Traumatic brain injury is associated with subsequent neurologic and psychiatric disease: a meta-analysis

Abstract

INTRODUCTION

Since the 1928 description of the “punch drunk” condition,⁴⁸ there has been speculation about a connection between traumatic brain injury (TBI) and late-life neurologic or psychiatric illness. Though this syndrome was later referred to as “dementia pugilistica” because it was thought to uniquely affect boxers,¹⁴ an accumulation of cases in recent years have suggested that repeated brain injury in other sports such as football, soccer, and wrestling might also predispose to neurodegenerative disease⁵² and that non-sports-related TBI, such as that sustained on the battlefield, can lead to this same illness.³⁰ It has recently been proposed that a history of even minor brain injury may predispose certain individuals to develop this pathologic process, now referred to as “chronic traumatic encephalopathy” or CTE⁵². The presentation of CTE is variable and may include neurologic and/or psychiatric manifestations. The current CTE literature suggests two common syndromes: a behavior and mood predominant illness, frequently accompanied by paranoia, which would be diagnosed as psychiatric illness and a predominantly cognitive disorder that is frequently diagnosed as Alzheimer’s disease ⁸². A third syndrome, which was emphasized by the prior literature on boxers includes motor dysfunction with parkinsonism¹⁴. Some CTE cases have also been described with motor neuron disease^{53, 54}. Epidemiological study of CTE has been significantly limited since it is a pathological, rather than clinical diagnosis, and its presence can only be definitively confirmed after death. There is accumulating evidence, however, that CTE may be a pathologic process that unites seemingly disparate clinical syndromes and reflects a shared vulnerability to cognitive-behavioral-motor dysfunction. Recent studies have found support for a relationship between TBI and risk for later development of these individual neurologic and psychiatric syndromes. Since James Parkinson himself theorized a causative link to trauma in 1817, there has been continuing debate regarding the relationship between TBI and Parkinson’s disease,¹⁹ with many^{17, 29, 87} but not all^{3, 43, 49} studies finding a positive association. Epidemiological studies investigating the risk of Alzheimer’s disease after TBI have also shown mixed results. Meta-analyses of these studies in 1991⁵⁸ and in 2003²⁴ have shown an elevated risk. Prior TBI has also been associated with a significantly elevated risk of frontotemporal dementia⁷⁰ and although a prior meta-analysis of the risk of TBI on development of amyotrophic lateral sclerosis (ALS) showed a mildly elevated risk,¹¹ others have disputed the connection.⁹³ Although psychiatric symptoms (e.g., depression and anxiety) are common acutely after TBI,^{6, 35, 40} whether there are protracted psychiatric sequelae from earlier-life TBI remains poorly understood.⁹⁶

Our aim was to determine the association of mild TBI with the later development of those neurologic and psychiatric illnesses that have previously been linked to TBI and are potential manifestations of CTE. To investigate the wide range of disorders associated with prior TBI, we reviewed the literature examining TBI and subsequent neurologic or psychiatric diagnoses and performed a meta-analysis according to current guidelines^{56, 84}. Consistent with the notion that mild TBI may make certain individuals vulnerable to a number of neurologic and psychiatric conditions, we hypothesized that there would be an association between all diagnoses and a history of TBI, including mild TBI.

METHODS

Identification of the studies

Searches were conducted in Medline (1995 to February 2012) using a comprehensive search strategy. We used two components in each search: component A identified papers with keywords “craniocerebral trauma,” “head injury,” “brain injury,” or “concussion.” This was combined with component B or component C. Component B identified papers pertaining to the neurologic disorders of interest (i.e., “neurodegenerative diseases," "mild cognitive impairment," "Alzheimer," "Parkinson," "frontotemporal dementia," "amyotrophic lateral sclerosis," "vascular dementia," or "dementia"), and component C identified papers pertaining to the psychiatric illnesses of interest (i.e., "anxiety disorders," "mood disorders," or "schizophrenia and disorders with psychotic features"). We limited our search to papers in English and humans.

Three additional steps were taken to ensure search comprehensiveness: (1) references from included papers were reviewed, (2) to avoid any bias toward positive results inherent in the search strategy an additional search for “risk factors” for each diagnosis was performed to capture studies with weak or null findings that did not include our search terms in their title, abstract or keywords, (3) the citation lists in review papers were examined. For papers in which the required metrics were not easily identified the authors were contacted. A pair of reviewers (a neurologist and a neuropsychologist) discussed all papers at each stage of the process (Figure 1). Concordance between the reviewers for determining study inclusion was high; in cases of disagreement, studies were discussed until a consensus decision was reached. Ethics committee approval was not needed for this study as it included only analysis of previously published data.

