ARTICLE OPEN ACCESS

Longitudinal change in regional brain volumeswith exposure to repetitive head impactsCharles Bernick MD MPH Guogen Shan PhD Henrik Zetterberg MD Sarah Banks PhD

Virendra R Mishra PhD Lynn Bekris PhD James B Leverenz MD and Kaj Blennow MD

Neurologyreg 202094e232-e240 doi101212WNL0000000000008817

Correspondence

Dr Bernick

berniccccforg

AbstractObjectiveThis study tests the hypothesis that certain MRI-based regional brain volumes will showreductions over time in a cohort exposed to repetitive head impacts (RHI)

MethodsParticipants were drawn from the Professional Fighters Brain Health Study a longitudinalobservational study of professional fighters and controls Participants underwent annual 3Tbrain MRI computerized cognitive testing and blood sampling for determination of neuro-filament light (NfL) and tau levels Yearly change in regional brain volume was calculated forseveral predetermined cortical and subcortical brain volumes and the relationship with NfL andtau levels determined

ResultsA total of 204 participants who had at least 2 assessments were included in the analysesCompared to controls the active boxers had an average yearly rate of decline in volumes of theleft thalamus (1023 mm3y [p = 00004] mid anterior corpus callosum (102 mm3y [p =0018]) and central corpus callosum (165 mm3y [p = lt00001]) Retired boxers showed themost significant volumetric declines compared to controls in left (321 mm3y [p = 0002]) andright (306 mm3y [p = 0008]) amygdala and right hippocampus (335 mm3y [p = 001])Higher baseline NfL levels were associated with greater volumetric decline in left hippocampusand mid anterior corpus callosum

ConclusionVolumetric loss in different brain regions may reflect different pathologic processes at differenttimes among individuals exposed to RHI

RELATED ARTICLE

EditorialRegional brain atrophy inprofessional fightersDifferent patterns differentmechanisms

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PodcastDr Jeffrey Ratliff talkswith Dr Charles Bernickabout his paper on thelongitudinal change inregional brain volumeswith exposure to repetitivehead impacts

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From the Cleveland Clinic (CB VRM) Las Vegas University of Nevada (GS) Las Vegas Sahlgrenska Academy (HZ KB) University of Gothenburg Sweden University ofCalifornia (SB) San Diego and Cleveland Clinic (LB JBL) OH

Go to NeurologyorgN for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

The Article Processing Charge was funded by the August Rapone Family Fund

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

e232 Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology

The relationship between high levels of exposure to re-petitive head impacts (RHI) and long-term neurologic im-pairment has garnered much attention and debate in boththe medical and lay literature How often this exposure orwhich level or severity of exposure leads to a progressiveneurodegenerative condition such as chronic traumatic en-cephalopathy (CTE) is unknown (figure 1)12 Hinderingour ability to determine the natural history of exposure toRHI is the lack of biomarkers that can track change in brainstructure and function over time

Previous work has suggested that monitoring regional brainvolumes through MRI may serve as a potential tool to rec-ognize and follow structural brain changes3 Measurement ofhippocampal volumes has been well-studied in Alzheimerdisease (AD) and is commonly used as a secondary outcomemeasure in AD clinical trials4 Similarly we and others havereported associations between volumes of certain brainregions and exposure to RHI as well as clinical outcomes incross-sectional studies56 Less is known about using volu-metric MRI techniques in a longitudinal manner in thoseexposed to RHI

The Professional Fighters Brain Health Study (PFBHS) isa longitudinal study of professional fighters intended to betterunderstand the long-term effects of exposure to RHI Utilizingthis cohort where MRI is completed annually we test the hy-pothesis that certain regional brain volumes will show reduc-tions over time in those exposed to RHI and explore factors thatare associated with or modify the effect of those reductions

MethodsParticipants in the PFBHS consist of active and retired pro-fessional fighters (boxers and mixed martial arts [MMA]fighters) along with age- and education-matched controlsActive fighters were required to have at least 1 professional fightwithin 2 years of enrollment and be training with the intent tocompete information about the study was disseminated by theNevada Athletic Commission fight promoters and localtraining facilities Retired fighters were included if they hadbeen boxers had a minimum of 10 professional fights had nosanctioned fights for at least 2 years and did not intend toreturn to competition (there were too few retired MMA

