Association Between Statin Use and Risk of Dementia After a Concussion
Donald A. Redelmeier, MD, MSHSR1,2,3,4,5; Fizza Manzoor, BHSc1,2,3; Deva Thiruchelvam, MSc3
Author Affiliations Article Information
JAMA Neurol. Published online May 20, 2019. doi:10.1001/jamaneurol.2019.1148
editorial comment icon Editorial
Comment
author interview icon Interviews
Audio Interview (15:53)
Association Between Statin Use and Risk of Dementia After a Concussion
Key Points
Question Is statin use associated with an increased or decreased risk of subsequent dementia after a concussion?
Findings In this large extended population-based double cohort study following 28 815 patients after a concussion, the 5-year incidence of dementia was substantial and statin use was associated with a significantly reduced risk of subsequent dementia.
Meaning Concussions are associated with an increased long-term risk of dementia, which is modestly reduced for patients receiving a statin.
Abstract
Importance Concussions are an acute injury that may lead to chronic disability, while statin use might improve neurologic recovery.
Objective To test whether statin use is associated with an increased or decreased risk of subsequent dementia after a concussion.
Design, Setting, and Participants Large extended population-based double cohort study in Ontario, Canada, from April 1, 1993, to April 1, 2013 (enrollment), and continued until March 31, 2016 (follow-up). Dates of analysis were April 28, 2014, through March 21, 2019. Participants were older adults diagnosed as having a concussion, excluding severe cases resulting in hospitalization, individuals with a prior diagnosis of dementia or delirium, and those who died within 90 days.
Exposure Statin prescription within 90 days after a concussion.
Main Outcome and Measure Long-term incidence of dementia.
Results This study identified 28 815 patients diagnosed as having a concussion (median age, 76 years; 61.3% female), of whom 7058 (24.5%) received a statin, and 21 757 (75.5%) did not receive a statin. A total of 4727 patients subsequently developed dementia over a mean follow-up of 3.9 years, equal to an incidence of 1 case per 6 patients. Patients who received a statin had a 13% reduced risk of dementia compared with patients who did not receive a statin (relative risk, 0.87; 95% CI, 0.81-0.93; P < .001). The decreased risk of dementia associated with statin use applied to diverse patient groups, remained independent of other cardiovascular medication use, intensified over time, was distinct from the risk of subsequent depression, and was not observed in patients after an ankle sprain.
Conclusions and Relevance In this study, older adults had a substantial long-term risk of dementia after a concussion, which was associated with a modest reduction among patients receiving a statin.
Introduction
Concussions are a common cause of brain injury occurring in more than 1 million Americans each year and disproportionately involving older adults.1-4 The subacute consequences vary widely and include fatigue, headache, irritability, insomnia, inattention, photophobia, vertigo, and cognitive difficulties.5-9 Most patients recover from a concussion within weeks, although some can develop lingering mood disorders or chronic neuropsychiatric disorders.10-14 The extent of complications after a concussion is uncertain, and effective pharmacologic treatments remain elusive.15-17 Unfortunately, many medical treatments for traumatic brain injury that showed promise in animal models have subsequently failed in human clinical trials.18-22
Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are a class of medications prescribed for the treatment of hyperlipidemia.23,24 Preclinical data suggest that statin use might mitigate injury-related brain edema, oxidative stress, amyloid protein aggregation, and neuroinflammation.25-29 The potential neuroprotective benefits from statins have also been speculated and include preserved cerebral blood flow, leading to decreased risks of Alzheimer disease, vascular dementia, and age-related cognitive decline.30-35 Together, these findings suggest that statin use could contribute to microvascular homeostasis and immune modulation independent of systemic lipid levels. However, statins do not improve cognition for patients already diagnosed as having dementia.36-38
The role of statins in recovery after a concussion has rarely been investigated.39,40 Furthermore, small sample sizes, selective enrollment, and brief follow-up have limited past studies41-43 assessing the long-term consequences of concussion. On the one hand, the potential neuroprotective associations of statin use may prevent subsequent dysfunction by neuron preservation and neural stem cell activation.44-47 On the other hand, the neurohazardous associations of statin use might contribute to memory difficulties from altered neurophysiology.48-54 We conducted a large extended population-based double cohort study using linked databases to test whether statin use is associated with an increased or decreased risk of dementia in older adults after a concussion.
Methods
Study Setting
This population-based multicenter double cohort study of older adults diagnosed as having a concussion throughout Ontario, Canada, was performed from April 1, 1993, to April 1, 2013 (enrollment period of 20 years), providing a minimum follow-up for survivors of 3 years and reflecting all data available. Ontario is Canada’s largest province, with a population of 12 407 300 in 2004 (the study midpoint), an annual incidence of dementia was 19 cases per 1000 patients for adults 65 years and older, and societal costs of dementia estimated at $18 440 per patient-year.55-58 During our study, universal health insurance covered outpatient medical care for all individuals, with no out-of-pocket costs to patients.59 In addition, the Ontario Drug Benefit Program covered prescription medications for all patients 65 years and older.60 The study protocol was approved by the Research Ethics Board of Sunnybrook Health Sciences Centre, including a waiver for direct patient consent. All data are available through the Institute for Clinical Evaluative Sciences in Ontario.
Patient Identification
We identified patients 66 years and older diagnosed as having a concussion by assessing physician billing data using the concussion diagnostic criterion (International Classification of Diseases, Ninth Revision [ICD-9] code 850) from the Ontario Health Insurance Plan.61 This code for a concussion diagnosis has been validated with high specificity (99%) and moderate sensitivity (46%-76%).62,63 Patients who were admitted to a hospital within 2 days of a concussion or who survived less than 90 days were excluded to reduce confounding from severe brain injury.64 Patients with a history of dementia or delirium in the prior 5 years were also excluded to reduce confounding from past neuropsychiatric conditions.65 No patients were excluded otherwise. Patients with more than 1 concussion during the study were counted once based on the first incident.
Statin Medication Prescriptions
The prescription of a statin was identified through the Ontario Drug Benefit Program database, which has an accuracy exceeding 99% in this setting.66 The specific statins included were atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. We classified patients based on the specific statin received immediately after their concussion. The primary analysis compared patients who had received a statin prescription in the 90 days immediately after a concussion with patients who had not. Secondary analyses explored statin prescriptions in the 90 days before the concussion and also considered statins as time-dependent exposures in analyses to account for fluctuating prescriptions over time.67
Baseline Patient Characteristics
Additional baseline characteristics were defined on the day of the concussion and obtained by computerized linkage to health care records.68 A demographic registry was used to determine the patient’s age, sex, socioeconomic quintile, and home location.69,70 A physician services databases provided data on clinic visits, emergency department contacts, and hospitalizations in the prior year.60,71 The Ontario Drug Benefit Program database provided data on additional cardiovascular medications, neuropsychiatric medications, and miscellaneous medications.72-74 The available databases contained no information on smoking status, daily exercise, education level, family history, genetic factors, hearing loss, social isolation, or other factors that can alter dementia risk.75,76
Outcome Identification
The primary study outcome was a physician diagnosis of dementia (ICD-9 codes 290, 331, and 797) ascertained through the validated Ontario Health Insurance Plan database, as established in past research.77 These codes had a specificity of about 99% and a sensitivity of about 20% for dementia.78 To avoid false-positive results, we required a dementia diagnosis on 2 separate dates.79 Therefore, this outcome definition was highly specific and provided a conservative estimate of the incidence of dementia after a concussion. To corroborate this outcome, we also identified more extensive documentation of the diagnosis that could signify a worsening course over 3 years of follow-up. The available codes did not distinguish specific conditions underlying the dementia diagnosis.
Double Cohort Control Analysis
To test the importance of a potential association between statin use and subsequent dementia, we replicated our entire selection strategy and analysis, focusing instead on older adults diagnosed as having an ankle sprain rather than a concussion. The objective of this secondary parallel analysis was to distinguish the long-term prognosis for patients who had an acute neurologic injury (concussion cohort) from patients who had a peripheral orthopedic injury (ankle sprain). We then assessed the long-term incidence of dementia for patients who received a statin after an ankle sprain compared with patients who did not receive a statin after an ankle sprain. If a patient experienced both a concussion and an ankle sprain, the individual was included in both cohorts (the exclusion of overlap patients yielded similar results).
Statistical Analysis
Our primary analysis evaluated the incidence of dementia after a concussion, comparing patients who received a statin with patients who did not. Graphical displays were created using cumulative incidence curves. Statistical testing was based on proportional hazards analysis taking into account censoring for interval deaths and the study follow-up end date of March 31, 2016. Statistical testing examined associations before adjusting for measured baseline patient characteristics (basic analysis) and after adjusting for measured baseline patient characteristics (adjusted analysis) to check the robustness of relative risk estimates. All P values were 2 tailed, and .05 was the threshold for statistical significance.
Secondary Analyses
Additional analyses explored the potential role of statins in preventing dementia after a concussion. Lipophilic statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, and simvastatin) were compared with hydrophilic statins (pravastatin and rosuvastatin).80 Higher dosages of statins (maximum accepted treatment dosage for a specific statin) were compared with lower dosages of statins (all smaller dosages for a specific statin).81 We also evaluated the incidence of dementia among patients receiving the most commonly used statins separately. Patients who received a statin before and after the concussion (continuous use) were also distinguished from patients who received their statin only after the concussion (initiation) and patients who stopped their statin after the concussion (discontinuation).
We conducted 3 further statistical analyses to explore the robustness of the primary analysis. The first analysis applied 1:1 propensity score matching of patients receiving statins with control patients to account for possible imbalances in baseline characteristics and unmeasured indications for statins. The second analysis introduced time-dependent covariates to account for subsequent changes in statin prescriptions over time and fluctuating adherence to statins. The third analysis considered the possible competing risks of other causes of death that might obscure a subsequent diagnosis of dementia.82 Each of the 3 statistical analyses was conducted before and after adjusting for measured baseline patient characteristics to check the robustness of relative risk estimates.
In addition, we used tracer analysis to check for confounding by replacing the dementia outcome with an alternative clinical end point. Specifically, we reasoned that subsequent depression, instead of dementia, is a different adverse neuropsychiatric outcome that is frequent, serious, important, and similar in some shared clinical features to a dementia diagnosis in older patients.83 However, the risk of depression is not substantially reduced by statins (due to distinct pathophysiology) but can be associated with shared determinants (eg, alcohol use and physical inactivity).84-86 Therefore, we repeated the analyses and examined the risk of depression rather than the risk of dementia after a concussion.
Results
Descriptive Overview
A total of 28 815 patients (median age, 76 years; 61.3% female) were diagnosed as having a concussion during the study. Overall, 7058 patients (24.5%) received a statin during the 90 days after a concussion, and 21 757 patients (75.5%) did not receive a statin. The distribution of baseline demographic characteristics was similar for both groups (Table 1). The typical patient receiving a statin was a 76-year-old woman who was also taking additional medications. On average, patients receiving statins had more cardiovascular medications and more prior physician visits than control patients. The frequency of neuropsychiatric medication use also tended to be higher (not lower) for patients receiving statins. About one-quarter (23.6%) of patients had a hospital admission in the prior year, with no imbalance between the 2 groups.
Risk of Subsequent Dementia
A total of 4727 patients developed dementia over a mean follow-up of 3.9 years after a concussion (Figure 1A). The absolute incidence was 1 case per 6 patients, and most (83.4%) had extensive documentation of dementia during follow-up. Patients receiving statins accounted for 1050 dementia cases over 28 129 patient-years (mean, 4.0 years), equal to an incidence of 37 cases per 1000 patients annually (twice the population norm).87 Control patients accounted for 3677 dementia cases over 85 339 patient-years (mean, 3.9 years), equal to an incidence of 43 cases per 1000 patients annually (more than twice the population norm). Together, statin use was associated with a 13% (95% CI, 7%-19%; P < .001) reduced risk of dementia compared with patients who did not receive a statin (relative risk, 0.87; 95% CI, 0.81-0.93; P < .001), equal to a number needed to treat of about 50 patients.
Adjusting for Patient Characteristics
The decreased risk of dementia associated with statin use after a concussion was similar in the first half and second half of the cohort and persisted after adjusting for patient characteristics (Table 2). As expected, older age was associated with an increased risk of dementia, as was greater health care use (total prescriptions, physician visits, and prior hospitalizations). Patient sex was not associated with a consistent difference in dementia risk. Lower socioeconomic status and urban home location were associated with an increased risk of dementia. Adjustment for all measured baseline characteristics suggested that statin use was associated with a 16% (95% CI, 10%-22%; P < .001) reduction in the risk of subsequent dementia, equal to an E-value88 of 1.67.
Additional Medications
Analysis of additional medication use suggested that the decreased risk of subsequent dementia was specific to statins. In particular, other lipid-lowering medications were not associated with a significant difference in the risk of dementia (Table 2). Other cardiovascular medications were not associated with a consistent decrease in the risk of dementia, with the possible exception of angiotensin II receptor blockers. Similarly, benzodiazepines, thyroid supplements, gastric acid suppressors, inhaled bronchodilators, and glaucoma eyedrops were not associated with a significantly decreased risk of subsequent dementia. As expected, major neuropsychiatric medications were associated with an increased risk of dementia, perhaps as a proxy for cognitive frailty in older patients.
