Traumatic Brain Injury and Time to Onset of Alzheimer's Disease: A Population-based Study

Nemetz, Peter N.; Leibson, Cynthia L.; Naessens, James M.; Beard, Mary K.; Kokmen, Emre; Annegers, John F.; Kurland, Leonard T.

doi:10.1093/oxfordjournals.aje.a009724

Cited by 275 publications

(168 citation statements)

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“…[16][17][18] What is less clear is whether mild TBI can also lead to cognitive impairment, with several studies showing negative results. [19][20][21] More than one million concussions occur annually in this country, with 300,000 resulting from sports-related activities.…”

Section: Discussionmentioning

confidence: 99%

Multiple Episodes of Mild Traumatic Brain Injury Result in Impaired Cognitive Performance in Mice

Creeley¹,

Wozniak²,

Bayly³

et al. 2004

Acad Emergency Med

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Objectives: Results from recent studies on animal models of concussion suggest that multiple, rather than single, episodes of mild traumatic brain injury result in impaired cognitive performance in mice. The objective of the present study was to administer multiple impacts to the heads of mice while directly measuring the force of the impacts to determine how these parameters are related to transient loss of consciousness, cognitive deficits, and potential neuropathologic effects. Methods: Seven-week-old male C57BL/6 mice were randomly assigned to experimental conditions involving three impacts (weight-drop method) to the head to induce mild traumatic brain injury or to sham control procedures. Some impacted (n ¼ 10) and sham control (n ¼ 10) mice were evaluated behaviorally and tested for spatial learning using the Morris water maze (MWM), whereas other impacted (n ¼ 10) and sham control (n ¼ 5) mice were used for histopathologic analysis. Results: The mean (6SD) force of impact was 19 (63.5) N. Impacted mice took longer to regain consciousness compared with sham control mice (p \ 0.0005). Behavioral test results showed that the groups did not differ on activity or sensorimotor tests or during cued trials in the MWM. Impacted mice exhibited impaired spatial learning performance during place trials in the MWM (p \ 0.05). Silver staining revealed a contra-coup type of injury involving ventral brain structures in contact with or in close proximity to the skull. Conclusions: This multiple-impact model, delivered within a specifiable force range, results in transient, reversible loss of consciousness, a contra-coup brain injury, and cognitive impairment. Key words: traumatic brain injury; concussion; memory; cognition; mice. ACADEMIC EMERGENCY MED-ICINE 2004; 11:809-819. It is not clear whether mild traumatic brain injury (TBI) causes demonstrable long-term cognitive impairment in humans. A number of earlier epidemiologic studies suggest that this may be the case, but the use of retrospective designs, lack of appropriate control groups, and an inability to correct for several confounding factors did not allow for a straightforward interpretation of the results. [1][2][3][4] More recently, a number of studies of athletes who have experienced a sports-related concussion suggest that symptomatology and cognitive impairment can last for one week 5 and, in some cases, up to three months. 6 Animal models have been used to study the behavioral and neuropathologic sequelae associated with TBI. [7][8][9][10] In three of these studies, in which slightly different murine models of mild TBI were used, the results suggested that mild single impacts did not produce discernible learning/memory deficits when behavioral testing was conducted more than three days after impact. [8][9][10] In contrast, multiple mild impacts have usually been found to produce significant effects on behavior, but the nature of these changes has been inconsistent across studies. For example, DeFord et al. 10 reported that multiple mild impacts ...

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Section: Discussionmentioning

confidence: 99%

Multiple Episodes of Mild Traumatic Brain Injury Result in Impaired Cognitive Performance in Mice

Creeley¹,

Wozniak²,

Bayly³

et al. 2004

Acad Emergency Med

View full text Add to dashboard Cite

show abstract

“…Furthermore, these associations remained strong after accounting for the competing risk of death, and there was evidence of an additive association between TBI and other dementia risk factors. Prior studies on the association between head injury and risk of dementia in the general population have been mixed, with some studies suggesting an increased risk 6,12,14 or earlier onset 5,10 and others suggesting no association. 2,3,8 Still others have found that the association between TBI and dementia is restricted to those positive for the APOE e4 allele 7,13 or is stronger in men.…”

Section: Traumatic Brain Injurymentioning

confidence: 99%

“…1 However, prior research on the relationship between TBI and risk of Alzheimer disease (AD) and all-cause dementia has been mixed. [2][3][4][5][6][7][8][9][10][11][12][13][14] Most prior studies have not adequately controlled for potential confounders, such as medical and psychiatric comorbidities, and none have considered death as a competing risk.…”

mentioning

confidence: 99%

Traumatic brain injury and risk of dementia in older veterans

et al. 2014

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Objectives: Traumatic brain injury (TBI) is common in military personnel, and there is growing concern about the long-term effects of TBI on the brain; however, few studies have examined the association between TBI and risk of dementia in veterans.Methods: We performed a retrospective cohort study of 188,764 US veterans aged 55 years or older who had at least one inpatient or outpatient visit during both the baseline (2000)(2001)(2002)(2003) and follow-up (2003-2012) periods and did not have a dementia diagnosis at baseline. TBI and dementia diagnoses were determined using ICD-9 codes in electronic medical records. Fine-Gray proportional hazards models were used to determine whether TBI was associated with greater risk of incident dementia, accounting for the competing risk of death and adjusting for demographics, medical comorbidities, and psychiatric disorders.Results: Veterans were a mean age of 68 years at baseline. During the 9-year follow-up period, 16% of those with TBI developed dementia compared with 10% of those without TBI (adjusted hazard ratio, 1.57; 95% confidence interval: 1.35-1.83). There was evidence of an additive association between TBI and other conditions on risk of dementia.Conclusions: TBI in older veterans was associated with a 60% increase in the risk of developing dementia over 9 years after accounting for competing risks and potential confounders. Our results suggest that TBI in older veterans may predispose toward development of symptomatic dementia and raise concern about the potential long-term consequences of TBI in younger veterans and civilians. There is growing evidence that traumatic brain injury (TBI) is associated with a variety of shortand long-term adverse health outcomes. A 2008 Institute of Medicine report concluded that TBIs are consistently associated with an increased risk of unprovoked seizures, premature mortality, and neurocognitive deficits in the affected region, with evidence strongest for penetrating wounds and severe or moderate TBIs.1 However, prior research on the relationship between TBI and risk of Alzheimer disease (AD) and all-cause dementia has been mixed. [2][3][4][5][6][7][8][9][10][11][12][13][14] Most prior studies have not adequately controlled for potential confounders, such as medical and psychiatric comorbidities, and none have considered death as a competing risk.Furthermore, to our knowledge, only one prior study has specifically focused on examining the relationship between TBI and risk of dementia in veterans.11 Many veterans have other combatrelated risk factors such as posttraumatic stress disorder (PTSD) and depression, which have been associated with an increased risk of dementia in veterans in prior studies, 15,16 and could act as either confounders or effect modifiers of the association between TBI and dementia in veterans.

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“…This finding was supported by research following up head injured World War II veterans (Plassman et al 2000). TBI may reduce the time to onset of Alzheimer's disease amongst those at risk of developing the disease (Nemetz et al 1999). Epidemiological studies and human autopsy data in small cohorts of patients with TBI and Alzheimer's disease indicate an increased risk of dementia after severe TBI compared with the general population (Jellinger, 2004).…”

Section: Aetiologymentioning

confidence: 87%