GlossaryAD = Alzheimer disease CTE = chronic traumatic encephalopathy MMA = mixed martial arts NfL = neurofilament lightPFBHS = Professional Fighters Brain Health Study RHI = repetitive head impacts SNR = signal-to-noise ratio

NeurologyorgN Neurology | Volume 94 Number 3 | January 21 2020 e233

fighters to include as a separate group) Control participantswere recruited from outreach efforts in the community andcould not have any history of neurologic disorders headtraumamilitary service or participation at a high school level orhigher in a combat sport or a sport in which head trauma can beanticipated to occur such as football wrestling hockey rugbysoccer or rodeo Enrollment in the PFBHS began in 2011 andhas been continuous since then Each participant is seen on anannual basis and for active fighters not sooner than 45 daysfrom a sanctioned fight The PFBHS was approved by the

Cleveland Clinic Institutional Review Board and written in-formed consent was obtained from all participants More de-tailed methods of recruitment and study procedures have beendescribed previously7

At baseline and each annual visit a battery of tests and in-formation are acquired including MRI brain computerizedcognitive testing and exposure history Participants answerquestionnaires with the assistance of the study coordinatorthat collect information on demographics educational

Figure 1 Average yearly change in left thalamic and central corpus callosum (CC) volumes among retired fighters activeboxers active mixed martial arts (MMA) fighters and control group

Average yearly change in (A) left thalamic and (B) central CC volumes (mLy) among retired fighters active boxers active MMA fighters and control group

e234 Neurology | Volume 94 Number 3 | January 21 2020 NeurologyorgN

attainment medical history including concurrent illnessesand prescribed medications previous head trauma both re-lated and unrelated to athletic activities and prior in-volvement in other contact sports Number of professionalfights was ascertained by review of commonly recognizeddatabases (boxreccom for boxers sherdogcom for MMAfighters) Information on the amount of sparring the partici-pant has engaged in as well as whether there have been anyconcussions or head injuries within the 2 weeks prior to thestudy visit is obtained through a structured questionnaire

Cognitive function was assessed by 2 computerized cognitivetest batteries One consists of 4 subtests of the CNS VitalSigns including verbal memory symbol digit coding Stroopand a finger-tapping test CNS Vital Signs offers robust andreliable measurements of cognition which are computerizedbut are supervised by a technician8 Results from these testsare used to make up scores in various clinical domains verbalmemory processing speed psychomotor speed and reactiontime The other cognitive assessment is the C3 an iPad-basedtest that includes symbol digit Trails A and B simple andchoice reaction time and a balance measure9

A high-resolution T1-weighted anatomical MRI was obtainedon all fighters at each visit A 3T MRI scanner (Siemens[Munich Germany] Verio from April 2011 through October2015 and Siemens Skyra from December 2016 to the present)with a 32-channel head coil was used to acquire structural 3DT1-weighted magnetization-prepared rapid acquisition gradi-ent echo images (repetition time msecho time ms 2300298 resolution 1 times 1 times 12 mm3) Only data with high-qualitycortical reconstruction from FreeSurfer were utilized This wasensured through a quality control procedure outlined byFreeSurferrsquos quality analysis tools (surfernmrmghharvardedufswikiQATools) and only data with signal-to-noise ratio(SNR) of at least 16 were included in this study (surfernmrmghharvardedupubdistfreesurfertutorial_packagesOSXfreesurferbi nwm-anat-snr) This SNR number was decidedupon based on our observation from randomly selected par-ticipants that the segmented images with an SNR of 16 orabove yielded maps that require no operator-controlled editsTherefore no manual edits were performed

Volumes of the hippocampus and amygdala and subcorticalgray matter including thalamus caudate and putamen alongwith corpus callosum were calculated using the automatedfull brain segmentation process in Freesurfer v6 softwareThese regions have been shown in pathologic series and ourprior work to be affected in those with extensive RHI510 Thevolumes of each structure weremeasured in both hemispheresseparately and adjusted for total intracranial volume