Specific Statin Analyses
Secondary analyses explored further nuances of statin use and the risk of subsequent dementia. Rosuvastatin use was associated with the largest risk reduction, and simvastatin use was associated with the smallest risk reduction (Table 3). Hydrophilic statins were marginally more beneficial than lipophilic statins. No greater benefit was found with higher dosages compared with lower dosages. Propensity score matching suggested that the risk reduction was not easily explained by baseline imbalances in measured patient characteristics. Patients who received a statin before and after the concussion explained most of the risk reduction. Those who initiated a statin after the concussion showed a significant risk reduction, and those who discontinued a statin after the concussion showed no significant risk reduction.
Dementia Risk After Ankle Sprain
The parallel analysis identified a total of 307 890 patients diagnosed as having an ankle sprain, of whom 77 898 (25.3%) received a statin and 229 992 (74.7%) did not receive a statin. A total of 25 956 patients developed dementia over a mean follow-up of 4.3 years (Figure 1B). Patients receiving statins accounted for 6239 dementia cases over 336 251 patient-years (mean, 4.3 years), equal to an incidence of 19 cases per 1000 patients annually. Control patients accounted for 19 717 dementia cases over 1 001 606 patient-years (mean, 4.4 years), equal to an incidence of 20 cases per 1000 patients annually. Both groups were at the population norm, and statin use was associated with a 5% (95% CI, 3%-8%; P < .001) reduction in the risk of dementia, equal to a number needed to treat of about 220 patients.
Depression Risk After a Concussion
The tracer analysis identified 1778 patients who were subsequently diagnosed as having depression after a concussion. The absolute incidence of depression was about 1 case per 16 patients (Figure 2). Patients receiving statins accounted for 440 cases of depression over 29 007 patient-years of follow-up, equal to an incidence of 15 cases per 1000 patients annually. Control patients accounted for 1338 cases of depression over 88 540 patient-years of follow-up, equal to an incidence of 15 cases per 1000 patients annually. Together, statin use was associated with an insignificant 4% (95% CI, −7% to 16%; P = .43) increased risk of depression before adjustment for measured baseline characteristics and an insignificant 4% (95% CI, −8% to 14%; P = .49) decreased risk of depression after adjustment for measured baseline characteristics.
Discussion
We studied 28 815 older adults diagnosed as having a concussion to test whether statin use might influence a patient’s recovery after the concussion. In patients receiving statins, we found that the subsequent incidence of dementia was twice the population norm, and it was further accentuated in control patients who were not taking a statin. The relative reduction in dementia risk associated with statin use after a concussion was greatest for those taking rosuvastatin, was consistent for those receiving lower dosages, was accentuated after adjustments for measured patient characteristics, and was distinct from the risks for patients after an ankle sprain. No other cardiovascular or noncardiovascular medications were associated with a decreased risk of dementia after a concussion (with the possible exception of angiotensin II receptor blockers).
Our study adds to prior research on statin use after traumatic brain injury due to a larger sample size, longer follow-up, more detailed statistical analysis, and a priority on concussions (eAppendix in the Supplement). Four prior randomized trials yielded conflicting results, with 2 studies89,90 reporting a positive protective effect of statins on neurocognitive outcomes and the other 2 studies91,92 reporting no significant effect. Eleven prior nonrandomized studies also yielded conflicting results, with 5 studies93-97 reporting a positive protective association on clinical outcomes and the other 6 studies98-103 reporting a negligible association. No prior studies indicated a detrimental influence of statin use after traumatic brain injury, but almost all previous studies focused on patients with moderate to severe injuries rather than concussions.
Limitations
Several limitations of our research merit attention. Our study was not a randomized trial, and the observed associations might reflect confounding due to earlier indications for statin use.104 Important missing covariates included smoking status, daily exercise, drug adherence, and other factors that influence the risk of developing dementia.105-108 These unknown differences in patients (healthy-user bias) might account for a reduction in the subsequent risk of dementia.109,110 Our study also lacks sufficient power to disentangle whether statins make a contribution before, during, or after a concussion. In addition, the diagnostic codes for concussion and dementia were not fully sensitive and may significantly underestimate the true incidence of dementia in patients after a concussion.111
The generalizability of our findings is also limited by a focus on older adults, the requirement for patients to survive at least 90 days after a concussion, and the exclusion of those already diagnosed as having dementia.112 We did not consider patients with severe brain injury that resulted in hospitalization; instead, we examined only concussion cases as the more common type of traumatic brain injury. We also lacked data on patients with injuries who did not seek medical care. Our study was based in Canada, did not account for geographic variances in health care delivery, and potentially underestimated risks due to random delays in diagnosing dementia. We also lacked nuanced data on functional status, and we found only a modest degree of healthy-user bias in our patients.113,114
Our study has further limitations for clinical care. Concussion and dementia are both varied disorders, so aggregate statistics do not necessarily apply to unique patients. The median follow-up duration was less than 5 years, whereas the course of dementia can span decades of subclinical changes. Our patients had years of unrecorded history and an unknown total number of concussions over a lifetime. The relative risks associated with concussions and with statin use were both modest because each addresses only one of many contributors to dementia. Our observational design also means that the unmeasured burden of cardiovascular and neuropsychiatric diseases may have been imbalanced against the patients receiving statins and may have led to analyses that underestimate the neuroprotection from statins.
The findings of our study suggest a potential long-term protective association between statin use and the risk of dementia after a concussion that justifies future research. The study also provides estimates of event rates, time profiles, effect sizes, and baseline frequencies needed for planning future trials. Of course, a randomized trial might face difficulties in patient enrollment because adults may not be willing to be randomized to receive a placebo rather than a statin.92 The 20-year patient enrollment interval of our study could also be prohibitive for a prospective trial. In addition, we know of no practical method to randomize patients to receive a statin immediately before a concussion. Therefore, analytic observational research may provide the best available data for the immediate future.
Conclusions
Concussion is often popularized as a problem in athletic youth and tends to be underdiagnosed in older individuals.115-117 The results of our study suggest that concussions are a common injury in older adults and indicate that dementia may be a frequent outcome years afterward. Therefore, more efforts to prevent concussions should be encouraged at all ages.118 Screening for past concussions might also offer new clinical insights for patients diagnosed as having dementia.119 A potential neuroprotective benefit may also encourage greater medication adherence for patients who are already prescribed a statin.120,121 In addition, a concussion should not be interpreted as a reason to stop statins, and a future randomized trial is justified.122 The long-term neurologic consequences of a concussion are substantial and merit attention.123
Back to top
Article Information
Accepted for Publication: January 10, 2019.
Corresponding Author: Donald A. Redelmeier, MD, MSHSR, Division of General Internal Medicine, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Ste G-151, Toronto, ON M4N 3M5, Canada (dar@ices.on.ca).
Published Online: May 20, 2019. doi:10.1001/jamaneurol.2019.1148
Author Contributions: Dr Redelmeier had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Redelmeier, Manzoor.
Acquisition, analysis, or interpretation of data: Redelmeier, Thiruchelvam.
Drafting of the manuscript: Redelmeier, Manzoor.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Redelmeier, Thiruchelvam.
Obtained funding: Redelmeier.
Administrative, technical, or material support: Redelmeier, Manzoor.
Supervision: Redelmeier.
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by a Canada Research Chair in Medical Decision Sciences, the Canadian Institutes of Health Research, the BrightFocus Foundation, and the Comprehensive Research Experience for Medical Students at the University of Toronto.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The views are those of the authors and do not necessarily reflect the views of the Ontario Ministry of Health and Long-Term Care.
Additional Contributions: The following individuals at the University of Toronto provided helpful comments: Sandra Black, MD, Anthony Feinstein, MD, Michael Fralick, MD, Andrea Gershon, MD, Taaha Muhammad, BHSc, Sheharyar Raza, MD, Charles Tator, MD, Jason Woodfine, MD, Christopher Yarnell, MD, Jonathan Zipursky, MD, and Jeremy Zung, MD. None received compensation.
References
1.
Bazarian JJ, McClung J, Shah MN, Cheng YT, Flesher W, Kraus J. Mild traumatic brain injury in the United States, 1998-2000. Brain Inj. 2005;19(2):85-91. doi:10.1080/02699050410001720158PubMedGoogle ScholarCrossref
2.
Styrke J, Stålnacke BM, Sojka P, Björnstig U. Traumatic brain injuries in a well-defined population: epidemiological aspects and severity. J Neurotrauma. 2007;24(9):1425-1436. doi:10.1089/neu.2007.0266PubMedGoogle ScholarCrossref
3.
Feigin VL, Theadom A, Barker-Collo S, et al; BIONIC Study Group. Incidence of traumatic brain injury in New Zealand: a population-based study. Lancet Neurol. 2013;12(1):53-64. doi:10.1016/S1474-4422(12)70262-4PubMedGoogle ScholarCrossref
4.
Marin JR, Weaver MD, Yealy DM, Mannix RC. Trends in visits for traumatic brain injury to emergency departments in the United States. JAMA. 2014;311(18):1917-1919. doi:10.1001/jama.2014.3979
ArticlePubMedGoogle ScholarCrossref
5.
Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. soldiers returning from Iraq. N Engl J Med. 2008;358(5):453-463. doi:10.1056/NEJMoa072972PubMedGoogle ScholarCrossref
6.
Jaffee MS, Winter WC, Jones CC, Ling G. Sleep disturbances in athletic concussion. Brain Inj. 2015;29(2):221-227. doi:10.3109/02699052.2014.983978PubMedGoogle ScholarCrossref
7.
Master CL, Mayer AR, Quinn D, Grady MF. Concussion. Ann Intern Med. 2018;169(1):ITC1-ITC16. doi:10.7326/AITC201807030PubMedGoogle ScholarCrossref
8.
Carroll LJ, Cassidy JD, Cancelliere C, et al. Systematic review of the prognosis after mild traumatic brain injury in adults: cognitive, psychiatric, and mortality outcomes: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis. Arch Phys Med Rehabil. 2014;95(3)(suppl):S152-S173. doi:10.1016/j.apmr.2013.08.300PubMedGoogle ScholarCrossref
9.
McInnes K, Friesen CL, MacKenzie DE, Westwood DA, Boe SG. Mild traumatic brain injury (mTBI) and chronic cognitive impairment: a scoping review. PLoS One. 2017;12(4):e0174847. doi:10.1371/journal.pone.0174847PubMedGoogle ScholarCrossref
10.
DeKosky ST, Ikonomovic MD, Gandy S. Traumatic brain injury: football, warfare, and long-term effects. N Engl J Med. 2010;363(14):1293-1296. doi:10.1056/NEJMp1007051PubMedGoogle ScholarCrossref
11.
Godbolt AK, Cancelliere C, Hincapié CA, et al. Systematic review of the risk of dementia and chronic cognitive impairment after mild traumatic brain injury: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis. Arch Phys Med Rehabil. 2014;95(3)(suppl):S245-S256. doi:10.1016/j.apmr.2013.06.036PubMedGoogle ScholarCrossref
12.
Fazel S, Wolf A, Pillas D, Lichtenstein P, Långström N. Suicide, fatal injuries, and other causes of premature mortality in patients with traumatic brain injury: a 41-year Swedish population study. JAMA Psychiatry. 2014;71(3):326-333. doi:10.1001/jamapsychiatry.2013.3935
ArticlePubMedGoogle ScholarCrossref
13.
Nordström A, Nordström P. Traumatic brain injury and the risk of dementia diagnosis: a nationwide cohort study. PLoS Med. 2018;15(1):e1002496. doi:10.1371/journal.pmed.1002496PubMedGoogle ScholarCrossref
14.
Fann JR, Ribe AR, Pedersen HS, et al. Long-term risk of dementia among people with traumatic brain injury in Denmark: a population-based observational cohort study. Lancet Psychiatry. 2018;5(5):424-431. doi:10.1016/S2215-0366(18)30065-8PubMedGoogle ScholarCrossref
15.
Petraglia AL, Maroon JC, Bailes JE. From the field of play to the field of combat: a review of the pharmacological management of concussion. Neurosurgery. 2012;70(6):1520-1533. doi:10.1227/NEU.0b013e31824cebe8PubMedGoogle ScholarCrossref
16.
Gravel J, D’Angelo A, Carrière B, et al. Interventions provided in the acute phase for mild traumatic brain injury: a systematic review. Syst Rev. 2013;2:63. doi:10.1186/2046-4053-2-63PubMedGoogle ScholarCrossref
17.
Kamins J, Bigler E, Covassin T, et al. What is the physiological time to recovery after concussion? a systematic review. Br J Sports Med. 2017;51(12):935-940. doi:10.1136/bjsports-2016-097464PubMedGoogle ScholarCrossref
18.
Schroeppel TJ, Fischer PE, Zarzaur BL, et al. Beta-adrenergic blockade and traumatic brain injury: protective? J Trauma. 2010;69(4):776-782. doi:10.1097/TA.0b013e3181e981b8PubMedGoogle ScholarCrossref
19.
Radosevich JJ, Patanwala AE, Erstad BL. Emerging pharmacological agents to improve survival from traumatic brain injury. Brain Inj. 2013;27(13-14):1492-1499. doi:10.3109/02699052.2013.823658PubMedGoogle ScholarCrossref
20.
Wright DW, Yeatts SD, Silbergleit R, et al; NETT Investigators. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med. 2014;371(26):2457-2466. doi:10.1056/NEJMoa1404304PubMedGoogle ScholarCrossref
21.
Robertson CS, Hannay HJ, Yamal JM, et al; Epo Severe TBI Trial Investigators. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA. 2014;312(1):36-47. doi:10.1001/jama.2014.6490
ArticlePubMedGoogle ScholarCrossref
22.
