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 neurological 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 has suggested that repeated brain injury in other sports, such as football, soccer, and wrestling, might also predispose to neurodegenerative disease52 and that nonsports-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 can predispose certain individuals to develop this pathological process, now referred to as “chronic traumatic encephalopathy” (CTE).52 The presentation of CTE is variable and can include neurological and/or psychiatric manifestations. The current CTE literature suggests 2 common syndromes: a behavior- and mood-predominant illness frequently accompanied by paranoia, which would be diagnosed as a psychiatric illness, and a predominantly cognitive disorder that is frequently diagnosed as Alzheimer’s disease.82 A third syndrome, which was emphasized in the prior literature on boxers, includes motor dysfunction with parkinsonism.14 Some CTE cases have also been described with motor neuron disease.53,54 The epidemiological study of CTE has been significantly limited since it is a pathological rather than a clinical diagnosis and its presence can only be definitively confirmed after death. However, there is accumulating evidence that CTE may be a pathological 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 the risk for later development of these individual neurological 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 many17,29,87 but not all3,43,49 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 dementia,70 and although a prior meta-analysis of the relationship between prior TBI and the subsequent development of amyotrophic lateral sclerosis (ALS) showed a mildly elevated risk,11 others have disputed the connection.93 Although psychiatric symptoms (for example, 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 clarify the association between mild TBI and the later development of those neurological and psychiatric illnesses that have 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 neurological or psychiatric diagnoses and performed a meta-analysis according to current guidelines.56,84 Given the notion that mild TBI may make certain individuals vulnerable to a number of neurological 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 Studies
Searches were conducted in MEDLINE (January 1995 to February 2012) using a comprehensive search strategy. We used 2 components in each search: component A identified papers with the key words “craniocerebral trauma,” “head injury,” “brain injury,” or “concussion.” This was combined with component B or C. Component B identified papers pertaining to the neurological disorders of interest (that is, “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 (that is, “anxiety disorders,” “mood disorders,” or “schizophrenia and disorders with psychotic features”). We limited our search to papers in English and in 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 key words; and 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 (Fig. 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.
Flowchart depicting study identification and screening.
Broad Inclusion Criteria
We first applied broad inclusion criteria (developed by a team of expert neurologists, neurosurgeons, and neuropsychologists) to select papers for further review: original, peer-reviewed research articles (no case reports); subjects older than 18 years of age at the time of evaluation (not TBI); TBI without accompanying structural lesion (for example, subdural hematoma or penetrating brain injury; although our goal was to specifically examine the effect of mild TBI, to capture all pertinent studies at this search stage, we broadly included studies employing the various definitions and labels that are used to refer to minor head trauma, for example, concussion); neurological or psychiatric diagnosis; and TBI occurred before the diagnosis of the neurological or psychiatric disorder (with at least 12 months between the TBI and outcome diagnosis, if specified).
Narrow Inclusion Criteria
Papers that met the broad inclusion criteria were next reviewed in detail. In addition to ensuring adherence to the broad criteria, we confirmed that papers met the narrow inclusion criteria. If some subjects in a study were reported to have structural lesions, but they could be separated from those without lesions, we included only those subjects with mild TBI. The narrow inclusion criteria consisted of the following: 1) the presence of a neurological or psychiatric disorder. For neurological disorders, studies must have used consensus diagnostic criteria or clinical evaluation. For psychiatric disorders, diagnoses were based on either criteria (for example, those in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) or scores from standardized measures (for example, Beck Depression Inventory). 2) The study had a control group. Included studies were cross-sectional, cohort, or case-control studies in which all subjects underwent identical assessment and diagnostic procedures. 3) The TBI preceded the neurological or psychiatric diagnosis. We excluded studies in which the diagnosis of the neurological or psychiatric disorder had been made less than 12 months post-TBI. For studies in which the date of the TBI was not reported, we included only those whose subjects with neurological or psychiatric illness had been asked about TBI earlier in life. 4) There could be no redundant subjects across studies. In cases where multiple papers used the same study cohort, we included the most recent papers to capture the largest sample size. If multiple outcome diagnoses were reported in 1 paper, we included each odds ratio (OR) if the diagnoses were mutually exclusive. If the diagnoses were not mutually exclusive, in the analyses that examined the association of TBI with any neurological or psychiatric outcome, we chose the broader diagnosis (for example, dementia was preferred over Alzheimer’s disease), or if that distinction was not possible, we chose the diagnosis with the larger number of subjects.