Blood samples were collected annually in EDTA tubes andcentrifuged at 3200 rpm for 10 minutes to separate plasmafrom blood cells The supernatant was aliquoted in 2 mLportions that were immediately frozen and stored at minus80degpending analysis Plasma tau and neurofilament light (NfL)

concentrations were measured using ultrasensitive singlemolecule array (Simoa) assays as previously described indetail1112 The lower limits of quantification for tau and NfLwere 122 and 69 pgmL respectively and intra-assay coef-ficients of variation were just above or below 10 All analyseswere performed by board-certified laboratory technicians whowere blinded to clinical data

Statistical analysisIn the table for the characteristics of the study cohort (table 1)mean and SD were computed for continuous variables (egage number of fights) and the number of events and pro-portion were calculated for dichotomous variables Analysis ofvariance was used to compare the group difference for eachcontinuous variable nonparametric Kruskal-Wallis test wasused for comparing groups when the outcome is ordinal andthe χ2 test was used when the outcome is dichotomized

Linear mixed models were used for the repeated measure-ments When the 4 groups (retired boxer active boxer activeMMA and control) were compared with regards to each brainvolume the main effects were visit group and their interactionafter adjustment for age education years ethnicity scannertype and total intracranial volume The variable scanner typewas added in the model because the scanner was upgradedduring the study When only the fighters were included in themodel the number of fights was added as another covariate

Yearly percentage change of volume for each brain regionwas determined by calculating the slope of all MRI timepoints this value was utilized for all the analyses Howeverto categorize the active fighters by rate of volume decline ofthe caudate only the volume at the first visit and that at thelast visit from the same scanner was used A 15 yearlypercentage decrease was considered as the cutoff to sepa-rate the participants into 2 subgroups a stable group withthe decreasing rate being less than the cutoff and a declininggroup with the decreasing rate being more than 15 yearlyThe repeated cognitive measurements were assessed inlinear mixed models with the main effects of group (de-cliner or not) visit and their interaction adjusted by ageeducation years ethnicity scanner type and number offights

All these tests were 2-sided at α level of 005 All statisticalanalyses were performed using SAS statistical software (ver-sion 94 SAS Institute Inc Cary NC)

Data availabilityAnonymized data will be shared by request from any qualifiedinvestigator

ResultsIn total 204 participants who had at least 2 assessments andcomplete data for those visits were included in the analyses

NeurologyorgN Neurology | Volume 94 Number 3 | January 21 2020 e235

Characteristics of the study group are shown in table 1 Asexpected the retired boxers were older and had more pro-fessional fights and years of fighting Demographics for activeboxers and MMA fighters were similar The controls werematched for age but tended to have a higher level of educationand were more likely to be Caucasian

Compared to controls the active boxers had a notableaverage yearly rate of decline in volumes of the leftthalamus (1023 mm3y [p = 00004]) mid anteriorcorpus callosum (102 mm3y [p = 0018]) and centralcorpus callosum (165 mm3y [p lt 00001]) (figure 1)For the MMA fighters the pattern was similar but toa slightly lesser extent in left thalamic decline (575 mm3y [p = 0036]) and central corpus callosum (97 mm3y [p= 0007]) Retired boxers on the other hand showed themost significant volumetric declines compared to con-trols in left (321 mm3y [p = 0002]) and right(306 mm3y [p = 0008]) amygdala and right hippo-campus (335 mm3y [p = 001]) Several other structuresshowed a trend toward decreasing volumes compared tocontrols (table 2)

To assess whether degree and timing of exposure to RHI wasinfluencing the pattern of regional volumetric decline seenbetween active and retired fighters we compared the differentfighter groups controlling for number of professional fightsAmong types of fighters with active MMA fighters as the ref-erence active boxers showed greater yearly volumetric declinein left thalamus (447mm3y [p = 00211]) right hippocampus(191 mm3y [p = 00067]) and central (717 mm3y [p =00053]) mid anterior (736 mmy [p = 00114]) and midposterior corpus callosum (630 mm3y [p = 00007]) retired

fighters showed greater decline in left amygdala (274 mm3y[p = 00011]) left hippocampus (327 mm3y [p = 00055])and right hippocampus (369 mm3y [p = 00002])

