Sports Concussions and Aging: A Neuroimaging Investigation.
ABSTRACT Recent epidemiological and experimental studies suggest a link between cognitive decline in late adulthood and sports concussions sustained in early adulthood. In order to provide the first in vivo neuroanatomical evidence of this relation, the present study probes the neuroimaging profile of former athletes with concussions in relation to cognition. Former athletes who sustained their last sports concussion >3 decades prior to testing were compared with those with no history of traumatic brain injury. Participants underwent quantitative neuroimaging (optimized voxel-based morphometry [VBM], hippocampal volume, and cortical thickness), proton magnetic resonance spectroscopy ((1)H MRS; medial temporal lobes and prefrontal cortices), and neuropsychological testing, and they were genotyped for APOE polymorphisms. Relative to controls, former athletes with concussions exhibited: 1) Abnormal enlargement of the lateral ventricles, 2) cortical thinning in regions more vulnerable to the aging process, 3) various neurometabolic anomalies found across regions of interest, 4) episodic memory and verbal fluency decline. The cognitive deficits correlated with neuroimaging findings in concussed participants. This study unveiled brain anomalies in otherwise healthy former athletes with concussions and associated those manifestations to the long-term detrimental effects of sports concussion on cognitive function. Findings from this study highlight patterns of decline often associated with abnormal aging.
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ABSTRACT: Nearly two million people suffer traumatic brain injury in the US each year. These injuries alter adversely the metabolism of myelin, a major lipid material in brain, both in people and in experimental injuries of animals. A newly discovered and severe human neuropathy from copper deficiency provides evidence that some people in the US are malnourished in copper. As it is well known among copper cognoscenti that it is impossible to synthesize myelin if copper nutriture is inadequate, it seems reasonable to assume that repair will be poor in this situation. Copper status of patients should be evaluated and experiments with injured animals should be repeated with graded doses of copper to determine if copper metabolism is important in this illness.Medical Hypotheses 09/2013; · 1.18 Impact Factor
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ABSTRACT: OBJECTIVES To assess cognitive impairment and depression in aging former professional football (National Football League [NFL]) players and to identify neuroimaging correlates of these dysfunctions. DESIGN We compared former NFL players with cognitive impairment and depression, cognitively normal retired players who were not depressed, and matched healthy control subjects. SETTING Research center in the North Texas region of the United States. PATIENTS Cross-sectional sample of former NFL players with and without a history of concussion recruited from the North Texas region and age-, education-, and IQ-matched controls. Thirty-four retired NFL players (mean age, 61.8 years) underwent neurological and neuropsychological assessment. A subset of 26 players also underwent detailed neuroimaging; imaging data in this subset were compared with imaging data acquired in 26 healthy matched controls. MAIN OUTCOME MEASURES Neuropsychological measures, clinical diagnoses of depression, neuroimaging mea-sures of white matter pathology, and a measure of cerebral blood flow. RESULTS Of the 34 former NFL players, 20 were cognitively normal. Four were diagnosed as having a fixed cognitive deficit; 8, mild cognitive impairment; 2, dementia; and 8, depression. Of the subgroup in whom neuroimaging data were acquired, cognitively impaired participants showed the greatest deficits on tests of naming, word finding, and visual/verbal episodic memory. We found significant differences in white matter abnormalities in cognitively impaired and depressed retired players compared with their respective controls. Regional blood flow differences in the cognitively impaired group (left temporal pole, inferior parietal lobule, and superior temporal gyrus) corresponded to regions associated with impaired neurocognitive performance (problems with memory, naming, and word finding). CONCLUSIONS Cognitive deficits and depression appear to be more common in aging former NFL players compared with healthy controls. These deficits are correlated with white matter abnormalities and changes in regional cerebral blood flow.JAMA neurology. 01/2013;
