REVIEW ARTICLE

Systematic Review of the Risk of Dementia andChronic Cognitive Impairment After Mild TraumaticBrain Injury: Results of the InternationalCollaboration on Mild Traumatic Brain InjuryPrognosis

Alison K. Godbolt, MBChB, MD,a Carol Cancelliere, DC, MPH,b,c

Cesar A. Hincapie, DC, MHSc,b,d Connie Marras, MD, PhD,e,f Eleanor Boyle, PhD,d,g

Vicki L. Kristman, PhD,d,h,i,j Victor G. Coronado, MD, MPH,k

J. David Cassidy, PhD, DrMedScb,c,d,g

From the aUniversity Department of Rehabilitation Medicine, Danderyd Hospital, Karolinska Institute, Stockholm, Sweden; bDivision of HealthCare and Outcomes Research, Toronto Western Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada;cInstitute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; dDivision of Epidemiology, DallaLana School of Public Health, University of Toronto, Toronto, Ontario, Canada; eDepartment of Medicine, University of Toronto, Toronto,Ontario, Canada; fMorton and Gloria Shulman Movement Disorders Centre, and the Edmond J. Safra Program in Parkinson’s Research, TorontoWestern Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; gFaculty of Health, Institute of Sport Scienceand Clinical Biomechanics, University of Southern Denmark, Odense, Denmark; hDepartment of Health Sciences, Lakehead University, ThunderBay, Ontario, Canada; iInstitute for Work and Health, Toronto, Ontario, Canada; jDivision of Human Sciences, Northern Ontario School ofMedicine, Lakehead University, Thunder Bay, Ontario, Canada; and kNational Center for Injury Prevention and Control, Centers for DiseaseControl and Prevention, Atlanta, GA.

AbstractObjective: To synthesize the best available evidence regarding the risk of dementia and chronic cognitive impairment (CCI) after mild traumaticbrain injury (MTBI).Data Sources: MEDLINE and other databases were searched (2001e2012) using a previously published search strategy and predefined criteria.Peer-reviewed reports in 6 languages were considered.Study Selection: Systematic reviews, meta-analyses, randomized controlled trials, cohort studies, and case-control studies, with a minimum of 30MTBI cases in subjects of any age, assessing the risk of dementia or CCI after MTBI were selected.Data Extraction: Eligible studies were critically appraised using a modification of the Scottish Intercollegiate Guidelines Network criteria. Tworeviewers independently reviewed each study and extracted data from accepted articles (ie, with a low risk of bias) into evidence tables.Data Synthesis: Evidence from accepted studies was synthesized qualitatively according to modified Scottish Intercollegiate Guidelines Networkcriteria, and prognostic information was prioritized as exploratory or confirmatory according to design. Of 77,914 records screened, 299 articleswere eligible and reviewed. Methodological quality was acceptable for 101 (34%) articles, of which 1 article considered dementia and 7 articlesconsidered CCI. The study examining the risk of dementia after MTBI did not find an association. One randomized controlled trial found thatbeing informed about possible cognitive dysfunction after MTBI was associated with worse cognitive performance on standard tests. Children

Supported by the Ontario Neurotrauma Foundation (grant reference no. 2010-ABI-MTBIWHO-871). The funder was involved neither in the design or preparation of the study protocol nor in the

management of the project, the analysis or interpretation of data, or the preparation of the final article.

No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are

associated.

The findings and conclusions in this research are those of the authors alone and do not necessarily represent the official views or policies of the Centers for Disease Control and Prevention or any agency

of the United States government. Inclusion of individuals, programs, or organizations in this article does not constitute endorsement by the United States government.

0003-9993/14/$36 - see front matter ª 2014 by the American Congress of Rehabilitation Medicinehttp://dx.doi.org/10.1016/j.apmr.2013.06.036

Archives of Physical Medicine and Rehabilitationjournal homepage: www.archives-pmr.org

Archives of Physical Medicine and Rehabilitation 2014;95(3 Suppl 2):S245-56

with MTBI and intracranial pathology (“complicated” MTBI) performed worse than did children without intracranial pathology. Children showedhigher rates of cognitive symptoms a year after MTBI than did a control group.Conclusions: There is a lack of evidence of an increased risk of dementia after MTBI. In children, objective evidence of CCI exists only forcomplicated MTBI. More definitive studies are needed to inform clinical decisions, assessment of prognosis, and public health policy.Archives of Physical Medicine and Rehabilitation 2014;95(3 Suppl 2):S245-56

ª 2014 by the American Congress of Rehabilitation Medicine

Mild traumatic brain injury (MTBI) or concussion is a major publichealth issue, with an incidence of 100 to 300 per 100,000 people peryear.1 Dementia is also amajor public health issue, and its incidenceand prevalence are strongly related to age. The incidence of de-mentia is estimated at approximately 7.5 per 1000 people per year,2

while prevalence data show that about 1.5% of 60- to 69-year-oldshave dementia, rising to more than 40% for those older than 90years.3 Treatment options for the common diseases causing de-mentia (eg, Alzheimer’s disease, vascular dementia, dementia withLewy bodies, frontotemporal dementia) are currently limited andfocus on the stabilization of symptoms rather than on modifying theunderlying pathological progress.4 Modification of risk factors as astrategy for minimizing the risk of developing dementia is thereforeof major importance in reducing the disease burden in society. Areview of the evidence regarding the risk of dementia after MTBIcould guide clinical practice and public health strategies.