Assessment of Study Characteristics
We recorded additional data regarding factors that could influence the relationship between TBI and outcome diagnoses, including 1) the rigor with which each study employed a 12-month TBI-outcome diagnosis interval; 2) the TBI characteristics required in each study (for example, whether subjects met accepted criteria for mild TBI or had any individual symptoms such as loss of consciousness [LOC]); 3) whether the TBI diagnosis was based on patient or informant self-report as opposed to being made by a clinician, derived from medical records, or based on diagnostic criteria; 4) the study design (cohort, case-control, or cross-sectional); and 5) whether information was provided about the number of TBIs sustained by each subject. These data were used in subgroup analyses geared toward assessing whether study characteristics influenced the meta-analysis results.
Statistical Analysis
Primary Analyses
The effect of interest for this meta-analysis was the pooled OR. For the majority of the studies (51 of 57), unadjusted ORs were directly calculated from data extraction. Standard errors were calculated from the logarithm of the OR to allow for symmetry of the estimate on both sides of unity.23 Where sample sizes were not available, the published unadjusted ORs were used. We then applied standard meta-analytical techniques,34 including weighted estimates of the pooled OR with a 95% confidence interval (CI). For those studies in which the raw cell frequencies did not exist and only the standard error of the OR was available, to provide appropriate weighting of the study in the meta-analysis, the standard error of the OR was transformed to the standard error of the logarithm of the OR by linear interpolation. To determine whether there was significant variation among studies, tests of heterogeneity were performed.34 All analyses were conducted using SAS version 9.3 (SAS Institute Inc.). A p value < 0.05 was significant.
Subgroup Analyses
Since the overall analysis was inclusive of various TBI definitions and study characteristics, we conducted 7 additional subgroup analyses to determine whether our results differed when pooling studies with more uniformity of TBI assessment, TBI diagnostic criteria, and study de sign. When possible, we selected only those subjects from the overall cohort who met the criteria for each subgroup analysis. Consequently, for some studies, a different number of subjects was included in the overall analysis compared with each subgroup analysis.
Subgroup 1: Effect of Time Interval Between TBI and Diagnosis
To ensure that studies with less stringent guidelines about the timing of TBI were not significantly impacting our results, in Subgroup 1 we excluded analyses in which the subjects had possibly less than a 12-month interval between TBI and a diagnosis.
Subgroups 2–4: Effect of TBI Features and Severity
Subgroup 2 included only studies that required an LOC not exceeding 30 minutes. This is the maximum duration established in the mild TBI criteria of the American Congress of Rehabilitation Medicine, Centers for Disease Control, and World Health Organization.10,42,59
Subgroup 3 included only studies that required brain injury with LOC. This subgroup considered the effect of TBI with a uniform minimum severity.
In Subgroup 4, to exclude extremely mild or asymptomatic brain injury, we performed an analysis of studies that required the brain injury to be accompanied by any 1 (or more than 1) common feature of mild TBI, including LOC, posttraumatic amnesia, Glasgow Coma Scale (GCS) score ≥ 13, focal neurological deficit, altered mental status, brain injury requiring medical care, or symptoms of the postconcussive syndrome (for example, headache, dizziness, nausea, photo- or phonophobia, fatigue, sleep difficulty, blurred vision).
Subgroups 5–6: Effect of Study Design
In Subgroup 5, to assess the impact of recall bias, we conducted an analysis excluding studies with self-reported TBI. In Subgroup 6, to eliminate recall bias, we also performed an analysis of only cohort studies (rather than cross-sectional or case-control studies).
Subgroup 7: Effect of Number of TBIs
Because we were also interested in whether there is a dose effect of TBI on the development of later illness, in Subgroup 7 we calculated the odds of a neurological or psychiatric diagnosis in subjects with more than 1 versus a single TBI using a subset of studies that provided this information.
Publication Bias Analysis
To assess for the effect of publication bias on our results, we used the Egger method18 to examine whether the logarithm of the included ORs were predicted by the standard error, which reflects the sample size. We visually examined funnel plots of ORs against sample size and the logarithm of the ORs against the standard error of the logarithm of the ORs and quantified the degree of bias by multiple regressions. Using standard error rather than sample size in funnel plots may provide a more accurate visual depiction of whether bias is present.83
Results
Fifty-seven papers met the narrow inclusion criteria and were used in the meta-analysis.1‑3,5,7‑9,11,15‑17,20,22,25,27,29,31‑33,37,43,45,47,49,51,55,57,60‑65,67‑76,79‑81,85‑87,90‑95,97,98 Among the included papers, a sufficient number were found to apply meta-analytical 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 < 0.001), justifying the use of the random-effects meta-analysis.
