Association of traumatic brain injury with subsequent neurological and psychiatric disease: a meta-analysis

Full access

OBJECT

Mild traumatic brain injury (TBI) has been proposed as a risk factor for the development of Alzheimer’s disease, Parkinson’s disease, depression, and other illnesses. This study’s objective was to determine the association of prior mild TBI with the subsequent diagnosis (that is, at least 1 year postinjury) of neurological or psychiatric disease.

METHODS

All studies from January 1995 to February 2012 reporting TBI as a risk factor for diagnoses of interest were identified by searching PubMed, study references, and review articles. Reviewers abstracted the data and assessed study designs and characteristics.

RESULTS

Fifty-seven studies met the inclusion criteria. A random effects meta-analysis revealed a significant association of prior TBI with subsequent neurological and psychiatric diagnoses. The pooled odds ratio (OR) for the development of any illness subsequent to prior TBI was 1.67 (95% CI 1.44–1.93, p < 0.0001). Prior TBI was independently associated with 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) outcomes. Analyses of individual diagnoses revealed higher odds of Alzheimer’s disease, Parkinson’s disease, mild cognitive impairment, depression, mixed affective disorders, and bipolar disorder in individuals with previous TBI as compared to those without TBI. This association was present when examining only studies of mild TBI and when considering the influence of study design and characteristics. Analysis of a subset of studies demonstrated no evidence that multiple TBIs were associated with higher odds of disease than a single TBI.

CONCLUSIONS

History of TBI, including mild TBI, is associated with the development of neurological and psychiatric illness. This finding indicates that either TBI is a risk factor for heterogeneous pathological processes or that TBI may contribute to a common pathological mechanism.

ABBREVIATIONSALS = amyotrophic lateral sclerosis; CI = confidence interval; CTE = chronic traumatic encephalopathy; LOC = loss of consciousness; OR = odds ratio; TBI = traumatic brain injury.

Abstract

OBJECT

Mild traumatic brain injury (TBI) has been proposed as a risk factor for the development of Alzheimer’s disease, Parkinson’s disease, depression, and other illnesses. This study’s objective was to determine the association of prior mild TBI with the subsequent diagnosis (that is, at least 1 year postinjury) of neurological or psychiatric disease.

METHODS

All studies from January 1995 to February 2012 reporting TBI as a risk factor for diagnoses of interest were identified by searching PubMed, study references, and review articles. Reviewers abstracted the data and assessed study designs and characteristics.

RESULTS

Fifty-seven studies met the inclusion criteria. A random effects meta-analysis revealed a significant association of prior TBI with subsequent neurological and psychiatric diagnoses. The pooled odds ratio (OR) for the development of any illness subsequent to prior TBI was 1.67 (95% CI 1.44–1.93, p < 0.0001). Prior TBI was independently associated with 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) outcomes. Analyses of individual diagnoses revealed higher odds of Alzheimer’s disease, Parkinson’s disease, mild cognitive impairment, depression, mixed affective disorders, and bipolar disorder in individuals with previous TBI as compared to those without TBI. This association was present when examining only studies of mild TBI and when considering the influence of study design and characteristics. Analysis of a subset of studies demonstrated no evidence that multiple TBIs were associated with higher odds of disease than a single TBI.

CONCLUSIONS

History of TBI, including mild TBI, is associated with the development of neurological and psychiatric illness. This finding indicates that either TBI is a risk factor for heterogeneous pathological processes or that TBI may contribute to a common pathological mechanism.

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.

FIG. 1.
FIG. 1.

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.13,5,79,11,1517,20,22,25,27,29,3133,37,43,45,47,49,51,55,57,6065,6776,7981,8587,9095,97,98 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).

FIG. 2.
FIG. 2.

Individual and pooled ORs for all included studies. Figure is available in color online only.

TABLE 1.

Individual and pooled ORs for all included studies

Authors & YearCases (no. w/ TBI/no. w/o TBI)Controls (no. w/ TBI/no. w/o TBI)OR95% CI
Neurological diagnosis
 Dementia
  Salib 1997b,c,d,e96/26623/1532.401.46–3.95
  Schofield 1997b,e,g6/4121/1981.380.52–3.61
  Mehta 1999d,e,g11/118788/57280.680.36–1.26
  Plassman 2000b,e,f,g28/26520/12022.491.45–4.29
  Sundström 2007b,e,h25/15646/3161.100.65–1.86
  Smith 2010e31/14154/1642.361.21–4.60
  Tripathi 2012e22/12835/1150.560.31–1.02
  Pooled OR1.360.84–2.19
 Alzheimer’s disease
  Forster 1995b25/8422/871.180.62–2.25
  Rasmusson 1995b,d,e20/481/3313.751.76–107.53
  Salib 1997a53/14523/1532.431.42–4.17
  Schofield 1997a4/3423/2051.050.34–3.22
  Tsolaki 199714/4715/541.070.47–2.45
  O’Meara 1997b,e32/31716/3262.061.11–3.82
  Boston 199930/19223/1170.790.44–1.43
  Mehta 1999a6/85788/57280.510.22–1.18
  Guo 2000e394/1782127/23134.033.27–4.96
  Plassman 2000a17/18520/12022.181.12–4.27
  Tyas 2000203/82193/6051.611.23–2.10
  Lindsay 2002g28/151603/29630.910.60–1.38
  Bachman 2003e397/153884/7602.341.82–3.00
  Guskiewicz 2005e15/71148/7321.370.56–3.37
  Ogunniyi Nigeria 2006g2/6011/4501.360.30–6.30
  Ogunniyi USA 2006g5/8437/3440.550.21–1.45
  Rippon 2006e72/78648/7001.000.71–1.40
  Suhanov 2006d,e46/21430/2301.651.00–2.71
  Fischer 2008g4/8637/3520.440.15–1.27
  Pooled OR1.401.02–1.90
 Parkinson’s disease
  Martyn 1995e11/15635/3010.610.30–1.23
  De Michele 1996d,e13/1033/1134.751.32–17.16
  Seidler 1996eNANA1.400.85–2.30
  McCann 1998d,eNANA1.100.64–1.90
  Smargiassi 1998d,e13/735/812.880.98–8.49
  Kuopio 1999d,e,h39/8484/1620.900.56–1.42
  Taylor 1999b,e35/10511/1364.122.00–8.50
  Werneck 199917/7514/961.550.72–3.35
  Tsai 2002b,e11/195/252.890.86–9.75
  Baldereschi 2003d,e,g8/105403/39800.750.36–1.56
  Bower 2003b,c,e,f2/1832/1931.050.15–7.57
  Goldman 2006b,c,e,h20/739/842.561.10–5.96
  Dick 2007d,eNANA1.301.09–1.55
  Rugbjerg 2008b,e,f409/13, 1941513/66, 7921.371.22–1.53
  Sanyal 201027/14825/3252.371.33–4.23
  Pooled OR1.451.18–1.78
 Amyotrophic lateral sclerosis
  Chen 2007b,e,h24/8542/2131.430.82–2.51
  Binazzi 2009b16/6123/1621.850.91–3.73
  Schmidt 2010b,e,h84/157185/4121.190.87–1.64
  Turner 2010b,e,f,g41/34106, 552/511, 8315.793.68–9.13
  Pooled OR2.070.94–4.56
 Frontotemporal dementia
  Rosso 2003b,e19/6110/1143.551.55–8.11
 Vascular dementia
  Boston 19993/3123/1170.490.14–1.75
 Mild cognitive impairment
  Guskiewicz 2005e19/3450/2864.031.18–13.73
  Unverzagt 2011gNANA2.401.34–4.30
  Pooled OR2.691.51–4.77
Pooled OR, neurological1.551.31–1.83
Psychiatric diagnosis
 Depression
  Malaspina 2001107/66122/3552.611.62–4.21
  Polusny 2001b,c,e,gNANA1.471.10–1.97
  Silver 2001e40/243321/44302.271.60–3.23
  Holsinger 2002b,c,e,f,g96/160387/9741.511.14–2.00
  Guskiewicz 2007e206/631272/8932.301.71–3.08
  Gao 200938/49728/11743.211.95–5.28
  Mollica 2009d,e10/36/2312.782.65–61.56
  Rajkumar 2009d,e19/10833/8404.482.46–8.15
  Vanderploeg 2009b,e,g36/43242/5051.751.09–2.79
  Bryant 2010b,c,e,f,g56/26577/4191.150.79–1.68
  Pooled OR2.141.65–2.77
 Psychotic disorder
  Malaspina 200122/10722/3553.321.77–6.23
  Nielsen 2002b,e,f278/78543394/78, 7100.820.72–0.93
  Silver 2001a12/89349/45841.770.96–3.27
  AbdelMalik 2003b23/4422/801.900.95–3.79
  Fann 2004aNANA1.100.39–3.10
  Pooled OR1.570.83–2.97
 Bipolar disorder
  DelBello 1999b,c,d,e,g4/173/131.020.19–5.37
  Malaspina 200128/20722/3552.181.22–3.91
  Silver 2001a6/51355/46221.530.65–3.59
  Pooled OR1.851.17–2.94
 Mixed affective disorder
  Fann 2004b,f,gNANA1.500.98–2.30
  Nelson 2007b76/248318/20451.971.49–2.62
  Pooled OR1.841.44–2.36
 Pooled OR, psychiatric2.001.50–2.66
Overall pooled OR1.671.44–1.93

