Traumatic brain injury (TBI) is increasingly recognized as a risk factor for dementia. New data provide further support for this association and demonstrate the influence of age at injury and injury severity on dementia risk after TBI, revealing that even mild TBI increases dementia risk in those aged ≥65 years.
The association between traumatic brain injury (TBI) and increased risk of dementia has garnered intense public and media interest in the past few years. In a newly published, comprehensive study of 164,611 patients with trauma aged ≥55 years at the time of injury, the strength of this association is explored further;1 the results highlight the influence of age on dementia risk following TBI. In support of previous work, Gardner and colleagues1 report an increased dementia risk following a single moderate to severe TBI across their patient cohort at up to 7 years of follow-up. Furthermore, an intriguing aspect of the analysis indicates that even a single, mild TBI confers increased dementia risk in older patients (defined as those aged ≥65 at the time of injury). Thus, the results of the study imply that risk of neurodegeneration after TBI is influenced not just by the severity of the initial injury, but also by the patient's age at the time of injury (Figure 1).
Considerable attention has been paid to the link between repetitive, mild TBI and neurodegenerative disease. This interest has, in large part, been driven by increasing numbers of reports of chronic traumatic encephalopathy (CTE) in autopsy studies of former athletes or military personnel.2,3 The association between exposure to a single moderate or severe TBI and increased risk of dementia has also been recognized for some time. Characterization of autopsy-acquired material from long-term survivors of a single TBI reveals a complex neuropathology in a proportion of patients. This complex neuropathology, best described as a 'polypathology', includes abnormal tau and amyloid-β protein accumulation,4 neuroinflammation, white matter degradation and axonal degeneration,5 adding further to our appreciation of the full range of CTE pathology. However, although the neurodegenerative pathology of TBI is increasingly understood, reports regarding the epidemiological association between a single TBI and altered risk of dementia are conflicting, possibly reflecting methodological limitations of studies on both sides of this debate.6
Several previous clinical studies have used a methodology that compares incidence of dementia in patients with TBI to that of the general population. In the new study by Gardner et al.,1 a more relevant index population of over 112,000 patients exposed to trauma without TBI (excluding fractures of head and neck) provides the 'control' population in which prevalence of dementia was compared with that of a cohort of almost 52,000 patients with TBI. As such, the authors attempted to mitigate potentially unknown behavioural or clinical confounders that might also confer an increased risk of dementia in patients exposed to trauma.
“...Gardner and colleagues report an increased dementia risk following a single moderate to severe TBI...”
Rather than relying on self-reporting or informant-reporting of dementia, only confirmed, hospital-based diagnoses (International Classification of Diseases, 9th Revision coded) were used to determine dementia outcome at follow-up. Importantly, patients who were diagnosed with dementia within 1 year following injury were excluded from the analysis to reduce the possibility that evolving subacute TBI pathology or pre-existing dementia as a risk factor for trauma might confound dementia diagnosis. According to Gardner and co-authors, after adjusting the data for covariables, patients who survived a moderate to severe TBI had a higher risk of dementia than patients with non-TBI trauma. This association was observed across all age groups.
Intriguingly, the study also reveals a potential association between age at injury, injury severity and subsequent risk of dementia. As mentioned above, moderate to severe TBI increased the risk of dementia across the cohort; however, in the older patients included in the study, a single, mild TBI was sufficient to increase dementia risk. Notably, TBI is a major public health problem in older individuals, with the highest rates of hospitalization from TBI observed in those aged ≥65.7
Research has resulted in an increased appreciation of the range of neuropathologies associated with 'normal' ageing, which show overlap with pathologies typically associated with neurodegenerative diseases, including brain atrophy, neurofibrillary tangles and amyloid-β plaques.8 To avoid the confounding influence of 'normal' ageing, many studies investigating TBI-associated neurodegenerative pathologies often exclude older individuals and focus on younger patients. However, the study by Gardner et al.1 underlines the pressing need to further examine the interplay between TBI, age and dementia risk.
“...even a single, mild TBI confers increased dementia risk in older patients...”
The presence of comorbidities, and their potential contribution to pathophysiology is of particular relevance in the older age group. In this respect, the population of patients with TBI included in this study was slightly older, had a higher percentage of males and a higher incidence of cardiovascular comorbidities than the counterpart cohort of patients with trauma without TBI. Although the association with dementia risk remained after adjustment for these covariates, the need for robust accounting for comorbidities is critical to further investigate the potential mechanisms of disease, particularly in mild TBI.
Owing to the inherent restrictions of retrospective analyses, one limitation of this work is the inability to exclude previous TBIs that might have occurred before the period of study, including repetitive mild exposures. To date, the association between repetitive mild TBI and chronic neurodegeneration has not been robustly explored at a population level, with the vast majority of data being derived from relatively small and highly selective patient series.2,3 As such, any speculation as to how this potential variable might influence dementia risk is limited. However, Gardner et al.1 did note that patients with a second TBI during follow-up had twice the dementia risk, suggesting a dose–response relationship.
Overall, the work by Gardner and colleagues represents an important contribution to our understanding of the association between TBI and increased risk of dementia. These findings also underscore the pressing need for further, well-constructed, longitudinal studies examining the chronic and progressive consequences of TBI across all age groups. Risk of a worse outcome in the acute period following TBI is known to increase with older age.9,10 Given the advancing average age in many societies, further understanding of any age-associated vulnerability to progressive neurodegenerative outcomes following TBI will be of critical importance.
Gardner, R. C. et al. Dementia risk after traumatic brain injury vs nonbrain trauma: the role of age and severity. JAMA Neurol. 71, 1490–1497 (2014).
McKee, A. C. et al. The spectrum of disease in chronic traumatic encephalopathy. Brain 136, 43–64 (2013).
Smith, D. H., Johnson, V. E. & Stewart, W. Chronic neuropathologies of single and repetitive TBI: substrates of dementia? Nat. Rev. Neurol. 9, 211–221 (2013).
Johnson, V. E., Stewart, W. & Smith, D. H. Widespread tau and amyloid-β pathology many years after a single traumatic brain injury in humans. Brain Pathol. 22, 142–149 (2012).
Johnson, V. E. et al. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain 136, 28–42 (2013).
Fleminger, S. et al. Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication. J. Neurol. Neurosurg. Psychiatry 74, 857–862 (2003).
Faul, M., Xu, L., Wald, M. M. & Coronado, V. Traumatic brain injury in the United States: emergency department visits, hospitalizations and deaths 2002–2006, Centers for Disease Control and Prevention [online] (2010).
Savva, G. M. et al. Age, neuropathology, and dementia. N. Engl. J. Med. 360, 2302–2309 (2009).
Susman, M. et al. Traumatic brain injury in the elderly: increased mortality and worse functional outcome at discharge despite lower injury severity. J. Trauma 53, 219–223 (2002).
Hukkelhoven, C. W. et al. Patient age and outcome following severe traumatic brain injury: an analysis of 5600 patients. J. Neurosurgery 99, 666–673 (2003).
The authors declare no competing financial interests.
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Johnson, V., Stewart, W. Age at injury influences dementia risk after TBI. Nat Rev Neurol 11, 128–130 (2015). https://doi.org/10.1038/nrneurol.2014.241
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