Bergold PJ. Treatment of traumatic brain injury with anti-inflammatory drugs. Exp Neurol. 2016;275(pt 3):367-380. doi:10.1016/j.expneurol.2015.05.024PubMedGoogle ScholarCrossref
23.
Mihaylova B, Emberson J, Blackwell L, et al; Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581-590. doi:10.1016/S0140-6736(12)60367-5PubMedGoogle ScholarCrossref
24.
Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;1(1):CD004816.PubMedGoogle Scholar
25.
Barkhoudarian G, Hovda DA, Giza CC. The molecular pathophysiology of concussive brain injury. Clin Sports Med. 2011;30(1):33-48, vii-iii. doi:10.1016/j.csm.2010.09.001PubMedGoogle ScholarCrossref
26.
Béziaud T, Ru Chen X, El Shafey N, et al. Simvastatin in traumatic brain injury: effect on brain edema mechanisms. Crit Care Med. 2011;39(10):2300-2307. doi:10.1097/CCM.0b013e3182227e4aPubMedGoogle ScholarCrossref
27.
Peng W, Yang J, Yang B, Wang L, Xiong XG, Liang Q. Impact of statins on cognitive deficits in adult male rodents after traumatic brain injury: a systematic review. Biomed Res Int. 2014;2014:261409. doi:10.1155/2014/261409PubMedGoogle Scholar
28.
Abrahamson EE, Ikonomovic MD, Dixon CE, DeKosky ST. Simvastatin therapy prevents brain trauma–induced increases in β-amyloid peptide levels. Ann Neurol. 2009;66(3):407-414. doi:10.1002/ana.21731PubMedGoogle ScholarCrossref
29.
Xu X, Gao W, Cheng S, et al. Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury. J Neuroinflammation. 2017;14(1):167. doi:10.1186/s12974-017-0934-2PubMedGoogle ScholarCrossref
30.
Lin FC, Chuang YS, Hsieh HM, et al. Early statin use and the progression of Alzheimer disease: a total population–based case-control study. Medicine (Baltimore). 2015;94(47):e2143. doi:10.1097/MD.0000000000002143PubMedGoogle ScholarCrossref
31.
Schilling S, Tzourio C, Soumaré A, et al. Differential associations of plasma lipids with incident dementia and dementia subtypes in the 3C Study: a longitudinal, population-based prospective cohort study. PLoS Med. 2017;14(3):e1002265. doi:10.1371/journal.pmed.1002265PubMedGoogle ScholarCrossref
32.
Reed B, Villeneuve S, Mack W, DeCarli C, Chui HC, Jagust W. Associations between serum cholesterol levels and cerebral amyloidosis. JAMA Neurol. 2014;71(2):195-200. doi:10.1001/jamaneurol.2013.5390
ArticlePubMedGoogle ScholarCrossref
33.
McFarland AJ, Anoopkumar-Dukie S, Arora DS, et al. Molecular mechanisms underlying the effects of statins in the central nervous system. Int J Mol Sci. 2014;15(11):20607-20637. doi:10.3390/ijms151120607PubMedGoogle ScholarCrossref
34.
Carlsson CM, Xu G, Wen Z, et al. Effects of atorvastatin on cerebral blood flow in middle-aged adults at risk for Alzheimer’s disease: a pilot study. Curr Alzheimer Res. 2012;9(8):990-997. doi:10.2174/156720512803251075PubMedGoogle ScholarCrossref
35.
Giannopoulos S, Katsanos AH, Kosmidou M, Tsivgoulis G. Statins and vascular dementia: a review. J Alzheimers Dis. 2014;42(suppl 3):S315-S320. doi:10.3233/JAD-132366PubMedGoogle ScholarCrossref
36.
Butterfield DA, Barone E, Mancuso C. Cholesterol-independent neuroprotective and neurotoxic activities of statins: perspectives for statin use in Alzheimer disease and other age-related neurodegenerative disorders. Pharmacol Res. 2011;64(3):180-186. doi:10.1016/j.phrs.2011.04.007PubMedGoogle ScholarCrossref
37.
Feldman HH, Doody RS, Kivipelto M, et al; LEADe Investigators. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology. 2010;74(12):956-964. doi:10.1212/WNL.0b013e3181d6476aPubMedGoogle ScholarCrossref
38.
Fink HA, Jutkowitz E, McCarten JR, et al. Pharmacologic interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: a systematic review. Ann Intern Med. 2018;168(1):39-51. doi:10.7326/M17-1529PubMedGoogle ScholarCrossref
39.
Maegele M. Traumatic brain injury in 2017: exploring the secrets of concussion. Lancet Neurol. 2018;17(1):13-15. doi:10.1016/S1474-4422(17)30419-2PubMedGoogle ScholarCrossref
40.
Power MC, Weuve J, Sharrett AR, Blacker D, Gottesman RF. Statins, cognition, and dementia: systematic review and methodological commentary. Nat Rev Neurol. 2015;11(4):220-229. doi:10.1038/nrneurol.2015.35PubMedGoogle ScholarCrossref
41.
Smith DH, Johnson VE, Stewart W. Chronic neuropathologies of single and repetitive TBI: substrates of dementia? Nat Rev Neurol. 2013;9(4):211-221. doi:10.1038/nrneurol.2013.29PubMedGoogle ScholarCrossref
42.
Kristman VL, Borg J, Godbolt AK, et al. Methodological issues and research recommendations for prognosis after mild traumatic brain injury: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis. Arch Phys Med Rehabil. 2014;95(3)(suppl):S265-S277. doi:10.1016/j.apmr.2013.04.026PubMedGoogle ScholarCrossref
43.
McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev. 2016;(1):CD003160.PubMedGoogle Scholar
44.
Mendoza-Oliva A, Zepeda A, Arias C. The complex actions of statins in brain and their relevance for Alzheimer’s disease treatment: an analytical review. Curr Alzheimer Res. 2014;11(9):817-833.PubMedGoogle Scholar
45.
Xie C, Cong D, Wang X, et al. The effect of simvastatin treatment on proliferation and differentiation of neural stem cells after traumatic brain injury. Brain Res. 2015;1602:1-8. doi:10.1016/j.brainres.2014.03.021PubMedGoogle ScholarCrossref
46.
Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science. 2016;353(6301):777-783. doi:10.1126/science.aag2590PubMedGoogle ScholarCrossref
47.
Chou A, Krukowski K, Jopson T, et al. Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury. Proc Natl Acad Sci U S A. 2017;114(31):E6420-E6426. doi:10.1073/pnas.1707661114PubMedGoogle ScholarCrossref
48.
Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Med. 2004;117(11):823-829. doi:10.1016/j.amjmed.2004.07.041PubMedGoogle ScholarCrossref
49.
Miron VE, Zehntner SP, Kuhlmann T, et al. Statin therapy inhibits remyelination in the central nervous system. Am J Pathol. 2009;174(5):1880-1890. doi:10.2353/ajpath.2009.080947PubMedGoogle ScholarCrossref
50.
Schilling JM, Cui W, Godoy JC, et al. Long-term atorvastatin treatment leads to alterations in behavior, cognition, and hippocampal biochemistry. Behav Brain Res. 2014;267:6-11. doi:10.1016/j.bbr.2014.03.014PubMedGoogle ScholarCrossref
51.
Strom BL, Schinnar R, Karlawish J, Hennessy S, Teal V, Bilker WB. Statin therapy and risk of acute memory impairment. JAMA Intern Med. 2015;175(8):1399-1405. doi:10.1001/jamainternmed.2015.2092
ArticlePubMedGoogle ScholarCrossref
52.
Tuccori M, Montagnani S, Mantarro S, et al. Neuropsychiatric adverse events associated with statins: epidemiology, pathophysiology, prevention and management. CNS Drugs. 2014;28(3):249-272. doi:10.1007/s40263-013-0135-1PubMedGoogle ScholarCrossref
53.
Russo MV, McGavern DB. Inflammatory neuroprotection following traumatic brain injury. Science. 2016;353(6301):783-785. doi:10.1126/science.aaf6260PubMedGoogle ScholarCrossref
54.
Roy S, Weinstock JL, Ishino AS, et al. Association of cognitive impairment in patients on 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors. J Clin Med Res. 2017;9(7):638-649. doi:10.14740/jocmr3066wPubMedGoogle ScholarCrossref
55.
Statistics Canada. Population estimates on July 1st, by age and sex. Frequency: annual. Table: 17-10-0005-01 (formerly CANSIM 051-0001). Geography: Canada, province or territory. http://www.statcan.gc.ca/tables-tableaux/sum-som/l01/cst01/demo02a-eng.htm. Accessed June 6, 2014.
56.
Ng R, Maxwell CJ, Yates EA, et al. Brain Disorders in Ontario: Prevalence, Incidence and Costs From Health Administrative Data. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences; July 2015. http://www.ices.on.ca/~/media/Files/Atlases-Reports/2015/Brain-Disorders-in-Ontario/Full-Report.ashx. Accessed July 26, 2017.
57.
Prince M, Wimo A, Guerchet M, Ali GC, Wu YT, Prina M. World Alzheimer Report 2015: The Global Impact of Dementia: An Analysis of Prevalence, Incidence, Cost and Trends. London, England: Alzheimer’s Disease International; 2015. https://www.alz.co.uk/research/WorldAlzheimerReport2015.pdf. Accessed December 3, 2017.
58.
Alzheimer Society of Canada. Report summary prevalence and monetary costs of dementia in Canada (2016): a report by the Alzheimer Society of Canada [in French]. Health Promot Chronic Dis Prev Can. 2016;36(10):231-232. doi:10.24095/hpcdp.36.10.04PubMedGoogle ScholarCrossref
59.
Sessions SY, Detsky AS. Washington, Ottawa, and health care reform: a tale of 2 capitals. JAMA. 2010;303(20):2078-2079. doi:10.1001/jama.2010.654
ArticlePubMedGoogle ScholarCrossref
60.
Williams JI, Young W. A summary of studies on the quality of health care administrative databases in Canada. In: Goel V, Williams JI, Anderson GM, et al, eds. Patterns of Health Care in Ontario: The ICES Practice Atlas. Ottawa, Ontario: Canadian Medical Association; 1996.
61.
Macpherson AK, Schull M, Manuel D, Cernat G, Redelmeier DA, Laupacis A. Injuries in Ontario: ICES Atlas. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences; 2005.
62.
Carroll CP, Cochran JA, Guse CE, Wang MC. Are we underestimating the burden of traumatic brain injury? surveillance of severe traumatic brain injury using Centers for Disease Control International Classification of Disease, Ninth Revision, Clinical Modification, traumatic brain injury codes. Neurosurgery. 2012;71(6):1064-1070. doi:10.1227/NEU.0b013e31826f7c16PubMedGoogle ScholarCrossref
63.
Bazarian JJ, Veazie P, Mookerjee S, Lerner EB. Accuracy of mild traumatic brain injury case ascertainment using ICD-9 codes. Acad Emerg Med. 2006;13(1):31-38. doi:10.1197/j.aem.2005.07.038PubMedGoogle ScholarCrossref
64.
Morrish J, Carey S. Concussions in Canada. Toronto, Ontario: Canada Injury Compass; 2013:1-3.
65.
Davis DH, Muniz Terrera G, Keage H, et al. Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study. Brain. 2012;135(pt 9):2809-2816. doi:10.1093/brain/aws190PubMedGoogle ScholarCrossref
66.
Levy AR, O’Brien BJ, Sellors C, Grootendorst P, Willison D. Coding accuracy of administrative drug claims in the Ontario Drug Benefit database. Can J Clin Pharmacol. 2003;10(2):67-71.PubMedGoogle Scholar
67.
Ko DT, Wijeysundera HC, Jackevicius CA, Yousef A, Wang J, Tu JV. Diabetes mellitus and cardiovascular events in older patients with myocardial infarction prescribed intensive-dose and moderate-dose statins. Circ Cardiovasc Qual Outcomes. 2013;6(3):315-322. doi:10.1161/CIRCOUTCOMES.111.000015PubMedGoogle ScholarCrossref
68.
Canadian Institute for Health Information. CIHI Data Quality Study of Emergency Department Visits for 2004-2005: Executive Summary. Ottawa, Ontario, Canada: Canadian Institute for Health Information; 2008.
69.
Iron K, Zagorski BM, Sykora K, Manuel DG. Living and Dying in Ontario: An Opportunity for Improved Health Information: ICES Investigative Report. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences; March 2008.
70.
Wilkins R. Automated Geographic Coding Based on the Statistics Canada Postal Code Conversion Files, Including Postal Codes to December 2003. Ottawa, Ontario: Health Analysis and Measurement Group, Statistics Canada; 2004.
71.
Juurlink DN, Preyra C, Croxford R, et al. Canadian Institute for Health Information Discharge Abstract Database: A Validation Study. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences; 2006.
72.
Levy AR, Tamblyn RM, Fitchett D, McLeod PJ, Hanley JA. Coding accuracy of hospital discharge data for elderly survivors of myocardial infarction. Can J Cardiol. 1999;15(11):1277-1282.PubMedGoogle Scholar
73.
Paterson JM, Suleiman A, Hux JE, Bell C. How complete are drug history profiles that are based on public drug benefit claims? Can J Clin Pharmacol. 2008;15(1):e108-e116.PubMedGoogle Scholar
74.
Proulx J, Hunt J. Drug use among seniors on public drug programs in Canada, 2012. Healthc Q. 2015;18(1):11-13. doi:10.12927/hcq.2015.24250PubMedGoogle ScholarCrossref
75.