Prior TBI was associated with the development of any of the neurological and psychiatric illnesses of interest (OR 1.67, 95% CI 1.44–1.93, p < 0.0001). This association was found for both neurological (OR 1.55, 95% CI 1.31–1.83, p < 0.0001) and psychiatric (OR 2.00, 95% CI 1.50–2.66, p < 0.0001) diseases in individuals with TBI and was also found for the following diagnoses: Alzheimer’s disease (OR 1.40, 95% CI 1.02–1.90, p < 0.05), Parkinson’s disease (OR 1.45, 95% CI 1.18–1.78, p < 0.001), mild cognitive impairment (OR 2.69, 95% CI 1.51–4.77, p < 0.001), depression (OR 2.14, 95% CI 1.65–2.77, p < 0.0001), bipolar disorder (OR 1.85, 95% CI 1.17–2.94, p < 0.01), and mixed affective disorder (OR 1.84, 95% CI 1.50–2.66, p < 0.0001; Table 1 and Fig. 2).
Individual and pooled ORs for all included studies. Figure is available in color online only.
Individual and pooled ORs for all included studies
| Authors & Year | Cases (no. w/ TBI/no. w/o TBI) | Controls (no. w/ TBI/no. w/o TBI) | OR | 95% CI |
|---|---|---|---|---|
| Neurological diagnosis | ||||
| Dementia | ||||
| Salib 1997b,c,d,e | 96/266 | 23/153 | 2.40 | 1.46–3.95 |
| Schofield 1997b,e,g | 6/41 | 21/198 | 1.38 | 0.52–3.61 |
| Mehta 1999d,e,g | 11/118 | 788/5728 | 0.68 | 0.36–1.26 |
| Plassman 2000b,e,f,g | 28/26 | 520/1202 | 2.49 | 1.45–4.29 |
| Sundström 2007b,e,h | 25/156 | 46/316 | 1.10 | 0.65–1.86 |
| Smith 2010e | 31/14 | 154/164 | 2.36 | 1.21–4.60 |
| Tripathi 2012e | 22/128 | 35/115 | 0.56 | 0.31–1.02 |
| Pooled OR | 1.36 | 0.84–2.19 | ||
| Alzheimer’s disease | ||||
| Forster 1995b | 25/84 | 22/87 | 1.18 | 0.62–2.25 |
| Rasmusson 1995b,d,e | 20/48 | 1/33 | 13.75 | 1.76–107.53 |
| Salib 1997a | 53/145 | 23/153 | 2.43 | 1.42–4.17 |
| Schofield 1997a | 4/34 | 23/205 | 1.05 | 0.34–3.22 |
| Tsolaki 1997 | 14/47 | 15/54 | 1.07 | 0.47–2.45 |
| O’Meara 1997b,e | 32/317 | 16/326 | 2.06 | 1.11–3.82 |
| Boston 1999 | 30/192 | 23/117 | 0.79 | 0.44–1.43 |
| Mehta 1999a | 6/85 | 788/5728 | 0.51 | 0.22–1.18 |
| Guo 2000e | 394/1782 | 127/2313 | 4.03 | 3.27–4.96 |
| Plassman 2000a | 17/18 | 520/1202 | 2.18 | 1.12–4.27 |
| Tyas 2000 | 203/821 | 93/605 | 1.61 | 1.23–2.10 |
| Lindsay 2002g | 28/151 | 603/2963 | 0.91 | 0.60–1.38 |
| Bachman 2003e | 397/1538 | 84/760 | 2.34 | 1.82–3.00 |
| Guskiewicz 2005e | 15/7 | 1148/732 | 1.37 | 0.56–3.37 |
| Ogunniyi Nigeria 2006g | 2/60 | 11/450 | 1.36 | 0.30–6.30 |
| Ogunniyi USA 2006g | 5/84 | 37/344 | 0.55 | 0.21–1.45 |
| Rippon 2006e | 72/78 | 648/700 | 1.00 | 0.71–1.40 |
| Suhanov 2006d,e | 46/214 | 30/230 | 1.65 | 1.00–2.71 |
| Fischer 2008g | 4/86 | 37/352 | 0.44 | 0.15–1.27 |
| Pooled OR | 1.40 | 1.02–1.90 | ||
| Parkinson’s disease | ||||
| Martyn 1995e | 11/156 | 35/301 | 0.61 | 0.30–1.23 |
| De Michele 1996d,e | 13/103 | 3/113 | 4.75 | 1.32–17.16 |
| Seidler 1996e | NA | NA | 1.40 | 0.85–2.30 |
| McCann 1998d,e | NA | NA | 1.10 | 0.64–1.90 |
| Smargiassi 1998d,e | 13/73 | 5/81 | 2.88 | 0.98–8.49 |
| Kuopio 1999d,e,h | 39/84 | 84/162 | 0.90 | 0.56–1.42 |
| Taylor 1999b,e | 35/105 | 11/136 | 4.12 | 2.00–8.50 |
| Werneck 1999 | 17/75 | 14/96 | 1.55 | 0.72–3.35 |
| Tsai 2002b,e | 11/19 | 5/25 | 2.89 | 0.86–9.75 |