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).

TABLE 2.

Summary of study and TBI features for each included study

Authors & YearStudy DesignMean Age at Head Injury (yrs)Mean Interval Btwn Injury & DiagnosisRequired TBI CharacteristicsAdditional TBI Information
Neurological diagnosis
 Dementia
  Salib 1997Case-control7.3 yrsNone givenGrouped as w/ or w/o LOC
  Schofield 1997CohortLOC or PTA
  Mehta 1999CohortGroupedLOCGrouped by LOC ≤ or >15 min
  Plassman 2000CohortMC & LOC or PTA or non-displaced skull fractureExcluded 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 2007Case-control≥5yrsMC
  Smith 2010Cross-sectionalNone given
  Tripathi 2012Case-controlLOC or PTA or a symptom of PCS
 Alzheimer’s disease
  Forster 1995Case-controlGrouped (adulthood or childhood)None given
  Rasmusson 1995Case-control27.2 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 givenExcluded 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 1997Case-control7.9 yrsNone givenGrouped as w/ or w/o LOC
  Schofield 1997Cohort14.5 yrsLOCorPTA
  Tsolaki 1997Case-controlNone given
  O’Meara 1997Case-control46 (range 10–85)34 yrs (range 1–72 yrs)MC or LOC
  Boston 1999Case-controlNone given
  Mehta 1999CohortGroupedLOCGrouped by LOC ≤ or > 15 min
  Guo 2000Case-controlMC or LOC
  Plassman 2000CohortMC & LOC or PTA or non-displaced skull fractureExcluded 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 2000Cross-sectionalNone given
  Lindsay 2002CohortNone givenBoth w/& w/o LOC
  Bachman 2003Case-controlMC
  Guskiewicz 2005Cross-sectionalAMS & 1 symptom of PCS
  Ogunniyi Nigeria 2006CohortNone given
  Ogunniyi USA 2006CohortNone given
  Rippon 2006Cross-sectionalLOCorPTA
  Suhanov 2006Case-controlLOC
  Fischer 2008CohortNone given
 Parkinson’s disease
  Martyn 1995Case-controlLOC or MC
  De Michele 1996Case-controlLOC
  Seidler 1996Case-controlPTA or PCS
  McCann 1998Case-controlLOC
  Smargiassi 1998Case-controlLOC
  Kuopio 1999Case-controlNone givenRecords number w/ & w/o LOC & duration of LOC < or ≥ 5 min
  Taylor 1999Case-control16.336.5 yrsLOC or AMS or ND or PCS
  Werneck 1999Case-controlNone given
  Tsai 2002Case-control18.517.2 yrsLOC or PTA or PCS or ND
  Baldereschi 2003CohortLOC
  Bower 2003Case-control>3 yrs (range 3–55 yrs, median 29 yrs for TBI of all severities in study)PTAExcluded from this group if LOC >1 min, PTA >30 min, or imaging abnormal; mild TBI w/ LOC, moderate, and severe TBI analyzed separately
  Goldman 2006Case-control25.736.9 yrs (range 2–70 yrs), separate analysis of only those w/>10 yrsLOC or PTA
  Dick 2007Case-controlLOC
  Rugbjerg 2008Case-controlGrouped, >1 yr data usedMCExcluded if imaging abnormal
  Sanyal 2010Case-controlNone given
 ALS
  Chen 2007Case-controlGroupedGroupedMC
  Binazzi 2009Case-controlGroupedGroupedNone given
  Schmidt 2010Case-controlGroupedGrouped (2−80+ yrs)LOCorMC
  Turner 2010CohortMC
 Frontotemporal dementia
  Rosso 2003Case-controlPCS or LOC or PTA
 Vascular dementia
  Boston 1999Case-controlNone given
 Mild cognitive impairment
  Guskiewicz 2005Cross-sectionalAMS & 1 symptom of PCS
  Unverzagt 2011CohortNone given
Psychiatric diagnosis
 Depression
  Malaspina 2001Case-controlSeverity grouped by LOC duration w/ “severe” TBI having LOC >15 min 
  Polusny 2001Cohort>1 yr (1–2.33 yrs)AMS or LOCLOC >20 min excluded
  Silver 2001Cross-sectionalLOC or AMS
  Holsinger 2002Cohort20.9 (includes some not in analysis)MC & LOC or PTA or non-displaced skull fractureExcluded if penetrated dura or resulted in significant sequelae 3 mos after TBI
  Guskiewicz 2007Cross-sectionalAMS & 1 symptom of PCS
  Gao 2009Cross-sectionalNone given
  Mollica 2009Cross-sectionalLOC, PTA, & ND
  Rajkumar 2009Cross-sectionalLOC
  Vanderploeg 2009Cohort16 yrsLOC or PTA or AMSExcluded if admitted to hospital
  Bryant 2010Cohort37.81 yrGCS score ≥13Excluded if focal deficit, imaging abnormal, or LOC >30 min
 Psychotic disorder
  Malaspina 2001Case-controlNone givenSeverity grouped by duration LOC w/ “severe” TBI having LOC >15 min
  Nielsen 2002Case-controlGrouped (>1 yr)MCICD-9 code for concussion included, excluded if skull fracture or intracranial hemorrhage
  Silver 2001Cross-sectionalLOC or AMS
  AbdelMalik 2003Case-control<17Median 12 yrsClosed head injuries w/o intracranial hemorrhage or other immediate sequelae
  Fann 2004Cohort3 yrsBy ICD-9 codes; excluded if imaging abnormal or LOC >1 hr
 Bipolar disorder
  DelBello 1999Cross-sectional10.76.3 yrsLOC
  Malaspina 2001Case-controlNone givenSeverity grouped by duration of LOC w/ “severe” TBI having LOC >15 min
  Silver 2001Cross-sectionalLOC or AMS
 Mixed affective disorder
  Fann 2004Cohort3 yrsBy ICD-9 codes; excluded if imaging abnormal or LOC >1 hr
  Nelson 2007Cross-sectional>1 yrNone 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.