Daviglus ML, Bell CC, Berrettini W, et al. National Institutes of Health State-of-the-Science Conference statement: preventing Alzheimer disease and cognitive decline. Ann Intern Med. 2010;153(3):176-181. doi:10.7326/0003-4819-153-3-201008030-00260PubMedGoogle ScholarCrossref
76.
Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113):2673-2734. doi:10.1016/S0140-6736(17)31363-6PubMedGoogle ScholarCrossref
77.
Bronskill SE, Camacho X, Gruneir A, Ho MM. Health System Use by Frail Ontario Seniors: An In-depth Examination of Four Vulnerable Cohorts. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences; November 2011. https://www.ices.on.ca/flip-publication/health-system-use-by-frail-ontario-seniors/files/assets/basic-html/index.html#1. Accessed January 3, 2019.
78.
Wilchesky M, Tamblyn RM, Huang A. Validation of diagnostic codes within medical services claims. J Clin Epidemiol. 2004;57(2):131-141. doi:10.1016/S0895-4356(03)00246-4PubMedGoogle ScholarCrossref
79.
St Germaine-Smith C, Metcalfe A, Pringsheim T, et al. Recommendations for optimal ICD codes to study neurologic conditions: a systematic review. Neurology. 2012;79(10):1049-1055. doi:10.1212/WNL.0b013e3182684707PubMedGoogle ScholarCrossref
80.
Haag MD, Hofman A, Koudstaal PJ, Stricker BH, Breteler MM. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity: the Rotterdam Study. J Neurol Neurosurg Psychiatry. 2009;80(1):13-17. doi:10.1136/jnnp.2008.150433PubMedGoogle ScholarCrossref
81.
Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19(1):117-125. doi:10.1111/j.1472-8206.2004.00299.xPubMedGoogle ScholarCrossref
82.
Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94(446):496-509. doi:10.1080/01621459.1999.10474144Google ScholarCrossref
83.
Bombardier CH, Fann JR, Temkin NR, Esselman PC, Barber J, Dikmen SS. Rates of major depressive disorder and clinical outcomes following traumatic brain injury. JAMA. 2010;303(19):1938-1945. doi:10.1001/jama.2010.599
ArticlePubMedGoogle ScholarCrossref
84.
Barkow K, Maier W, Ustün TB, Gänsicke M, Wittchen HU, Heun R. Risk factors for depression at 12-month follow-up in adult primary health care patients with major depression: an international prospective study. J Affect Disord. 2003;76(1-3):157-169. doi:10.1016/S0165-0327(02)00081-2PubMedGoogle ScholarCrossref
85.
Taylor WD, Aizenstein HJ, Alexopoulos GS. The vascular depression hypothesis: mechanisms linking vascular disease with depression. Mol Psychiatry. 2013;18(9):963-974. doi:10.1038/mp.2013.20PubMedGoogle ScholarCrossref
86.
Redlich C, Berk M, Williams LJ, Sundquist J, Sundquist K, Li X. Statin use and risk of depression: a Swedish national cohort study. BMC Psychiatry. 2014;14:348. doi:10.1186/s12888-014-0348-yPubMedGoogle ScholarCrossref
87.
Public Health Agency of Canada. Dementia in Canada, including Alzheimer’s disease: highlights from the Canadian Chronic Disease Surveillance System. https://www.canada.ca/content/dam/phac-aspc/documents/services/publications/diseases-conditions/dementia-highlights-canadian-chronic-disease-surveillance/dementia-highlights-canadian-chronic-disease-surveillance.pdf. Published 2017. Accessed January 4, 2018.
88.
VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med. 2017;167(4):268-274. doi:10.7326/M16-2607PubMedGoogle ScholarCrossref
89.
Tapia-Perez J, Sanchez-Aguilar M, Torres-Corzo JG, et al. Effect of rosuvastatin on amnesia and disorientation after traumatic brain injury (NCT003229758). J Neurotrauma. 2008;25(8):1011-1017. doi:10.1089/neu.2008.0554PubMedGoogle ScholarCrossref
90.
Farzanegan GR, Derakhshan N, Khalili H, Ghaffarpasand F, Paydar S. Effects of atorvastatin on brain contusion volume and functional outcome of patients with moderate and severe traumatic brain injury: a randomized double-blind placebo-controlled clinical trial. J Clin Neurosci. 2017;44:143-147. doi:10.1016/j.jocn.2017.06.010PubMedGoogle ScholarCrossref
91.
Sánchez-Aguilar M, Tapia-Pérez JH, Sánchez-Rodríguez JJ, et al. Effect of rosuvastatin on cytokines after traumatic head injury. J Neurosurg. 2013;118(3):669-675. doi:10.3171/2012.12.JNS121084PubMedGoogle ScholarCrossref
92.
Robertson CS, McCarthy JJ, Miller ER, Levin H, McCauley SR, Swank PR. Phase II clinical trial of atorvastatin in mild traumatic brain injury. J Neurotrauma. 2017;34:1394-1401. doi:10.1089/neu.2016.4717PubMedGoogle ScholarCrossref
93.
Efron DT, Sorock G, Haut ER, et al. Preinjury statin use is associated with improved in-hospital survival in elderly trauma patients. J Trauma. 2008;64(1):66-73. doi:10.1097/TA.0b013e31815b842aPubMedGoogle ScholarCrossref
94.
Schneider EB, Efron DT, MacKenzie EJ, Rivara FP, Nathens AB, Jurkovich GJ. Premorbid statin use is associated with improved survival and functional outcomes in older head-injured individuals. J Trauma. 2011;71(4):815-819. doi:10.1097/TA.0b013e3182319de5PubMedGoogle ScholarCrossref
95.
Orlando A, Bar-Or D, Salottolo K, et al. Unintentional discontinuation of statins may increase mortality after traumatic brain injury in elderly patients: a preliminary observation. J Clin Med Res. 2013;5(3):168-173.PubMedGoogle Scholar
96.
Khokhar B, Simoni-Wastila L, Slejko JF, Perfetto E, Zhan M, Smith GS. In-hospital mortality following traumatic brain injury among older Medicare beneficiaries, comparing statin users with nonusers. J Pharm Technol. 2017;33(6):225-236. doi:10.1177/8755122517735656PubMedGoogle ScholarCrossref
97.
Khokhar B, Simoni-Wastila L, Slejko JF, Perfetto E, Zhan M, Smith GS. Mortality and associated morbidities following traumatic brain injury in older Medicare statin users. J Head Trauma Rehabil. 2018;33(6):E68-E76. PubMedGoogle Scholar
98.
Wang D, Li T, Tian Y, et al. Effects of atorvastatin on chronic subdural hematoma: a preliminary report from three medical centers. J Neurol Sci. 2014;336(1-2):237-242. doi:10.1016/j.jns.2013.11.005PubMedGoogle ScholarCrossref
99.
Neilson SJ, See AA, King NK. Effect of prior statin use on outcome after severe traumatic brain injury in a South-East Asian population. Brain Inj. 2016;30(8):993-998. doi:10.3109/02699052.2016.1147599PubMedGoogle ScholarCrossref
100.
Wee HY, Ho CH, Liang FW, et al. Increased risk of new-onset depression in patients with traumatic brain injury and hyperlipidemia: the important role of statin medications. J Clin Psychiatry. 2016;77(4):505-511. doi:10.4088/JCP.14m09749PubMedGoogle ScholarCrossref
101.
Xu M, Chen P, Zhu X, Wang C, Shi X, Yu B. Effects of atorvastatin on conservative and surgical treatments of chronic subdural hematoma in patients. World Neurosurg. 2016;91:23-28. doi:10.1016/j.wneu.2016.03.067PubMedGoogle ScholarCrossref
102.
Chan DY, Chan DT, Sun TF, Ng SC, Wong GK, Poon WS. The use of atorvastatin for chronic subdural haematoma: a retrospective cohort comparison study. Br J Neurosurg. 2017;31(1):72-77. doi:10.1080/02688697.2016.1208806PubMedGoogle ScholarCrossref
103.
Orlando A, Thomas C, Carrick M, Slone DS, Mains CW, Bar-Or D. Statin discontinuation and mortality in an older adult population with traumatic brain injury: a four-year, multi-centre, observational cohort study. Injury. 2017;48(5):1040-1046. doi:10.1016/j.injury.2016.11.027PubMedGoogle ScholarCrossref
104.
Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273(5):408-412. doi:10.1001/jama.1995.03520290060030
ArticlePubMedGoogle ScholarCrossref
105.
Brasure M, Desai P, Davila H, et al. Physical activity interventions in preventing cognitive decline and Alzheimer-type dementia: a systematic review. Ann Intern Med. 2018;168(1):30-38. doi:10.7326/M17-1528PubMedGoogle ScholarCrossref
106.
Gardener H, Wright CB, Rundek T, Sacco RL. Brain health and shared risk factors for dementia and stroke. Nat Rev Neurol. 2015;11(11):651-657. doi:10.1038/nrneurol.2015.195PubMedGoogle ScholarCrossref
107.
Downey A, Stroud C, Landis S, Leshner AI, eds; Committee on Preventing Dementia and Cognitive Impairment; Board on Health Sciences Policy; Health and Medicine Division; National Academies of Sciences, Engineering, and Medicine. Preventing Cognitive Decline and Dementia: A Way Forward. Washington, DC: National Academies Press; June 2017. https://www.ncbi.nlm.nih.gov/books/NBK436397/. Accessed January 4, 2018.
108.
Wang HX, MacDonald SW, Dekhtyar S, Fratiglioni L. Association of lifelong exposure to cognitive reserve–enhancing factors with dementia risk: a community-based cohort study. PLoS Med. 2017;14(3):e1002251. doi:10.1371/journal.pmed.1002251PubMedGoogle ScholarCrossref
109.
Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000;57(10):1439-1443. doi:10.1001/archneur.57.10.1439
ArticlePubMedGoogle ScholarCrossref
110.
Shrank WH, Patrick AR, Brookhart MA. Healthy user and related biases in observational studies of preventive interventions: a primer for physicians. J Gen Intern Med. 2011;26(5):546-550. doi:10.1007/s11606-010-1609-1PubMedGoogle ScholarCrossref
111.
Roozenbeek B, Maas AI, Menon DK. Changing patterns in the epidemiology of traumatic brain injury. Nat Rev Neurol. 2013;9(4):231-236. doi:10.1038/nrneurol.2013.22PubMedGoogle ScholarCrossref
112.
Hernán MA, Hernández-Díaz S, Robins JM. A structural approach to selection bias. Epidemiology. 2004;15(5):615-625. doi:10.1097/01.ede.0000135174.63482.43PubMedGoogle ScholarCrossref
113.
Brookhart MA, Patrick AR, Dormuth C, et al. Adherence to lipid-lowering therapy and the use of preventive health services: an investigation of the healthy user effect. Am J Epidemiol. 2007;166(3):348-354. doi:10.1093/aje/kwm070PubMedGoogle ScholarCrossref
114.
Kinjo M, Chia-Cheng Lai E, Korhonen MJ, McGill RL, Setoguchi S. Potential contribution of lifestyle and socioeconomic factors to healthy user bias in antihypertensives and lipid-lowering drugs. Open Heart. 2017;4(1):e000417. doi:10.1136/openhrt-2016-000417PubMedGoogle ScholarCrossref
115.
Harvey LA, Close JC. Traumatic brain injury in older adults: characteristics, causes and consequences. Injury. 2012;43(11):1821-1826. doi:10.1016/j.injury.2012.07.188PubMedGoogle ScholarCrossref
116.
Maas AIR, Menon DK, Adelson PD, et al; InTBIR Participants and Investigators. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017;16(12):987-1048. doi:10.1016/S1474-4422(17)30371-XPubMedGoogle ScholarCrossref
117.
Gardner RC, Dams-O’Connor K, Morrissey MR, Manley GT. Geriatric traumatic brain injury: epidemiology, outcomes, knowledge gaps, and future directions [published online February 15, 2018]. J Neurotrauma. doi:10.1089/neu.2017.5371PubMedGoogle Scholar
118.
Redelmeier DA, Raza S. Concussions and repercussions. PLoS Med. 2016;13(8):e1002104. doi:10.1371/journal.pmed.1002104PubMedGoogle ScholarCrossref
119.
Bardach NS, Wang JJ, De Leon SF, et al. Effect of pay-for-performance incentives on quality of care in small practices with electronic health records: a randomized trial. JAMA. 2013;310(10):1051-1059. doi:10.1001/jama.2013.277353
ArticlePubMedGoogle ScholarCrossref
120.
Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013;158(7):526-534. doi:10.7326/0003-4819-158-7-201304020-00004PubMedGoogle ScholarCrossref
121.
Yusuf S. Why do people not take life-saving medications? the case of statins. Lancet. 2016;388(10048):943-945. doi:10.1016/S0140-6736(16)31532-XPubMedGoogle ScholarCrossref
122.
Gurwitz JH, Go AS, Fortmann SP. Statins for primary prevention in older adults: uncertainty and the need for more evidence. JAMA. 2016;316(19):1971-1972. doi:10.1001/jama.2016.15212
ArticlePubMedGoogle ScholarCrossref
123.