| Baldereschi 2003d,e,g | 8/105 | 403/3980 | 0.75 | 0.36–1.56 |
| Bower 2003b,c,e,f | 2/183 | 2/193 | 1.05 | 0.15–7.57 |
| Goldman 2006b,c,e,h | 20/73 | 9/84 | 2.56 | 1.10–5.96 |
| Dick 2007d,e | NA | NA | 1.30 | 1.09–1.55 |
| Rugbjerg 2008b,e,f | 409/13, 194 | 1513/66, 792 | 1.37 | 1.22–1.53 |
| Sanyal 2010 | 27/148 | 25/325 | 2.37 | 1.33–4.23 |
| Pooled OR | 1.45 | 1.18–1.78 | ||
| Amyotrophic lateral sclerosis | ||||
| Chen 2007b,e,h | 24/85 | 42/213 | 1.43 | 0.82–2.51 |
| Binazzi 2009b | 16/61 | 23/162 | 1.85 | 0.91–3.73 |
| Schmidt 2010b,e,h | 84/157 | 185/412 | 1.19 | 0.87–1.64 |
| Turner 2010b,e,f,g | 41/34 | 106, 552/511, 831 | 5.79 | 3.68–9.13 |
| Pooled OR | 2.07 | 0.94–4.56 | ||
| Frontotemporal dementia | ||||
| Rosso 2003b,e | 19/61 | 10/114 | 3.55 | 1.55–8.11 |
| Vascular dementia | ||||
| Boston 1999 | 3/31 | 23/117 | 0.49 | 0.14–1.75 |
| Mild cognitive impairment | ||||
| Guskiewicz 2005e | 19/3 | 450/286 | 4.03 | 1.18–13.73 |
| Unverzagt 2011g | NA | NA | 2.40 | 1.34–4.30 |
| Pooled OR | 2.69 | 1.51–4.77 | ||
| Pooled OR, neurological | 1.55 | 1.31–1.83 | ||
| Psychiatric diagnosis | ||||
| Depression | ||||
| Malaspina 2001 | 107/661 | 22/355 | 2.61 | 1.62–4.21 |
| Polusny 2001b,c,e,g | NA | NA | 1.47 | 1.10–1.97 |
| Silver 2001e | 40/243 | 321/4430 | 2.27 | 1.60–3.23 |
| Holsinger 2002b,c,e,f,g | 96/160 | 387/974 | 1.51 | 1.14–2.00 |
| Guskiewicz 2007e | 206/63 | 1272/893 | 2.30 | 1.71–3.08 |
| Gao 2009 | 38/497 | 28/1174 | 3.21 | 1.95–5.28 |
| Mollica 2009d,e | 10/3 | 6/23 | 12.78 | 2.65–61.56 |
| Rajkumar 2009d,e | 19/108 | 33/840 | 4.48 | 2.46–8.15 |
| Vanderploeg 2009b,e,g | 36/43 | 242/505 | 1.75 | 1.09–2.79 |
| Bryant 2010b,c,e,f,g | 56/265 | 77/419 | 1.15 | 0.79–1.68 |
| Pooled OR | 2.14 | 1.65–2.77 | ||
| Psychotic disorder | ||||
| Malaspina 2001 | 22/107 | 22/355 | 3.32 | 1.77–6.23 |
| Nielsen 2002b,e,f | 278/7854 | 3394/78, 710 | 0.82 | 0.72–0.93 |
| Silver 2001a | 12/89 | 349/4584 | 1.77 | 0.96–3.27 |
| AbdelMalik 2003b | 23/44 | 22/80 | 1.90 | 0.95–3.79 |
| Fann 2004a | NA | NA | 1.10 | 0.39–3.10 |
| Pooled OR | 1.57 | 0.83–2.97 | ||
| Bipolar disorder | ||||
| DelBello 1999b,c,d,e,g | 4/17 | 3/13 | 1.02 | 0.19–5.37 |
| Malaspina 2001 | 28/207 | 22/355 | 2.18 | 1.22–3.91 |
| Silver 2001a | 6/51 | 355/4622 | 1.53 | 0.65–3.59 |
| Pooled OR | 1.85 | 1.17–2.94 | ||
| Mixed affective disorder | ||||
| Fann 2004b,f,g | NA | NA | 1.50 | 0.98–2.30 |
| Nelson 2007b | 76/248 | 318/2045 | 1.97 | 1.49–2.62 |
| Pooled OR | 1.84 | 1.44–2.36 | ||
| Pooled OR, psychiatric | 2.00 | 1.50–2.66 | ||
| Overall pooled OR | 1.67 | 1.44–1.93 | ||
NA = data not available.
aStudies not included in the overall analysis or pooled neurological/psychiatric analyses because diagnostic groups within the study were not mutually exclusive. Studies included in subgroup analyses
bthose with the clearest interval between TBI and symptom onset
cthose meeting mild TBI criteria for LOC
dthose requiring LOC
ethose requiring at least 1 mild TBI feature
fthose with TBI diagnoses not based on self-reports
gcohort studies, and
hthose analyzing the risk of repeated TBI.