There were no significant differences in trajectory of cog-nitive test scores between controls and active or retiredfighters at a group level However after separating the activefighters into those with and without yearly caudate volu-metric decline as described above one additional variable(dichotomized variable decliner or nondecliner) was cre-ated and included in the repeated measures statistical modelwith all visits included We found that decliners had signif-icant yearly worsening in both Trails A (267 sy [p =0004]) and Trails B (472 sy [p = 0015]) tests (figure 2)No differences in symbol digit or simple or choice reactiontime tests were seen between decliners and nondecliners

Higher baseline NfL levels were associated with greater volu-metric decline in left hippocampus (332 mm3y p lt 0001)and mid anterior corpus callosum (768 mm3 p = 0015) witha trend seen in the left amygdala right thalamus and midcorpus callosum Higher baseline tau levels were not correlatedwith regional volumetric changes Moreover there was nodifference in change over time in plasma tau or NfL levelsbetween the active fighter decliners and nondecliners

DiscussionIdentifying biomarkers that can track change in brain struc-ture or function over time in those exposed to RHI may haveimportant implications prognostically and in clinical trials asa means to select cohorts or as a possible outcome measure

Table 1 Characteristics of the study cohort

Boxer retired Boxer active MMA active Control p Value

No 23 (11) 50 (25) 100 (49) 31 (15)

Age y 4548 (997) 2856 (604) 2919 (481) 3055 (1053) lt00001

Education y 12 (12ndash15) 12 (12ndash14) 14 (12ndash16) 14 (12ndash17) lt00001

No of fights 38 (23ndash56) 5 (0ndash18) 75 (1ndash165) 0 lt00001

Years of fighting 1047 (571) 489 (508) 489 (444) 0 lt00001

Years of follow-up 261 (153) 302 (163) 256 (158) 229 (137) 01915

Male 22 (96) 48 (96) 90 (90) 26 (84) 02360

Race 00588

African American 7 (30) 13 (26) 25 (25) 5 (16)

White 13 (57) 22 (44) 63 (64) 22 (71)

Asian 0 (0) 2 (4) 4 (4) 2 (6)

Other 3 (13) 13 (26) 7 (7) 2 (6)

Abbreviation MMA = mixed martial artsFor ordinal outcomes (education year and number of fights) median (interquartile range) are reported Other values are n ()

e236 Neurology | Volume 94 Number 3 | January 21 2020 NeurologyorgN

One potential modality that is already commercially availableis MRI-based regional volumetric measures13 This study ex-amined longitudinal change in MRI volumes in a cohort ofactive and retired professional fighters Among the activefighters thalamic and corpus callosum volumes significantlydeclined over time compared to controls whereas in the re-tired fighters the amygdala and hippocampus were thestructures that showed the most decline controlling for ageMoreover the group of fighters that had significant decline incaudate volume also demonstrated reduction in processingspeed on a cognitive measure Higher baseline NfL levels wereassociated with declining volumes in certain cortical andsubcortical volumes

Previous studies including our own work have reported dif-ferences compared to controls in thalamic and corpus callosumvolumes in disorders that affect the white matter includingtraumatic brain injury and multiple sclerosis514ndash16 Animalstudies of head trauma indicate that blows to the head can resultin physical injury to axons17 Because the thalamus has abun-dant afferent and efferent fibers the progressive loss of volumeseen may reflect Wallerian degeneration of the axons withsubsequent neuronal dropout though other mechanisms thatmay reduce thalamic volume are also possible18

In the retired fighters the structures that showed the greatestdecline in volumes over time differed from those in the

younger active fighters In this retired group who weregenerally older the most significant changes were in theamygdala and hippocampus Postmortem studies of CTEsuggest that the characteristic tau pathology is more scatteredin frontal and temporal regions in lower stages and with moreadvanced disease and tends to accumulate in the temporallobe structures with accompanying gross atrophy19 One in-terpretation of our findings is that MRI volumetric changes inthalamus and corpus callosum in younger individuals par-ticularly those actively exposed to RHI is primarily the resultof accumulating axonal injury whereas in the older retiredcohort change in hippocampal and amygdala volumes may bereflective of a different process such as CTE or other types ofneurodegeneration such as Alzheimer-type pathology