TABLE 3.

Results of subgroup analyses

AnalysisOR95% CIp Value
Risk of TBI, including only studies w/ clearest interval
 All neurological & psychiatric outcomes1.751.43–2.14<0.001
 All neurological outcomes2.051.55–2.71<0.001
 All psychiatric outcomes1.380.95–2.000.09
Risk of TBI, including only studies meeting mild TBI requirements for max duration of LOC1.541.18–2.010.001
Risk of TBI, including only studies requiring associated LOC
 All neurological & psychiatric outcomes1.691.18–2.44<0.01
 All neurological outcomes1.331.00–1.75<0.05
 All psychiatric outcomes4.091.36–12.320.01
Risk of TBI, including only studies requiring a mild TBI feature
 All neurological & psychiatric outcomes1.701.42–2.05<0.0001
 All neurological outcomes1.671.36–2.07<0.0001
 All psychiatric outcomes1.811.23–2.66<0.01
Risk of TBI, eliminating studies w/ TBI diagnosis based on self-report
 All neurological & psychiatric outcomes1.621.14–2.31<0.01
 All neurological outcomes2.381.01–5.62<0.05
 All psychiatric outcomes1.180.81–1.710.39
Risk of TBI, including only cohort studies
 All neurological & psychiatric outcomes1.381.02–1.87<0.05
 All neurological outcomes1.270.72–2.250.41
 All psychiatric outcomes1.451.23–1.71<0.0001
Risk of multiple TBIs vs 1 TBI on any outcome diagnosis1.100.72–1.700.65

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).

FIG. 3.
FIG. 3.

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.

References

  • 1

    AbdelMalik PHusted JChow EWBassett AS: Childhood head injury and expression of schizophrenia in multiply affected families. Arch Gen Psychiatry 60:2312362003

  • 2

    Bachman DLGreen RCBenke KSCupples LAFarrer LA: Comparison of Alzheimer’s disease risk factors in white and African American families. Neurology 60:137213742003

  • 3

    Baldereschi MDi Carlo AVanni PGhetti ACarbonin PAmaducci L: Lifestyle-related risk factors for Parkinson’s disease: a population-based study. Acta Neurol Scand 108:2392442003

  • 4

    Beydoun MABeydoun HAWang Y: Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and meta-analysis. Obes Rev 9:2042182008

  • 5

    Binazzi ABelli SUccelli RDesiato MTTalamanca IFAntonini G: An exploratory case-control study on spinal and bulbar forms of amyotrophic lateral sclerosis in the province of Rome. Amyotroph Lateral Scler 10:3613692009

  • 6

    Bombardier CHFann JRTemkin NREsselman PCBarber JDikmen SS: Rates of major depressive disorder and clinical outcomes following traumatic brain injury. JAMA 303:193819452010

  • 7

    Boston PFDennis MSJagger C: Factors associated with vascular dementia in an elderly community population. Int J Geriatr Psychiatry 14:7617661999

  • 8

    Bower JHMaraganore DMPeterson BJMcDonnell SKAhlskog JERocca WA: Head trauma preceding PD: a case-control study. Neurology 60:161016152003

  • 9

    Bryant RAO’Donnell MLCreamer MMcFarlane ACClark CRSilove D: The psychiatric sequelae of traumatic injury. Am J Psychiatry 167:3123202010

  • 10

    Carroll LJCassidy JDHolm LKraus JCoronado VG: Methodological issues and research recommendations for mild traumatic brain injury: the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med 43:43 Suppl1131252004

  • 11

    Chen HRichard MSandler DPUmbach DMKamel F: Head injury and amyotrophic lateral sclerosis. Am J Epidemiol 166:8108162007

  • 12

    Chen XHSiman RIwata AMeaney DFTrojanowski JQSmith DH: Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma. Am J Pathol 165:3573712004

  • 13

    Chiò ABenzi GDossena MMutani RMora G: Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain 128:4724762005

  • 14

    Corsellis JABruton CJFreeman-Browne D: The aftermath of boxing. Psychol Med 3:2703031973

  • 15

    De Michele GFilla AVolpe GDe Marco VGogliettino AAmbrosio G: Environmental and genetic risk factors in Parkinson’s disease: a case-control study in southern Italy. Mov Disord 11:17231996

  • 16

    DelBello MPSoutullo CAZimmerman MESax KWWilliams JRMcElroy SL: Traumatic brain injury in individuals convicted of sexual offenses with and without bipolar disorder. Psychiatry Res 89:2812861999

  • 17

    Dick FDDe Palma GAhmadi AScott NWPrescott GJBennett J: Environmental risk factors for Parkinson’s disease and parkinsonism: the Geoparkinson study. Occup Environ Med 64:6666722007

  • 18

    Egger MDavey Smith GSchneider MMinder C: Bias in meta-analysis detected by a simple, graphical test. BMJ 315:6296341997

  • 19

    Factor SASanchez-Ramos JWeiner WJ: Trauma as an etiology of parkinsonism: a historical review of the concept. Mov Disord 3:30361988