MTBI could alter the risk of developing any of the above diseasescausing dementia or could cause a distinct neuropathological pro-cess. Indeed, traumatic brain injury (TBI) was first linked to de-mentia via studies of boxers5 who developed a distinct clinicalsyndrome “dementia pugilistica.” Since then, neuropathologicalcase series have demonstrated primarily tau-related pathology in thebrains of individuals who suffered from a clinical syndromeencompassing dementia andmovement disorders after repeated headtrauma.6 The syndrome has been called chronic traumatic enceph-alopathy (CTE). However, there are no established clinical criteriafor CTE,6 and uncertainties remain regarding the relation betweenbrain injury and dementia, especially when the brain injury is mild.

Repeated MTBIs may occur in many contexts, for example insports,7 and the hypothesis that these injuries could have signifi-cant long-term consequences has face validity. However, theactual consequences of such injuries remain to be elucidated. Therelevance of CTE to, for example, a young football player whomay suffer 1 or more concussions during his playing career isunknown. The severity and frequency of brain injury may beconsiderably less than that suffered by the boxers studied in theoriginal descriptions of CTE. Numbers of reported cases of CTEin nonboxers remain extremely small, both in terms of absolutenumbers (a recent review reported neuropathologically verifiedCTE in 5 football players, 1 wrestler, and 1 soccer player8) and inrelation to the large numbers of youths and adults exposed to therisk of sports-related concussion.

Dementia in its many forms is a devastating, largely untreat-able condition, and any person, young or old, will want to do allhe/she can to minimize the risk of developing dementia later inlife. Some authorities have already acted to warn athletes of therisk of CTE: the nonprofit Sports Legacy Institute issued a pressrelease in June 2012 calling on the National Collegiate AthleticAssociation to begin to warn athletes about the risk of developingCTE from repetitive brain trauma in sports. Since 2010, the Na-tional Football League players have received concussion educa-tion materials9 developed by the National Football League, theNational Football League Players Association, and the Centers forDisease Control and Prevention. Some of these include warningsabout the risk of early-onset dementia. It is important to considerthe strength of the evidence underlying such statements.

An analysis of the strength of the evidence linking MTBI todementia is also necessary to allow appropriate consideration ofpossible negative effects of such advice. Inactivity and obesityhave been linked to a rise in diabetes and cardiovascular disease,which are in themselves major public health issues.10 Many sportsinvolve some risk of MTBI, and it is possible (though notdemonstrated) that overcautious efforts to avoid such injuries mayresult in increased inactivity, and actually have a negative impacton public health.

A previous systematic review of prognosis after MTBI11 foundthat the evidence regarding the role of MTBI as a risk factor fordementia was inconclusive. Only 3 studies of acceptable qualityaddressed this issue,12-14 and the results were inconsistent. Thisstudy aimed to provide an update, through a systematic review ofthe literature published since the previous review, regarding therisk of dementia and/or chronic cognitive impairment (CCI) afterMTBI. Findings of this review may inform both public healthagencies and individual clinicians working with patientsafter MTBI.

Methods

This systematic review is part of the work of the InternationalCollaboration on MTBI Prognosis (ICoMP). The objective is toprovide a systematic update of the evidence published since theWorld Health Organization Collaborating Centre Task Force onMild Traumatic Brain Injury findings,11 which considered studiesthrough 2000. The protocol registration, case definition, literaturesearch, critical review strategy, and data synthesis were compliantwith the Preferred Reporting Items for Systematic Reviews andMeta-Analyses guidelines and are described in detail elsewhere.15,16

Briefly, the electronic databases MEDLINE, PsycINFO, Embase,CINAHL, and SPORTDiscus were systematically searched from2001 to 2012. The search terms included “craniocerebral trauma,”“prognosis,” and “recovery of function.”

The reference lists of all reviews and meta-analyses related toMTBI and articles meeting the eligibility criteria were screenedfor additional studies. In addition, ICoMP members provided

List of abbreviations:CCI chronic cognitive impairment

CSHA Canadian Study of Health and AgingCTE chronic traumatic encephalopathy

ICoMP International Collaboration on MTBI PrognosisMCI mild cognitive impairment

MTBI mild traumatic brain injuryRCT randomized controlled trialTBI traumatic brain injury

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information about studies of which they had knowledge but thatwere not found in the databases or reference lists, as an extrameasure to ensure completeness. In fact, only 1 additional studyfor the whole project, and no studies relevant to this article, wasidentified in this way.

Articles were screened for eligibility according to predefinedcriteria. Inclusion criteria included original, published, peer-reviewed research reports in English, French, Swedish, Norwe-gian, Danish, and Spanish, human participants of all ages, anaccepted definition of MTBI, and (additionally for this article)examination of the risk of dementia or cognitive impairment 1year or more after injury.