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Figure 1

Flow chart depicting study identification and screening

RESULTS

57 papers met narrow inclusion criteria and were used in the meta-analyses.^{3, 11, 17, 29, 43, 49, 70, 87 1, 2, 5, 7, 8, 9, 15, 16, 20, 22, 25, 27, 31, 32, 33, 37, 45, 47, 51, 55, 57, 60, 61, 62, 63, 64, 65, 67, 68, 69, 71, 72, 73, 74, 75, 76, 79, 80, 81, 85, 86, 90, 91, 92, 93, 94, 95, 97, 98} Among the included papers, a sufficient number were found to apply meta-analytic methods for the diagnoses of dementia, Alzheimer’s disease, Parkinson’s disease, ALS, mild cognitive impairment, depression, psychotic disorders, bipolar disorder, and mixed affective disorder (a combined group of depression and anxiety). Insufficient numbers of studies were found to calculate a pooled OR for frontotemporal dementia, vascular dementia, or anxiety disorders. There was significant heterogeneity among studies (Q = 381.99, df = 58, p<.001), justifying the use of the random effects meta-analysis.

Prior TBI was associated with development of any of the neurologic and psychiatric illnesses of interest [OR 1.67 (95% CI 1.44–1.93), p<.0001]. This association was found for both neurologic [OR 1.55 (95% CI 1.31–1.83, p<.0001)] and psychiatric [OR 2.00 (95% CI 1.50–2.66, p<.0001)] disease in individuals with TBI, and was also found in the following diagnoses: Alzheimer’s disease [OR 1.40 (95% CI 1.02–1.90, p<.05)], Parkinson’s disease [OR 1.45 (95% CI 1.18–1.78, p<.001)], mild cognitive impairment [OR 2.69 (95% CI 1.51–4.77, p<.001)], depression [OR 2.14 (95% CI 1.65–2.77, p<.0001)], bipolar disorder [OR 1.85 (95% CI 1.17–2.94, p<.01)], and mixed affective disorder [OR 1.84 (95% CI 1.50–2.66, p<.0001)]. See Table 1 and Figure 2.

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Figure 2

Individual and pooled odds ratios for all included studies (to be aligned with Table 1).

Analyses of subgroups revealed a robust relationship between TBI and remote neurologic and psychiatric outcomes. The studies included in each subgroup analysis are specified in Table 1. Table 2 includes the features reported in each study regarding the time interval between TBI and diagnosis, the TBI features and severity, and the study design. Results of the subgroup analyses are reported in Table 3. Overall odds and the independent OR for neurologic, but not psychiatric disease remained significant when only including studies with the clearest greater than 12-month interval between TBI and diagnosis (Subgroup 1). The overall OR was significant among those studies that adhered to mild TBI criteria limiting duration of loss of consciousness to less than 30 minutes (Subgroup 2). The overall OR and OR for any of the studied neurologic and psychiatric diagnoses were also significant when only including studies that required loss of consciousness (Subgroup 3). When including studies that required the presence of at least one mild TBI symptom (Subgroup 4), the overall OR and OR for any of the neurologic and all psychiatric diagnoses of interest remained significant. After eliminating the studies with TBI diagnoses based on self-report (Subgroup 5), the overall OR and OR for neurologic disorders remained significant, though the OR for psychiatric outcomes no longer reached significance. When only cohort studies were included (Subgroup 6), the OR for neurologic outcomes was not significant though the overall OR and OR for psychiatric illness remained significant. The odds were not higher among those that reported more than one TBI compared to those with a single injury (Subgroup 7).

Publication bias analyses did not show evidence of bias in the included studies. Visual inspection of a funnel plot based on sample size showed that three studies with large samples strongly influenced the appearance (Figure 3A). When these studies are removed a more expected funnel shape is appreciated (Figure 3B). Regression indicates that the effects size (the logarithm of the OR) is not significantly predicted by the standard error when all studies are included (F(1,60)=3.08, p=.08) or when the three large sample studies are excluded (F(1,57)=1.11, p=.30, Figure 3C).

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Figure 3

Publication bias analysis. (A) Funnel plot of OR versus total sample size. (B) Funnel plot of OR versus total sample size after excluding the three studies with largest sample sizes (Rugbjerg 2008, Nielson 2001, and Turner 2010). (C) Plot of the logarithm of the OR after excluding the three largest sample size studies compared to the standard error of the logarithm of the OR showing a regression line and 95% confidence interval with slope that is not statistically significantly different from 0.

