The authors have declared that no competing interests exist.
Conceived and designed the experiments: YKL YCS. Performed the experiments: YCS. Analyzed the data: YCS CYH. Contributed reagents/materials/analysis tools: CCL SWH. Wrote the paper: YSH YCS.
It is known that the risk of dementia in patients with moderate to severe traumatic brain injury (TBI) is higher. However, the relationship between mild traumatic brain injury (mTBI) and dementia has never been established.
We investigated the incidences of dementia among patients with mTBI in Taiwan to evaluate if there is higher risk compared with general population.
We utilized a sampled National Health Insurance (NHI) claims data containing one million beneficiaries. We followed all adult beneficiaries from January 1, 2005 till December 31, 2009 to see if they had been diagnosed with dementia. We further identify patients with mTBI and compared their risk of dementia with the general population.
We identified 28551 patients with mTBI and 692382 without. After controlled for age, gender, urbanization level, socioeconomic status, diabetes, hypertension, coronary artery disease, hyperlipidemia, history of alcohol intoxication, history of ischemic stroke, history of intracranial hemorrhage and Charlson Comorbidity Index Score, the adjusted hazard ratio is 3.26 (95% Confidence interval, 2.69–3.94).
TBI is an independent significant risk factor of developing dementia even in the mild type.
Dementia is a disorder defined by impairment of memory with at least one other cognitive deficit (aphasia, apraxia, agnosia, executive function) from previous level of function.
Although the etiology is not well known, risk factors of dementia such as age, family histories and genetic factors have been extensively studied. Recently, traumatic brain injury (TBI) has been evoked as one possible precipitating factor.
A Systematic review has found that AD was associated with moderate and severe TBI, but not with mild TBI unless there was loss of consciousness, and the evidence for the latter was limited.
This study was initiated after approved by the Institutional Review Board of Buddhist Dalin Tzu Chi General Hospital, Taiwan. Since all identifying personal information was stripped from the secondary files before analysis, the review board waived the requirement for written informed consent from the patients involved.
The National Health Insurance (NHI) program, which provides compulsory universal health insurance, was implemented in Taiwan in 1995. It enrolls up to 99% of the Taiwanese population and contracts with 97% of all medical providers. The database contains comprehensive information on insured subjects, including gender, date of birth, residential or work area, dates of clinical visits, the International Classification of Diseases (Ninth Revision) Clinical Modification (ICD-9-CM) codes of diagnoses, details of prescriptions, expenditure amounts and outcome at hospital discharge (recovered, died, or transferred out). A random sample with 1,000,000 people based on the 2005 reimbursement data was established for public access, and the group did not differ statistically significantly from the larger cohort in age, gender or health care costs, as reported by the Taiwan National Health Research Institute.
To avoid financial issues for patients with major illnesses, the NHI specifies 31 categories of catastrophic illness (e.g., dementia, cancers, chronic renal failure, etc.) that are exempt from co-payment. The attending physician of a patient diagnosed as catastrophic illness can submit related information in application for a catastrophic illness certificate (CIC). A committee formally reviews applications, and if approved, patients are then exempted from co-payment.
The sampled population has been followed from January 1, 2002 to December 31, 2009 (a total of eight years). First, We identified people older than 18 years who were still alive in 2005 as our study cohort. Mild traumatic brain injury (mTBI) was defined by ICD-9-CM code head concussion (850.0, 850.1, 850.5, or 850.9), intracranial injury of other and unspecified nature (854.0), or head injury, unspecified (959.01).
To better understand the risk of mTBI on dementia, several covariates were included for analysis. First, patient demographics included age, gender, urbanization level (urban, suburban, and rural areas) and socio-economic status (SES). The insurance enrollee category was used as a proxy measure of SES. Second, prevalence of selected comorbid conditions (diabetes, hypertension, coronary artery disease, hyperlipidemia, history of alcohol intoxication, history of ischemic stroke and intracranial hemorrhage) and Charlson comorbidity index (CCI) were included. CCI is a scoring system that includes weighting factors on important concomitant diseases that has been validated for use with ICD-9-CM coded administrative databases.
The SAS statistical package, version 9.2 (SAS Institute, Inc., Cary, NC) was used for data analysis. Pearson’s chi-square test was used for categorical variables. The Nelson-Aalen cumulative hazard estimates were plotted to show different trends between patients with mTBI and those without. Cox proportional hazard regression model was then used to calculate the hazard ratio of dementia for people with mTBI after adjustments for age, gender, urbanization level, SES, diabetes, hypertension, coronary artery disease, hyperlipidemia, history of ischemic stroke, history of intracranial hemorrhage and CCI.
We did a subgroup analysis based on people older than 65 years to check if the effects of mTBI on developing dementia are similar. We also evaluate the risk of dementia in patients who had been hospitalized because of TBI to see if there is ‘dose-response’ effect in the relation of TBI and dementia.
To further assess the robustness of our results, we did sensitivity analyses
The distribution of demographic characteristics and selected morbidities is shown in
mTBI Group (n = 28551) | Control Group (n = 692382) | ||||
Variables | No. | % | No. | % | |
Gender | 0.030 | ||||
Male | 13705 | 48.0 | 336897 | 48.7 | |
Patient age | <0.001 | ||||
18–44 yrs | 14766 | 51.7 | 402098 | 58.1 | |
45–54 yrs | 4555 | 16.0 | 134834 | 19.5 | |
55–64 yrs | 3202 | 11.2 | 71058 | 10.3 | |
65–74 yrs | 2854 | 10.0 | 50657 | 7.3 | |
75 yrs and more | 3174 | 11.1 | 33735 | 4.9 | |
Mean Age | 45.9 | 43.1 | |||
Charlson Comorbidity Index Score | <0.001 | ||||
0 | 15201 | 53.2 | 419637 | 60.6 | |
1 | 7365 | 25.8 | 163851 | 23.7 | |
≥2 | 5985 | 21.0 | 108894 | 15.7 | |
Diabetes | 3035 | 10.6 | 54672 | 7.9 | <0.001 |
Hyperlipidemia | 3345 | 11.7 | 71930 | 10.4 | <0.001 |
Hypertension | 5860 | 20.5 | 111459 | 16.1 | <0.001 |
Coronary artery disease | 2869 | 10.1 | 49241 | 7.1 | <0.001 |
History of alcohol intoxication | 504 | 1.8 | 5635 | 0.8 | <0.001 |
Ischemic stroke | 220 | 0.8 | 2334 | 0.3 | <0.001 |
Intracranial hemorrhage | 1871 | 6.6 | 26247 | 3.8 | <0.001 |
Socioeconomic status | <0.001 | ||||
Low | 14631 | 51.3 | 303420 | 43.8 | |
Moderate | 11299 | 39.6 | 275842 | 39.8 | |
High | 2621 | 9.2 | 113120 | 16.3 | |
Urbanization level | <0.001 | ||||
Urban | 8117 | 28.4 | 214843 | 31.0 | |
Suburban | 12278 | 43 | 297038 | 42.9 | |
Rural | 8156 | 28.6 | 180501 | 26.1 | |
Dementia | 127 | 0.4 | 944 | 0.1 | <0.001 |
We then performed the multivariate Cox regression model to evaluate the adjusted HRs of dementia. After controlling for age, gender, urbanization level, SES, diabetes, hyperlipidemia coronary artery disease, history of alcohol intoxication, ischemic stroke, intracranial hemorrhage and CCI, patients with mTBI still had high HR. (3.26; 95% CI, 2.69–3.94) Other independent risk factors of dementia included females, older age, diabetes, higher CCI, ischemic stroke, intracranial hemorrhage, lower SES and living outside of urban area. The statistical results are summarized in
Variables | Hazard ratio | 95% confidence interval | P-value |
mTBI | 3.26 | 2.69–3.94 | <0.001 |
Male | 0.65 | 0.57–0.73 | <0.001 |
Patient age | 1.12 | 1.11–1.12 | <0.001 |
Charlson Comorbidity Index Score | |||
0 | 1 | – | – |
1 | 1.29 | 1.06–1.56 | 0.01 |
≥2 | 1.47 | 1.21–1.79 | <0.001 |
Diabetes | 1.47 | 1.27–1.69 | <0.001 |
Hypertension | 1.06 | 0.92–1.22 | 0.445 |
Coronary artery disease | 1.00 | 0.87–1.15 | 0.995 |
Hyperlipidemia | 0.90 | 0.78–1.04 | 0.157 |
History of alcohol intoxication | 1.12 | 0.53–2.36 | 0.766 |
Ischemic stroke | 2.05 | 1.43–2.94 | <0.001 |
Intracranial hemorrhage | 1.43 | 1.24–1.66 | <0.001 |
Socioeconomic status | |||
Low | 1 | – | – |
Moderate | 0.73 | 0.62–0.84 | <0.001 |
High | 0.26 | 0.13–0.52 | 0.002 |
Urbanization level | |||
Urban | 1 | – | – |
Suburban | 1.22 | 1.04–1.42 | 0.014 |
Rural | 1.22 | 1.02–1.45 | 0.027 |
A subgroup analysis based on patients older than 65 years was performed. There were 6028 patients in the mTBI group and 84392 in the control group. After controlling for the same covariates, the risk in patients with mTBI is still significant. (HR 3.27; 95% CI, 2.67–4.00). The statistical results are similar with the primary study cohort and are summarized in
Variables | Hazard ratio | 95% confidence interval | P-value |
mTBI | 3.27 | 2.67–4.00 | <0.001 |
Male | 0.62 | 0.54–0.71 | <0.001 |
Patient age | 1.08 | 1.07–1.09 | <0.001 |
Charlson Comorbidity Index Score | |||
0 | 1 | – | – |
1 | 1.26 | 1.02–1.56 | 0.031 |
≥2 | 1.43 | 1.16–1.77 | 0.001 |
Diabetes | 1.36 | 1.17–1.58 | <0.001 |
Hypertension | 0.99 | 0.85–1.14 | 0.839 |
Coronary artery disease | 1.04 | 0.90–1.21 | 0.559 |
Hyperlipidemia | 0.83 | 0.71–0.97 | 0.017 |
History of alcohol intoxication | 1.48 | 0.70–3.12 | 0.303 |
Ischemic stroke | 1.47 | 0.95–2.28 | 0.084 |
Intracranial hemorrhage | 1.39 | 1.20–1.62 | <0.001 |
Socioeconomic status | |||
Low | 1 | – | – |
Moderate | 0.79 | 0.67–0.93 | 0.005 |
High | 1.05 | 0.43–2.53 | 0.922 |
Urbanization level | |||
Urban | 1 | – | – |
Suburban | 1.17 | 0.99–1.38 | 0.070 |
Rural | 1.11 | 0.92–1.35 | 0.276 |
Another analysis focusing on patients admitted with TBI was performed. There were 6138 patients in the hospitalized group and 692382 in the control group. After controlling for the same covariates, we observed a higher HR in the hospitalized group (HR 4.44; 95% CI, 3.23–6.10). (