The definition of MTBI had to fall within the definitions pro-vided by the World Health Organization Collaborating CentreTask Force on Mild Traumatic Brain Injury and the Centers forDisease Control and Prevention. The task force states that

MTBI is an acute brain injury resulting from mechanical en-ergy to the head from external physical forces. Operationalcriteria for clinical identification include: (i) one or more of thefollowing: confusion or disorientation, loss of consciousnessfor 30 minutes or less, post-traumatic amnesia for less than 24hours, and/or other transient neurological abnormalities suchas focal signs, seizure, and intracranial lesion not requiringsurgery; and (ii) Glasgow Coma Scale score of 13e15 after 30minutes post-injury or later upon presentation for healthcare.These manifestations of MTBI must not be due to drugs,alcohol, medications, caused by other injuries or treatment forother injuries (e.g. systemic injuries, facial injuries or intuba-tion), caused by other problems (e.g. psychological trauma,language barrier or coexisting medical conditions) or causedby penetrating craniocerebral injury.15

Persons with fractured skulls were included if they fit this casedefinition. The Centers for Disease Control and Prevention pro-vides an additional definition based on clinical records data. MTBIis recognized if an Abbreviated Injury Severity Scale score of 2for the head region is documented.15 An administrative datadefinition for surveillance or research is also provided.17 Specifi-cally, cases of MTBI are recognized among persons who areassigned certain International Classification of Diseases, NinthRevision, Clinical Modification diagnostic codes.

Eligible study designs were systematic reviews and meta-analyses, randomized controlled trials (RCTs), cohort studies, andcase-control studies. Exclusion criteria included study designssuch as cross-sectional studies, case reports and case series, andcadaveric studies, biomechanical studies, and laboratory studies.Studies with fewer than 30 subjects with MTBI were alsoexcluded to provide a sufficient sample size to validly estimateassociations between exposures and outcomes. Systematic reviewsand meta-analyses that did not consider the methodologicalquality of included articles were also excluded.

For the first level of screening, 1 reviewer read the titles of allthe citations retrieved from the electronic database searches andremoved all citations that were clearly not related to TBI. Thesecond level of screening involved abstract review. Full-textarticles were obtained for all abstracts except for those thatclearly did not meet the eligibility criteria. If after analyzing thefull text, the eligibility of an article was still uncertain, a secondreviewer undertook a full-text analysis of the article to deter-mine eligibility. A third reviewer was consulted in the event ofany disagreements.

All eligible articles were critically appraised using a modifi-cation of the Scottish Intercollegiate Guidelines Networkcriteria.17 These criteria are well established and appropriate toevaluate common design points and biases of different study de-signs including RCTs, cohort studies, and case-control studies.Detailed information on modifications can be found in a pre-viously published article on methodology.15 In brief, the followingwere added: a checklist on definitions of MTBI, a section onreferences to be checked, and general comments on strengths andweaknesses to optimize later integration of findings.

Two reviewers performed independent, in-depth reviews ofeach eligible study, and a third reviewer was consulted in case ofdisagreements. Data from accepted articles (ie, those with a lowrisk of bias) were independently extracted into evidence tables by2 reviewers, and the evidence was synthesized according to themodified Scottish Intercollegiate Guidelines Network criteria andthe phases of study framework described by Cote et al.18 Phase Istudies are hypothesis-generating investigations that explore theassociations between potential prognostic factors and diseaseoutcomes in a descriptive or univariate way. Phase II studies areextensive exploratory analyses that focus on particular sets ofprognostic factors or attempt to discover which factors have thehighest prognostic value. Last, phase III studies are large confir-matory studies of explicit prestated hypotheses that allow for afocused examination of the strength, direction, and independenceof the proposed relation between a prognostic factor and theoutcome of interest. Information from accepted phase III studies isconsidered the strongest evidence, followed by evidence fromaccepted phase II studies. Phase I studies do not consider con-founding and are considered more limited evidence. A best-evidence synthesis was performed with the most emphasisplaced on the better quality studies (ie, phase III studies) to pro-vide clear and useful conclusions.

This process yielded only a small number of studies ofacceptable methodological quality. It was considered important toidentify reasons for this, given the degree of clinical and publichealth importance. The database of articles identified in thesearches was therefore rescreened, via article abstracts, to identifyany further articles relevant to the risk of dementia or CCI that didnot meet the inclusion criteria or that had been found to have ahigh risk of bias by 2 independent reviewers. Rescreening wasperformed by A.K.G. and C.C., with reference to in-depth reviewsalready performed by ICoMP members. Reasons for exclusion orunacceptable bias were summarized to inform future research.

Results

After applying the inclusion and exclusion criteria to 77,914 titlesand abstracts for our entire review, 299 articles were determined tobe eligible and were critically reviewed. Of these, 101 (34%) ar-ticles were judged scientifically admissible, with a low risk ofbias.15 Eight of these studies were eligible for inclusion in thissubstudy on dementia and CCI after MTBI (figure 1, table 1 andtable 2). These encompass 6 studies of children (1 phase I, 4 phaseII, and 1 phase III) and 2 studies of adults (1 phase III and 1 RCT).Length of follow-up was 1 year for all 6 studies of children and 1to 5 years for studies of adults.

