DNA damage as a marker of brain damage in individuals with history of concussions

Abstract

Mild traumatic brain injury (mTBI) is common in many populations, including athletes, veterans, and domestic abuse victims. mTBI can cause chronic symptoms, including depression, irritability, memory problems, and attention deficits. A history of repetitive mTBI has been epidemiologically associated with developing early-onset dementia and neurodegenerative diseases and, in particular, is thought to be the underlying cause of chronic traumatic encephalopathy (CTE)—a progressive tauopathy diagnosed by the presence of perivascular hyperphosphorylated tau protein (p-tau) in the depths of cortical sulci. However, the scarce and focal pathology often seen in CTE does not correlate with the severity of symptoms experienced by patients. This paper proposes accumulation of γH2AX, a marker of double-stranded DNA damage, as a novel pathological marker to identify brain damage post-mTBI. We present two cases of men with history of mTBI. Immunohistochemistry revealed extensive DNA damage throughout the frontal cortex, hippocampus, and brainstem areas. Furthermore, gene expression profiling showed increases of ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (CHEK2), two serine/threonine kinases recruited in response to double-strand breaks in the DNA damage response pathway. These cases highlight the complex pathophysiology of head trauma, and suggest DNA damage as the molecular mechanism behind mTBI-induced pathology and symptoms.