Skip to main content
Download PDF

Is traumatic brain injury a risk factor for neurodegeneration? A meta-analysis of population-based studies

BMC Neurology volume 18, Article number: 184 (2018) Cite this article

Abstract

Background

To determine the association of prior traumatic brain injury (TBI) with subsequent diagnosis of neurodegeneration disease.

Methods

All studies from 1980 to 2016 reporting TBI as a risk factor for diagnoses of interest were identified by searching PubMed, Embase, study references, and review articles. The data and study design were assessed by 2 investigators independently. A meta-analysis was performed by RevMan 5.3.

Results

There were 18 studies comprising 3,263,207 patients. Meta-analysis revealed a significant association of prior TBI with subsequent dementia. The pooled odds ratio (OR) for TBI on development of dementia, FTD and TDP-43 associated disease were 1.93 (95% CI 1.47–2.55, p < 0.001), 4.44 (95% CI 3.86–5.10, p < 0.001), and 2.97 (95% CI 1.35–6.53, p < 0.001). However, analyses of individual diagnoses found no evidence that the risk of Alzheimer’s disease, and Parkinson’s disease in individuals with previous TBI compared to those without TBI.

Conclusions

History of TBI is not associated with the development of subsequent neurodegeneration disease. Care must be taken in extrapolating from these results because no suitable criteria define post TBI neurodegenerative processes. Therefore, further research in this area is needed to confirm these questions and uncover the link between TBI and neurodegeneration disease.

Peer Review reports

Introduction

Traumatic brain injury (TBI) occurs when an external force injures the brain. Motor vehicle accidents cause most TBIs in young adults, while falls are the leading cause of TBIs in people over 65 years of age [1]. Owing to the increasing use of motor vehicles in developed countries, the incidence of TBI is rapidly growing. TBI is a major cause of death and disabilities—especially in children and young adults—that result in high societal costs [1, 2]. Men sustain TBIs more frequently than women do. These observations suggest that TBIs result in major health and socioeconomic problems throughout the world. Indeed, the World Health Organization has reported that traffic accidents are the third highest contributor to the global burden of disease and injury [1, 2].

Neurological damage occurs not only at the moment of impact (primary injury) in a TBI, but also it further develops overtime post-impact. Several processes, such as neurotransmitter release, free-radical generation, calcium-mediated damage, gene activation, mitochondrial dysfunction, and inflammatory responses, have been investigated in studies of the secondary injuries that are associated with TBI [3,4,5]. These mechanisms might occur continuously over patients’ lifetimes. Interestingly, a history of TBI has been reported to increase the incidence of Alzheimer disease (AD) [6] and other neurodegenerative conditions, including Parkinson’s disease (PD) [7], amyotrophic lateral sclerosis (ALS) [8], and frontotemporal dementia (FTD) [5]. However, other studies have yielded contradicting results [9,10,11,12,13].

The goal of our study was to determine whether TBI was associated with an increased risk of neurodegeneration by conducting a systematic review of cohort studies of patients with TBI. In addition, we examined which neurodegenerative process occurred most often.

Methods

Data sources

We conducted systematic literature searches of the association between neurodegeneration and TBI in the Medical Literature Analysis and Retrieval System Online (MEDLINE®)/PubMed (US National Library of Medicine, National Institutes of Health, Bethesda, MD; http://www.ncbi.nlm.nih.gov/pubmed) database and Excerpta Medica Database (EMBASE®, Elsevier, Amsterdam, Netherlands; http://www.elsevier.com/solutions/embase-biomedical-research). We used the following keywords to generate a list of potentially useful studies: ([traumatic brain injury] OR [head injury] OR [brain injury] OR [TBI]) AND ([neurodegeneration] OR [cognitive dysfunction] OR [dementia] OR [alzheimer’s disease] OR [AD] OR [parkinson’s disease] OR [parkinsonism] OR [frontotemporal dementia] OR [Amyotrophic Lateral Sclerosis]) [14,15,16]. The search was performed through December 2016. The reference lists in the selected studies, as well as the list of studies included in earlier meta-analyses on similar topics, were reviewed for additional references. This review considered observational studies, and case series.