McCrory P, Meeuwisse WH, Aubry M, et al. Consensus statement on concussion in sport: the 4th International Conference on Concussion in Sport held in Zurich, November 2012. Br J Sports Med. 2013;47(5):250-258. doi:10.1136/bjsports-2013-092313PubMedGoogle ScholarCrossref
Donald A. Redelmeier, MD, MSHSR1,2,3,4,5; Fizza Manzoor, BHSc1,2,3; Deva Thiruchelvam, MSc3
Author Affiliations Article Information
JAMA Neurol. Published online May 20, 2019. doi:10.1001/jamaneurol.2019.1148
editorial comment icon Editorial
Comment
author interview icon Interviews
Audio Interview (15:53)
Association Between Statin Use and Risk of Dementia After a Concussion
Key Points
Question Is statin use associated with an increased or decreased risk of subsequent dementia after a concussion?
Findings In this large extended population-based double cohort study following 28 815 patients after a concussion, the 5-year incidence of dementia was substantial and statin use was associated with a significantly reduced risk of subsequent dementia.
Meaning Concussions are associated with an increased long-term risk of dementia, which is modestly reduced for patients receiving a statin.
Abstract
Importance Concussions are an acute injury that may lead to chronic disability, while statin use might improve neurologic recovery.
Objective To test whether statin use is associated with an increased or decreased risk of subsequent dementia after a concussion.
Design, Setting, and Participants Large extended population-based double cohort study in Ontario, Canada, from April 1, 1993, to April 1, 2013 (enrollment), and continued until March 31, 2016 (follow-up). Dates of analysis were April 28, 2014, through March 21, 2019. Participants were older adults diagnosed as having a concussion, excluding severe cases resulting in hospitalization, individuals with a prior diagnosis of dementia or delirium, and those who died within 90 days.
Exposure Statin prescription within 90 days after a concussion.
Main Outcome and Measure Long-term incidence of dementia.
Results This study identified 28 815 patients diagnosed as having a concussion (median age, 76 years; 61.3% female), of whom 7058 (24.5%) received a statin, and 21 757 (75.5%) did not receive a statin. A total of 4727 patients subsequently developed dementia over a mean follow-up of 3.9 years, equal to an incidence of 1 case per 6 patients. Patients who received a statin had a 13% reduced risk of dementia compared with patients who did not receive a statin (relative risk, 0.87; 95% CI, 0.81-0.93; P < .001). The decreased risk of dementia associated with statin use applied to diverse patient groups, remained independent of other cardiovascular medication use, intensified over time, was distinct from the risk of subsequent depression, and was not observed in patients after an ankle sprain.
Conclusions and Relevance In this study, older adults had a substantial long-term risk of dementia after a concussion, which was associated with a modest reduction among patients receiving a statin.
Introduction
Concussions are a common cause of brain injury occurring in more than 1 million Americans each year and disproportionately involving older adults.1-4 The subacute consequences vary widely and include fatigue, headache, irritability, insomnia, inattention, photophobia, vertigo, and cognitive difficulties.5-9 Most patients recover from a concussion within weeks, although some can develop lingering mood disorders or chronic neuropsychiatric disorders.10-14 The extent of complications after a concussion is uncertain, and effective pharmacologic treatments remain elusive.15-17 Unfortunately, many medical treatments for traumatic brain injury that showed promise in animal models have subsequently failed in human clinical trials.18-22
Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are a class of medications prescribed for the treatment of hyperlipidemia.23,24 Preclinical data suggest that statin use might mitigate injury-related brain edema, oxidative stress, amyloid protein aggregation, and neuroinflammation.25-29 The potential neuroprotective benefits from statins have also been speculated and include preserved cerebral blood flow, leading to decreased risks of Alzheimer disease, vascular dementia, and age-related cognitive decline.30-35 Together, these findings suggest that statin use could contribute to microvascular homeostasis and immune modulation independent of systemic lipid levels. However, statins do not improve cognition for patients already diagnosed as having dementia.36-38
The role of statins in recovery after a concussion has rarely been investigated.39,40 Furthermore, small sample sizes, selective enrollment, and brief follow-up have limited past studies41-43 assessing the long-term consequences of concussion. On the one hand, the potential neuroprotective associations of statin use may prevent subsequent dysfunction by neuron preservation and neural stem cell activation.44-47 On the other hand, the neurohazardous associations of statin use might contribute to memory difficulties from altered neurophysiology.48-54 We conducted a large extended population-based double cohort study using linked databases to test whether statin use is associated with an increased or decreased risk of dementia in older adults after a concussion.
Methods
Study Setting
This population-based multicenter double cohort study of older adults diagnosed as having a concussion throughout Ontario, Canada, was performed from April 1, 1993, to April 1, 2013 (enrollment period of 20 years), providing a minimum follow-up for survivors of 3 years and reflecting all data available. Ontario is Canada’s largest province, with a population of 12 407 300 in 2004 (the study midpoint), an annual incidence of dementia was 19 cases per 1000 patients for adults 65 years and older, and societal costs of dementia estimated at $18 440 per patient-year.55-58 During our study, universal health insurance covered outpatient medical care for all individuals, with no out-of-pocket costs to patients.59 In addition, the Ontario Drug Benefit Program covered prescription medications for all patients 65 years and older.60 The study protocol was approved by the Research Ethics Board of Sunnybrook Health Sciences Centre, including a waiver for direct patient consent. All data are available through the Institute for Clinical Evaluative Sciences in Ontario.
Patient Identification
We identified patients 66 years and older diagnosed as having a concussion by assessing physician billing data using the concussion diagnostic criterion (International Classification of Diseases, Ninth Revision [ICD-9] code 850) from the Ontario Health Insurance Plan.61 This code for a concussion diagnosis has been validated with high specificity (99%) and moderate sensitivity (46%-76%).62,63 Patients who were admitted to a hospital within 2 days of a concussion or who survived less than 90 days were excluded to reduce confounding from severe brain injury.64 Patients with a history of dementia or delirium in the prior 5 years were also excluded to reduce confounding from past neuropsychiatric conditions.65 No patients were excluded otherwise. Patients with more than 1 concussion during the study were counted once based on the first incident.
Statin Medication Prescriptions
The prescription of a statin was identified through the Ontario Drug Benefit Program database, which has an accuracy exceeding 99% in this setting.66 The specific statins included were atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. We classified patients based on the specific statin received immediately after their concussion. The primary analysis compared patients who had received a statin prescription in the 90 days immediately after a concussion with patients who had not. Secondary analyses explored statin prescriptions in the 90 days before the concussion and also considered statins as time-dependent exposures in analyses to account for fluctuating prescriptions over time.67
Baseline Patient Characteristics
Additional baseline characteristics were defined on the day of the concussion and obtained by computerized linkage to health care records.68 A demographic registry was used to determine the patient’s age, sex, socioeconomic quintile, and home location.69,70 A physician services databases provided data on clinic visits, emergency department contacts, and hospitalizations in the prior year.60,71 The Ontario Drug Benefit Program database provided data on additional cardiovascular medications, neuropsychiatric medications, and miscellaneous medications.72-74 The available databases contained no information on smoking status, daily exercise, education level, family history, genetic factors, hearing loss, social isolation, or other factors that can alter dementia risk.75,76
Outcome Identification
The primary study outcome was a physician diagnosis of dementia (ICD-9 codes 290, 331, and 797) ascertained through the validated Ontario Health Insurance Plan database, as established in past research.77 These codes had a specificity of about 99% and a sensitivity of about 20% for dementia.78 To avoid false-positive results, we required a dementia diagnosis on 2 separate dates.79 Therefore, this outcome definition was highly specific and provided a conservative estimate of the incidence of dementia after a concussion. To corroborate this outcome, we also identified more extensive documentation of the diagnosis that could signify a worsening course over 3 years of follow-up. The available codes did not distinguish specific conditions underlying the dementia diagnosis.
Double Cohort Control Analysis
To test the importance of a potential association between statin use and subsequent dementia, we replicated our entire selection strategy and analysis, focusing instead on older adults diagnosed as having an ankle sprain rather than a concussion. The objective of this secondary parallel analysis was to distinguish the long-term prognosis for patients who had an acute neurologic injury (concussion cohort) from patients who had a peripheral orthopedic injury (ankle sprain). We then assessed the long-term incidence of dementia for patients who received a statin after an ankle sprain compared with patients who did not receive a statin after an ankle sprain. If a patient experienced both a concussion and an ankle sprain, the individual was included in both cohorts (the exclusion of overlap patients yielded similar results).
Statistical Analysis
Our primary analysis evaluated the incidence of dementia after a concussion, comparing patients who received a statin with patients who did not. Graphical displays were created using cumulative incidence curves. Statistical testing was based on proportional hazards analysis taking into account censoring for interval deaths and the study follow-up end date of March 31, 2016. Statistical testing examined associations before adjusting for measured baseline patient characteristics (basic analysis) and after adjusting for measured baseline patient characteristics (adjusted analysis) to check the robustness of relative risk estimates. All P values were 2 tailed, and .05 was the threshold for statistical significance.
Secondary Analyses
Additional analyses explored the potential role of statins in preventing dementia after a concussion. Lipophilic statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, and simvastatin) were compared with hydrophilic statins (pravastatin and rosuvastatin).80 Higher dosages of statins (maximum accepted treatment dosage for a specific statin) were compared with lower dosages of statins (all smaller dosages for a specific statin).81 We also evaluated the incidence of dementia among patients receiving the most commonly used statins separately. Patients who received a statin before and after the concussion (continuous use) were also distinguished from patients who received their statin only after the concussion (initiation) and patients who stopped their statin after the concussion (discontinuation).
We conducted 3 further statistical analyses to explore the robustness of the primary analysis. The first analysis applied 1:1 propensity score matching of patients receiving statins with control patients to account for possible imbalances in baseline characteristics and unmeasured indications for statins. The second analysis introduced time-dependent covariates to account for subsequent changes in statin prescriptions over time and fluctuating adherence to statins. The third analysis considered the possible competing risks of other causes of death that might obscure a subsequent diagnosis of dementia.82 Each of the 3 statistical analyses was conducted before and after adjusting for measured baseline patient characteristics to check the robustness of relative risk estimates.
In addition, we used tracer analysis to check for confounding by replacing the dementia outcome with an alternative clinical end point. Specifically, we reasoned that subsequent depression, instead of dementia, is a different adverse neuropsychiatric outcome that is frequent, serious, important, and similar in some shared clinical features to a dementia diagnosis in older patients.83 However, the risk of depression is not substantially reduced by statins (due to distinct pathophysiology) but can be associated with shared determinants (eg, alcohol use and physical inactivity).84-86 Therefore, we repeated the analyses and examined the risk of depression rather than the risk of dementia after a concussion.
Results
Descriptive Overview
A total of 28 815 patients (median age, 76 years; 61.3% female) were diagnosed as having a concussion during the study. Overall, 7058 patients (24.5%) received a statin during the 90 days after a concussion, and 21 757 patients (75.5%) did not receive a statin. The distribution of baseline demographic characteristics was similar for both groups (Table 1). The typical patient receiving a statin was a 76-year-old woman who was also taking additional medications. On average, patients receiving statins had more cardiovascular medications and more prior physician visits than control patients. The frequency of neuropsychiatric medication use also tended to be higher (not lower) for patients receiving statins. About one-quarter (23.6%) of patients had a hospital admission in the prior year, with no imbalance between the 2 groups.
Risk of Subsequent Dementia
A total of 4727 patients developed dementia over a mean follow-up of 3.9 years after a concussion (Figure 1A). The absolute incidence was 1 case per 6 patients, and most (83.4%) had extensive documentation of dementia during follow-up. Patients receiving statins accounted for 1050 dementia cases over 28 129 patient-years (mean, 4.0 years), equal to an incidence of 37 cases per 1000 patients annually (twice the population norm).87 Control patients accounted for 3677 dementia cases over 85 339 patient-years (mean, 3.9 years), equal to an incidence of 43 cases per 1000 patients annually (more than twice the population norm). Together, statin use was associated with a 13% (95% CI, 7%-19%; P < .001) reduced risk of dementia compared with patients who did not receive a statin (relative risk, 0.87; 95% CI, 0.81-0.93; P < .001), equal to a number needed to treat of about 50 patients.
Adjusting for Patient Characteristics
The decreased risk of dementia associated with statin use after a concussion was similar in the first half and second half of the cohort and persisted after adjusting for patient characteristics (Table 2). As expected, older age was associated with an increased risk of dementia, as was greater health care use (total prescriptions, physician visits, and prior hospitalizations). Patient sex was not associated with a consistent difference in dementia risk. Lower socioeconomic status and urban home location were associated with an increased risk of dementia. Adjustment for all measured baseline characteristics suggested that statin use was associated with a 16% (95% CI, 10%-22%; P < .001) reduction in the risk of subsequent dementia, equal to an E-value88 of 1.67.
Additional Medications
Analysis of additional medication use suggested that the decreased risk of subsequent dementia was specific to statins. In particular, other lipid-lowering medications were not associated with a significant difference in the risk of dementia (Table 2). Other cardiovascular medications were not associated with a consistent decrease in the risk of dementia, with the possible exception of angiotensin II receptor blockers. Similarly, benzodiazepines, thyroid supplements, gastric acid suppressors, inhaled bronchodilators, and glaucoma eyedrops were not associated with a significantly decreased risk of subsequent dementia. As expected, major neuropsychiatric medications were associated with an increased risk of dementia, perhaps as a proxy for cognitive frailty in older patients.