The relationship between decline in regional volumes andlongitudinal performance on cognitive measures requiresscrutiny We did not find any differences at a group levelbetween active and retired fighters and controls after adjustingfor age and education This may be due to the limited scope ofour cognitive test battery lack of sensitivity to the type ofcognitive changes one might encounter in those exposed tohead trauma or variability of the tests themselves

Experience with other neurodegenerative diseases has shownthat more obvious clinically apparent cognitive decline maylag behind structural changes2021 To investigate this

Table 2 Average regional yearly rate of volume change in mm3

Region Baseline total volume of control

Yearly rate of change from the fitted statistical model

Control Retied boxer Active boxer Active MMA

Left thalamus 37730 425 minus968 (0121) minus1448 (0001) minus1000 (0036)

Left putamen 28531 minus26 383 (0605) 609 (0077) 587 (0081)

Left hippocampus 22825 minus66 minus187 (0080) 49 (0889) 140 (0512)

Left amygdala 7718 162 minus482 (0002) minus265 (0231) minus212 (0540)

Left caudate 14463 minus95 20 (0465) 02(0271) 61 (0676)

Right thalamus 34059 47 minus169 (0612) minus336 (0149) minus98 (0787)

Right putamen 31632 138 minus77 (0814) minus175 (0860) minus168 (0881)

Right hippocampus 23495 97 minus432 (0010) minus251 (0152) minus60 (0714)

Right amygdala 7956 247 minus553 (0008) minus432 (0051) minus430 (0043)

Right caudate 11643 37 minus173 (0302) minus225 (0084) minus175 (0183)

Anterior CC 2851 minus03 minus67 (0195) minus23 (0558) minus41 (0298)

Central CC 4932 61 minus176 (0012) minus226 (lt00001) minus158 (0007)

Mid anterior CC 3006 36 minus103 (0196) minus138 (0018) minus67 (0452)

Mid posterior CC 3647 minus59 101 (0204) 30 (0282) 90 (0240)

Posterior CC 3115 minus54 43 (0877) 105 (0417) 71 (0777)

Abbreviation CC = corpus callosum MMA = mixed martial artsp Values are presented in parentheses comparing each group with the control group Estimated regional brain volumes are presented in the column forcontrols

NeurologyorgN Neurology | Volume 94 Number 3 | January 21 2020 e237

possibility in our cohort we dichotomized the study partic-ipants into decliners and nondecliners using a greater than 15SD per year drop in caudate volume compared to controlsThe caudate was chosen because damage to this structure canresult in cognitive and behavioral impairment we have pre-viously reported a relationship between caudate volumes andcognitive performance and it provided a reasonable number ofparticipants in each group (decliners and nondecliners)52223

Those who had decline in caudate volumes showed a greater

yearly lowering in scores on the Trails A and B tests Trail-making tests are thought to reflect a wide range of cognitivefunctions including attention sequencing and shifting cog-nitive flexibility abstraction psychomotor speed and abilityto simultaneously maintain 2 trains of thought24

NfL is highly expressed in large-caliber myelinated axons of thewhitematter and is an established biochemical marker of axonalinjury2526 Elevations in NfL have been reported not only after

Figure 2 Average yearly change in performance on Trail-Making Test (TMT) parts A and B between active fighters whoshowed gt15 average yearly decline in caudate volumes (decliners) and those who did not exceed this rate ofdecline

Average yearly change in performance on TMT parts A (A) and B (B) in seconds between active fighters who showed gt15 average yearly decline in caudatevolumes (decliners) compared to those who did not exceed this rate of decline

e238 Neurology | Volume 94 Number 3 | January 21 2020 NeurologyorgN

concussion but also after cardiac arrest as well as in a num-ber of chronic neurologic disorders27ndash30 We have previouslyreported that serum NfL levels are higher in active fighterscompared to retired fighters and controls with very littleoverlap between NfL levels in active fighters and controls31

Thus the current finding that within the active fighter groupthose with higher baseline NfL levels were more likely toshow regional volumetric decline suggests that this measuremay have predictive properties in identifying individuals whomay be at risk of ongoing structural brain injury Whethercessation of exposure to RHI in those who have elevated NfLlevels will halt this volume loss over time needs furtherinvestigation