Inclusion criteria

We included published articles on the risk of neurodegeneration, including cognitive dysfunction, dementia, AD, PD, FTD, and ALS, among individuals with TBIs compared with the risk of neurodegeneration in individuals in a nonbrain-injured population-based control group. A risk estimate was calculated with the data provided in the article. TBI was not limited in accordance with its severity.

Exclusion criteria

Studies were excluded if (1) they were reviews, case reports, or case series; (2) they only consisted of a follow-up study of a cohort of patients with brain injury with no comparison group; (3) there was a non-population-based control group (i.e., a patient control group); or (4) insufficient information was available to allow for calculations of risk estimates [14,15,16].

Study selection

The outcomes recorded were neurodegeneration, dementia, PD, and transactive response DNA-binding protein of 43 kDa (TDP-43) aggregation-associated disease. ALS and FTD, which are closely related conditions with overlapping clinical, pathological, radiological, and genetic characteristics, are characterized by TDP-43 aggregation [17]. Therefore, we defined ALS and FTD as TDP-43-associated diseases. Two authors (H.K. Wang or Y.C. Tai) examined the titles and abstracts of the studies found in the systematic literature search. The entire articles of potentially eligible studies were assessed to determine if the studies met the criteria. The study selection process was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and documented with a PRISMA flow diagram.

Data analysis

The effects of TBI on the neurodegeneration outcomes were assessed with a random effects model because the designs and patient populations of the observational studies were expected to be heterogeneous. The Odds Ratio (OR) and 95% confidence intervals (CIs) were calculated. Statistical heterogeneity was examined with chi-square and I-squared (I2) tests of heterogeneity. The data were analyzed with Review Manager (RevMan) Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).

Results

The systematic search

Using the search terms, our literature and reference list searches yielded 1317 references. After examination of the abstracts and, when indicated, the full texts of the articles, 68 studies were considered potentially relevant [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37] . Finally, 18 studies met our inclusion criteria and were included in the meta-analysis. The characteristics of the included trials are listed in Table 1. Methodologic qualities of are shown in Table 2.

Table 1 Individual for all included studies
Full size table
Table 2 Consensus ACROBAT-NRSI judgments between two reviewers by domain of bias
Full size table

The subgroup meta-analyses

There was an association between TBI and subsequent dementia (pooled OR = 1.93, 95% CI = 1.47–2.55) (Fig. 1). However, this association does not concur with the apolipoprotein E (APOE) genotype (pooled OR = 1.82, 95% CI = 0.74–4.46) (Fig. 2). The studies associated with AD yielded a pooled OR of 1.03 (95% CI = 0.06–16.33) with heterogeneity (I2 = 98%, P < 0.001) (Fig. 3). The analysis of the risk of TBI that was associated with PD yielded a pooled OR of 1.19 (95% CI = 0.50–2.84) with heterogeneity (I2 = 98%, P < 0.001) (Fig. 4). The analysis of the risk associated with TDP-43 and FTD yielded a pooled OR of 2.97 (95% CI = 1.35–6.53) and 4.44 (95% CI = 3.86–5.10) (Figs. 5 and 6).

Fig. 1
figure 1

Individual and pooled odds ratios for dementia

Full size image
Fig. 2
figure 2

Individual and pooled odds ratios for dementia with APOE

Full size image
Fig. 3
figure 3

Individual and pooled odds ratios for Alzheimer’s Disease (AD)

Full size image
Fig. 4
figure 4

Individual and pooled odds ratios for Parkinson’s Disease (PD)

Full size image
Fig. 5
figure 5

Individual and pooled odds ratios for transactive response DNA-binding protein of 43 kDa (TDP-43)

Full size image
Fig. 6
figure 6

Individual and pooled odds ratios for frontotemporal dementia (FTD)

Full size image

Discussion

Concerns about the relationship between TBI and neurodegeneration have long existed. Our principal finding was that TBI is a potential risk factor for subsequent dementia (1.93, 95% CI = 1.47–2.55), TDP-43 (2.97, 95% CI = 1.35–6.53) and FTD (4.44, 95% CI = 3.86–5.10). However, when we analyzed the associations of the incidences of AD, PD, or dementia with APOE genotype, we found that TBI was not a risk.

