaging, behavioral, and psychological sequelae of repetitive combined blast/impact mild traumatic brain injury in Iraq and Afghanistan war veterans. J Neurotrauma 31:425-36
Peskind, Elaine R; Brody, David; Cernak, Ibolja et al. (2013) Military- and sports-related mild traumatic brain injury: clinical presentation, management, and long-term consequences. J Clin Psychiatry 74:180-8; quiz 188

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