While this study benefits from having well-characterizedparticipants who either are or have been exposed to re-petitive head impacts along with a control group free fromreported head trauma there are certain limitations to beacknowledged For one the cohort examined was nota random sample of active and retired fighters introducingpotential bias in the results that is it may be that partic-ipants who are the most symptomatic and have more con-cern about their health might be more likely to continue inthe study Arguing against this is the finding that only a smallproportion showed decline in cognitive function Thoughour study group included both men and women the num-ber of women was small making it difficult to determine ifsex influences volumetric change However repeat analysesthat were restricted to men did not significantly change anyresults The timeframe for follow-up was brief althoughsome participants had up to 6 years between baseline andlast visit the average follow-up time was 26 years In ad-dition we used a brief computerized cognitive battery andmay have found more correlations between volumetric de-cline and cognitive change if we employed more exhaustivetesting In a clinical setting though it may not be realistic toobtain full neuropsychological testing on a frequent basis sothat identifying brief readily available tests that correlatewith structural change may be more practical

One major concern with studies using MRI volumetrics isthe variability or noise that may occur with repeatedmeasures Studies of test and retest stability of volumesconsistently report a certain amount of variability includinggain or loss of volume3233 Our sample is no exceptionthough we benefit from including multiple imaging datapoints to determine yearly rate of change We employed anautomated quality control procedure for the MRI volu-metrics in this study and there may be some imperfectionsin exact reconstruction of the brain regions However wespeculate that the statistical effects due to lack of manuallyediting those minor imperfections on brain regions utilizedin this study should be minimal34 In addition we haveprocessed the longitudinal data with cross-sectional analysisin FreeSurfer To minimize the effect of brain volume atdifferent time points this study utilized intracranial volumeas a nuisance regressor

Inclusion of this nuisance variable does not eliminate the biasinherent due to lack of longitudinal reconstruction and futurestudies will evaluate the effects of cross-sectional and longi-tudinal reconstruction on the results we report Finally theaverage yearly percentage change in regional brain volumes isrelatively small Yet the magnitude of volume change in thebrain regions we found to be significant exceed the within-scanner testndashretest variability reported in the literature Still itis not known if this reliability would apply in general clinicalpractice and further work is needed to determine how usefulthis could be on an individual basis or if these small changesare prognostic

Despite these limitations this study is one of the largest tolongitudinally follow MRI brain volumetric changes amongactive and retired professional athletes exposed to RHI Thefindings reported shed some light on how longitudinal re-gional volumetric MRI may be employed in tracking the long-term neurologic effects of repetitive head trauma Volumetricloss in different brain regions may reflect different pathologicprocesses at different times among individuals exposed toRHI Further research is needed to determine if this pattern ofvolumetric change continues over a longer follow-up periodand can be replicated in other cohorts exposed to RHI

Study fundingKB holds the Torsten Soderberg Professorship in Medicineat the Royal Swedish Academy of Sciences and is supportedby the Swedish Research Council (2017ndash00915) the SwedishAlzheimer Foundation (AF-742881) Hjarnfonden Sweden(FO2017-0243) and a grant (ALFGBG-715986) from theSwedish state under the agreement between the Swedishgovernment and the County Councils the ALF agreementHZ is a Wallenberg Academy Fellow supported by grantsfrom the Swedish Research Council (2018-02532) the Eu-ropean Research Council (681712) the UK Dementia Re-search Institute at UCL and a grant (ALFGBG-720931) fromthe Swedish state under the agreement between the Swedishgovernment and the County Councils the ALF agreementThe Article Processing Charge was funded by the AugustRapone Family Fund

DisclosureC Bernick received research funding from UFC Top RankPromotions Haymon Boxing BellatorSpike TV and UCLADream Fund G Shan reports no disclosures relevant to themanuscript H Zetterberg has served on scientific advisoryboards for Roche Diagnostics Samumed CogRx and Waveand is a cofounder of Brain Biomarker Solutions in Gothen-burg AB a GU Venturesndashbased platform company at theUniversity of Gothenburg all unrelated to the work pre-sented S Banks and VR Mishra report no disclosures rele-vant to the manuscript L Bekris is supported by a grant fromthe Department of Defense Peer Reviewed Alzheimerrsquos Re-search Program (PRARP) Convergence Science Research(AZ160058) JB Leverenz has consulted for Acadia AptinyxEisai Sanofi and Takeda He has research support from GE