Analyses of subgroups revealed a robust relationship between TBI and remote neurological 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 ORs for neurological, but not psychiatric, disease remained significant when including only studies with the clearest interval longer than 12 months between TBI and diagnosis (Subgroup 1). The overall OR was significant among studies that adhered to mild TBI criteria limiting the duration of LOC to less than 30 minutes (Subgroup 2). The overall OR and the ORs for any of the studied neurological and psychiatric diagnoses were also significant when including only studies that required LOC (Subgroup 3). When including studies that required the presence of at least 1 mild TBI symptom (Subgroup 4), the overall OR and the OR for any of the neurological and all psychiatric diagnoses of interest remained significant. After eliminating studies with TBI diagnoses based on self-reports (Subgroup 5), the overall OR and the OR for neurological disorders remained significant, although the OR for psychiatric outcomes no longer reached significance. When only cohort studies were included (Subgroup 6), the OR for neurological outcomes was not significant, although the overall OR and the OR for psychiatric illness remained significant. The odds were not higher among studies that reported more than 1 TBI versus those with a single injury (Subgroup 7).
Summary of study and TBI features for each included study
| Authors & Year | Study Design | Mean Age at Head Injury (yrs) | Mean Interval Btwn Injury & Diagnosis | Required TBI Characteristics | Additional TBI Information |
|---|---|---|---|---|---|
| Neurological diagnosis | |||||
| Dementia | |||||
| Salib 1997 | Case-control | 7.3 yrs | None given | Grouped as w/ or w/o LOC | |
| Schofield 1997 | Cohort | LOC or PTA | |||
| Mehta 1999 | Cohort | Grouped | LOC | Grouped by LOC ≤ or >15 min | |
| Plassman 2000 | Cohort | MC & LOC or PTA or non-displaced skull fracture | Excluded if penetrated dura or resulted in significant sequelae 3 mos after TBI; severity ranked w/ mild group having LOC or PTA <30 min & no skull fracture | ||
| Sundström 2007 | Case-control | ≥5yrs | MC | ||
| Smith 2010 | Cross-sectional | None given | |||
| Tripathi 2012 | Case-control | LOC or PTA or a symptom of PCS | |||
| Alzheimer’s disease | |||||
| Forster 1995 | Case-control | Grouped (adulthood or childhood) | None given | ||
| Rasmusson 1995 | Case-control | 27.2 in sporadic Alzheimer’s group, 45.2 in familial Alzheimer’s group | >5 yrs (mean 33.4 yrs in sporadic Alzheimer’s group, 18.67 yrs in familial Alzheimer’s group) | None given | Excluded if head injury resulted in “immediate, permanent cognitive or functional impairment”; head injury w/ LOC reported separately; distinction made btwn mild & severe but not defined |
| Salib 1997 | Case-control | 7.9 yrs | None given | Grouped as w/ or w/o LOC | |
| Schofield 1997 | Cohort | 14.5 yrs | LOCorPTA | ||
| Tsolaki 1997 | Case-control | None given | |||
| O’Meara 1997 | Case-control | 46 (range 10–85) | 34 yrs (range 1–72 yrs) | MC or LOC | |
| Boston 1999 | Case-control | None given | |||
| Mehta 1999 | Cohort | Grouped | LOC | Grouped by LOC ≤ or > 15 min | |
| Guo 2000 | Case-control | MC or LOC | |||
| Plassman 2000 | Cohort | MC & LOC or PTA or non-displaced skull fracture | Excluded if penetrated dura or resulted in significant sequelae 3 mos after TBI; severity ranked w/ mild group having LOC or PTA <30 min & no skull fracture | ||
| Tyas 2000 | Cross-sectional | None given | |||
| Lindsay 2002 | Cohort | None given | Both w/& w/o LOC | ||
| Bachman 2003 | Case-control | MC | |||
| Guskiewicz 2005 | Cross-sectional | AMS & 1 symptom of PCS | |||
| Ogunniyi Nigeria 2006 | Cohort | None given | |||
| Ogunniyi USA 2006 | Cohort | None given | |||
| Rippon 2006 | Cross-sectional | LOCorPTA | |||
| Suhanov 2006 | Case-control | LOC | |||
| Fischer 2008 | Cohort | None given | |||
| Parkinson’s disease | |||||
| Martyn 1995 | Case-control | LOC or MC | |||