Only 1 study19 directly considered the risk of dementia afterMTBI (phase III cohort study) and found that a history of MTBIwas not associated with a future diagnosis of dementia according

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to Diagnostic and Statistical Manual Version 3 revised criteria orwith other cognitive outcomes. This study analyzed data collectedin the 1990s from 2 waves of the community-based CanadianStudy of Health and Aging (CSHA).20 Following screening ofmore than 10,000 potential participants from 18 centers, detailedclinical assessments were performed for 2,914 participants in thefirst wave (CSHA-1) in 1991 and 2,431 in the second wave(CSHA-2) 5 years later. In CSHA-1, patients were noted to havesuffered a previous head injury if this was reported by the patientor by an informant. Injury was defined as mild if there was noreported loss of consciousness or loss of consciousness of less

than 30 minutes. At follow-up after 5 years, a consensus diagnosiswas reached regarding cognitive status, with possible diagnoses:dementia (Diagnostic and Statistical Manual Version 3 revisedcriteria), no cognitive impairment, or cognitive impairment notdementia. The latter group was excluded from further analysis. Ofthe 648 patients with head injury before CSHA-1, 137 had mildinjury. Head injury occurred a mean of 27.8!22.6 years beforeCSHA-1 (median age, 57y). A history of MTBI before study entrywas not associated with the development of dementia 5 years later.

The other low risk of bias studies evaluated possible CCI(rather than dementia) after MTBI, with 6 of 7 of these studies

Fig 1 Flow chart of literature review. Abbreviations: dat, date; def, definition; des, study design; I, ineligibility code; lan, language; out,outcomes; pop, population; typ, publication type. From Moher et al.62 For more information, visit www.prisma-statement.org.

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Table 1 Studies with objective measures of cognition or documented diagnosis of dementia as outcome measure

Author, Year, Country,Study Phase

Source Population, StudySize, Participation Rate,Follow-Up, Time AfterInjury Inclusion/Exclusion Criteria MTBI Case Definition Risk Factors/Outcomes Findings

Cohort studiesBabikian et al, 2011,U.S.,21 phase II

Injured children (MTBI,other injury) recruitedfrom 14 EDs in California.Uninjured control groupfrom demographicallymatched schools. Datacollection 1989e1997.Follow-up to 12mopostinjury for nZ124(MTBI), nZ94 (otherinjury), nZ106(uninjured).Participation rates notreported. Attrition 17%e30%

Inclusion:Injured subjects: aged 8e17y; no injuries aboveAIS 2; unintentionalinjury; no litigation; nopreexisting CNSpathology;Additional criteria:MTBI group: AIShead 1e2; “other injuries”group: injury AIS 1e2 tononhead area of body.Exclusion: injuriesimpacting hand functionduring testing

Concussion causingAIShead 1 (GCS scorew15) or AIShead 2 (GCSscore w13e14)

Risk factors:MTBI, other injury, noinjury.Preinjury learning andbehavior, alcohol use,parental educationOutcomes:Performance onneuropsych tests

No difference in proportionof MTBI and other injurygroups scoring "1.5 SDsbelow the mean on "3neuropsych tests: 29%MTBI group, 32% “otherinjury” group, 18% of thenoninjured control group

Helmes et al, 2011,Canada,19 phase III

Community-based CSHA.Extended analysis of datafrom first 2 waves. 10,263potential participantsscreened in 1991. Clinicalassessments (nZ2431)performed for all thosescoring under a cutoff ona cognitive screeningtool and for a randomselection of those scoringabove the cutoff.Reassessment 5y later.At first assessment,nZ648 had a history ofTBI (nZ137 of thesemild) and nZ2115 hadno history of TBIMTBI group: nZ137

Inclusion:age > 65y

Self- or informant report ofTBI with LOC 0e<30 min

Risk factors: age, MTBI,neuropsych test scores,comorbid medicalconditions (CIRS)Outcomes:dementia diagnosis (DSM-III-R)

History of MTBI did notimprove the prediction ofdiagnosis of dementia.Age is related to thediagnosis of dementia

Levin et al, 2008, U.S.and Canada,23 phase II

Children with MTBI from 4trauma centers in theUnited States and

Inclusion:GCS score 13e15,AOC or LOC #30min,

See inclusion criteria Risk factors:presence (CMTBI) orabsence (MTBI) of

Poorer performance forprocessing speed,response inhibition,

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entiaand

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entafter

mild

TBI

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Table 1 (continued )

Author, Year, Country,Study Phase

Source Population, StudySize, Participation Rate,Follow-Up, Time AfterInjury Inclusion/Exclusion Criteria MTBI Case Definition Risk Factors/Outcomes Findings

Canada, recruited 1998e2002. 82%participation rate, nZ80Complicated MTBI(CMTBI) group: nZ32,intracranial pathology onbrain CTUncomplicated MTBIgroup: nZ48, normal CTfindings or limited to alinear skull fractureF/U: 3, 6, and 12mopostinjury

closed head trauma, CTwithin 24h after injury,age 5e15yExclusion:Child abuse; preexistingneurological disorder,autism, schizophrenia; EDattendance >24h afterinjury; penetrating braininjury

intracranial pathology onacute CT brain Moderatorvariables: other injuries(AIS, ISS), SES, preinjuryADHDOutcomes:performance onneuropsych tests 12mopostinjury

calculation ability, letter-word identification forchildren with CMTBI.Working memory worse inCMTBI, if there was nopreinjury ADHD

Roncadin et al, 2004,Canada,22 phase I

126 school-aged children,recruited from “bothresearch studies andclinical sources” at aCanadian Children’shospital. Subgroup withMTBI (nZ40); sufferingMTBI a mean of3.66!1.7y earlier.Participation rates notreported

Inclusion:single MTBI "1 y beforetesting, verbal PIQ >70Exclusion:preexisting neurologicdisorder, severepreexisting psychiatricdisorder, inflicted orgunshot injury

MTBI subgroup: GCS score13e15, LOC or AOC<15min, noneurosurgery, negativeneuroimaging.

