The Presence and Role of Iron in Mild Traumatic Brain Injury: An Imaging Perspective

Abstract

Mild traumatic brain injury (mTBI), although often presenting without the gross structural abnormalities seen in more severe forms of brain trauma, can nonetheless result in lingering cognitive and behavioral problems along with subtle alterations in brain structure and function. Repeated injuries are associated with brain atrophy and dementia in the form of chronic traumatic encephalopathy (CTE). The mechanisms underlying these dysfunctions are poorly understood. There is a growing body of evidence that brain iron is abnormal after TBI, and brain iron has also been implicated in a host of neurodegenerative disorders. The purpose of this article is to review evidence about the function of iron in the pathophysiology of mTBI and the role that advanced imaging modalities can play in further elucidating said function. MRI techniques sensitive to field inhomogeneities provide supporting evidence for both deep gray matter non-heme iron accumulation as well as focal microhemorrhage resulting from mTBI. In addition, there is evidence that iron may contribute to pathology after mTBI through a number of mechanisms, including generation of reactive oxygen species (ROS), exacerbation of oxidative stress from other sources, and encouragement of tau phosphorylation and the formation of neurofibrillary tangles. Finally, recent animal studies suggest that iron may serve as a therapeutic target in mitigating the effects of mTBI. However, research on the presence and role of iron in mTBI and CTE is still relatively sparse, and further work is necessary to elucidate issues such as the sources of increased iron and the chain of secondary injury.

MR Imaging Applications in Mild Traumatic Brain Injury: An Imaging Update

“…Abnormal susceptibility after mTBI has also been studied as it relates to brain iron. Nisenbaum et al recently reviewed this topic in depth (93). Briefly, animal models show abnormal iron handling in the central nervous system after TBI (94).…”

“…Increased iron, implicated in a number of neurodegenerative conditions, can contribute to oxidative stress and facilitate neuronal degeneration (97,98). This is of particular interest in mTBI patients who have persistent symptoms, longterm complications, and poor outcome (93), and further studies are ongoing in this area to determine the importance of iron content in mTBI pathogenesis.…”

Trehalose improves traumatic brain injury-induced cognitive impairment

“…Fe deposition is a consistent and enduring pathological consequence of TBI [17–19,58], and has also been shown to be positively related to cognitive impairment in mild traumatic brain injury [59]. However, apart from some significant time point specific observations, trehalose failed to significantly modify the overall Fe profile in any manner inconsistent with the observed Fe trends of both treatment groups.…”

Role of Microvascular Disruption in Brain Damage from Traumatic Brain Injury

“…Specifically, the traumatic force causes an intracranial pressure spike which causes cerebral microvessels to burst (10). When an external force damages brain microvessels they can release cytotoxic levels of iron into the brain parenchyma (98, 125). Iron promotes Ca 2+ -dependent mechanisms, which can stimulate cell survival, or trigger cell death depending on severity and duration of iron exposure (119, 120).…”