  • 20

    Fann JRBurington BLeonetti AJaffe KKaton WJThompson RS: Psychiatric illness following traumatic brain injury in an adult health maintenance organization population. Arch Gen Psychiatry 61:53612004

  • 21

    Fedoroff JPStarkstein SEForrester AWGeisler FHJorge REArndt SV: Depression in patients with acute traumatic brain injury. Am J Psychiatry 149:9189231992

  • 22

    Fischer PZehetmayer SJungwirth SWeissgram SKrampla WHinterberger M: Risk factors for Alzheimer dementia in a community-based birth cohort at the age of 75 years. Dement Geriatr Cogn Disord 25:5015072008

  • 23

    Fleiss JLLevin BAPaik MC: Statistical Methods for Rates and Proportions New YorkWiley2003

  • 24

    Fleminger SOliver DLLovestone SRabe-Hesketh SGiora A: Head injury as a risk factor for Alzheimer’s disease: the evidence 10 years on; a partial replication. J Neurol Neurosurg Psychiatry 74:8578622003

  • 25

    Forster DPNewens AJKay DWEdwardson JA: Risk factors in clinically diagnosed presenile dementia of the Alzheimer type: a case-control study in northern England. J Epidemiol Community Health 49:2532581995

  • 26

    Gabbita SPScheff SWMenard RMRoberts KFugaccia IZemlan FP: Cleaved-tau: a biomarker of neuronal damage after traumatic brain injury. J Neurotrauma 22:83942005

  • 27

    Gao SJin YUnverzagt FWLiang CHall KSMa F: Correlates of depressive symptoms in rural elderly Chinese. Int J Geriatr Psychiatry 24:135813662009

  • 28

    Gavett BEStern RACantu RCNowinski CJMcKee AC: Mild traumatic brain injury: a risk factor for neurodegeneration. Alzheimers Res Ther 2:182010

  • 29

    Goldman SMTanner CMOakes DBhudhikanok GSGupta ALangston JW: Head injury and Parkinson’s disease risk in twins. Ann Neurol 60:65722006

  • 30

    Goldstein LEFisher AMTagge CAZhang XLVelisek LSullivan JA: Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Sci Transl Med 4:134ra602012

  • 31

    Guo ZCupples LAKurz AAuerbach SHVolicer LChui H: Head injury and the risk of AD in the MIRAGE study. Neurology 54:131613232000

  • 32

    Guskiewicz KMMarshall SWBailes JMcCrea MCantu RCRandolph C: Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery 57:7197262005

  • 33

    Guskiewicz KMMarshall SWBailes JMcCrea MHarding HP JrMatthews A: Recurrent concussion and risk of depression in retired professional football players. Med Sci Sports Exerc 39:9039092007

  • 34

    Hedges LVOlkin I: Statistical Methods for Meta-Analysis Orlando, FLAcademic Press1985

  • 35

    Hibbard MRUysal SKepler KBogdany JSilver J: Axis I psychopathology in individuals with traumatic brain injury. J Head Trauma Rehabil 13:24391998

  • 36

    Ho LZhao WDams-O’Connor KTang CYGordon WPeskind ER: Elevated plasma MCP-1 concentration following traumatic brain injury as a potential “predisposition” factor associated with an increased risk for subsequent development of Alzheimer’s disease. J Alzheimers Dis 31:3013132012

  • 37

    Holsinger TSteffens DCPhillips CHelms MJHavlik RJBreitner JC: Head injury in early adulthood and the lifetime risk of depression. Arch Gen Psychiatry 59:17222002

  • 38

    Jordan BDRelkin NRRavdin LDJacobs ARBennett AGandy S: Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA 278:1361401997

  • 39

    Jordan SEGreen GAGalanty HLMandelbaum BRJabour BA: Acute and chronic brain injury in United States National Team soccer players. Am J Sports Med 24:2052101996

  • 40

    Jorge RERobinson RGStarkstein SEArndt SV: Depression and anxiety following traumatic brain injury. J Neuropsychiatry Clin Neurosci 5:3693741993

  • 41

    Jun GNaj ACBeecham GWWang LSBuros JGallins PJ: Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol 67:147314842010

  • 42

    Kay THarrington DEAdams RAnderson TBerrol SCicerone K: Definition of mild traumatic brain injury. J Head Trauma Rehabil 8:86871993

  • 43

    Kuopio AMMarttila RJHelenius HRinne UK: Environmental risk factors in Parkinson’s disease. Mov Disord 14:9289391999

  • 44

    Lehman EJHein MJBaron SLGersic CM: Neurodegenerative causes of death among retired National Football League players. Neurology 79:197019742012

  • 45

    Lindsay JLaurin DVerreault RHébert RHelliwell BHill GB: Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol 156:4454532002

  • 46

    Lolekha PPhanthumchinda KBhidayasiri R: Prevalence and risk factors of Parkinson’s disease in retired Thai traditional boxers. Mov Disord 25:189519012010

  • 47

    Malaspina DGoetz RRFriedman JHKaufmann CAFara-one SVTsuang M: Traumatic brain injury and schizophrenia in members of schizophrenia and bipolar disorder pedigrees. Am J Psychiatry 158:4404462001

  • 48

    Martland HS: Punch drunk. JAMA 91:110311071928

  • 49

    Martyn CNOsmond C: Parkinson’s disease and the environment in early life. J Neurol Sci 132:2012061995

  • 50

    Mayeux ROttman RMaestre GNgai CTang MXGinsberg H: Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer’s disease. Neurology 45:5555571995

  • 51

    McCann SJLeCouteur DGGreen ACBrayne CJohnson AGChan D: The epidemiology of Parkinson’s disease in an Australian population. Neuroepidemiology 17:3103171998

  • 52

    McKee ACCantu RCNowinski CJHedley-Whyte ETGavett BEBudson AE: Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 68:7097352009

  • 53

    McKee ACGavett BEStern RANowinski CJCantu RCKowall NW: TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol 69:9189292010

  • 54

    McKee ACStern RANowinski CJStein TDAlvarez VEDaneshvar DH: The spectrum of disease in chronic traumatic encephalopathy. Brain 136:43642013

  • 55

    Mehta KMOtt AKalmijn SSlooter AJvan Duijn CMHofman A: Head trauma and risk of dementia and Alzheimer’s disease: The Rotterdam Study. Neurology 53:195919621999

  • 56

    Moher DLiberati ATetzlaff JAltman DG: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e10000972009

  • 57

    Mollica RFLyoo IKChernoff MCBui HXLavelle JYoon SJ: Brain structural abnormalities and mental health sequelae in South Vietnamese ex-political detainees who survived traumatic head injury and torture. Arch Gen Psychiatry 66:122112322009

  • 58

    Mortimer JAvan Duijn CMChandra VFratiglioni LGraves ABHeyman A: Head trauma as a risk factor for Alzheimer’s disease: a collaborative re-analysis of case-control studies. Int J Epidemiol 20:Suppl 2S28S351991