Risk factors:MTBI Moderator variables:age at injury, time sinceinjuryOutcome:Working memory

Normal distribution ofworking memory scores inMTBI subgroup.Moderator variables werenot predictive of workingmemory

Author, Year, and Country

Source Population,Participation Rate, Follow-Up

MTBI Definition, Inclusion/Exclusion Criteria

Factor Evaluated, ComparedTreatment, Number perTreatment Arm Outcome Measures Findings

RCTSuhr et al, 2005, U.S.27 2000 university students

screened in return forcourse credits. 17% metinclusion criteria. Arandom selection of thesecontacted and 81% ofthose contactedparticipated (nZ53).Random allocation to

MTBI definition:Self-reported MTBI withLOC 1 #30minInclusion:history of self-reportedMTBI "1y beforeparticipation in the studyExclusion: neurologicalor psychiatric disorder,

Intervention evaluatednZ28 “diagnosticthreat”: writteninformation beforetesting that MTBI cancause deficits onneuropych testsCompared treatmentnZ25

1. Between-groupcomparisons for each ofthe neuropsych tests2. Proportion impaired on"1 neuropsych test(“impaired” Zperformance <1.5 SDbelow the mean)

1.“Diagnostic threat” groupperformed worse thancontrols on attention/working memory,psychomotor speed, andmemory tasks, but not onexecutive functioning,posttest anxiety, or effort2. 46% of “diagnostic

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etal

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evaluating children. These pediatric studies will be describedfirst. Two studies (phase II21and phase I22) used objectiveoutcome measures (neuropsychological tests) and found no evi-dence of cognitive impairment 1 year after injury in school-agedchildren with MTBI whose brain imaging showed no evidence ofintracranial pathology (ie, “uncomplicated” MTBI). However,another phase II study provided some evidence that children aged5 to 15 years, with acute intracranial pathology identified withcomputed tomography scanning of the brain after MTBI (ie,“complicated” MTBI), have worse cognition, as assessed withneuropsychological tests, a year after injury than do thosewithout intracranial pathology.23

Three studies24-26 used subjective outcome measures (cogni-tive symptoms) and were all based on the same cohort of Ohiochildren aged 8 to 15 years (phases II and III).24-26 Taylor et al25

(phase II) found that parents of children who had suffered MTBIreported more cognitive symptoms in their children a year afterinjury than did parents of children who had suffered orthopedicinjuries. Children who had suffered MTBI themselves reportedmore postconcussive symptoms a year after injury than did con-trols who had suffered orthopedic injury. However, group differ-ences in child self-ratings specific to cognitive symptoms were notsignificantly different between groups. Fay et al24 (phase III) foundthat ratings of postconcussive symptoms were moderated jointly bycognitive ability and injury severity in children. Children of lowercognitive ability who had trauma-related intracranial abnormalitiesseen on magnetic resonance imaging (“complicated” MTBI) wereespecially prone to symptoms. Yeates et al26 (phase II) evaluatedpatterns of symptom variation with increasing time since injury andfound that children with MTBI were more likely than those withorthopedic injuries to have patterns of either a high number ofsymptoms in the acute phase, followed by resolution of symptomsat follow-up (1y), or a high number of symptoms in the acute phase,followed by persistence of symptoms. The latter pattern howeveraffected only 9% of children with MTBI and 1% of children withorthopedic injuries. In this study, a standard measure of post-concussive symptoms was used (ie, Postconcussive SymptomInterview), which included both cognitive (nZ3) and noncognitive(nZ12) symptoms. Results were not reported separately forcognitive symptoms.

In addition, an RCT in adults27 assessed the impact of supplyingdifferent forms of written information before neuropsychologicalevaluation 1 year or more after MTBI. Written information waseither neutral, without reference toMTBI, or threatening by alertingto the possibility of cognitive changes after MTBI (ie, “diagnosticthreat”). The threat consisted of informing subjects that they hadbeen selected for testing because of reported head injury and thatreports exist stating that head injury can cause deficits on neuro-psychological testing. The study found worse cognitive perfor-mance in the group receiving the diagnostic threat. These resultssuggest that expectations influence cognitive outcomes.