| De Michele 1996 | Case-control | LOC | |||
| Seidler 1996 | Case-control | PTA or PCS | |||
| McCann 1998 | Case-control | LOC | |||
| Smargiassi 1998 | Case-control | LOC | |||
| Kuopio 1999 | Case-control | None given | Records number w/ & w/o LOC & duration of LOC < or ≥ 5 min | ||
| Taylor 1999 | Case-control | 16.3 | 36.5 yrs | LOC or AMS or ND or PCS | |
| Werneck 1999 | Case-control | None given | |||
| Tsai 2002 | Case-control | 18.5 | 17.2 yrs | LOC or PTA or PCS or ND | |
| Baldereschi 2003 | Cohort | LOC | |||
| Bower 2003 | Case-control | >3 yrs (range 3–55 yrs, median 29 yrs for TBI of all severities in study) | PTA | Excluded from this group if LOC >1 min, PTA >30 min, or imaging abnormal; mild TBI w/ LOC, moderate, and severe TBI analyzed separately | |
| Goldman 2006 | Case-control | 25.7 | 36.9 yrs (range 2–70 yrs), separate analysis of only those w/>10 yrs | LOC or PTA | |
| Dick 2007 | Case-control | LOC | |||
| Rugbjerg 2008 | Case-control | Grouped, >1 yr data used | MC | Excluded if imaging abnormal | |
| Sanyal 2010 | Case-control | None given | |||
| ALS | |||||
| Chen 2007 | Case-control | Grouped | Grouped | MC | |
| Binazzi 2009 | Case-control | Grouped | Grouped | None given | |
| Schmidt 2010 | Case-control | Grouped | Grouped (2−80+ yrs) | LOCorMC | |
| Turner 2010 | Cohort | MC | |||
| Frontotemporal dementia | |||||
| Rosso 2003 | Case-control | PCS or LOC or PTA | |||
| Vascular dementia | |||||
| Boston 1999 | Case-control | None given | |||
| Mild cognitive impairment | |||||
| Guskiewicz 2005 | Cross-sectional | AMS & 1 symptom of PCS | |||
| Unverzagt 2011 | Cohort | None given | |||
| Psychiatric diagnosis | |||||
| Depression | |||||
| Malaspina 2001 | Case-control | Severity grouped by LOC duration w/ “severe” TBI having LOC >15 min | |||
| Polusny 2001 | Cohort | >1 yr (1–2.33 yrs) | AMS or LOC | LOC >20 min excluded | |
| Silver 2001 | Cross-sectional | LOC or AMS | |||
| Holsinger 2002 | Cohort | 20.9 (includes some not in analysis) | MC & LOC or PTA or non-displaced skull fracture | Excluded if penetrated dura or resulted in significant sequelae 3 mos after TBI | |
| Guskiewicz 2007 | Cross-sectional | AMS & 1 symptom of PCS | |||
| Gao 2009 | Cross-sectional | None given | |||
| Mollica 2009 | Cross-sectional | LOC, PTA, & ND | |||
| Rajkumar 2009 | Cross-sectional | LOC | |||
| Vanderploeg 2009 | Cohort | 16 yrs | LOC or PTA or AMS | Excluded if admitted to hospital | |
| Bryant 2010 | Cohort | 37.8 | 1 yr | GCS score ≥13 | Excluded if focal deficit, imaging abnormal, or LOC >30 min |
| Psychotic disorder | |||||
| Malaspina 2001 | Case-control | None given | Severity grouped by duration LOC w/ “severe” TBI having LOC >15 min | ||
| Nielsen 2002 | Case-control | Grouped (>1 yr) | MC | ICD-9 code for concussion included, excluded if skull fracture or intracranial hemorrhage | |
| Silver 2001 | Cross-sectional | LOC or AMS | |||
| AbdelMalik 2003 | Case-control | <17 | Median 12 yrs | Closed head injuries w/o intracranial hemorrhage or other immediate sequelae | |
| Fann 2004 | Cohort | 3 yrs | By ICD-9 codes; excluded if imaging abnormal or LOC >1 hr | ||
| Bipolar disorder | |||||
| DelBello 1999 | Cross-sectional | 10.7 | 6.3 yrs | LOC | |
| Malaspina 2001 | Case-control | None given | Severity grouped by duration of LOC w/ “severe” TBI having LOC >15 min | ||
| Silver 2001 | Cross-sectional | LOC or AMS | |||
| Mixed affective disorder | |||||
| Fann 2004 | Cohort | 3 yrs | By ICD-9 codes; excluded if imaging abnormal or LOC >1 hr | ||
| Nelson 2007 | Cross-sectional | >1 yr | None given | ||
AMS = alteration in mental status; GCS = Glasgow Coma Scale; Grouped = data presented in the paper by stratification or division of subjects into groups without an available mean; MC = injury for which medical care was received; ND = neurological deficit; PCS = postconcussion syndrome (for example, headache, dizziness, nausea, photo- or phonophobia, fatigue, sleep difficulty, blurred vision); PTA = posttraumatic amnesia.