  • 59

    National Center for Injury Prevention and Control: Report to Congress on Mild Traumatic Brain Injury in the United States: Steps to Prevent a Serious Public Health Problem AtlantaCenters for Disease Control and Prevention2003

  • 60

    Nelson LARhoades DANoonan CManson SM: Traumatic brain injury and mental health among two American Indian populations. J Head Trauma Rehabil 22:1051122007

  • 61

    Nielsen ASMortensen PBO’Callaghan EMors OEwald H: Is head injury a risk factor for schizophrenia?. Schizophr Res 55:93982002

  • 62

    Ogunniyi AHall KSGureje OBaiyewu OGao SUnverzagt FW: Risk factors for incident Alzheimer’s disease in African Americans and Yoruba. Metab Brain Dis 21:2352402006

  • 63

    O’Meara ESKukull WASheppard LBowen JDMcCormick WCTeri L: Head injury and risk of Alzheimer’s disease by apolipoprotein E genotype. Am J Epidemiol 146:3733841997

  • 64

    Plassman BLHavlik RJSteffens DCHelms MJNewman TNDrosdick D: Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology 55:115811662000

  • 65

    Polusny MAKehle SMNelson NWErbes CRArbisi PAThuras P: Longitudinal effects of mild traumatic brain injury and posttraumatic stress disorder comorbidity on postdeployment outcomes in National Guard soldiers deployed to Iraq. Arch Gen Psychiatry 68:79892011

  • 66

    Priyadarshi AKhuder SASchaub EAShrivastava S: A meta-analysis of Parkinson’s disease and exposure to pesticides. Neurotoxicology 21:4354402000

  • 67

    Rajkumar APThangadurai PSenthilkumar PGayathri KPrince MJacob KS: Nature, prevalence and factors associated with depression among the elderly in a rural south Indian community. Int Psychogeriatr 21:3723782009

  • 68

    Rasmusson DXBrandt JMartin DBFolstein MF: Head injury as a risk factor in Alzheimer’s disease. Brain Inj 9:2132191995

  • 69

    Rippon GATang MXLee JHLantigua RMedrano MMayeux R: Familial Alzheimer disease in Latinos: interaction between APOE, stroke, and estrogen replacement. Neurology 66:35402006

  • 70

    Rosso SMLandweer EJHouterman MDonker Kaat Lvan Duijn CMvan Swieten JC: Medical and environmental risk factors for sporadic frontotemporal dementia: a retrospective case-control study. J Neurol Neurosurg Psychiatry 74:157415762003

  • 71

    Rugbjerg KRitz BKorbo LMartinussen NOlsen JH: Risk of Parkinson’s disease after hospital contact for head injury: population based case-control study. BMJ 337:a24942008

  • 72

    Salib EHillier V: Head injury and the risk of Alzheimer’s disease: a case control study. Int J Geriatr Psychiatry 12:3633681997

  • 73

    Sanyal JChakraborty DPSarkar BBanerjee TKMukherjee SCRay BC: Environmental and familial risk factors of Parkinsons disease: case-control study. Can J Neurol Sci 37:6376422010

  • 74

    Schmidt SKwee LCAllen KDOddone EZ: Association of ALS with head injury, cigarette smoking and APOE genotypes. J Neurol Sci 291:22292010

  • 75

    Schofleld PWTang MMarder KBell KDooneief GChun M: Alzheimer’s disease after remote head injury: an incidence study. J Neurol Neurosurg Psychiatry 62:1191241997

  • 76

    Seidler AHellenbrand WRobra BPVieregge PNischan PJoerg J: Possible environmental, occupational, and other etiologic factors for Parkinson’s disease: a case-control study in Germany. Neurology 46:127512841996

  • 77

    Shitaka YTran HTBennett RESanchez LLevy MADikranian K: Repetitive closed-skull traumatic brain injury in mice causes persistent multifocal axonal injury and microglial reactivity. J Neuropathol Exp Neurol 70:5515672011

  • 78

    Shively SScher AIPerl DPDiaz-Arrastia R: Dementia resulting from traumatic brain injury: what is the pathology?. Arch Neurol 69:124512512012

  • 79

    Silver JMKramer RGreenwald SWeissman M: The association between head injuries and psychiatric disorders: findings from the New Haven NIMH Epidemiologic Catchment Area Study. Brain Inj 15:9359452001

  • 80

    Smargiassi AMutti ADe Rosa ADe Palma GNegrotti ACalzetti S: A case-control study of occupational and environmental risk factors for Parkinson’s disease in the Emilia-Romagna region of Italy. Neurotoxicology 19:7097121998

  • 81

    Smith KFlicker LDwyer AAtkinson DAlmeida OPLautenschlager NT: Factors associated with dementia in Aboriginal Australians. Aust N Z J Psychiatry 44:8888932010

  • 82

    Stern RADaneshvar DHBaugh CMSeichepine DRMontenigro PHRiley DO: Clinical presentation of chronic traumatic encephalopathy. Neurology 81:112211292013

  • 83

    Sterne JAEgger M: Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. J Clin Epidemiol 54:104610552001

  • 84

    Stroup DFBerlin JAMorton SCOlkin IWilliamson GDRennie D: Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283:200820122000

  • 85

    Suhanov AVPilipenko PIKorczyn ADHofman AVoevoda MIShishkin SV: Risk factors for Alzheimer’s disease in Russia: a case-control study. Eur J Neurol 13:9909952006

  • 86

    Sundström ANilsson LGCruts MAdolfsson RVan Broeckhoven CNyberg L: Increased risk of dementia following mild head injury for carriers but not for non-carriers of the APOE epsilon4 allele. Int Psychogeriatr 19:1591652007

  • 87

    Taylor CASaint-Hilaire MHCupples LAThomas CABurchard AEFeldman RG: Environmental, medical, and family history risk factors for Parkinson’s disease: a New England-based case control study. Am J Med Genet 88:7427491999

  • 88

    Terrell TRBostick RMAbramson RXie DBarfleld WCantu R: APOE, APOE promoter, and Tau genotypes and risk for concussion in college athletes. Clin J Sport Med 18:10172008

  • 89

    Tran HTLaFerla FMHoltzman DMBrody DL: Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-b accumulation and independently accelerates the development of tau abnormalities. J Neurosci 31:951395252011

  • 90

    Tripathi MVibha DGupta PBhatia RSrivastava MVVivekanandhan S: Risk factors of dementia in North India: a case-control study. Aging Ment Health 16:2282352012

  • 91

    Tsai CHLo SKSee LCChen HZChen RSWeng YH: Environmental risk factors of young onset Parkinson’s disease: a case-control study. Clin Neurol Neurosurg 104:3283332002

