• ACQUIRED BRAIN INJURY
• BIOCHEMISTRY
• DEMENTIA
• TRAUMATIC BRAIN INJURY

Traumatic brain injuries (TBIs) have been a common consequence of combat since prehistoric times, and injuries to the cranium are commonly found in skeletal remains of prehistoric humans, most of which are likely a consequence of warfare.1 While physicians have long recognised the consequences of severe TBIs,2 far more common are so-called ‘mild’ TBIs, which were mostly ignored by the medical system until this century.3 Not surprisingly, these mild TBIs are highly prevalent in military veterans, and a US Army study found that approximately 15% of service members reported a mild TBI during a 1-year deployment,4 and multiple injuries are common. TBI exposure during military service has been linked to neurocognitive disorders in later life5 and to psychological distress such as anxiety, depression and post-traumatic stress disorder. To adequately fulfil the obligation society has to young people sent into combat, understanding the long-term consequences of these injuries and having access to biomarkers that can help properly diagnose and monitor the consequences of these injuries is a critical need.6

Graham et al seek to uncover the long-term neuropsychiatric implications of combat-associated TBI in British combat veterans who participated in the ADVANCE-TBI study after having served in Afghanistan.7 The recent recognition that proteins detected at elevated levels in blood after TBI8 reflect neurodegenerative processes9 presents opportunities to evaluate the biochemical consequences of TBI, which has major implications for the provision of appropriate rehabilitative and mental health services. This article makes significant strides towards further elucidating the relationship between TBI exposure, neuropsychological outcomes and blood biomarker levels years after military injuries.

A major strength of this paper is the ADVANCE cohort, which enrolled a large number (n=1145) of active duty and retired UK military personnel both with and without a history of major battlefield trauma requiring aeromedical evacuation from the combat theatre, who were followed for up to 8 years postinjury. Among those with trauma exposure, a subset sustained extracranial injury without TBI, providing an important subgroup for TBI comparison. The prevalence of chronic neuropsychiatric complications in the extracranial-only injury group more closely mirrored that of the uninjured group, while the TBI subset demonstrated significantly higher rates of anxiety and depressive symptoms. The authors went further to demonstrate that a history of neurotrauma was also associated with a significantly worse reported quality of life and poorer motor function as compared with those without injury or with extracranial injury alone.

The authors also probed the relationships between TBI, its chronic complications and blood biomarkers relevant to neuropsychiatric disorders. These included glial fibrillar acidic protein (GFAP), neurofilament light (NfL), total τ, phospho-tau181 and amyloid-β peptides (Aβ 42 and 40). Of these, only GFAP demonstrated a significant chronic elevation specific to the TBI group, although, among this group, both GFAP and NfL levels reflected injury severity (ie, higher in patients with moderate-severe TBI as compared with mild). Importantly, the authors sampled levels annually following the index encounter and noted that GFAP and Aβ 42 decreased over time. These relationships are of particular interest given that these biomarkers are thought to be associated with Alzheimer’s disease (AD) and AD-related dementias, thus representing a potential pathophysiological mechanism connecting TBI and cognitive impairment.

The findings related to GFAP levels suggest alterations in brain biochemistry persist for many years following initial injury. Moreover, by linking this finding to TBI sequelae, the authors make steps towards gaining a mechanistic understanding of chronic TBI. These results confirm the profound toll that combat-associated neurotrauma, even seemingly mild injuries, can have on long-term neurocognitive and quality-of-life metrics and open a new window into how molecular biomarkers may provide mechanistic insights and accelerate the day when effective disease-modifying therapies are available.