Specific Statin Analyses
Secondary analyses explored further nuances of statin use and the risk of subsequent dementia. Rosuvastatin use was associated with the largest risk reduction, and simvastatin use was associated with the smallest risk reduction (Table 3). Hydrophilic statins were marginally more beneficial than lipophilic statins. No greater benefit was found with higher dosages compared with lower dosages. Propensity score matching suggested that the risk reduction was not easily explained by baseline imbalances in measured patient characteristics. Patients who received a statin before and after the concussion explained most of the risk reduction. Those who initiated a statin after the concussion showed a significant risk reduction, and those who discontinued a statin after the concussion showed no significant risk reduction.
Dementia Risk After Ankle Sprain
The parallel analysis identified a total of 307 890 patients diagnosed as having an ankle sprain, of whom 77 898 (25.3%) received a statin and 229 992 (74.7%) did not receive a statin. A total of 25 956 patients developed dementia over a mean follow-up of 4.3 years (Figure 1B). Patients receiving statins accounted for 6239 dementia cases over 336 251 patient-years (mean, 4.3 years), equal to an incidence of 19 cases per 1000 patients annually. Control patients accounted for 19 717 dementia cases over 1 001 606 patient-years (mean, 4.4 years), equal to an incidence of 20 cases per 1000 patients annually. Both groups were at the population norm, and statin use was associated with a 5% (95% CI, 3%-8%; P < .001) reduction in the risk of dementia, equal to a number needed to treat of about 220 patients.
Depression Risk After a Concussion
The tracer analysis identified 1778 patients who were subsequently diagnosed as having depression after a concussion. The absolute incidence of depression was about 1 case per 16 patients (Figure 2). Patients receiving statins accounted for 440 cases of depression over 29 007 patient-years of follow-up, equal to an incidence of 15 cases per 1000 patients annually. Control patients accounted for 1338 cases of depression over 88 540 patient-years of follow-up, equal to an incidence of 15 cases per 1000 patients annually. Together, statin use was associated with an insignificant 4% (95% CI, −7% to 16%; P = .43) increased risk of depression before adjustment for measured baseline characteristics and an insignificant 4% (95% CI, −8% to 14%; P = .49) decreased risk of depression after adjustment for measured baseline characteristics.
Discussion
We studied 28 815 older adults diagnosed as having a concussion to test whether statin use might influence a patient’s recovery after the concussion. In patients receiving statins, we found that the subsequent incidence of dementia was twice the population norm, and it was further accentuated in control patients who were not taking a statin. The relative reduction in dementia risk associated with statin use after a concussion was greatest for those taking rosuvastatin, was consistent for those receiving lower dosages, was accentuated after adjustments for measured patient characteristics, and was distinct from the risks for patients after an ankle sprain. No other cardiovascular or noncardiovascular medications were associated with a decreased risk of dementia after a concussion (with the possible exception of angiotensin II receptor blockers).
Our study adds to prior research on statin use after traumatic brain injury due to a larger sample size, longer follow-up, more detailed statistical analysis, and a priority on concussions (eAppendix in the Supplement). Four prior randomized trials yielded conflicting results, with 2 studies89,90 reporting a positive protective effect of statins on neurocognitive outcomes and the other 2 studies91,92 reporting no significant effect. Eleven prior nonrandomized studies also yielded conflicting results, with 5 studies93-97 reporting a positive protective association on clinical outcomes and the other 6 studies98-103 reporting a negligible association. No prior studies indicated a detrimental influence of statin use after traumatic brain injury, but almost all previous studies focused on patients with moderate to severe injuries rather than concussions.
Limitations
Several limitations of our research merit attention. Our study was not a randomized trial, and the observed associations might reflect confounding due to earlier indications for statin use.104 Important missing covariates included smoking status, daily exercise, drug adherence, and other factors that influence the risk of developing dementia.105-108 These unknown differences in patients (healthy-user bias) might account for a reduction in the subsequent risk of dementia.109,110 Our study also lacks sufficient power to disentangle whether statins make a contribution before, during, or after a concussion. In addition, the diagnostic codes for concussion and dementia were not fully sensitive and may significantly underestimate the true incidence of dementia in patients after a concussion.111
The generalizability of our findings is also limited by a focus on older adults, the requirement for patients to survive at least 90 days after a concussion, and the exclusion of those already diagnosed as having dementia.112 We did not consider patients with severe brain injury that resulted in hospitalization; instead, we examined only concussion cases as the more common type of traumatic brain injury. We also lacked data on patients with injuries who did not seek medical care. Our study was based in Canada, did not account for geographic variances in health care delivery, and potentially underestimated risks due to random delays in diagnosing dementia. We also lacked nuanced data on functional status, and we found only a modest degree of healthy-user bias in our patients.113,114
Our study has further limitations for clinical care. Concussion and dementia are both varied disorders, so aggregate statistics do not necessarily apply to unique patients. The median follow-up duration was less than 5 years, whereas the course of dementia can span decades of subclinical changes. Our patients had years of unrecorded history and an unknown total number of concussions over a lifetime. The relative risks associated with concussions and with statin use were both modest because each addresses only one of many contributors to dementia. Our observational design also means that the unmeasured burden of cardiovascular and neuropsychiatric diseases may have been imbalanced against the patients receiving statins and may have led to analyses that underestimate the neuroprotection from statins.
The findings of our study suggest a potential long-term protective association between statin use and the risk of dementia after a concussion that justifies future research. The study also provides estimates of event rates, time profiles, effect sizes, and baseline frequencies needed for planning future trials. Of course, a randomized trial might face difficulties in patient enrollment because adults may not be willing to be randomized to receive a placebo rather than a statin.92 The 20-year patient enrollment interval of our study could also be prohibitive for a prospective trial. In addition, we know of no practical method to randomize patients to receive a statin immediately before a concussion. Therefore, analytic observational research may provide the best available data for the immediate future.
Conclusions
Concussion is often popularized as a problem in athletic youth and tends to be underdiagnosed in older individuals.115-117 The results of our study suggest that concussions are a common injury in older adults and indicate that dementia may be a frequent outcome years afterward. Therefore, more efforts to prevent concussions should be encouraged at all ages.118 Screening for past concussions might also offer new clinical insights for patients diagnosed as having dementia.119 A potential neuroprotective benefit may also encourage greater medication adherence for patients who are already prescribed a statin.120,121 In addition, a concussion should not be interpreted as a reason to stop statins, and a future randomized trial is justified.122 The long-term neurologic consequences of a concussion are substantial and merit attention.123
Back to top
Article Information
Accepted for Publication: January 10, 2019.
Corresponding Author: Donald A. Redelmeier, MD, MSHSR, Division of General Internal Medicine, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Ste G-151, Toronto, ON M4N 3M5, Canada (dar@ices.on.ca).
Published Online: May 20, 2019. doi:10.1001/jamaneurol.2019.1148
Author Contributions: Dr Redelmeier had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Redelmeier, Manzoor.
Acquisition, analysis, or interpretation of data: Redelmeier, Thiruchelvam.
Drafting of the manuscript: Redelmeier, Manzoor.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Redelmeier, Thiruchelvam.
Obtained funding: Redelmeier.
Administrative, technical, or material support: Redelmeier, Manzoor.
Supervision: Redelmeier.
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by a Canada Research Chair in Medical Decision Sciences, the Canadian Institutes of Health Research, the BrightFocus Foundation, and the Comprehensive Research Experience for Medical Students at the University of Toronto.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The views are those of the authors and do not necessarily reflect the views of the Ontario Ministry of Health and Long-Term Care.
Additional Contributions: The following individuals at the University of Toronto provided helpful comments: Sandra Black, MD, Anthony Feinstein, MD, Michael Fralick, MD, Andrea Gershon, MD, Taaha Muhammad, BHSc, Sheharyar Raza, MD, Charles Tator, MD, Jason Woodfine, MD, Christopher Yarnell, MD, Jonathan Zipursky, MD, and Jeremy Zung, MD. None received compensation.
References
1.
Bazarian JJ, McClung J, Shah MN, Cheng YT, Flesher W, Kraus J. Mild traumatic brain injury in the United States, 1998-2000. Brain Inj. 2005;19(2):85-91. doi:10.1080/02699050410001720158PubMedGoogle ScholarCrossref
2.
Styrke J, Stålnacke BM, Sojka P, Björnstig U. Traumatic brain injuries in a well-defined population: epidemiological aspects and severity. J Neurotrauma. 2007;24(9):1425-1436. doi:10.1089/neu.2007.0266PubMedGoogle ScholarCrossref
3.
Feigin VL, Theadom A, Barker-Collo S, et al; BIONIC Study Group. Incidence of traumatic brain injury in New Zealand: a population-based study. Lancet Neurol. 2013;12(1):53-64. doi:10.1016/S1474-4422(12)70262-4PubMedGoogle ScholarCrossref
4.
Marin JR, Weaver MD, Yealy DM, Mannix RC. Trends in visits for traumatic brain injury to emergency departments in the United States. JAMA. 2014;311(18):1917-1919. doi:10.1001/jama.2014.3979
ArticlePubMedGoogle ScholarCrossref
5.
Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. soldiers returning from Iraq. N Engl J Med. 2008;358(5):453-463. doi:10.1056/NEJMoa072972PubMedGoogle ScholarCrossref
6.
Jaffee MS, Winter WC, Jones CC, Ling G. Sleep disturbances in athletic concussion. Brain Inj. 2015;29(2):221-227. doi:10.3109/02699052.2014.983978PubMedGoogle ScholarCrossref
7.
Master CL, Mayer AR, Quinn D, Grady MF. Concussion. Ann Intern Med. 2018;169(1):ITC1-ITC16. doi:10.7326/AITC201807030PubMedGoogle ScholarCrossref
8.
Carroll LJ, Cassidy JD, Cancelliere C, et al. Systematic review of the prognosis after mild traumatic brain injury in adults: cognitive, psychiatric, and mortality outcomes: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis. Arch Phys Med Rehabil. 2014;95(3)(suppl):S152-S173. doi:10.1016/j.apmr.2013.08.300PubMedGoogle ScholarCrossref
9.
McInnes K, Friesen CL, MacKenzie DE, Westwood DA, Boe SG. Mild traumatic brain injury (mTBI) and chronic cognitive impairment: a scoping review. PLoS One. 2017;12(4):e0174847. doi:10.1371/journal.pone.0174847PubMedGoogle ScholarCrossref
10.
DeKosky ST, Ikonomovic MD, Gandy S. Traumatic brain injury: football, warfare, and long-term effects. N Engl J Med. 2010;363(14):1293-1296. doi:10.1056/NEJMp1007051PubMedGoogle ScholarCrossref
11.
Godbolt AK, Cancelliere C, Hincapié CA, et al. Systematic review of the risk of dementia and chronic cognitive impairment after mild traumatic brain injury: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis. Arch Phys Med Rehabil. 2014;95(3)(suppl):S245-S256. doi:10.1016/j.apmr.2013.06.036PubMedGoogle ScholarCrossref
12.
Fazel S, Wolf A, Pillas D, Lichtenstein P, Långström N. Suicide, fatal injuries, and other causes of premature mortality in patients with traumatic brain injury: a 41-year Swedish population study. JAMA Psychiatry. 2014;71(3):326-333. doi:10.1001/jamapsychiatry.2013.3935
ArticlePubMedGoogle ScholarCrossref
13.
Nordström A, Nordström P. Traumatic brain injury and the risk of dementia diagnosis: a nationwide cohort study. PLoS Med. 2018;15(1):e1002496. doi:10.1371/journal.pmed.1002496PubMedGoogle ScholarCrossref
14.
Fann JR, Ribe AR, Pedersen HS, et al. Long-term risk of dementia among people with traumatic brain injury in Denmark: a population-based observational cohort study. Lancet Psychiatry. 2018;5(5):424-431. doi:10.1016/S2215-0366(18)30065-8PubMedGoogle ScholarCrossref
15.
Petraglia AL, Maroon JC, Bailes JE. From the field of play to the field of combat: a review of the pharmacological management of concussion. Neurosurgery. 2012;70(6):1520-1533. doi:10.1227/NEU.0b013e31824cebe8PubMedGoogle ScholarCrossref
16.
Gravel J, D’Angelo A, Carrière B, et al. Interventions provided in the acute phase for mild traumatic brain injury: a systematic review. Syst Rev. 2013;2:63. doi:10.1186/2046-4053-2-63PubMedGoogle ScholarCrossref
17.
Kamins J, Bigler E, Covassin T, et al. What is the physiological time to recovery after concussion? a systematic review. Br J Sports Med. 2017;51(12):935-940. doi:10.1136/bjsports-2016-097464PubMedGoogle ScholarCrossref
18.
Schroeppel TJ, Fischer PE, Zarzaur BL, et al. Beta-adrenergic blockade and traumatic brain injury: protective? J Trauma. 2010;69(4):776-782. doi:10.1097/TA.0b013e3181e981b8PubMedGoogle ScholarCrossref
19.
Radosevich JJ, Patanwala AE, Erstad BL. Emerging pharmacological agents to improve survival from traumatic brain injury. Brain Inj. 2013;27(13-14):1492-1499. doi:10.3109/02699052.2013.823658PubMedGoogle ScholarCrossref
20.
Wright DW, Yeatts SD, Silbergleit R, et al; NETT Investigators. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med. 2014;371(26):2457-2466. doi:10.1056/NEJMoa1404304PubMedGoogle ScholarCrossref
21.
Robertson CS, Hannay HJ, Yamal JM, et al; Epo Severe TBI Trial Investigators. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA. 2014;312(1):36-47. doi:10.1001/jama.2014.6490
ArticlePubMedGoogle ScholarCrossref
22.