DISCUSSION

This meta-analysis supports an association between prior TBI and later diagnosis of the relevant neurologic or psychiatric diseases. This association was found independently for both neurologic and psychiatric outcomes. Alzheimer’s disease, Parkinson’s disease, mild cognitive impairment, depression, mixed affective disorders, and bipolar disorder showed a statistically significant association with prior TBI. The magnitude of effect is comparable across diagnoses, with mild cognitive impairment, depression, and bipolar disorder having the highest OR among those results that reached significance. The OR of Alzheimer’s disease in this analysis is comparable to the findings of prior meta-analyses.^{24, 58} The OR of ALS was among the highest in the study, and there was some evidence of an association of TBI with dementia and psychotic disorders, but these did not reach statistical significance.

The overall combined OR for the selected neurologic and psychiatric illnesses and for neurologic illness independently in individuals with TBI remained significant when including only articles that explicitly specified a minimum 12-month interval between TBI and outcome diagnosis. The magnitude of association with psychiatric illness, however, did not remain significant. These results suggest that there may be a different time course in which psychiatric and neurologic symptoms manifest after TBI. While psychiatric symptoms are common in the acute phase after mild TBI^{6, 21, 35, 40} and some of these may be short-lived manifestations of the injury, others may reflect a more sustained susceptibility to mental illness. The results of this study suggest that TBI is a risk factor for both remote psychiatric and neurologic disease and are consistent with the possibility that both types of illness arise secondary to a common shared pathologic mechanism.

We conducted additional subgroup analyses to determine whether TBI characteristics or methodological factors would influence our findings. The overall OR of TBI remained significant when including only studies that required adherence to typical loss of consciousness criteria for mild TBI, the presence of any specific mild TBI symptom, or loss of consciousness. Though TBI definitions varied widely among studies, these additional analyses support an association of mild TBI with the studied neurologic and psychiatric outcomes. A significant OR for combined neurologic and psychiatric outcomes was also found when eliminating studies that used self-reported diagnosis of TBI and when including only cohort studies. Though statistical significance was lost when assessing the association with psychiatric outcomes when eliminating self-report and the odds of neurologic outcomes among cohort studies, the magnitudes of the ORs were largely consistent with the main analysis, and the change in significance is likely due to the small number of articles in these analyses and resulting loss of power rather than reflecting a weaker association due to recall bias, though this cannot be excluded. Our analyses also suggest that the finding of an association with TBI is unlikely to be due to publication bias, though low power may affect the publication bias test.

The results of this meta-analysis support an association of illness with a single TBI. A relevant associated question is whether this effect is compounded by multiple TBIs. In our analysis of multiple head traumas, the results do not show strong evidence for elevated odds of illness associated with having more than one head trauma compared to a single TBI. Given that only six studies were included in this analysis, lower power may have influenced these results. More research on the relationship between TBI exposure and diagnostic outcomes is needed.

The magnitude of the OR of TBI in this meta-analysis is relatively modest, but comparable to other strongly implicated risk factors. For example, for Alzheimer’s disease, the Apolipoprotein E e4 allele is associated with an OR of 1.80–9.05,⁴¹ and obesity with an OR of 1.80.⁴ The OR for pesticide exposure and Parkinson’s disease is 1.94.⁶⁶ Therefore, the presence of a risk factor in an individual does not indicate an inevitable development of disease. The ORs found in this study suggest that others factors modify an individual’s susceptibility to develop a neuropsychiatric disorder after TBI. These factors are largely unknown and worthy of further investigation.

The fact that multiple neurodegenerative and psychiatric diagnoses are associated with the same exposure raises questions about possible mechanisms of shared vulnerability. Trauma could predispose the brain to different types of neurodegeneration through common mechanisms such as oxidative stress and microglial activation^{77, 99} or induction of plasma proteins associated with degeneration such as MCP-1.³⁶ Trauma might also activate molecular pathways leading to specific degenerative diseases, such as the finding that Alzheimer’s disease-associated proteins including beta amyloid, beta secretase, presenilin-1, and caspase-3 accumulate in axons of brain injured animals.¹² Cleaved forms of the tau protein, which is associated with Alzheimer’s disease and frontotemporal lobar degeneration, accumulate after trauma²⁶ and tau abnormalities after trauma have been found to be independent of beta amyloid effects.⁸⁹ The nature of the TBI could also influence the clinical presentation in an individual. For example, boxers may suffer from more torsional injury that could injury brainstem structures such as the substantia nigra, leading to parkinsonism⁸². Genetic variation could also help to explain the susceptibility of individuals to late-life effects of TBI. For example, apolipoprotein E, which is associated with risk of Alzheimer’s disease, has shown a variable interaction with mild TBI.^{50, 63, 88}