A common factor between TBI and different neurodegenerative disorders is the abnormal aggregation, accumulation, and/or disposition of proteins in the brain. Patients with TBI have beta-amyloid deposition in their brains, and the pattern of deposition is similar to that observed in patients with AD. Amyloid precursor protein, β-Amyloid precursor protein-cleaving enzyme-1, and presenilin-1, which is a γ-secretase complex protein, serve as sources of amyloid-β peptide deposition after TBI [5, 29,30,31].

TBI may also exacerbate nigrostriatal dopaminergic degeneration by modulating PD-associated genes. These results suggest that α-synuclein is a pathological link between the chronic effects of TBI and PD symptoms [32,33,34].

Another mechanism that might link TBI to neurodegeneration is the accumulation of TDP-43 in patients with FTD and ALS [5, 24, 37]. Patients with chronic traumatic encephalopathy (CTE) exhibit widespread TDP-43 proteinopathy in multiple areas of the brain [38]. Some patients also had TDP-43 protein in their spinal cords, and these patients developed a progressive motor neuron disease several years before their deaths [38, 39]. These findings suggest that TDP-43-associated neurodegeneration and head trauma are connected.

The mechanisms underlying the association of TBI and the incidence of neurodegeneration are exceedingly complex. In fact, in TBI, multiple pathologies occur simultaneously. However, systematic analyses of multiple pathologies in individual cases in a large TBI and control population have not been conducted [9,10,11,12,13, 39]. Therefore, a significant association of AD, PD, and APOE-associated dementia was not observed, and no evidence that head trauma was a risk factor for patients with these disorders was found.

Another noteworthy finding of our study was that AD is not the most common form of neurodegeneration. Several studies have reported that TBI does not affect the development of AD. Whether a single occurrence of moderate-to-severe TBI triggers the development of neurodegeneration remains somewhat controversial [9,10,11,12,13]. In addition, brain injury has been shown to lead to the development of non-AD dementias. However, accurate clinical diagnostic criteria for neurodegeneration that results from TBI do not exist. Therefore, the true risk of neurodegeneration following TBI is hard to define.

Examinations of patients with CTE may help resolve this problem. The symptoms of CTE, which include behavioral disturbances, cognitive dysfunction, and/or motor-related symptoms, generally begin 8–10 years after repetitive mild TBIs are experienced [40,41,42]. However, the clinical diagnostic criteria for traumatic encephalopathy syndrome have only recently been reported. CTE can be seen after a single moderate or severe TBI while traumatic encephalopathy syndrome exhibits progressive deterioration over time. Therefore, clinical judgment must be used to determine whether the amount of progression is greater than what is expected for the age and comorbidities of the patient [39,40,41,42]. Multiple neurodegeneration processes have been used to describe the behavioral disturbances and cognitive dysfunction in patients following TBI owing to the lack of suitable diagnoses. This diagnosis can now be used to define those symptoms.

A major strength of this meta-analysis was the inclusion of a variety of different neurodegenerative outcomes rather than a single diagnosis. The literature search was comprehensive because it focused on diagnoses rather than self-reported symptoms, which resulted in a rigorous examination of the topic.

However, several limitations of this meta-analysis warrant consideration. First, the initial severities of the TBIs varied within and across studies. Since our meta-analyses examined only published data, some important parameters, such as sex, alcohol consumption, and comorbidities were missing. Therefore, we were not able to control for these potential confounding factors. Patients with severe TBI had loss of high cortical function and presented in a vegetative state. In our studies, we included only patients who sought treatment for TBI and neurodegeneration disease, but not important parameters indicating clinical severity and imaging information on TBI. Therefore, it is hard to understand the relationship between the severity of TBI and neurodegeneration disease.