Discussion

Risk of dementia after MTBI

This review of studies published 2001 through February 2012identified no evidence of an increased risk of dementia followingsingle or repetitive MTBI. There was only 1 methodologicallyacceptable study on this issue.19 A previous systematic review11

considering studies published before 2001 did not findTable1(continu

ed)

Autho

r,Year,andCoun

try

Source

Popu

lation

,ParticipationRate,Follo

w-

Up

MTBIDefinition

,Inclusion/

ExclusionCriteria

Factor

Evaluated,

Compared

Treatm

ent,Num

berper

Treatm

entArm

OutcomeMeasures

Find

ings

“diagn

osticthreat”grou

p(nZ28

)or

“neutral”

grou

p(nZ

25)

learning

disability,ADHD

“neutral”cond

ition:

Written

inform

ationthat

thestud

ycomprises

routineneurop

sych

tests,

witho

utanydiscussion

ofMTBI

threat”grou

pand12

%of

controlsimpaired

on"1

neurop

sych

test

Effort,anxiety,

and

depression

notrelatedto

cogn

itiveperformance

Abb

reviations:ADHD,attentiondeficit/hyperactivitydisorder;AIS,Abb

reviated

Injury

ScaleScore;

AIShead,Abbreviated

Injury

ScaleScoreforthehead

region

;AOC,

alteration

ofconsciou

sness;

CIRS,

CumulativeIllnessRating

Scale;

CMTBI,complicated

mildtraumaticbraininjury;CN

S,centraln

ervous

system

;CT,compu

tedtomog

raph

y;DSM

-III-R,DiagnosticandStatisticalM

anualVersion

IIIrevisedcriteria

fordementia;

ED,em

ergencydepartment;

F/U,follo

wup

;GCS,Glasgow

ComaScale;

ISS,

injury

severity

score;

LOC,

loss

ofconsciou

sness;

neuropsych,neuropsychological;PIQ,Performance

Intelligence

Quo

tient;SES,

socioecono

mic

status;TBI,traumatic

braininjury

(unspecified

severity).

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Table 2 Studies without objective measures of cognition, but with subjective measures encompassing cognitive symptoms as the outcomemeasure*

Source Population, Study Size,Participation Rate, Follow-Up Inclusion/Exclusion Criteria MTBI Case Definition

Daily screening of injured childrenat EDs of 2 children’s hospitalsin OhioParticipation rates 35% in theorthopedic injury (OI) group(nZ99) and 48% in the MTBIgroup (nZ186)Parents and children ratedcurrent PC symptoms at theinitial assessment within 3wk ofinjury, and again at 1, 3, and12mo89% completed the 12-moassessment

Inclusion:aged 8e15y. MTBI (seedefinition) or OI (upper- orlower-extremity fractures withAIS #3 without MTBI)Exclusion:MTBI excluded if delayedneurological deterioration. OIexcluded if head injury orsymptoms of concussion.Additional exclusions for bothgroups: neurosurgical or surgicalintervention; an injury thatwould interfere with neuropsychtesting, hypoxia, hypotension,shock; ethanol or drugingestion; history of head injuryrequiring medical treatment;premorbid neurological disorderor mental retardation; injury dueto child abuse or assault; severepsychiatric disorder;contraindication to MRI

Blunt head trauma resulting in LOC#30min or GCS score of 13e14,or "2 acute signs or symptomsof concussion as noted bymedical personnel (ie, transientneurological deficits, persistentPTA, vomiting, nausea,headache, diplopia, dizziness,disorientation, or other mentalstatus changes)

Author, Year, Country, Phase ofStudy Risk Factors/Outcomes Findings

Fay et al, 2010, U.S.,24 phase III Risk factors:Cognitive ability, as representedby a single overall compositescore of acceptable neuropsychtests, MRI brain findingsOutcomes:PC symptoms assessed using thePostconcussive SymptomInterview and the Health andBehavior Inventory

Hierarchical linear modelingindicated that ratings of PCsymptoms were moderatedjointly by cognitive ability andinjury severity. Children of lowercognitive ability with a CMTBIwere especially prone topersisting cognitive symptoms.Conclusion that cognitivereserve is an importantmoderator of the outcomes ofMTBI in children andadolescents

Taylor et al, 2010, U.S.,25 phase II Risk factors:MTBI or OI, MRI brain findingsOutcomes:PC symptoms measured by usingHealth and Behavior Inventoryand Postconcussive SymptomInterview

PARENT-REPORT MEASURES:Somatic PC symptoms and countsof PC symptoms: Initial groupdifferences had resolved by12mo postinjury.Cognitive PC symptoms: moresymptoms in children with MTBIthan in children with OI 12moafter injuryCHILD-REPORT MEASURES:Higher total counts of PCsymptoms at 12mo in childrenwith MTBI than in children withOI. No group differences inmeasures of somatic or cognitivePC symptoms at 12mo

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conclusive evidence regarding MTBI as a possible risk factor fordementia. Taken together, there is insufficient evidence to drawany conclusion about a potential risk of dementia after MTBI(either single or repetitive injury). Clinicians and policymakersshould be cautious about attempting to address this issue untilmore evidence is available.28

Currently, there are divergent opinions about the risk of de-mentia after MTBI. Possible explanations for this include previousreliance on studies with designs not appropriate for demonstratingcausality. Such studies were excluded from this review. Cross-sectional studies,29 uncontrolled case series,30 and studies withsmall sample sizes31 all yield important and interesting pre-liminary results but cannot demonstrate causality. It is inappro-priate to consider this evidence sufficient to inform clinicalpractice and public health policy. Systematic reviews and meta-analyses are valuable ways of synthesizing the evidence, but thefindings are difficult to interpret if the methodological quality ofincluded studies has not been assessed.32 Further, methodologi-cally sound and appropriately powered studies of MTBI and de-mentia are needed.33