  • 92

    Tsolaki MFountoulakis KChantzi EKazis A: Risk factors for clinically diagnosed Alzheimer’s disease: a case-control study of a Greek population. Int Psychogeriatr 9:3273411997

  • 93

    Turner MRAbisgold JYeates DGTalbot KGoldacre MJ: Head and other physical trauma requiring hospitalisation is not a significant risk factor in the development of ALS. J Neurol Sci 288:45482010

  • 94

    Tyas SLPederson LLKoval JJ: Is smoking associated with the risk of developing Alzheimer’s disease? Results from three Canadian data sets. Ann Epidemiol 10:4094162000

  • 95

    Unverzagt FWOgunniyi ATaler VGao SLane KABaiyewu O: Incidence and risk factors for cognitive impairment no dementia and mild cognitive impairment in African Americans. Alzheimer Dis Assoc Disord 25:4102011

  • 96

    van Reekum RCohen TWong J: Can traumatic brain injury cause psychiatric disorders?. J Neuropsychiatry Clin Neurosci 12:3163272000

  • 97

    Vanderploeg RDBelanger HGCurtiss G: Mild traumatic brain injury and posttraumatic stress disorder and their associations with health symptoms. Arch Phys Med Rehabil 90:108410932009

  • 98

    Werneck ALAlvarenga H: Genetics, drugs and environmental factors in Parkinson’s disease. A case-control study Arq Neuropsiquiatr 57:2B3473551999

  • 99

    Zhang QGLaird MDHan DNguyen KScott EDong Y: Critical role of NADPH oxidase in neuronal oxidative damage and microglia activation following traumatic brain injury. PLoS One 7:e345042012

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Correspondence David C. Perry, MD, University of California, San Francisco, Memory and Aging Center MC: 1207, 675 Nelson Rising Lane, Suite 190, San Francisco, CA 94158. email: dperry@memory.ucsf.edu.

INCLUDE WHEN CITING Published online August 28, 2015; DOI: 10.3171/2015.2.JNS14503.

Disclosure Drs. Perry, Pieper, Berger, Guskiewicz, Kramer, and Bullock report no competing interests. Dr. Boeve has served as an investigator for clinical trials sponsored by Cephalon Inc., Allon Pharmaceuticals, and GE Healthcare. He receives royalties from the publication of a book entitled Behavioral Neurology of Dementia (Cambridge Medicine, 2009). He has received honoraria from the American Academy of Neurology. He serves on the Scientific Advisory Board of the Tau Consortium. Dr. Welsh-Bohmer received funding from Takeda and Zinfandel Pharmaceutical companies.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Flowchart depicting study identification and screening.

  • View in gallery

    Individual and pooled ORs for all included studies. Figure is available in color online only.

  • View in gallery

    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.

References

1

AbdelMalik PHusted JChow EWBassett AS: Childhood head injury and expression of schizophrenia in multiply affected families. Arch Gen Psychiatry 60:2312362003

2

Bachman DLGreen RCBenke KSCupples LAFarrer LA: Comparison of Alzheimer’s disease risk factors in white and African American families. Neurology 60:137213742003

3

Baldereschi MDi Carlo AVanni PGhetti ACarbonin PAmaducci L: Lifestyle-related risk factors for Parkinson’s disease: a population-based study. Acta Neurol Scand 108:2392442003

4

Beydoun MABeydoun HAWang Y: Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and meta-analysis. Obes Rev 9:2042182008

5

Binazzi ABelli SUccelli RDesiato MTTalamanca IFAntonini G: An exploratory case-control study on spinal and bulbar forms of amyotrophic lateral sclerosis in the province of Rome. Amyotroph Lateral Scler 10:3613692009

6

Bombardier CHFann JRTemkin NREsselman PCBarber JDikmen SS: Rates of major depressive disorder and clinical outcomes following traumatic brain injury. JAMA 303:193819452010

7

Boston PFDennis MSJagger C: Factors associated with vascular dementia in an elderly community population. Int J Geriatr Psychiatry 14:7617661999

8

Bower JHMaraganore DMPeterson BJMcDonnell SKAhlskog JERocca WA: Head trauma preceding PD: a case-control study. Neurology 60:161016152003

9

Bryant RAO’Donnell MLCreamer MMcFarlane ACClark CRSilove D: The psychiatric sequelae of traumatic injury. Am J Psychiatry 167:3123202010

10

Carroll LJCassidy JDHolm LKraus JCoronado VG: Methodological issues and research recommendations for mild traumatic brain injury: the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med 43:43 Suppl1131252004

11

Chen HRichard MSandler DPUmbach DMKamel F: Head injury and amyotrophic lateral sclerosis. Am J Epidemiol 166:8108162007

12

Chen XHSiman RIwata AMeaney DFTrojanowski JQSmith DH: Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma. Am J Pathol 165:3573712004

13

Chiò ABenzi GDossena MMutani RMora G: Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain 128:4724762005

14

Corsellis JABruton CJFreeman-Browne D: The aftermath of boxing. Psychol Med 3:2703031973

15

De Michele GFilla AVolpe GDe Marco VGogliettino AAmbrosio G: Environmental and genetic risk factors in Parkinson’s disease: a case-control study in southern Italy. Mov Disord 11:17231996

16

DelBello MPSoutullo CAZimmerman MESax KWWilliams JRMcElroy SL: Traumatic brain injury in individuals convicted of sexual offenses with and without bipolar disorder. Psychiatry Res 89:2812861999

17

Dick FDDe Palma GAhmadi AScott NWPrescott GJBennett J: Environmental risk factors for Parkinson’s disease and parkinsonism: the Geoparkinson study. Occup Environ Med 64:6666722007

18

Egger MDavey Smith GSchneider MMinder C: Bias in meta-analysis detected by a simple, graphical test. BMJ 315:6296341997

19

Factor SASanchez-Ramos JWeiner WJ: Trauma as an etiology of parkinsonism: a historical review of the concept. Mov Disord 3:30361988

20

Fann JRBurington BLeonetti AJaffe KKaton WJThompson RS: Psychiatric illness following traumatic brain injury in an adult health maintenance organization population. Arch Gen Psychiatry 61:53612004

21

Fedoroff JPStarkstein SEForrester AWGeisler FHJorge REArndt SV: Depression in patients with acute traumatic brain injury. Am J Psychiatry 149:9189231992

22

Fischer PZehetmayer SJungwirth SWeissgram SKrampla WHinterberger M: Risk factors for Alzheimer dementia in a community-based birth cohort at the age of 75 years. Dement Geriatr Cogn Disord 25:5015072008

23

Fleiss JLLevin BAPaik MC: Statistical Methods for Rates and Proportions New YorkWiley2003

24

Fleminger SOliver DLLovestone SRabe-Hesketh SGiora A: Head injury as a risk factor for Alzheimer’s disease: the evidence 10 years on; a partial replication. J Neurol Neurosurg Psychiatry 74:8578622003