Second, we were not able to examine the effects of the locations of the TBIs in this analysis. Some investigators have proposed that temporal and frontal lobe lesions are more likely to be associated with an increased risk of later dementia compared with lesions in other brain regions [5]. In addition, preinjury intelligence and education level are also associated with TBI and dementia. However, the effects of these factors in this study were difficult to determine.

Another limitation was that none of the studies included in this review provided information on genetics [8]. The estimated effect of the apolipoprotein E (APOE) gene 4 on functional outcome might be greatly confounded by such factors, which could thus influence the validity of any meta-analysis that uses unadjusted results. Therefore, future studies on the relationship between APOE 4 expression and the functional outcome of TBI should consider these important confounding factors. The age may also have an effect on the patients with neurodegeneration diseases. The risk between early-onset and late-onset neurodegeneration diseases maybe different. The patient with young onset neurodegeneration diseases more likely has a genetic or metabolic disease. However, neurodegeneration diseases are far more common in geriatric population, and researches in neurodegeneration disease are focused mainly on old persons. Therefore, it is hard to understand the association between age and neurodegeneration diseases in our study.

Conclusion

Patients with TBI frequently exhibit neurodegeneration. The symptoms of these neurodegenerative processes include behavioral disturbances, cognitive dysfunction, and/or motor-related symptoms. TBI is a potential risk factor only for subsequent dementia, TDP-43, and FTD, but not for AD, PD, or APOE-associated neurodegeneration. The epidemiology and pathology of this association have been difficult to establish. No suitable criteria define these neurodegenerative processes. However, the diagnosis of CTE may help to resolve this problem. Although the evidence suggested that TBI was a risk factor for neurodegeneration, there is limited information on the type, frequency, or amount of trauma that was necessary to induce the neurodegenerative processes. Therefore, further studies in this area are necessary to answer these questions and determine whether the proper management of TBI is effective in reducing the incidence of neurodegeneration.

Abbreviations

AD:

Alzheimer disease

ALS:

amyotrophic lateral sclerosis

APOE:

apolipoprotein E

FTD:

frontotemporal dementia (FTD)

PD:

Parkinson’s disease

TBI:

traumatic brain injury

TDP-43:

transactive response DNA-binding protein of 43 kDa

References

  1. Ghajar J. Traumatic brain injury. Lancet. 2000;356(9233):923–9.

    Article  CAS  Google Scholar 

  2. Risdall JE, Menon DK. Traumatic brain injury. Philos Trans R Soc Lond Ser B Biol Sci. 2011 Jan 27;366(1562):241–50.

    Article  Google Scholar 

  3. Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM, Gentleman S, Heckemann RA, Gunanayagam K, Gelosa G, Sharp DJ. Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol. 2011 Sep;70(3):374–83.

    Article  Google Scholar 

  4. Masel BE, DeWitt DS. Traumatic brain injury: a disease process, not an event. J Neurotrauma. 2010 Aug;27(8):1529–40. https://doi.org/10.1089/neu.2010.1358.

    Article  PubMed  Google Scholar 

  5. Wang HK, Lee YC, Huang CY, Liliang PC, Lu K, Chen HJ, Li YC, Tsai KJ. Traumatic brain injury causes frontotemporal dementia and TDP-43 proteolysis. Neuroscience. 2015 Aug 6;300:94–103.

    Article  CAS  Google Scholar 

  6. Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora A. Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication. J Neurol Neurosurg Psychiatry. 2003;74(7):857–62.

    Article  CAS  Google Scholar 

  7. Rugbjerg K, Ritz B, Korbo L, Martinussen N, Olsen JH. Risk of Parkinson's disease after hospital contact for head injury: population based case-control study. BMJ. 2008;337:a2494.

    Article  Google Scholar 

  8. Schmidt S, Kwee LC, Allen KD, Oddone EZ. Association of ALS with head injury, cigarette smoking and APOE genotypes. J Neurol Sci. 2010;291:22e9.