Risk of CCI after MTBI

In our review of the evidence, there were no methodologicallyadmissible studies of CCI (ie, not meeting criteria for dementia) inadults after MTBI. In the studies of children, there is somedisparity between studies using objective and subjective outcomemeasures. Uncomplicated MTBI in children does not seem to leadto persistent cognitive impairment as assessed by neuropsycho-logical tests 1 year after injury,21,22 although this may not be true

of complicated MTBI.23 There is, however, some evidence ofhigher rates of cognitive symptoms a year after injury from a studythat included both complicated and uncomplicated MTBI.25 Howsuch symptoms may or may not be associated with underlyingneuropathological changes in the brain is unknown. If they arepresent, whether such changes will gradually improve, are static,or are progressive and to what extent any progressive changes mayrelate to symptoms are further unanswered questions. What isknown from studies of elderly subjects with and without memorycomplaints is that the relation between symptoms and underlyingpathological abnormalities is variable.34

Our findings on CCI need to be considered from severaldifferent perspectives. A persistent reduction in cognitive functionafter MTBI could have a negative impact on an individual’sparticipation in society, and is an important endpoint in its ownright. It could also possibly represent a temporary stage of aprogressive neurodegenerative process, and as such could be anearly proxy for the later development of dementia. Conceptualparallels could be drawn with the diagnosis “mild cognitiveimpairment” (MCI), which is a well-defined entity among elderlysubjects without dementia,35 and which is associated with anincreased risk of the development of dementia in the me-dium term.

However, a key difference between possible cognitive impair-ment after MTBI and cognitive impairment in the elderly is that thenormal clinical course after MTBI11 is rapid recovery and notprogressive decline. Other articles in this series examine short-termprognosis (<1y) after MTBI.36 Briefly, after MTBI, there will oftenbe some period (minutes to weeks) of impaired cognition beforefull recovery in the majority. The nature of longer-term cognitivesymptoms and/or impairment ("1y after injury) in the minority

Table 2 (continued )

Author, Year, Country, Phase ofStudy Risk Factors/Outcomes Findings

Yeates et al, 2009, U.S.,26 phase II Risk factors:LOC, GCS score <15, otherinjuries, MTBI or OI, intracranialabnormalities on MRI brain,preinjury symptoms.Outcomes: PC symptoms wereassessed by using the Post-concussive Symptom Interview

Finite mixture modeling identified4 patterns of PC symptoms:1. None (64% of MTBI, 79% ofOI)2. Moderate persistent (12%MTBI, 15% OI)3. High acute/resolved (15%MTBI, 5% OI)4. High acute/persistent (9%MTBI, 1% OI)Children with MTBI more likelythan children with OI to havepatterns of high acute/resolvedand high acute/persistent.Presence of LOC, PTA, GCS score<15, disorientation, and othermental status changes gavehigher overall odds of belongingto high acute/persistent PCsymptom group

Abbreviations: AIS, Abbreviated Injury Severity Score; CMTBI, complicated mild traumatic brain injury; ED, emergency department; GCS, Glasgow ComaScale; LOC, loss of consciousness; MRI, magnetic resonance imaging; neuropsych, neuropsychological; OI, orthopedic injury; PC, postconcussion; PTA,posttraumatic amnesia.* The following 3 publications are based on 1 cohort study of Ohio children: Fay et al22; Taylor et al23; and Yeates et al.24

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who experience less than full recovery remains incompletely un-derstood. One possible theoretical explanation is an irreversibleimpairment in brain function due to MTBI-related pathology,either as a result of static changes that do not recover or due totriggering of some persistent or progressive neuropathologicalprocess leading to progressive cognitive impairment that may intime lead to a form of dementia (as is postulated to occur in CTE8).

A recent study found that subjective memory complaints inelderly subjects (ie, at risk of dementia due to age) are associatedwith an adjusted hazard ratio of 2.3 for a dementia diagnosis within4 years.37 The elderly with MCI develop dementia at the rate of 6%to 10% per year in community samples (10%e15% per year inclinic samples), whereas 1% to 2% of elderly without MCI developdementia every year.35 In summary, even in elderly subjects at riskof dementia there is an incomplete relation between memorycomplaints, cognitive impairment, and the development of de-mentia. It is perhaps not surprising that it has not been possible torelate subjective cognitive complaints after MTBI in children topossible altered dementia risk, given the long latency involved.

Reasons for the low number of articles admissible forthis systematic review

Inclusion criteriaThree further studies with a low risk of bias were initially iden-tified from the list of all studies accepted for inclusion in theumbrella review, but these were found not to meet the inclusioncriteria for this substudy on the risk of dementia and CCI. Reasonsinclude the possible inclusion of some subjects assessed less thana year after injury,38,39 or only post hoc analysis related to CCI.40

Review of all abstracts identified by the searches found anadditional 242 articles, published within our review time frame(2001-February 2012), and with a title related to CCI or dementiaafter brain injury, but did not otherwisemeet the inclusion criteria forthis review. Reasons for exclusionwere case definition (117 articles;mixed acquired brain injury, not TBI, mixed severity of TBI withoutstratified results, lack of MTBI definition), sample size (75 articleswith n<30), design (42 were cross-sectional studies, narrative re-views, or systematic reviews without assessment of quality ofincluded articles), type (2 were abstracts and 1 was a dissertation),and outcomes (5 articles were not related to prognosis).

