Mild traumatic brain injury (mTBI) caused by blast concussion from improvised explosive devices and other explosive ordnance is the signature injury of United States Service Members deployed to Operation Enduring Freedom in Afghanistan and Operations Iraqi Freedom and New Dawn in Iraq (OEF/OIF/OND). Repetitive mTBIs increase the risk for two progressive neurodegenerative disorders that cause dementia: chronic traumatic encephalopathy (CTE) with onset in midlife and Alzheimer's disease (AD) with onset in later life. Production and deposition of neurotoxic peptides are believed central to the pathogenesis of CTE and AD. Both CTE and AD are characterized by the intraneuronal deposition of hyperphosphorylated tau peptide (p- tau181) as neurofibrillary tangles. AD is further characterized by the deposition in brain parenchyma of beta amyloid (A?42) peptide as plaques. Concentrations of tau, p-tau181 and AB42 in cerebrospinal fluid (CSF) are established biomarkers of neurodegeneration in AD. The recently described brain glymphatic system is a major mechanism for clearance of neurotoxic proteins and other molecules from the brain. Increasing brain clearance of tau, p-tau181, A?42 and other neurotoxic molecules by increasing brain glymphatic flow is a potentially effective approach to mitigating the increased risk of CTE and AD following mTBI. Preclinical studies have established that mTBI reduces glymphatic flow, thus decreasing brain tau clearance and increasing brain tau deposition. Fortunately, brain glymphatic flow and neurotoxin clearance are substantially increased in preclinical studies by the alpha-1 adrenoreceptor antagonist prazosin, a clinically available drug widely prescribed for nighttime PTSD symptoms. We propose a proof-of-concept randomized placebo controlled pilot study in Veterans with repetitive mTBIs to determine if prazosin decreases concentrations of tau, p-tau181 and A?42 in CSF. Such a finding would be consistent with increased glymphatic clearance of neurotoxic molecules from brain and provide rationale for larger scale studies of clinical evaluation of prazosin for prevention of CTE and AD subsequent to TBI. Forty OEF/OIF Veterans with a history of multiple mTBIs will be randomized to prazosin or placebo for 8 weeks. CSF will be collected by lumbar puncture at pretreatment baseline and again after 10 weeks of study drug treatment. It is hypothesized that prazosin (but not placebo) will decrease CSF concentrations of tau, p- tau181 and A?42. If this hypothesis is confirmed, this study will support further trials of prazosin as a potential primary prevention treatment to reduce risk of CTE and AD following mTBIs. CSF tau, p-tau181 and A?42 concentrations will be determined by Luminex multibead assays.

Public Health Relevance

Mild traumatic brain injury (mTBI) from explosions is the 'signature injury' of Veterans who have deployed to the wars in Afghanistan and Iraq. Although the immediate effects of a single mTBI usually resolve over days or weeks, multiple mTBIs can lead to both persistent symptoms and, years later, to two fatal progressive brain diseases, chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD). It is believed that CTE and AD are caused by nerve damaging chemicals called tau and beta amyloid produced by the brain but which are not removed from the brain in a normal manner in persons with mTBIs. We will determine in Veterans who experienced mTBIs whether a clinically available drug called prazosin increases removal of tau and beta amyloid from the brain. This will be accomplished by seeing if prazosin reduces the amount of tau and beta amyloid in the spinal fluid that surrounds the brain. If we find such reductions, prazosin will be evaluated as a preventative treatment for CTE and AD in future studies.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (I21)
Project #
1I21RX002180-01
Application #
9136966
Study Section
Rehabilitation Research and Development SPiRE Program (RRDS)
Project Start
2016-07-01
Project End
2018-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
VA Puget Sound Healthcare System
Department
Type
DUNS #
020232971
City
Seattle
State
WA
Country
United States
Zip Code
98108