NeurologyorgN Neurology | Volume 94 Number 3 | January 21 2020 e239

Healthcare and Sanofi unrelated to work presented KBlennow has served as a consultant or on advisory boards forAlector Alzheon CogRx Biogen Lilly Novartis and RocheDiagnostics and is a cofounder of Brain Biomarker Solutionsin Gothenburg AB a GU Venturesndashbased platform companyat the University of Gothenburg all unrelated to the workpresented Go to NeurologyorgN for full disclosures

Publication historyReceived by Neurology February 11 2019 Accepted in final formJuly 25 2019

References1 Asken BM Sullan MJ DeKosky ST Jaffe MS Bauer RM Research gaps and controversies

in chronic traumatic encephalopathy a review JAMA Neurol 20177411256ndash112622 Gardner BE Iverson GL McCrory P Chronic traumatic encephalopathy in sport

a systematic review Br J Sports Med 20144884ndash903 Reiter K Nielson KA Durgerian S et al Five-year longitudinal brain volume change in

healthy elders at genetic risk for Alzheimerrsquos disease J Alzheimers Dis 2017551363ndash13774 Platero C Lin L Tobar MC Longitudinal neuroimaging hippocampal markers for

diagnosing Alzheimerrsquos disease Neuroinformatics 20191743ndash615 Bernick C Banks SJ Shin W et al Repeated head trauma is associated with smaller

thalamic volumes and slower processing speed the Professional Fighters Brain HealthStudy Br J Sports Med 201591007ndash1011

6 Misquitta K Dadar M Tarazi A et al The relationship between brain atrophy andcognitive-behavioural symptoms in retired Canadian football players with multipleconcussions Neuroimage Clin 201819551ndash558

7 Bernick C Banks S Phillips M et al Professional Fighters Brain Health Studyrationale and methods Am J Epidemiol 201315280ndash286

8 Gualtieri CT Johnson LG Reliability and validity of a computerized neurocognitivetest battery CNS vital signs Arch Clin Neuropsychol 200621623ndash643

9 Alberts JL Hirsch JR Koop MM et al Using accelerometer and gyroscopic measuresto quantify postural stability J Athl Train 201550578ndash588

10 McKee AC Stein TD Kiernan PT Alvarez VE The neuropathology of chronictraumatic encephalopathy Brain Pathol 201525350ndash364

11 Rohrer JD Woollacott IO Dick KM et al Serum neurofilament light chain protein isa measure of disease intensity in frontotemporal dementia Neurology 2016871329ndash1336

12 Mattsson N Zetterberg H Janelidze S et al Plasma tau in Alzheimer disease Neu-rology 2016871827ndash1835

13 Ross DE Ochs AL Tate DF et al High correlations between MRI brain volumemeasurements based on NeuroQuantreg and FreeSurfer Psychiatry Res Neuroimaging201827869ndash76

14 Minagar A Barnett MH Benedict RHB The thalamus and multiple sclerosis modernviews on pathologic imaging and clinical aspects Neurology 201380210ndash219

15 Wu L Zhou F Zhang Y et al Thalamic atrophy and dysfunction in patients with mild-to-moderate traumatic diffuse axonal injury a short-term and mid-term MRI studyNeuroreport 2018291282ndash1287

16 Pischiutta F Micotti E Hay JR et al Single severe traumatic brain injury producesprogressive pathology with ongoing contralateral white matter damage one year afterinjury Exp Neurol 2018300167ndash178

17 Fehily B Fitzgerald M Repeatedmild traumatic brain injury potential mechanisms ofdamage Cel Transpl 2017261131ndash1155

18 Behrens TE Johansen-Berg H Woolrich MW et al Non-invasive mapping of con-nections between human thalamus and cortex using diffusion imaging Nat Neurosci20036750ndash757

19 Stein TD Alvarez VE McKee AC Chronic traumatic encephalopathy a spectrum ofneuropathological changes following repetitive brain trauma in athletes and militarypersonnel Alzheimers Res Ther 201464