    Google Scholar 

  9. Launer LJ, Andersen K, Dewey ME, et al. Rates and risk factors for dementia and Alzheimer’s disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups European Studies of Dementia Neurology. 1999;52:78e84.

    Google Scholar 

  10. Fratiglioni L, Ahlbom A, Viitanen M, et al. Risk factors for late-onset Alzheimer’s disease: a population-based, case-control study. Ann Neurol. 1993;33:258e66.

    Google Scholar 

  11. Williams DB, Annegers JF, Kokmen E, et al. Brain injury and neurologic sequelae: a cohort study of dementia, parkinsonism, and amyotrophic lateral sclerosis. Neurology. 1991;41:1554e7.

    Google Scholar 

  12. Levy G, Tang MX, Cote LJ, et al. Do risk factors for Alzheimer’s disease predict dementia in Parkinson’s disease? An exploratory study. Mov Disord. 2002;17:250e7.

    Google Scholar 

  13. Turner MR, Abisgold J, Yeates DG, et al. Head and other physical trauma requiring hospitalisation is not a significant risk factor in the development of ALS. J Neurol Sci. 2010;288:45e8.

    Article  Google Scholar 

  14. Barthélemy EJ, Melis M, Gordon E, Ullman JS, Germano IM. Decompressive Craniectomy for severe traumatic brain injury: a systematic review. World Neurosurg. 2016 Apr;88:411–20.

    Article  Google Scholar 

  15. Perry DC, Sturm VE, Peterson MJ, Pieper CF, Bullock T, Boeve BF, Miller BL, Guskiewicz KM, Berger MS, Kramer JH, Welsh-Bohmer KA. Association of traumatic brain injury with subsequent neurological and psychiatric disease: a meta-analysis. J Neurosurg. 2015;28:1–16.

    Google Scholar 

  16. Zhang BF, Wang J, Liu ZW, Zhao YL, Li DD, Huang TQ, Gu H, Song JN. Meta-analysis of the efficacy and safety of therapeutic hypothermia in children with acute traumatic brain injury. World Neurosurg. 2015;83(4):567–73.

    Article  Google Scholar 

  17. Ferrari R, Kapogiannis D, Huey ED, Momeni P. FTD and ALS: a tale of two diseases. Curr Alzheimer Res. 2011;8(3):273–94.

    Article  CAS  Google Scholar 

  18. Rapoport M, Wolf U, Herrmann N, Kiss A, Shammi P, Reis M, Phillips A, Feinstein A. Traumatic brain injury, apolipoprotein E-epsilon4, and cognition in older adults: a two-year longitudinal study. J Neuropsychiatry Clin Neurosci. 2008 Winter;20(1):68–73.

    Article  Google Scholar 

  19. Tanner CM, Goldman SM, Ross GW, Grate SJ. The disease intersection of susceptibility and exposure: chemical exposures and neurodegenerative disease risk. Alzheimers Dement. 2014;10(3 Suppl):S213–25.

    Article  Google Scholar 

  20. Mehta KM, Ott A, Kalmijn S, Slooter AJ, van Duijn CM, Hofman A, Breteler MM. Head trauma and risk of dementia and Alzheimer's disease: the Rotterdam study. Neurology. 1999;53(9):1959–62.

    Article  CAS  Google Scholar 

  21. Luukinen H, Viramo P, Herala M, Kervinen K, Kesäniemi YA, Savola O, Winqvist S, Jokelainen J, Hillbom M. Fall-related brain injuries and the risk of dementia in elderly people: a population-based study. Eur J Neurol. 2005;12(2):86–92.

    Article  CAS  Google Scholar 

  22. Sundström A, Nilsson LG, Cruts M, Adolfsson R, Van Broeckhoven C, Nyberg L. Increased risk of dementia following mild head injury for carriers but not for non-carriers of the APOE epsilon4 allele. Int Psychogeriatr. 2007;19(1):159–65.