25

Forster DPNewens AJKay DWEdwardson JA: Risk factors in clinically diagnosed presenile dementia of the Alzheimer type: a case-control study in northern England. J Epidemiol Community Health 49:2532581995

26

Gabbita SPScheff SWMenard RMRoberts KFugaccia IZemlan FP: Cleaved-tau: a biomarker of neuronal damage after traumatic brain injury. J Neurotrauma 22:83942005

27

Gao SJin YUnverzagt FWLiang CHall KSMa F: Correlates of depressive symptoms in rural elderly Chinese. Int J Geriatr Psychiatry 24:135813662009

28

Gavett BEStern RACantu RCNowinski CJMcKee AC: Mild traumatic brain injury: a risk factor for neurodegeneration. Alzheimers Res Ther 2:182010

29

Goldman SMTanner CMOakes DBhudhikanok GSGupta ALangston JW: Head injury and Parkinson’s disease risk in twins. Ann Neurol 60:65722006

30

Goldstein LEFisher AMTagge CAZhang XLVelisek LSullivan JA: Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Sci Transl Med 4:134ra602012

31

Guo ZCupples LAKurz AAuerbach SHVolicer LChui H: Head injury and the risk of AD in the MIRAGE study. Neurology 54:131613232000

32

Guskiewicz KMMarshall SWBailes JMcCrea MCantu RCRandolph C: Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery 57:7197262005

33

Guskiewicz KMMarshall SWBailes JMcCrea MHarding HP JrMatthews A: Recurrent concussion and risk of depression in retired professional football players. Med Sci Sports Exerc 39:9039092007

34

Hedges LVOlkin I: Statistical Methods for Meta-Analysis Orlando, FLAcademic Press1985

35

Hibbard MRUysal SKepler KBogdany JSilver J: Axis I psychopathology in individuals with traumatic brain injury. J Head Trauma Rehabil 13:24391998

36

Ho LZhao WDams-O’Connor KTang CYGordon WPeskind ER: Elevated plasma MCP-1 concentration following traumatic brain injury as a potential “predisposition” factor associated with an increased risk for subsequent development of Alzheimer’s disease. J Alzheimers Dis 31:3013132012

37

Holsinger TSteffens DCPhillips CHelms MJHavlik RJBreitner JC: Head injury in early adulthood and the lifetime risk of depression. Arch Gen Psychiatry 59:17222002

38

Jordan BDRelkin NRRavdin LDJacobs ARBennett AGandy S: Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA 278:1361401997

39

Jordan SEGreen GAGalanty HLMandelbaum BRJabour BA: Acute and chronic brain injury in United States National Team soccer players. Am J Sports Med 24:2052101996

40

Jorge RERobinson RGStarkstein SEArndt SV: Depression and anxiety following traumatic brain injury. J Neuropsychiatry Clin Neurosci 5:3693741993

41

Jun GNaj ACBeecham GWWang LSBuros JGallins PJ: Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol 67:147314842010

42

Kay THarrington DEAdams RAnderson TBerrol SCicerone K: Definition of mild traumatic brain injury. J Head Trauma Rehabil 8:86871993

43

Kuopio AMMarttila RJHelenius HRinne UK: Environmental risk factors in Parkinson’s disease. Mov Disord 14:9289391999

44

Lehman EJHein MJBaron SLGersic CM: Neurodegenerative causes of death among retired National Football League players. Neurology 79:197019742012

45

Lindsay JLaurin DVerreault RHébert RHelliwell BHill GB: Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol 156:4454532002

46

Lolekha PPhanthumchinda KBhidayasiri R: Prevalence and risk factors of Parkinson’s disease in retired Thai traditional boxers. Mov Disord 25:189519012010

47

Malaspina DGoetz RRFriedman JHKaufmann CAFara-one SVTsuang M: Traumatic brain injury and schizophrenia in members of schizophrenia and bipolar disorder pedigrees. Am J Psychiatry 158:4404462001

48

Martland HS: Punch drunk. JAMA 91:110311071928

49

Martyn CNOsmond C: Parkinson’s disease and the environment in early life. J Neurol Sci 132:2012061995

50

Mayeux ROttman RMaestre GNgai CTang MXGinsberg H: Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer’s disease. Neurology 45:5555571995

51

McCann SJLeCouteur DGGreen ACBrayne CJohnson AGChan D: The epidemiology of Parkinson’s disease in an Australian population. Neuroepidemiology 17:3103171998

52

McKee ACCantu RCNowinski CJHedley-Whyte ETGavett BEBudson AE: Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 68:7097352009

53

McKee ACGavett BEStern RANowinski CJCantu RCKowall NW: TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol 69:9189292010

54

McKee ACStern RANowinski CJStein TDAlvarez VEDaneshvar DH: The spectrum of disease in chronic traumatic encephalopathy. Brain 136:43642013

55

Mehta KMOtt AKalmijn SSlooter AJvan Duijn CMHofman A: Head trauma and risk of dementia and Alzheimer’s disease: The Rotterdam Study. Neurology 53:195919621999

56

Moher DLiberati ATetzlaff JAltman DG: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e10000972009

57

Mollica RFLyoo IKChernoff MCBui HXLavelle JYoon SJ: Brain structural abnormalities and mental health sequelae in South Vietnamese ex-political detainees who survived traumatic head injury and torture. Arch Gen Psychiatry 66:122112322009

58

Mortimer JAvan Duijn CMChandra VFratiglioni LGraves ABHeyman A: Head trauma as a risk factor for Alzheimer’s disease: a collaborative re-analysis of case-control studies. Int J Epidemiol 20:Suppl 2S28S351991

59

National Center for Injury Prevention and Control: Report to Congress on Mild Traumatic Brain Injury in the United States: Steps to Prevent a Serious Public Health Problem AtlantaCenters for Disease Control and Prevention2003

60

Nelson LARhoades DANoonan CManson SM: Traumatic brain injury and mental health among two American Indian populations. J Head Trauma Rehabil 22:1051122007

61

Nielsen ASMortensen PBO’Callaghan EMors OEwald H: Is head injury a risk factor for schizophrenia?. Schizophr Res 55:93982002

62

Ogunniyi AHall KSGureje OBaiyewu OGao SUnverzagt FW: Risk factors for incident Alzheimer’s disease in African Americans and Yoruba. Metab Brain Dis 21:2352402006

63

O’Meara ESKukull WASheppard LBowen JDMcCormick WCTeri L: Head injury and risk of Alzheimer’s disease by apolipoprotein E genotype. Am J Epidemiol 146:3733841997

64

Plassman BLHavlik RJSteffens DCHelms MJNewman TNDrosdick D: Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology 55:115811662000