An alternate explanation for the association across diagnostic groups is that the various clinical presentations could be different expressions of a common pathology^{28, 78}. Although CTE has been described as a distinct pathological process, the clinical characterization is not clearly established, and case reports suggest cognitive, motor, and psychiatric presentations. This phenotypic variability could lead to a diagnosis of dementia, Parkinson’s disease, motor neuron disease, or primary psychiatric illness in different individuals. A study of causes of death among retired National Football League players found a three-fold higher rate of dying from neurodegenerative disease compared to the typical population frequency, with Alzheimer’s disease and ALS being the most overrepresented⁴⁴, which would be consistent either a shared vulnerability hypothesis across neurodegenerative diseases or a common pathology. This meta-analysis examined clinical, not pathological, studies. Thus, it is unknown whether any of the subjects would have shown characteristic CTE pathology rather than (or in addition to) the more typical neuropathological features associated with their syndromes.

Among the articles that were reviewed, several addressed the association between TBI and clinical outcomes among athletes. These articles assessed the risk of Parkinson’s disease among retired Thai traditional boxers,⁴⁶ depression and dementia among retired football players,^{32, 33} ALS or chronic encephalopathy among soccer players,^{13, 39} and chronic TBI in boxers.³⁸ Only two of the articles^{32, 33} that directly evaluated TBI in sports met strict inclusion criteria for this study. The ability of this meta-analysis to inform the questions surrounding the long-term consequences of sports-related mild TBI is therefore limited by this lack in the existing literature. Further longitudinal studies among athletes with appropriate control groups, characterization of head injuries (including severity, number, and exposure to repetitive subconcussive trauma), and assessment of late-life neurologic and psychiatric outcomes will be needed to address this question.

Several limitations of this meta-analysis warrant consideration. One is the possible bias of the included studies. We took several steps to mitigate this possibility. Our search strategy included a variety of epidemiological studies that focused on many possible risk factors, not just TBI, thereby capturing negative studies that might otherwise have not been published. Our formal analyses also did not support publication bias. Although the strict inclusion criteria should reduce this possibility, variation in the studies themselves (e.g., different criteria for diagnosis of illness, or co-morbid environmental and genetic factors of the study population) limits the generalizability of the results. Variable study quality could also have resulted in heterogeneity, and it is possible that the presence of other confounding factors could have led to the observed association between TBI and later clinical outcomes. For example, patients who sustain a TBI as a result of a fall or motor vehicle accident may have other medical comorbidities (e.g., vascular disease or substance abuse) or differences in socioeconomic status that could predispose to neurologic or psychiatric illness. Another possibility is that the TBI itself could lead to injury of change in lifestyle that could modify risk of a mood disorder. Finally, ill patients who fall and suffer TBI may also undergo more medical testing and therefore be more likely to receive one of these neurologic or psychiatric diagnoses. Only English language studies were reviewed, which could have led to exclusion of some relevant studies. In spite of our criteria regarding an interval between TBI and illness onset, an alternative explanation for the observed association is that some head injuries may have been early manifestations of neurologic or psychiatric disease rather than an independent predisposing factor for illness. The authors of one of the studies concluded this reverse causality was responsible for their findings. They stratified the interval between TBI and diagnosis and found the association between TBI and Parkinson’s was no longer present when only looking at TBI that occurred greater than 10 years prior to diagnosis⁷¹.

A major strength of this meta-analysis was the inclusion of a variety of different neurologic and psychiatric outcomes rather than a single diagnosis. By focusing on diagnoses rather than self-reported symptoms or performance on cognitive tests, this study assessed outcomes of sufficient magnitude to affect quality of life. The included studies also come from countries around the world, allowing for more generalizable results. The literature search was comprehensive, making this a rigorous examination of the topic.

CONCLUSIONS

This study supports an association of TBI, including mild TBI, on subsequent development of neurologic and psychiatric illness, including Alzheimer’s disease, Parkinson’s disease, mild cognitive impairment, depression, mixed affective disorders, and bipolar disorder. Due to limitations and heterogeneity in the existing studies, prospective studies with uniform assessment will be needed to confirm this result and determine the risk conferred by the number and severity of TBI in different settings, such as sports or the military.

Acknowledgments

Footnotes

REFERENCES