    Article  Google Scholar 

  23. Luukinen H, Jokelainen J, Kervinen K, Kesäniemi YA, Winqvist S, Hillbom M. Risk of dementia associated with the ApoE epsilon4 allele and falls causing head injury without explicit traumatic brain injury. Acta Neurol Scand. 2008;118(3):153–8.

    Article  CAS  Google Scholar 

  24. Savica R, Parisi JE, Wold LE, Josephs KA, Ahlskog JE. High school football and risk of neurodegeneration: a community-based study. Mayo Clin Proc. 2012;87(4):335–40.

    Article  Google Scholar 

  25. Wang HK, Lin SH, Sung PS, Wu MH, Hung KW, Wang LC, Huang CY, Lu K, Chen HJ, Tsai KJ. Population based study on patients with traumatic brain injury suggests increased risk of dementia. J Neurol Neurosurg Psychiatry. 2012;83(11):1080–5.

    Article  Google Scholar 

  26. Gardner RC, Burke JF, Nettiksimmons J, Kaup A, Barnes DE, Yaffe K. Dementia risk after traumatic brain injury vs nonbrain trauma: the role of age and severity. JAMA Neurol. 2014;71(12):1490–7. https://doi.org/10.1001/jamaneurol.2014.2668.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Nordström P, Michaëlsson K, Gustafson Y, Nordström A. Traumatic brain injury and young onset dementia: a nationwide cohort study. Ann Neurol. 2014;75(3):374–81.

    Article  Google Scholar 

  28. Abner EL, Nelson PT, Schmitt FA, Browning SR, Fardo DW, Wan L, Jicha GA, Cooper GE, Smith CD, Caban-Holt AM, Van Eldik LJ, Kryscio RJ. Self-reported head injury and risk of late-life impairment and AD pathology in an AD center cohort. Dement Geriatr Cogn Disord. 2014;37(5–6):294–306.

    Article  Google Scholar 

  29. Rasmusson DX, Brandt J, Martin DB, Folstein MF. Head injury as a risk factor in Alzheimer's disease. Brain Inj. 1995;9(3):213–9.

    Article  CAS  Google Scholar 

  30. Nemetz PN, Leibson C, Naessens JM, Beard M, Kokmen E, Annegers JF, Kurland LT. Traumatic brain injury and time to onset of Alzheimer's disease: a population-based study. Am J Epidemiol. 1999;149(1):32–40.

    Article  CAS  Google Scholar 

  31. Barnes DE, Kaup A, Kirby KA, Byers AL, Diaz-Arrastia R, Yaffe K. Traumatic brain injury and risk of dementia in older veterans. Neurology. 2014;83(4):312–9.

    Article  Google Scholar 

  32. Spangenberg S, Hannerz H, Tüchsen F, Mikkelsen KL. A nationwide population study of severe head injury and Parkinson's disease. Parkinsonism Relat Disord. 2009;15(1):12–4.

    Article  Google Scholar 

  33. Lee PC, Bordelon Y, Bronstein J, Ritz B. Traumatic brain injury, paraquat exposure, and their relationship to Parkinson disease. Neurology. 2012;79(20):2061–6.

    Article  CAS  Google Scholar 

  34. Taylor KM, Saint-Hilaire MH, Sudarsky L, Simon DK, Hersh B, Sparrow D, Hu H, Weisskopf MG. Head injury at early ages is associated with risk of Parkinson's disease. Parkinsonism Relat Disord. 2015.

  35. Gardner RC, Burke JF, Nettiksimmons J, Goldman S, Tanner CM, Yaffe K. Traumatic brain injury in later life increases risk for Parkinson disease. Ann Neurol. 2015;77(6):987–95.

    Article  Google Scholar 

  36. Kalkonde YV, Jawaid A, Qureshi SU, Shirani P, Wheaton M, Pinto-Patarroyo GP, Schulz PE. Medical and environmental risk factors associated with frontotemporal dementia: a case-control study in a veteran population. Alzheimers Dement. 2012;8(3):204–10.