65

Polusny MAKehle SMNelson NWErbes CRArbisi PAThuras P: Longitudinal effects of mild traumatic brain injury and posttraumatic stress disorder comorbidity on postdeployment outcomes in National Guard soldiers deployed to Iraq. Arch Gen Psychiatry 68:79892011

66

Priyadarshi AKhuder SASchaub EAShrivastava S: A meta-analysis of Parkinson’s disease and exposure to pesticides. Neurotoxicology 21:4354402000

67

Rajkumar APThangadurai PSenthilkumar PGayathri KPrince MJacob KS: Nature, prevalence and factors associated with depression among the elderly in a rural south Indian community. Int Psychogeriatr 21:3723782009

68

Rasmusson DXBrandt JMartin DBFolstein MF: Head injury as a risk factor in Alzheimer’s disease. Brain Inj 9:2132191995

69

Rippon GATang MXLee JHLantigua RMedrano MMayeux R: Familial Alzheimer disease in Latinos: interaction between APOE, stroke, and estrogen replacement. Neurology 66:35402006

70

Rosso SMLandweer EJHouterman MDonker Kaat Lvan Duijn CMvan Swieten JC: Medical and environmental risk factors for sporadic frontotemporal dementia: a retrospective case-control study. J Neurol Neurosurg Psychiatry 74:157415762003

71

Rugbjerg KRitz BKorbo LMartinussen NOlsen JH: Risk of Parkinson’s disease after hospital contact for head injury: population based case-control study. BMJ 337:a24942008

72

Salib EHillier V: Head injury and the risk of Alzheimer’s disease: a case control study. Int J Geriatr Psychiatry 12:3633681997

73

Sanyal JChakraborty DPSarkar BBanerjee TKMukherjee SCRay BC: Environmental and familial risk factors of Parkinsons disease: case-control study. Can J Neurol Sci 37:6376422010

74

Schmidt SKwee LCAllen KDOddone EZ: Association of ALS with head injury, cigarette smoking and APOE genotypes. J Neurol Sci 291:22292010

75

Schofleld PWTang MMarder KBell KDooneief GChun M: Alzheimer’s disease after remote head injury: an incidence study. J Neurol Neurosurg Psychiatry 62:1191241997

76

Seidler AHellenbrand WRobra BPVieregge PNischan PJoerg J: Possible environmental, occupational, and other etiologic factors for Parkinson’s disease: a case-control study in Germany. Neurology 46:127512841996

77

Shitaka YTran HTBennett RESanchez LLevy MADikranian K: Repetitive closed-skull traumatic brain injury in mice causes persistent multifocal axonal injury and microglial reactivity. J Neuropathol Exp Neurol 70:5515672011

78

Shively SScher AIPerl DPDiaz-Arrastia R: Dementia resulting from traumatic brain injury: what is the pathology?. Arch Neurol 69:124512512012

79

Silver JMKramer RGreenwald SWeissman M: The association between head injuries and psychiatric disorders: findings from the New Haven NIMH Epidemiologic Catchment Area Study. Brain Inj 15:9359452001

80

Smargiassi AMutti ADe Rosa ADe Palma GNegrotti ACalzetti S: A case-control study of occupational and environmental risk factors for Parkinson’s disease in the Emilia-Romagna region of Italy. Neurotoxicology 19:7097121998

81

Smith KFlicker LDwyer AAtkinson DAlmeida OPLautenschlager NT: Factors associated with dementia in Aboriginal Australians. Aust N Z J Psychiatry 44:8888932010

82

Stern RADaneshvar DHBaugh CMSeichepine DRMontenigro PHRiley DO: Clinical presentation of chronic traumatic encephalopathy. Neurology 81:112211292013

83

Sterne JAEgger M: Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. J Clin Epidemiol 54:104610552001

84

Stroup DFBerlin JAMorton SCOlkin IWilliamson GDRennie D: Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283:200820122000

85

Suhanov AVPilipenko PIKorczyn ADHofman AVoevoda MIShishkin SV: Risk factors for Alzheimer’s disease in Russia: a case-control study. Eur J Neurol 13:9909952006

86

Sundström ANilsson LGCruts MAdolfsson RVan Broeckhoven CNyberg L: Increased risk of dementia following mild head injury for carriers but not for non-carriers of the APOE epsilon4 allele. Int Psychogeriatr 19:1591652007

87

Taylor CASaint-Hilaire MHCupples LAThomas CABurchard AEFeldman RG: Environmental, medical, and family history risk factors for Parkinson’s disease: a New England-based case control study. Am J Med Genet 88:7427491999

88

Terrell TRBostick RMAbramson RXie DBarfleld WCantu R: APOE, APOE promoter, and Tau genotypes and risk for concussion in college athletes. Clin J Sport Med 18:10172008

89

Tran HTLaFerla FMHoltzman DMBrody DL: Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-b accumulation and independently accelerates the development of tau abnormalities. J Neurosci 31:951395252011

90

Tripathi MVibha DGupta PBhatia RSrivastava MVVivekanandhan S: Risk factors of dementia in North India: a case-control study. Aging Ment Health 16:2282352012

91

Tsai CHLo SKSee LCChen HZChen RSWeng YH: Environmental risk factors of young onset Parkinson’s disease: a case-control study. Clin Neurol Neurosurg 104:3283332002

92

Tsolaki MFountoulakis KChantzi EKazis A: Risk factors for clinically diagnosed Alzheimer’s disease: a case-control study of a Greek population. Int Psychogeriatr 9:3273411997

93

Turner MRAbisgold JYeates DGTalbot KGoldacre MJ: Head and other physical trauma requiring hospitalisation is not a significant risk factor in the development of ALS. J Neurol Sci 288:45482010

94

Tyas SLPederson LLKoval JJ: Is smoking associated with the risk of developing Alzheimer’s disease? Results from three Canadian data sets. Ann Epidemiol 10:4094162000

95

Unverzagt FWOgunniyi ATaler VGao SLane KABaiyewu O: Incidence and risk factors for cognitive impairment no dementia and mild cognitive impairment in African Americans. Alzheimer Dis Assoc Disord 25:4102011

96

van Reekum RCohen TWong J: Can traumatic brain injury cause psychiatric disorders?. J Neuropsychiatry Clin Neurosci 12:3163272000

97

Vanderploeg RDBelanger HGCurtiss G: Mild traumatic brain injury and posttraumatic stress disorder and their associations with health symptoms. Arch Phys Med Rehabil 90:108410932009

98

Werneck ALAlvarenga H: Genetics, drugs and environmental factors in Parkinson’s disease. A case-control study Arq Neuropsiquiatr 57:2B3473551999

99

Zhang QGLaird MDHan DNguyen KScott EDong Y: Critical role of NADPH oxidase in neuronal oxidative damage and microglia activation following traumatic brain injury. PLoS One 7:e345042012

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 578 578 121
PDF Downloads 341 341 41
EPUB Downloads 0 0 0

PubMed

Google Scholar