20 Jack CR Jr Knopman DS Jagust WJ et al Hypothetical model of dynamic bio-markers of the Alzheimerrsquos pathological cascade Lancet Neurol 20109119ndash128

21 Fotenos AF MintunMA Snyder AZ Morris JC Buckner RL Brain volume decline inaging evidence for a relation between socioeconomic status preclinical Alzheimerdisease and reserve Arch Neurol 200865113ndash120

22 Mori E Impact of subcortical ischemic lesions on behavior and cognition Ann NYAcad Sci 2002977141ndash148

23 De Simoni S Jenkins PO Bourke NJ et al Altered caudate connectivity is associatedwith executive dysfunction after traumatic brain injury Brain 2018141148ndash164

24 Salthouse TA Cognitive correlates of cross-sectional differences and longitudinalchanges in trail making performance J Clin Exp Neuropsychol 201133242ndash248

25 Zetterberg H BlennowK Fluid biomarkers for mild traumatic brain injury and relateddisorders Nat Rev 201612563ndash574

26 Shahim P Zetterberg H Tegner Y Blennow K Serum neurofilament light as a bio-marker for mild traumatic brain injury in contact sports Neurology 2017881788ndash1794

27 Rojas JC Karydas A Bang J et al Plasma neurofilament light chain predicts pro-gression in progressive supranuclear palsy Ann Clin Transl Neurol 20163216ndash225

28 Lu CH Macdonald-Wallis C Gray E et al Neurofilament light chain a prognosticbiomarker in amyotrophic lateral sclerosis Neurology 2015842247ndash2257

29 Mattsson N Andreasson U Zetterberg H Blennow K Association of plasma neu-rofilament light with neurodegeneration in patients with Alzheimerrsquos disease JAMANeurol 201774557ndash566

30 Moseby-KnappeMMattsson N Nielsen N et al Serum neurofilament light chain forprognosis of outcome after cardiac arrest JAMA Neurol 20197664ndash71

31 Bernick C Zetterberg H Shan G Banks S Blennow K Longitudinal performance ofplasma neurofilament light and tau in professional fighters the Professional FightersBrain Health Study J Neurotrauma 2018352351ndash2356

32 Jovicich J Czanner S Han X et al MRI-derived measurements of human subcorticalventricular and intracranial brain volumes reliability effects of scan sessions acqui-sition sequences data analyses scanner upgrade scanner vendors and field strengthsNeuroimage 200946177ndash192

33 Maclaren J Han Z Vos S Fischbein N Bammer R Reliability of brain volumemeasurements a test-retest dataset Sci Data 20141140037 eCollection 2014

34 Guenette JP Stern RA Tripodis Y et al Automated versus manual segmentation ofbrain region volumes in former football players Neuroimage Clin 201818888ndash896

Appendix Authors

Name Location Role Contribution

CharlesBernickMD MPH

Cleveland ClinicLas Vegas NV

Author Design data acquisitionand analysis manuscriptpreparation

GuogenShan PhD

UNLV LasVegas NV

Author Data analysis manuscriptpreparation

HenrikZetterbergMD PhD

SahlgrenskaAcademyGothenbergSweden

Author Data acquisitionmanuscript review forintellectual content

SarahBanks PhD

UCSD SanDiego CA

Author Data analysis manuscriptreview and preparationmanuscript review forintellectual content

VirendraMishraPhD

Cleveland ClinicLas Vegas NV

Author Data acquisitionmanuscript preparation

LynnBekris PhD

Cleveland ClinicOH

Author Data acquisitionmanuscript review

JamesLeverenzMD

Cleveland ClinicOH

Author Manuscript review forintellectual content

KajBlennowMD

SahlgrenskaAcademyGothenbergSweden

Author Manuscript review forintellectual content

e240 Neurology | Volume 94 Number 3 | January 21 2020 NeurologyorgN

DOI 101212WNL0000000000008817202094e232-e240 Published Online before print December 23 2019Neurology

Charles Bernick Guogen Shan Henrik Zetterberg et al impacts

Longitudinal change in regional brain volumes with exposure to repetitive head

This information is current as of December 23 2019

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0028-3878 Online ISSN 1526-632XKluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print ISSN1951 it is now a weekly with 48 issues per year Copyright copy 2019 The Author(s) Published by Wolters

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