Results of subgroup analyses
| Analysis | OR | 95% CI | p Value |
|---|---|---|---|
| Risk of TBI, including only studies w/ clearest interval | |||
| All neurological & psychiatric outcomes | 1.75 | 1.43–2.14 | <0.001 |
| All neurological outcomes | 2.05 | 1.55–2.71 | <0.001 |
| All psychiatric outcomes | 1.38 | 0.95–2.00 | 0.09 |
| Risk of TBI, including only studies meeting mild TBI requirements for max duration of LOC | 1.54 | 1.18–2.01 | 0.001 |
| Risk of TBI, including only studies requiring associated LOC | |||
| All neurological & psychiatric outcomes | 1.69 | 1.18–2.44 | <0.01 |
| All neurological outcomes | 1.33 | 1.00–1.75 | <0.05 |
| All psychiatric outcomes | 4.09 | 1.36–12.32 | 0.01 |
| Risk of TBI, including only studies requiring a mild TBI feature | |||
| All neurological & psychiatric outcomes | 1.70 | 1.42–2.05 | <0.0001 |
| All neurological outcomes | 1.67 | 1.36–2.07 | <0.0001 |
| All psychiatric outcomes | 1.81 | 1.23–2.66 | <0.01 |
| Risk of TBI, eliminating studies w/ TBI diagnosis based on self-report | |||
| All neurological & psychiatric outcomes | 1.62 | 1.14–2.31 | <0.01 |
| All neurological outcomes | 2.38 | 1.01–5.62 | <0.05 |
| All psychiatric outcomes | 1.18 | 0.81–1.71 | 0.39 |
| Risk of TBI, including only cohort studies | |||
| All neurological & psychiatric outcomes | 1.38 | 1.02–1.87 | <0.05 |
| All neurological outcomes | 1.27 | 0.72–2.25 | 0.41 |
| All psychiatric outcomes | 1.45 | 1.23–1.71 | <0.0001 |
| Risk of multiple TBIs vs 1 TBI on any outcome diagnosis | 1.10 | 0.72–1.70 | 0.65 |
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 3 studies with large samples strongly influenced the appearance of the plot (Fig. 3A). When these 3 studies were removed, a more expected funnel shape could be appreciated (Fig. 3B). Regression indicated that the effects size (the logarithm of the ORs) was not significantly predicted by the standard error when all studies were included (F(1, 60) = 3.08, p = 0.08) or when the 3 large sample studies were excluded (F(1, 57) = 1.11, p = 0.30; Fig. 3C).
Publication bias analysis. A: Funnel plot of ORs versus total sample size. B: Funnel plot of ORs versus total sample size after excluding the 3 studies with the largest sample sizes (Rugbjerg 2008, Nielsen 2002, and Turner 2010). C: Plot of the logarithm of the ORs after excluding the 3 largest sample size studies compared with the standard error of the logarithm of the ORs showing a regression line and 95% CI with slope that is not statistically significantly different from 0. Figure is available in color online only.
Discussion
This meta-analysis supports an association between prior TBI and later diagnosis of the relevant neurological or psychiatric diseases. This association was found independently for both neurological 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 results that reached significance. The OR for Alzheimer’s disease in this analysis is comparable to the findings of prior meta-analyses.24,58 The OR for 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 associations did not reach statistical significance. The overall combined OR for the selected neurological and psychiatric illnesses and for neurological 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 neurological symptoms manifest after TBI. While psychiatric symptoms are common in the acute phase after mild TBI6,21,35,40 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 neurological disease and are consistent with the possibility that both types of illness arise secondary to a common shared pathological mechanism.