Bergold PJ. Treatment of traumatic brain injury with anti-inflammatory drugs. Exp Neurol. 2016;275(pt 3):367-380. doi:10.1016/j.expneurol.2015.05.024PubMedGoogle ScholarCrossref
23.
Mihaylova B, Emberson J, Blackwell L, et al; Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581-590. doi:10.1016/S0140-6736(12)60367-5PubMedGoogle ScholarCrossref
24.
Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;1(1):CD004816.PubMedGoogle Scholar
25.
Barkhoudarian G, Hovda DA, Giza CC. The molecular pathophysiology of concussive brain injury. Clin Sports Med. 2011;30(1):33-48, vii-iii. doi:10.1016/j.csm.2010.09.001PubMedGoogle ScholarCrossref
26.
Béziaud T, Ru Chen X, El Shafey N, et al. Simvastatin in traumatic brain injury: effect on brain edema mechanisms. Crit Care Med. 2011;39(10):2300-2307. doi:10.1097/CCM.0b013e3182227e4aPubMedGoogle ScholarCrossref
27.
Peng W, Yang J, Yang B, Wang L, Xiong XG, Liang Q. Impact of statins on cognitive deficits in adult male rodents after traumatic brain injury: a systematic review. Biomed Res Int. 2014;2014:261409. doi:10.1155/2014/261409PubMedGoogle Scholar
28.
Abrahamson EE, Ikonomovic MD, Dixon CE, DeKosky ST. Simvastatin therapy prevents brain trauma–induced increases in β-amyloid peptide levels. Ann Neurol. 2009;66(3):407-414. doi:10.1002/ana.21731PubMedGoogle ScholarCrossref
29.
Xu X, Gao W, Cheng S, et al. Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury. J Neuroinflammation. 2017;14(1):167. doi:10.1186/s12974-017-0934-2PubMedGoogle ScholarCrossref
30.
Lin FC, Chuang YS, Hsieh HM, et al. Early statin use and the progression of Alzheimer disease: a total population–based case-control study. Medicine (Baltimore). 2015;94(47):e2143. doi:10.1097/MD.0000000000002143PubMedGoogle ScholarCrossref
31.
Schilling S, Tzourio C, Soumaré A, et al. Differential associations of plasma lipids with incident dementia and dementia subtypes in the 3C Study: a longitudinal, population-based prospective cohort study. PLoS Med. 2017;14(3):e1002265. doi:10.1371/journal.pmed.1002265PubMedGoogle ScholarCrossref
32.
Reed B, Villeneuve S, Mack W, DeCarli C, Chui HC, Jagust W. Associations between serum cholesterol levels and cerebral amyloidosis. JAMA Neurol. 2014;71(2):195-200. doi:10.1001/jamaneurol.2013.5390
ArticlePubMedGoogle ScholarCrossref
33.
McFarland AJ, Anoopkumar-Dukie S, Arora DS, et al. Molecular mechanisms underlying the effects of statins in the central nervous system. Int J Mol Sci. 2014;15(11):20607-20637. doi:10.3390/ijms151120607PubMedGoogle ScholarCrossref
34.
Carlsson CM, Xu G, Wen Z, et al. Effects of atorvastatin on cerebral blood flow in middle-aged adults at risk for Alzheimer’s disease: a pilot study. Curr Alzheimer Res. 2012;9(8):990-997. doi:10.2174/156720512803251075PubMedGoogle ScholarCrossref
35.
Giannopoulos S, Katsanos AH, Kosmidou M, Tsivgoulis G. Statins and vascular dementia: a review. J Alzheimers Dis. 2014;42(suppl 3):S315-S320. doi:10.3233/JAD-132366PubMedGoogle ScholarCrossref
36.
Butterfield DA, Barone E, Mancuso C. Cholesterol-independent neuroprotective and neurotoxic activities of statins: perspectives for statin use in Alzheimer disease and other age-related neurodegenerative disorders. Pharmacol Res. 2011;64(3):180-186. doi:10.1016/j.phrs.2011.04.007PubMedGoogle ScholarCrossref
37.
Feldman HH, Doody RS, Kivipelto M, et al; LEADe Investigators. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology. 2010;74(12):956-964. doi:10.1212/WNL.0b013e3181d6476aPubMedGoogle ScholarCrossref
38.
Fink HA, Jutkowitz E, McCarten JR, et al. Pharmacologic interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: a systematic review. Ann Intern Med. 2018;168(1):39-51. doi:10.7326/M17-1529PubMedGoogle ScholarCrossref
39.
Maegele M. Traumatic brain injury in 2017: exploring the secrets of concussion. Lancet Neurol. 2018;17(1):13-15. doi:10.1016/S1474-4422(17)30419-2PubMedGoogle ScholarCrossref
40.
Power MC, Weuve J, Sharrett AR, Blacker D, Gottesman RF. Statins, cognition, and dementia: systematic review and methodological commentary. Nat Rev Neurol. 2015;11(4):220-229. doi:10.1038/nrneurol.2015.35PubMedGoogle ScholarCrossref
41.
Smith DH, Johnson VE, Stewart W. Chronic neuropathologies of single and repetitive TBI: substrates of dementia? Nat Rev Neurol. 2013;9(4):211-221. doi:10.1038/nrneurol.2013.29PubMedGoogle ScholarCrossref
42.
Kristman VL, Borg J, Godbolt AK, et al. Methodological issues and research recommendations for prognosis after mild traumatic brain injury: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis. Arch Phys Med Rehabil. 2014;95(3)(suppl):S265-S277. doi:10.1016/j.apmr.2013.04.026PubMedGoogle ScholarCrossref
43.
McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev. 2016;(1):CD003160.PubMedGoogle Scholar
44.
Mendoza-Oliva A, Zepeda A, Arias C. The complex actions of statins in brain and their relevance for Alzheimer’s disease treatment: an analytical review. Curr Alzheimer Res. 2014;11(9):817-833.PubMedGoogle Scholar
45.
Xie C, Cong D, Wang X, et al. The effect of simvastatin treatment on proliferation and differentiation of neural stem cells after traumatic brain injury. Brain Res. 2015;1602:1-8. doi:10.1016/j.brainres.2014.03.021PubMedGoogle ScholarCrossref
46.
Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science. 2016;353(6301):777-783. doi:10.1126/science.aag2590PubMedGoogle ScholarCrossref
47.
Chou A, Krukowski K, Jopson T, et al. Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury. Proc Natl Acad Sci U S A. 2017;114(31):E6420-E6426. doi:10.1073/pnas.1707661114PubMedGoogle ScholarCrossref
48.
Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Med. 2004;117(11):823-829. doi:10.1016/j.amjmed.2004.07.041PubMedGoogle ScholarCrossref
49.
Miron VE, Zehntner SP, Kuhlmann T, et al. Statin therapy inhibits remyelination in the central nervous system. Am J Pathol. 2009;174(5):1880-1890. doi:10.2353/ajpath.2009.080947PubMedGoogle ScholarCrossref
50.
Schilling JM, Cui W, Godoy JC, et al. Long-term atorvastatin treatment leads to alterations in behavior, cognition, and hippocampal biochemistry. Behav Brain Res. 2014;267:6-11. doi:10.1016/j.bbr.2014.03.014PubMedGoogle ScholarCrossref
51.
Strom BL, Schinnar R, Karlawish J, Hennessy S, Teal V, Bilker WB. Statin therapy and risk of acute memory impairment. JAMA Intern Med. 2015;175(8):1399-1405. doi:10.1001/jamainternmed.2015.2092
ArticlePubMedGoogle ScholarCrossref
52.
Tuccori M, Montagnani S, Mantarro S, et al. Neuropsychiatric adverse events associated with statins: epidemiology, pathophysiology, prevention and management. CNS Drugs. 2014;28(3):249-272. doi:10.1007/s40263-013-0135-1PubMedGoogle ScholarCrossref
53.
Russo MV, McGavern DB. Inflammatory neuroprotection following traumatic brain injury. Science. 2016;353(6301):783-785. doi:10.1126/science.aaf6260PubMedGoogle ScholarCrossref
54.
Roy S, Weinstock JL, Ishino AS, et al. Association of cognitive impairment in patients on 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors. J Clin Med Res. 2017;9(7):638-649. doi:10.14740/jocmr3066wPubMedGoogle ScholarCrossref
55.
Statistics Canada. Population estimates on July 1st, by age and sex. Frequency: annual. Table: 17-10-0005-01 (formerly CANSIM 051-0001). Geography: Canada, province or territory. http://www.statcan.gc.ca/tables-tableaux/sum-som/l01/cst01/demo02a-eng.htm. Accessed June 6, 2014.
56.
Ng R, Maxwell CJ, Yates EA, et al. Brain Disorders in Ontario: Prevalence, Incidence and Costs From Health Administrative Data. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences; July 2015. http://www.ices.on.ca/~/media/Files/Atlases-Reports/2015/Brain-Disorders-in-Ontario/Full-Report.ashx. Accessed July 26, 2017.
57.
Prince M, Wimo A, Guerchet M, Ali GC, Wu YT, Prina M. World Alzheimer Report 2015: The Global Impact of Dementia: An Analysis of Prevalence, Incidence, Cost and Trends. London, England: Alzheimer’s Disease International; 2015. https://www.alz.co.uk/research/WorldAlzheimerReport2015.pdf. Accessed December 3, 2017.
58.
Alzheimer Society of Canada. Report summary prevalence and monetary costs of dementia in Canada (2016): a report by the Alzheimer Society of Canada [in French]. Health Promot Chronic Dis Prev Can. 2016;36(10):231-232. doi:10.24095/hpcdp.36.10.04PubMedGoogle ScholarCrossref
59.
Sessions SY, Detsky AS. Washington, Ottawa, and health care reform: a tale of 2 capitals. JAMA. 2010;303(20):2078-2079. doi:10.1001/jama.2010.654
ArticlePubMedGoogle ScholarCrossref
60.
Williams JI, Young W. A summary of studies on the quality of health care administrative databases in Canada. In: Goel V, Williams JI, Anderson GM, et al, eds. Patterns of Health Care in Ontario: The ICES Practice Atlas. Ottawa, Ontario: Canadian Medical Association; 1996.
61.
Macpherson AK, Schull M, Manuel D, Cernat G, Redelmeier DA, Laupacis A. Injuries in Ontario: ICES Atlas. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences; 2005.
62.
Carroll CP, Cochran JA, Guse CE, Wang MC. Are we underestimating the burden of traumatic brain injury? surveillance of severe traumatic brain injury using Centers for Disease Control International Classification of Disease, Ninth Revision, Clinical Modification, traumatic brain injury codes. Neurosurgery. 2012;71(6):1064-1070. doi:10.1227/NEU.0b013e31826f7c16PubMedGoogle ScholarCrossref
63.
Bazarian JJ, Veazie P, Mookerjee S, Lerner EB. Accuracy of mild traumatic brain injury case ascertainment using ICD-9 codes. Acad Emerg Med. 2006;13(1):31-38. doi:10.1197/j.aem.2005.07.038PubMedGoogle ScholarCrossref
64.
Morrish J, Carey S. Concussions in Canada. Toronto, Ontario: Canada Injury Compass; 2013:1-3.
65.
Davis DH, Muniz Terrera G, Keage H, et al. Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study. Brain. 2012;135(pt 9):2809-2816. doi:10.1093/brain/aws190PubMedGoogle ScholarCrossref
66.
Levy AR, O’Brien BJ, Sellors C, Grootendorst P, Willison D. Coding accuracy of administrative drug claims in the Ontario Drug Benefit database. Can J Clin Pharmacol. 2003;10(2):67-71.PubMedGoogle Scholar
67.
Ko DT, Wijeysundera HC, Jackevicius CA, Yousef A, Wang J, Tu JV. Diabetes mellitus and cardiovascular events in older patients with myocardial infarction prescribed intensive-dose and moderate-dose statins. Circ Cardiovasc Qual Outcomes. 2013;6(3):315-322. doi:10.1161/CIRCOUTCOMES.111.000015PubMedGoogle ScholarCrossref
68.
Canadian Institute for Health Information. CIHI Data Quality Study of Emergency Department Visits for 2004-2005: Executive Summary. Ottawa, Ontario, Canada: Canadian Institute for Health Information; 2008.
69.
Iron K, Zagorski BM, Sykora K, Manuel DG. Living and Dying in Ontario: An Opportunity for Improved Health Information: ICES Investigative Report. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences; March 2008.
70.
Wilkins R. Automated Geographic Coding Based on the Statistics Canada Postal Code Conversion Files, Including Postal Codes to December 2003. Ottawa, Ontario: Health Analysis and Measurement Group, Statistics Canada; 2004.
71.
Juurlink DN, Preyra C, Croxford R, et al. Canadian Institute for Health Information Discharge Abstract Database: A Validation Study. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences; 2006.
72.
Levy AR, Tamblyn RM, Fitchett D, McLeod PJ, Hanley JA. Coding accuracy of hospital discharge data for elderly survivors of myocardial infarction. Can J Cardiol. 1999;15(11):1277-1282.PubMedGoogle Scholar
73.
Paterson JM, Suleiman A, Hux JE, Bell C. How complete are drug history profiles that are based on public drug benefit claims? Can J Clin Pharmacol. 2008;15(1):e108-e116.PubMedGoogle Scholar
74.
Proulx J, Hunt J. Drug use among seniors on public drug programs in Canada, 2012. Healthc Q. 2015;18(1):11-13. doi:10.12927/hcq.2015.24250PubMedGoogle ScholarCrossref
75.