High risk of biasAll studies that met the inclusion criteria15 for the umbrella reviewof prognosis after MTBI were rescreened for potential relevanceto the risk of dementia or CCI after MTBI. An additional 19studies41-59 were identified that fulfilled the inclusion criteria forthis review of the risk of dementia or CCI after MTBI, but hadbeen assessed on consensus review as having a high risk of bias.Methodological issues giving rise to a high risk of bias includedinadequate information on selection and/or participation rates,high attrition, risk of confounding, underpowered studies, orinadequate MTBI definition. Eleven studies were found to haveproblems in more than 1 area.

To illustrate some of the methodological factors causing a highrisk of bias, 1 highly cited study59 reviewed by the ICoMP, butfound to have a high risk of bias, will be discussed further. Theobjective of this study was directly relevant to the subject of thisreview: to investigate the association between previous headinjury and the likelihood of developing MCI and Alzheimer’sdisease in a unique group of retired professional football players

with previous head injury exposure. However, methodologicalweaknesses include incomplete information about participationrates, potential differential recall bias of concussion history, lackof control for potential confounders (eg, depression, chronic pain,drug and alcohol abuse), cross-sectional aspects to the design,selection bias (unknown whether respondents differed from non-respondents), and risk of information bias (self-reported outcomesof memory problems might not indicate real or objective memoryproblems). Differential recall bias is a problem in this and otherretrospective studies based on subjects’ recall of past concussionsand may cause misclassification of exposure and therefore majordifficulties in interpreting findings. Both underestimation andoverestimation of the number of past concussions may occur, andsuch variation may be influenced by both the outcome of interest(CCI or neurodegenerative dementia) and possible confounders(eg, depression, alcohol overuse). Kerr et al60 valuated this issueby comparing the reliability of self-recall of concussions amongformer professional players in the same cohort as Guskiewiczet al.59 Questionnaires were sent to former players in 2001 and2010 enquiring about concussions that had occurred duringplayers’ playing careers (ie, before 2001) and measuring healthstatus. Most players (62.1%) reported the same number of con-cussions, but those who reported more had worse physical andmental health at follow-up. This differential recall bias wouldresult in an overestimation of the risk of MCI due to concussions.Although these authors should be congratulated on attempting tostudy this important issue, there were too many potential problemsfor us to rank their study59 as low risk of bias.

Study limitations

It is impossible to eliminate all components of subjectivity fromthe assessment of articles for risk of bias, and thereby on thedecision regarding whether or not to include any individual study.The ICoMP addressed this risk through the independent use ofstandardized, in-depth review forms by 2 reviewers, followed bydiscussion and referral to a third reviewer when consensus was notreached. Publication bias is possible because we reviewed onlythose studies that were published in peer-reviewed journals and inspecific languages between 2001 and 2012. Therefore, potentiallyrelevant studies may have been missed.

Methodological difficulties and researchrecommendations

It is inherently difficult to conduct a methodologically robuststudy of the risk of dementia after MTBI. Recall bias, the need foran appropriate control group, difficulties associated with control-ling for confounding given the long follow-up periods needed, andeven financial constraints are some relevant factors. However,strategies such as twin studies, the use of biomarkers, and the useof linkage between hospital databases recording MTBI and de-mentia diagnoses are examples of strategies that have not beenexhausted and should be pursued. Such issues are discussedfurther in another article in this series.61

Conclusions

This review identified no evidence published between 2001 and2012 of an increased risk of dementia after MTBI. A previousreview concluded that studies published before 2001 were

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inconclusive regarding the risk of dementia after MTBI.11 There isobjective evidence for CCI measured at 12 months postinjury onlyafter complicated MTBI in children. Uncomplicated MTBI maycause higher rates of cognitive symptoms in children a year afterinjury. There is an urgent need for further, methodologicallyrobust and appropriately designed studies to provide evidence onpossible altered risk of CCI and dementia after MTBI.

Keywords

Cognition disorders; Craniocerebral trauma; Dementia; Outcomeassessment; Prognosis; Rehabilitation

Corresponding author

Alison K. Godbolt, MBChB, MD, University Department ofRehabilitation Medicine, Plan 3, Hus 39, Danderyd Hospital,18288 Stockholm, Sweden. E-mail address: alison.godbolt@ki.se.

Acknowledgments

We thank the other members of ICoMP: Jean-Luc af Geijerstam,MD, PhD, Jorgen Borg, MD, PhD, Linda J. Carroll, PhD, PierreCote, DC, PhD, James Donovan, DC, Jan Hartvigsen, PhD, LenaW. Holm, DrMedSc, Ryan Hung, MD, MSc, Michelle Keightley,PhD, Catharina Nygren-de Boussard, MD, PhD, Peter Rumney,MD, and Britt-Marie Stalnacke, MD, PhD. AKG acknowledgesthe support of an “ALF” grant from Karolinska Institute, Dan-deryd Hospital, Stockholm, Sweden, and that of colleagues at theBrain Injury Rehabilitation Unit at Danderyd Hospital. We thankPanos Lambiris, Information Scientist, University HealthNetwork, for assisting in developing, testing, and updating thesearch strategies. We also thank Meijia Zhou for assisting inretrieving and screening articles.

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