    Article  Google Scholar 

  37. Chen H, Richard M, Sandler DP, Umbach DM, Kamel F. Head injury and amyotrophic lateral sclerosis. Am J Epidemiol. 2007;166(7):810–6.

    Article  Google Scholar 

  38. McKee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW, Perl DP, Hedley-Whyte ET, Price B, Sullivan C, Morin P, Lee HS, Kubilus CA, Daneshvar DH, Wulff M, Budson AE. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. 2010;69(9):918–29.

    Article  CAS  Google Scholar 

  39. Daneshvar DH, Goldstein LE, Kiernan PT, Stein TD, McKee AC. Post-traumatic neurodegeneration and chronic traumatic encephalopathy. Mol Cell Neurosci. 2015;66(Pt B):81–90.

    Article  CAS  Google Scholar 

  40. Washington PM, Villapol S, Burns MP. Polypathology and dementia after brain trauma: does brain injury trigger distinct neurodegenerative diseases, or should they be classified together as traumatic encephalopathy? Exp Neurol. 2016;275(Pt 3):381–8.

    Article  Google Scholar 

  41. Perrine K, Helcer J, Tsiouris AJ, Pisapia DJ, Stieg P. The Current Status of Research on Chronic Traumatic Encephalopathy. World Neurosurg. 2017.

  42. Ojo JO, Mouzon BC, Crawford F. Repetitive head trauma, chronic traumatic encephalopathy and tau: challenges in translating from mice to men. Exp Neurol. 2016 Jan;275(Pt 3):389–404.

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by Center for Database Research, E-DA HEALTHCARE GROUP.

Funding

No funding was received.

Availability of data and materials

The datasets analyzed during the current study are listed in Table 1.

Author information

Authors and Affiliations

  1. Department of Family Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan

    Chi-Hsien Huang, Chi-Wei Lin & Ru-Yi Huang

  2. School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan

    Chi-Hsien Huang, Chi-Wei Lin, Yi-Che Lee, Ru-Yi Huang, Kuo-Wei Wang, San-Nan Yang & Hao-kuang Wang

  3. Department of Nephrology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan

    Yi-Che Lee

  4. Neurosurgical Service, Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan

    Chih-Yuan Huang

  5. Department of Neurology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan

    Yi-Cheng Tai

  6. Department of Neurosurgery, E-Da Hospital, I-Shou University, No.1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City, 82445, Taiwan

    Kuo-Wei Wang & Hao-kuang Wang

  7. Department of Neurology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Yuan-Ting Sun

Authors
  1. Chi-Hsien Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chi-Wei Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi-Che Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chih-Yuan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ru-Yi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi-Cheng Tai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kuo-Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. San-Nan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yuan-Ting Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hao-kuang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CHH analyzed the data; CWL analyzed the data; YCL analyzed the data; CYH searched the papers; RYH analyzed the data; YCT examined the titles and abstracts of the studies found in the systematic literature search; KWW searched the papers and analyzed the data; SNY analyzed the data; YTS searched the papers; HKW examined the titles and abstracts of the studies found in the systematic literature search and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Hao-kuang Wang.

Ethics declarations

Ethics approval and consent to participate

This study was based in part on data from the Medical Literature Analysis and Retrieval System Online (MEDLINE®)/PubMed (US National Library of Medicine, National Institutes of Health, Bethesda, MD; http://www.ncbi.nlm.nih.gov/pubmed) database and Excerpta Medica Database (EMBASE®, Elsevier, Amsterdam, Netherlands; http://www.elsevier.com/solutions/embase-biomedical-research).

Consent for publication

Not applicable.

Competing interests

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, CH., Lin, CW., Lee, YC. et al. Is traumatic brain injury a risk factor for neurodegeneration? A meta-analysis of population-based studies. BMC Neurol 18, 184 (2018). https://doi.org/10.1186/s12883-018-1187-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12883-018-1187-0

Keywords

BMC Neurology

ISSN: 1471-2377

Contact us