Daviglus ML, Bell CC, Berrettini W, et al. National Institutes of Health State-of-the-Science Conference statement: preventing Alzheimer disease and cognitive decline. Ann Intern Med. 2010;153(3):176-181. doi:10.7326/0003-4819-153-3-201008030-00260PubMedGoogle ScholarCrossref
76.
Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113):2673-2734. doi:10.1016/S0140-6736(17)31363-6PubMedGoogle ScholarCrossref
77.
Bronskill SE, Camacho X, Gruneir A, Ho MM. Health System Use by Frail Ontario Seniors: An In-depth Examination of Four Vulnerable Cohorts. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences; November 2011. https://www.ices.on.ca/flip-publication/health-system-use-by-frail-ontario-seniors/files/assets/basic-html/index.html#1. Accessed January 3, 2019.
78.
Wilchesky M, Tamblyn RM, Huang A. Validation of diagnostic codes within medical services claims. J Clin Epidemiol. 2004;57(2):131-141. doi:10.1016/S0895-4356(03)00246-4PubMedGoogle ScholarCrossref
79.
St Germaine-Smith C, Metcalfe A, Pringsheim T, et al. Recommendations for optimal ICD codes to study neurologic conditions: a systematic review. Neurology. 2012;79(10):1049-1055. doi:10.1212/WNL.0b013e3182684707PubMedGoogle ScholarCrossref
80.
Haag MD, Hofman A, Koudstaal PJ, Stricker BH, Breteler MM. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity: the Rotterdam Study. J Neurol Neurosurg Psychiatry. 2009;80(1):13-17. doi:10.1136/jnnp.2008.150433PubMedGoogle ScholarCrossref
81.
Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19(1):117-125. doi:10.1111/j.1472-8206.2004.00299.xPubMedGoogle ScholarCrossref
82.
Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94(446):496-509. doi:10.1080/01621459.1999.10474144Google ScholarCrossref
83.
Bombardier CH, Fann JR, Temkin NR, Esselman PC, Barber J, Dikmen SS. Rates of major depressive disorder and clinical outcomes following traumatic brain injury. JAMA. 2010;303(19):1938-1945. doi:10.1001/jama.2010.599
ArticlePubMedGoogle ScholarCrossref
84.
Barkow K, Maier W, Ustün TB, Gänsicke M, Wittchen HU, Heun R. Risk factors for depression at 12-month follow-up in adult primary health care patients with major depression: an international prospective study. J Affect Disord. 2003;76(1-3):157-169. doi:10.1016/S0165-0327(02)00081-2PubMedGoogle ScholarCrossref
85.
Taylor WD, Aizenstein HJ, Alexopoulos GS. The vascular depression hypothesis: mechanisms linking vascular disease with depression. Mol Psychiatry. 2013;18(9):963-974. doi:10.1038/mp.2013.20PubMedGoogle ScholarCrossref
86.
Redlich C, Berk M, Williams LJ, Sundquist J, Sundquist K, Li X. Statin use and risk of depression: a Swedish national cohort study. BMC Psychiatry. 2014;14:348. doi:10.1186/s12888-014-0348-yPubMedGoogle ScholarCrossref
87.
Public Health Agency of Canada. Dementia in Canada, including Alzheimer’s disease: highlights from the Canadian Chronic Disease Surveillance System. https://www.canada.ca/content/dam/phac-aspc/documents/services/publications/diseases-conditions/dementia-highlights-canadian-chronic-disease-surveillance/dementia-highlights-canadian-chronic-disease-surveillance.pdf. Published 2017. Accessed January 4, 2018.
88.
VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med. 2017;167(4):268-274. doi:10.7326/M16-2607PubMedGoogle ScholarCrossref
89.
Tapia-Perez J, Sanchez-Aguilar M, Torres-Corzo JG, et al. Effect of rosuvastatin on amnesia and disorientation after traumatic brain injury (NCT003229758). J Neurotrauma. 2008;25(8):1011-1017. doi:10.1089/neu.2008.0554PubMedGoogle ScholarCrossref
90.
Farzanegan GR, Derakhshan N, Khalili H, Ghaffarpasand F, Paydar S. Effects of atorvastatin on brain contusion volume and functional outcome of patients with moderate and severe traumatic brain injury: a randomized double-blind placebo-controlled clinical trial. J Clin Neurosci. 2017;44:143-147. doi:10.1016/j.jocn.2017.06.010PubMedGoogle ScholarCrossref
91.
Sánchez-Aguilar M, Tapia-Pérez JH, Sánchez-Rodríguez JJ, et al. Effect of rosuvastatin on cytokines after traumatic head injury. J Neurosurg. 2013;118(3):669-675. doi:10.3171/2012.12.JNS121084PubMedGoogle ScholarCrossref
92.
Robertson CS, McCarthy JJ, Miller ER, Levin H, McCauley SR, Swank PR. Phase II clinical trial of atorvastatin in mild traumatic brain injury. J Neurotrauma. 2017;34:1394-1401. doi:10.1089/neu.2016.4717PubMedGoogle ScholarCrossref
93.
Efron DT, Sorock G, Haut ER, et al. Preinjury statin use is associated with improved in-hospital survival in elderly trauma patients. J Trauma. 2008;64(1):66-73. doi:10.1097/TA.0b013e31815b842aPubMedGoogle ScholarCrossref
94.
Schneider EB, Efron DT, MacKenzie EJ, Rivara FP, Nathens AB, Jurkovich GJ. Premorbid statin use is associated with improved survival and functional outcomes in older head-injured individuals. J Trauma. 2011;71(4):815-819. doi:10.1097/TA.0b013e3182319de5PubMedGoogle ScholarCrossref
95.
Orlando A, Bar-Or D, Salottolo K, et al. Unintentional discontinuation of statins may increase mortality after traumatic brain injury in elderly patients: a preliminary observation. J Clin Med Res. 2013;5(3):168-173.PubMedGoogle Scholar
96.
Khokhar B, Simoni-Wastila L, Slejko JF, Perfetto E, Zhan M, Smith GS. In-hospital mortality following traumatic brain injury among older Medicare beneficiaries, comparing statin users with nonusers. J Pharm Technol. 2017;33(6):225-236. doi:10.1177/8755122517735656PubMedGoogle ScholarCrossref
97.
Khokhar B, Simoni-Wastila L, Slejko JF, Perfetto E, Zhan M, Smith GS. Mortality and associated morbidities following traumatic brain injury in older Medicare statin users. J Head Trauma Rehabil. 2018;33(6):E68-E76. PubMedGoogle Scholar
98.
Wang D, Li T, Tian Y, et al. Effects of atorvastatin on chronic subdural hematoma: a preliminary report from three medical centers. J Neurol Sci. 2014;336(1-2):237-242. doi:10.1016/j.jns.2013.11.005PubMedGoogle ScholarCrossref
99.
Neilson SJ, See AA, King NK. Effect of prior statin use on outcome after severe traumatic brain injury in a South-East Asian population. Brain Inj. 2016;30(8):993-998. doi:10.3109/02699052.2016.1147599PubMedGoogle ScholarCrossref
100.
Wee HY, Ho CH, Liang FW, et al. Increased risk of new-onset depression in patients with traumatic brain injury and hyperlipidemia: the important role of statin medications. J Clin Psychiatry. 2016;77(4):505-511. doi:10.4088/JCP.14m09749PubMedGoogle ScholarCrossref
101.
Xu M, Chen P, Zhu X, Wang C, Shi X, Yu B. Effects of atorvastatin on conservative and surgical treatments of chronic subdural hematoma in patients. World Neurosurg. 2016;91:23-28. doi:10.1016/j.wneu.2016.03.067PubMedGoogle ScholarCrossref
102.
Chan DY, Chan DT, Sun TF, Ng SC, Wong GK, Poon WS. The use of atorvastatin for chronic subdural haematoma: a retrospective cohort comparison study. Br J Neurosurg. 2017;31(1):72-77. doi:10.1080/02688697.2016.1208806PubMedGoogle ScholarCrossref
103.
Orlando A, Thomas C, Carrick M, Slone DS, Mains CW, Bar-Or D. Statin discontinuation and mortality in an older adult population with traumatic brain injury: a four-year, multi-centre, observational cohort study. Injury. 2017;48(5):1040-1046. doi:10.1016/j.injury.2016.11.027PubMedGoogle ScholarCrossref
104.
Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273(5):408-412. doi:10.1001/jama.1995.03520290060030
ArticlePubMedGoogle ScholarCrossref
105.
Brasure M, Desai P, Davila H, et al. Physical activity interventions in preventing cognitive decline and Alzheimer-type dementia: a systematic review. Ann Intern Med. 2018;168(1):30-38. doi:10.7326/M17-1528PubMedGoogle ScholarCrossref
106.
Gardener H, Wright CB, Rundek T, Sacco RL. Brain health and shared risk factors for dementia and stroke. Nat Rev Neurol. 2015;11(11):651-657. doi:10.1038/nrneurol.2015.195PubMedGoogle ScholarCrossref
107.
Downey A, Stroud C, Landis S, Leshner AI, eds; Committee on Preventing Dementia and Cognitive Impairment; Board on Health Sciences Policy; Health and Medicine Division; National Academies of Sciences, Engineering, and Medicine. Preventing Cognitive Decline and Dementia: A Way Forward. Washington, DC: National Academies Press; June 2017. https://www.ncbi.nlm.nih.gov/books/NBK436397/. Accessed January 4, 2018.
108.
Wang HX, MacDonald SW, Dekhtyar S, Fratiglioni L. Association of lifelong exposure to cognitive reserve–enhancing factors with dementia risk: a community-based cohort study. PLoS Med. 2017;14(3):e1002251. doi:10.1371/journal.pmed.1002251PubMedGoogle ScholarCrossref
109.
Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000;57(10):1439-1443. doi:10.1001/archneur.57.10.1439
ArticlePubMedGoogle ScholarCrossref
110.
Shrank WH, Patrick AR, Brookhart MA. Healthy user and related biases in observational studies of preventive interventions: a primer for physicians. J Gen Intern Med. 2011;26(5):546-550. doi:10.1007/s11606-010-1609-1PubMedGoogle ScholarCrossref
111.
Roozenbeek B, Maas AI, Menon DK. Changing patterns in the epidemiology of traumatic brain injury. Nat Rev Neurol. 2013;9(4):231-236. doi:10.1038/nrneurol.2013.22PubMedGoogle ScholarCrossref
112.
Hernán MA, Hernández-Díaz S, Robins JM. A structural approach to selection bias. Epidemiology. 2004;15(5):615-625. doi:10.1097/01.ede.0000135174.63482.43PubMedGoogle ScholarCrossref
113.
Brookhart MA, Patrick AR, Dormuth C, et al. Adherence to lipid-lowering therapy and the use of preventive health services: an investigation of the healthy user effect. Am J Epidemiol. 2007;166(3):348-354. doi:10.1093/aje/kwm070PubMedGoogle ScholarCrossref
114.
Kinjo M, Chia-Cheng Lai E, Korhonen MJ, McGill RL, Setoguchi S. Potential contribution of lifestyle and socioeconomic factors to healthy user bias in antihypertensives and lipid-lowering drugs. Open Heart. 2017;4(1):e000417. doi:10.1136/openhrt-2016-000417PubMedGoogle ScholarCrossref
115.
Harvey LA, Close JC. Traumatic brain injury in older adults: characteristics, causes and consequences. Injury. 2012;43(11):1821-1826. doi:10.1016/j.injury.2012.07.188PubMedGoogle ScholarCrossref
116.
Maas AIR, Menon DK, Adelson PD, et al; InTBIR Participants and Investigators. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017;16(12):987-1048. doi:10.1016/S1474-4422(17)30371-XPubMedGoogle ScholarCrossref
117.
Gardner RC, Dams-O’Connor K, Morrissey MR, Manley GT. Geriatric traumatic brain injury: epidemiology, outcomes, knowledge gaps, and future directions [published online February 15, 2018]. J Neurotrauma. doi:10.1089/neu.2017.5371PubMedGoogle Scholar
118.
Redelmeier DA, Raza S. Concussions and repercussions. PLoS Med. 2016;13(8):e1002104. doi:10.1371/journal.pmed.1002104PubMedGoogle ScholarCrossref
119.
Bardach NS, Wang JJ, De Leon SF, et al. Effect of pay-for-performance incentives on quality of care in small practices with electronic health records: a randomized trial. JAMA. 2013;310(10):1051-1059. doi:10.1001/jama.2013.277353
ArticlePubMedGoogle ScholarCrossref
120.
Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013;158(7):526-534. doi:10.7326/0003-4819-158-7-201304020-00004PubMedGoogle ScholarCrossref
121.
Yusuf S. Why do people not take life-saving medications? the case of statins. Lancet. 2016;388(10048):943-945. doi:10.1016/S0140-6736(16)31532-XPubMedGoogle ScholarCrossref
122.
Gurwitz JH, Go AS, Fortmann SP. Statins for primary prevention in older adults: uncertainty and the need for more evidence. JAMA. 2016;316(19):1971-1972. doi:10.1001/jama.2016.15212
ArticlePubMedGoogle ScholarCrossref
123.
McCrory P, Meeuwisse WH, Aubry M, et al. Consensus statement on concussion in sport: the 4th International Conference on Concussion in Sport held in Zurich, November 2012. Br J Sports Med. 2013;47(5):250-258. doi:10.1136/bjsports-2013-092313PubMedGoogle ScholarCrossref
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου