Prazosin and CSF Biomarkers in mTBI

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 DESCRIPTION (provided by applicant): 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.