Variables | Hazard ratio | 95% confidence interval | P-value |
mTBI | 4.44 | 3.24–6.10 | <0.001 |
Male | 0.65 | 0.57–0.74 | <0.001 |
Patient age | 1.12 | 1.11–1.13 | <0.001 |
Charlson Comorbidity Index Score | |||
0 | 1 | – | – |
1 | 1.35 | 1.10–1.65 | 0.003 |
≥2 | 1.57 | 1.28–1.92 | 0.001 |
Diabetes | 1.38 | 1.19–1.60 | <0.001 |
Hypertension | 1.02 | 0.88–1.18 | 0.819 |
Coronary artery disease | 1.09 | 0.95–1.26 | 0.225 |
Hyperlipidemia | 0.94 | 0.80–1.09 | 0.403 |
History of alcohol intoxication | 1.58 | 0.82–3.05 | 0.175 |
Ischemic stroke | 2.00 | 1.37–2.94 | <0.001 |
Intracranial hemorrhage | 1.42 | 1.22–1.66 | <0.001 |
Socioeconomic status | |||
Low | 1 | – | – |
Moderate | 0.73 | 063–0.85 | <0.001 |
High | 0.24 | 0.11–0.50 | <0.001 |
Urbanization level | |||
Urban | 1 | – | – |
Suburban | 1.18 | 1.00–1.38 | 0.052 |
Rural | 1.15 | 0.96–1.38 | 0.132 |
Sensitivity analyses showed that an unmeasured confounder present in 10% of study population would be required to elevate the risk of dementia by a factor of 10 and would also have to have a prevalence among patients with mTBI that would be around 10 times that among the unexposed group to explain a lower 95% confidence limit HR of 2.69. (
First, our findings are generated from administrative data. The primary outcome of dementia was derived from ICD-9-CM code, which is good for insurance reimbursement rather than being the substitute of precise operative definition. The validity of the diagnosis, i.e. sensitivity, specificity and accuracy, cannot be assessed. To overcome this misclassification bias, we restricted our inclusion to patients who were registered in the CIC or those prescribed with medications solely for dementia, as there should be impossible for false positive cases on this side of disease spectrum. Epidemiologic study showed the prevalence of dementia in the elderly (older than 65 years old) in Taiwan ranged from 1.7% to 4.4%,
Second, Coding errors are also common in mTBI.
Third, we could not obtain the clinical information of patients with mTBI, such as the Glasgow Coma Scale, findings on computed tomography of head, the injury mechanism and the initial presentations. By definition, labeling our cases as ‘mTBI’ may be inappropriate. However, it has been validated that the ICD9-CM codes have high specificity regarding diagnosis of mTBI.
Fourth, the average duration from TBI to the diagnosis of dementia is short and we admitted that reverse causation (i.e., undiagnosed dementia resulted in TBI) might also exist. However, we excluded all dementia patients in the first 3 years of our study period to eliminate the effect as possible. Of note, patients in TBI group are older; it is possible the neurodegenerative impact after TBI could have stronger effect on the elderly. Furthermore, we found higher HR of dementia (4.44) in patients admitted with TBI and the reverse causation could not fully explain the ‘dose-response’ of injury severity.
In the last, although we extensively adjust for possible comorbidities, unmeasured cofounding is still an issue. Based on the nature of our dataset, we cannot take some important risk factors of dementia such as gene or family histories into account. However, these risk factors are unlikely associated with mTBI and it is reasonable that these are not confounders in our study.
Studies have found a history of head trauma was associated with increase in the risk for AD in the absence of a family history of dementia.
In our study, we further extend the impact of TBI to the mild type, utilizing the largest cohort study to date to identify that patients with single mTBI have higher risk of developing dementia later in their lives compared to general population. Our study is power enough to provide precise estimate of HR (3.26; 95% CI, 2.69–3.94), which is statistically and clinically significant. The database is well corresponded to the whole population; therefore, loss of follow-up or selection bias were not concerns.
Other findings in our study are consistent with previous publications. First, age is still the single strongest precipitating factor for dementia.
In conclusion, TBI is an independent significant risk factor of developing dementia even in the mild type. The result indicates that more emphasis on the head injury prevention would be worthy.