We conducted additional subgroup analyses to determine whether TBI characteristics or methodological factors would influence our findings. The overall OR for TBI remained significant when including only studies that required adherence to typical LOC criteria for mild TBI, the presence of any specific mild TBI symptom, or LOC. Though TBI definitions varied widely among studies, these additional analyses supported an association of mild TBI with the neurological and psychiatric outcomes of interest. A significant OR for combined neurological and psychiatric outcomes was also found when eliminating studies that used self-reported diagnoses of TBI and when including only cohort studies. Though statistical significance was lost when assessing the association with psychiatric outcomes when eliminating self-reports and the odds of neurological outcomes among cohort studies, the magnitudes of the ORs were largely consistent with the main analysis, and the change in significance was probably attributable to the small number of articles in these analyses and the resulting loss of power rather than a reflection of a weaker association due to recall bias, although this cannot be excluded. Our analyses also suggested that the finding of an association with TBI is unlikely to be attributable to publication bias, although low power may affect the publication bias test.
The results of our meta-analysis support an association between illness and 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 1 head trauma versus a single TBI. Given that only 6 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 for 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 other factors modify an individual’s susceptibility to develop a neuropsychiatric disorder after TBI. These factors are largely unknown and thus 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 activation77,99 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 trauma,26 and tau abnormalities after trauma have been found to be independent of beta amyloid effects.89 The nature of the TBI could also influence an individual’s clinical presentation. For example, boxers may suffer from more torsional injury that could damage brainstem structures such as the substantia nigra, leading to parkinsonism.82 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 the risk of Alzheimer’s disease, has shown 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, its 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 revealed a 3-fold higher rate of death from neurodegenerative disease compared with the typical population frequency, with Alzheimer’s disease and ALS being the most overrepresented,44 which would be consistent with either a shared vulnerability hypothesis across neurodegenerative diseases or a common pathology. In this meta-analysis we 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.
Several of the reviewed articles 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 2 of the articles32,33 that directly evaluated TBI in sports met the strict inclusion criteria for our study. The ability of our meta-analysis to inform questions surrounding the long-term consequences of sports-related mild TBI is therefore limited by restricted data 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 the assessment of late-life neurological 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, although 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, and thus 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 (for example, different criteria for the diagnosis of illness, or comorbid environmental and genetic factors of the study population) limits the generalizability of our 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 the result of a fall or motor vehicle accident may have other medical comorbidities (for example, vascular disease or substance abuse) or differences in socioeconomic status that could predispose to neurological or psychiatric illness. Another possibility is that the TBI itself could lead to an injury or a change in lifestyle that could modify the risk for a mood disorder. Finally, ill patients who fall and suffer TBI may also undergo more medical testing and therefore may be more likely to receive one of these neurological or psychiatric diagnoses. Only English-language studies were reviewed, which could have led to the exclusion of some relevant studies. Despite our criteria regarding an interval between TBI and the onset of illness, an alternative explanation for the observed association is that some head injuries may have been early manifestations of neurological or psychiatric disease rather than an independent predisposing factor for illness. The authors of 1 of the included studies concluded this reverse causality was responsible for their findings.71 They stratified the interval between TBI and diagnosis and found that the association between TBI and Parkinson’s was no longer present when only looking at TBI that occurred more than 10 years prior to diagnosis.
A major strength of our meta-analysis was the inclusion of a variety of different neurological and psychiatric outcomes rather than a single diagnosis. By focusing on diagnoses rather than self-reported symptoms or patient performance on cognitive tests, we assessed outcomes of sufficient magnitude to affect quality of life. The included studies also came 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, with the subsequent development of neurological and psychiatric illness, including Alzheimer’s disease, Parkinson’s disease, mild cognitive impairment, depression, mixed affective disorders, and bipolar disorder. Because of limitations in and the heterogeneity of existing studies, prospective studies with uniform assessment are 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
Dr. Sturm is supported by National Institute on Aging 1K23AG040127. Dr. Peterson is supported by National Cancer Institute Award KM1CA156687. Dr. Boeve receives research support from the National Institute on Aging (P50 AG0 16574, U01 AG006786, R01 AG032306, and R01 AG041797) and the Mangurian Foundation. Dr. Miller is funded by NIH grants P50AG023501, P01AG019724, P50 AG1657303, and the state of California. Dr. Welsh-Bohmer received funding from the National Institute of Aging (P30 AG28377) and from private donors to the Joseph & Kathleen Bryan Alzheimer’s Disease Center at Duke University.
Author Contributions
Conception and design: Perry, Sturm, Boeve, Miller, Guskiewicz, Berger, Kramer, Welsh-Bohmer. Acquisition of data: Perry, Sturm, Bullock. Analysis and interpretation of data: Perry, Sturm, Peterson, Pieper. Drafting the article: Perry, Sturm, Peterson, Pieper. Critically revising the article: Bullock, Boeve, Miller, Guskiewicz, Berger, Kramer, Welsh-Bohmer. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Perry. Statistical analysis: Peterson, Pieper.
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