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ABSTRACT: Previous research has demonstrated that sport-related concussions can have short-term effects on cognitive processes, but the long-term consequences are less understood and warrant more research. This study was the first to utilize event-related functional magnetic resonance imaging (fMRI) to examine long-term differences in neural activity during memory tasks in former athletes who have sustained multiple sport-related concussions. In an event-related fMRI study, former football players reporting multiple sport-related concussions (i.e., three or more) were compared to players who reported fewer than three concussions during a memory paradigm examining item memory (i.e., memory for the particular elements of an event) and relational memory (i.e., memory for the relationships between elements). Behaviorally, we observed that concussion history did not significantly affect behavioral performance, as individuals in the low and high concussion groups had equivalent performance on both memory tasks, and additionally, that concussion history was not associated with any behavioral memory measures. Despite demonstrating equivalent behavioral performance, the two groups of former players demonstrated different neural recruitment patterns during relational memory retrieval, suggesting that multiple concussions may be associated with functional inefficiencies in the relational memory network. In addition, the number of prior concussions significantly correlated with functional activity in a number of brain regions, including the medial temporal lobe and inferior parietal lobe. Our results provide important insights in understanding the long-term functional consequences of sustaining multiple sports-related concussions. Keywords: MRI, cognitive function, head trauma.Journal of neurotrauma 05/2013; · 4.25 Impact Factor
Sports Concussions and Aging: A Neuroimaging Investigation
Sebastien Tremblay1, Louis De Beaumont2,6, Luke C. Henry1, Yvan Boulanger3, Alan C. Evans7, Pierre Bourgouin4,
Judes Poirier8, Hugo Théoret1,5and Maryse Lassonde1,5
1Centre de Recherche en Neuropsychologie et Cognition,2Montreal Sacré-Cœur Hospital Research Center,3Department of
Radiology, CHUM Hospital Saint-Luc,4Department of Radiology and5Sainte-Justine Hospital Research Center, University of
Montreal, Montreal, Canada6Department of Psychology, Université du Québec à Trois-Rivière, Trois-Rivière, Canada7McConnell
Brain Imaging Centre, Montreal Neurological Institute and8Douglas Mental Health University Institute, McGill University,
Address correspondence to Maryse Lassonde, Department of Psychology, University of Montreal, C.P. 6128, Succ. Centre-Ville, Montreal,
Quebec, Canada H3C 3J7. Email: firstname.lastname@example.org
Recent epidemiological and experimental studies suggest a link
between cognitive decline in late adulthood and sports concussions
sustained in early adulthood. In order to provide the first in vivo
neuroanatomical evidence of this relation, the present study probes
the neuroimaging profile of former athletes with concussions in
relation to cognition. Former athletes who sustained their last
sports concussion >3 decades prior to testing were compared
with those with no history of traumatic brain injury. Participants
underwent quantitative neuroimaging (optimized voxel-based mor-
phometry [VBM], hippocampal volume, and cortical thickness),
proton magnetic resonance spectroscopy (1H MRS; medial temporal
lobes and prefrontal cortices), and neuropsychological testing, and
they were genotyped for APOE polymorphisms. Relative to controls,
former athletes with concussions exhibited: 1) Abnormal enlarge-
ment of the lateral ventricles, 2) cortical thinning in regions more
vulnerable to the aging process, 3) various neurometabolic
anomalies found across regions of interest, 4) episodic memory and
verbal fluency decline. The cognitive deficits correlated with neuroi-
maging findings in concussed participants. This study unveiled brain
anomalies in otherwise healthy former athletes with concussions
and associated those manifestations to the long-term detrimental
effects of sports concussion on cognitive function. Findings from
this study highlight patterns of decline often associated with abnor-
Keywords: aging, neuroimaging, sports concussion
Sports-related concussions have received growing scientific
and public attention over recent years. For one, the rapid in-
crease of their reported incidence, now estimated to an
annual occurrence of 1.6–3.8 million in the United States of
America alone (Langlois et al. 2006), make them the most sig-
nificant contributor to the silent epidemic of traumatic brain
injuries (TBIs) affecting the global population (Kelly, 1999;
Cassidy et al. 2004). Research conducted in young concussed
athletes has also revealed diverse chronic alterations of brain
function affecting the cognitive (Gaetz et al. 2000; Gosselin
et al. 2006; De Beaumont, Brisson, et al. 2007; Theriault et al.
2011), affective (Chen et al. 2008), and motor domains (Cava-
naugh et al. 2005; De Beaumont, Lassonde, et al. 2007; De
Beaumont et al. 2011), regardless of time since injury. At-
tempts to explain these chronic perturbations metabolically
have failed, in part because most brain metabolites, following
an initial imbalance (Giza and Hovda, 2001; Henry et al.
2010; Vagnozzi et al. 2010), return to a normal equilibrium 30
days postinjury (Vagnozzi et al. 2010). Very recently, young
asymptomatic concussed athletes were shown to exhibit im-
paired synaptic plasticity in the primary motor cortex that cor-
related with motor learning decline (De Beaumont et al.
2011), a finding suggesting that disrupted cellular mechan-
isms may relate to persistent brain function anomalies.
Sports-related concussions have also received a widespread
media coverage because of the recent uncovering of impor-
tant neuropathological and histological findings in the brains
of deceased professional American football and ice hockey
players (Miller, 2009). This emerging syndrome, known as
chronic traumatic encephalopathy (CTE), is grossly character-
ized by an atrophy of the cerebral hemispheres, including the
medial temporal lobes (MTLs), combined with the lateral ven-
tricle volume expansion (McKee et al. 2009; Costanza et al.
2011; Gavett et al. 2011; Omalu et al. 2011). Microscopically,
extensive tau-immunoreactive neurofibrillary tangles affect
the superficial cortical layers of the frontal and temporal
lobes. Although this pathology, initially termed dementia
pugilistica, has been known to affect professional boxers for
decades (Martland, 1928; Roberts et al. 1990), it has also been
documented only recently in athletes with lower exposure to
concussive and subconcussive blows to the head (McKee
et al. 2009; Omalu et al. 2011). CTE is currently thought to
result from multiple concussive impacts to the brain, although
no experimental evidence thus far has established a causal
relationship between the postmortem observations and mild
Further, the growing interest in the long-term effects of
sports concussion is partly based on the observation of clini-
cally relevant cognitive and motor decline in aging concussed
athletes (De Beaumont et al. 2009). While brain function
anomalies detected in young asymptomatic athletes are not
related to clinically significant impairments, those same
anomalies found in the brains of retired athletes who sus-
tained sports concussions >30 years ago were shown to relate
to the insidious installation of measurable memory and motor
system dysfunctions (De Beaumont et al. 2009). This inter-
action between the aging process and the persistent subclini-
cal effectsof concussions
epidemiological study that reported a 5-fold increased preva-
lence of diagnosis of a mild cognitive impairment (MCI) in
retired professional American football players who sustained
3 concussions or more during their career (Guskiewicz et al.
2005). MCI is a clinical condition where patients exhibit cog-
nitive decline without showing any impairment on activities
is substantiated by an
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Cerebral Cortex Advance Access published May 10, 2012
at McGill University Libraries on August 8, 2012
of daily living, which subsequently converts at an approxi-
mate rate of 10–20% annually into dementia (Petersen et al.
1999; Morris et al. 2001).
The recent emergence of these converging scientific find-
ings on the long-term effects of sports concussion is currently
fueling an important social debate regarding the safety of ath-
letes and regulations over violent contact in sports, particu-
larly for head shots. Unfortunately, this debate is hindered by
a lack of controlled experimental studies demonstrating a
causal relation between sports concussions and long-term de-
leterious consequences on brain tissue. Since most structural
evidence of brain tissue damage comes from postmortem neu-
ropathological studies, the latter anomalies have not yet been
directly related to cognitive symptoms documented in retired
Therefore, this study purports 2 main objectives: 1) To
document possible structural anomalies of a brain tissue in
vivo in retired athletes who sustained sports concussions
in early adulthood and 2) to establish neurocognitive
links between hypothesized structural and neurometabolic
anomalies in retired concussed athletes with cognitive decline.
With prior postmortem investigations suggesting that de-
ceased American football athletes exhibit abnormal ventricu-
lar enlargement combined with cortical thinning of the
frontal, temporal, and parietal lobes (McKee et al. 2009;
Omalu et al. 2011), it was hypothesized that retired concussed
athletes would feature the same pattern of anomalies,
imaging (MRI)-based measures of cerebral atrophy and corti-
cal thickness. In addition, since former athletes with concus-
sions were shown to exhibit decrements on episodic memory
function, in which hippocampal structures are centrally impli-
cated (De Beaumont et al. 2009),1H MRS was used to quan-
tify the neurometabolite concentration in this region of
interest (ROI). Finally, knowing that former athletes with con-
cussions exhibited a reduced performance on a selective at-
tention/executive task in association with the attenuated P3a
electrophysiological component (De Beaumont et al. 2009),
which is thought to reflect a frontal lobe dysfunction in allo-
cating attentional resources to novel stimuli (Comerchero and
Polich, 1999; Kopp et al. 2006), frontal lobe neurochemical
composition was also investigated using1H MRS. This neuroi-
maging technique has proven to be sensitive to age (Haga
et al. 2009), TBI (Brooks et al. 2001), as well as MCI (Chantal
et al. 2004; Kantarci et al. 2007, 2008), showing neurochemi-
cal modifications of the brain parenchyma under all 3
The second objective of the study was to establish neuro-
cognitive links between hypothesized structural and neuro-
metabolic anomalies in retired concussed athletes and their
cognitive performance. Knowing that a previous study re-
ported the episodic memory decline on standard neuropsy-
chological examination in this population (De Beaumont
et al. 2009), we attempted to replicate and detail those results
using a neuropsychological test battery designed to preferen-
tially assess memory function. As the CTE, the clinical profile
also indicates various cognitive symptoms (McKee et al.
2009), tests of verbal fluency, attention, and information pro-
cessing speed were added to the battery. Associations
between the cognitive decline of retired concussed athletes
and uncovered brain structural anomalies were then explored
using correlational analyses. Finally, as age is considered to
be the primary risk factor of Alzheimer’s disease (AD)
(Lindsay et al. 2002), and an important factor of clinically sig-
nificant cognitive decline in retired concussed athletes (Gus-
kiewicz et al. 2005; De Beaumont et al. 2009), its effects on
neurocognitive measures were modeled.
Materials and Methods
All 30 male participants included in this study were former university-
level athletes between the ages of 51 and 75 recruited with the help
of university athletics organizations. All participants played for their
respective college or university ice hockey (70%) or American football
(30%) team at the time they were students. Participants were included
if they met all of the following criteria: No history of alcohol abuse
and/or substance abuse; no medical condition requiring daily medi-
cation or radiotherapy (malignant cancers, diabetes, hypertension,
and/or other cardiovascular diseases); no previous history of psychia-
tric illness, learning disability, neurological history (seizure or brain
tumour), or TBI unrelated to contact sports. Participants included in
the present study had no history of concussion after their university
years. To better control for data contamination due to the protective
properties of regular physical activity on the development of AD
(Lindsay et al. 2002), participants had to report engaging regularly in
physical activity at least 3 times a week at the time of testing and have
maintained this level of activity since the end of their athletic career.
In addition, all participants had a body mass index <30 kg/m2, ac-
cording to the criteria for obesity of the World Health Organization.
Participants were divided into 2 groups. The experimental group
consisted of 15 former university-level athletes with a mean age of
60.87 years (standard deviation [SD] 7.51) and a mean level of edu-
cation of 16.67 years (SD 4.07) who sustained their last sports concus-
sion in early adulthood (mean 24.00 and SD 4.55). A standardized
concussion history questionnaire (Collins et al. 2002) was adminis-
tered in an interview setting by a sports physician to obtain detailed
information about the number of previous concussions, their approxi-
mate date, the description of the accident, and the nature and dur-
ation of on-field postconcussion severity markers (confusion and/or
disorientation, retrograde and/or anterograde amnesia, and loss of
consciousness [LOC]). Concussion was defined according to the latest
definition provided by the 2009 Consensus Statement on Concussion
in Sports (Mccrory et al. 2009) as "a complex pathophysiological
process affecting the brain, induced by traumatic biomechanical
forces, that results in the rapid onset of short-lived impairment of
neurologic function that may or may not include loss of consciousness
(LOC)." Using this methodology, we sought to retrospectively diag-
nose concussions that might have gone unnoticed by some partici-
pants who played their sport at a time where LOC was considered a
necessary condition for the diagnosis. Two participants who could
not recollect sufficient information about their concussion history to
enable the group classification were excluded from the study. The
number of reported concussions sustained ranged from 1 to 5 (mean
2.08 and SD 1.31) and the time elapsed since the last concussion
spanned from 29 to 53 years (mean 37.08 and SD 7.10). All brain in-
juries classified as "mild" on the Glasgow Coma Scale (scores ranging
from 13 to 15).
The control group included 15 former university-level athletes with
a mean age of 58.13 (SD 5.28) and a mean level of education of 17.27
(SD 3.45) who had no prior history of concussion. The 2 groups did
not differ according to the age (t(28)=1.15, P=0.259), level of edu-
cation (t(28)=0.44, P=0.666), or frequency of APOE ɛ-4 (Fisher’s
exact test P=1.00). The study was approved by the local ethics com-
mittees and all participants provided written informed consent prior
to testing in accordance with the Declaration of Helsinki.
All participants underwent 2 testing sessions. Session 1 included the
administration of the general health questionnaire to screen for
Sports Concussions and Aging
• Tremblay et al.
at McGill University Libraries on August 8, 2012
medical exclusion criteria (De Beaumont et al. 2009), the concussion
history questionnaire, and a neuropsychological test battery aiming to
assess age-related cognitive function changes. Session 2 was entirely
dedicated to neuroimaging.
The neuropsychological assessment included tests of general cog-
nitive function, verbal fluency, verbal and visual episodic memory,
visual attention, along with a depression symptom inventory. The
mini-mental status examination (MMSE) was administered as a rapid
screening tool for cognitive impairment (Folstein et al. 1975). Given
the presumed association between concussion and depressive symp-
toms (Chen et al. 2008), the Beck depression inventory II (BDI-II)
was used to control for symptoms of depression. The Taylor complex
figure test (TCFT) was administered to assess incidental learning and
visual memory. To evaluate verbal memory, the Rey auditory verbal
learning test (RAVLT) was administered. Both these tests were fol-
lowed by a 20-min delayed recall condition as well as a recognition
test. Verbal fluency over 60 s was assessed with letters "F," "A," "S"
(phonemic condition) and with categories "animals," "fruits," and "fur-
niture" (semantic condition). Visual attention and inhibition was as-
sessed with the symbol-digit modalities test (SDMT) and the color
trails test (A and B). This neuropsychological test battery was adminis-
tered by a trained neuropsychologist blinded to participants’ concus-
DNA extraction from saliva samples was performed using Oragene
OG-250s kits (DNA Genotek, Ottawa, Canada) and participants were
genotyped for APOE 112 (rs429358)-158 (rs7412) polymorphisms.
Polymerase chain reaction amplification was carried out as previously
described (Petersen et al. 2005). APOE polymorphisms were sub-
sequently determined via an established pyrosequencing protocol
(Petersen et al. 2005).
All MR examinations were performed on a Siemens 3T Magnetom
TIM TRIO scanner with a 12-channel head coil (Siemens, Erlangen,
Germany). Three-dimensional high-resolution T1-weighted images
of the brain were acquired using a sagittal MP-RAGE sequence (rep-
etition time (TR)=2300 ms; echo time (TE)=2.91 ms; number of
slices=176) with a 1-mm3resolution. T2-weighted images were ob-
tained using a turbo spin-echo sequence (TR=3000 ms; TE=78 ms;
number of slices=48) for neuroradiological diagnostic purposes. All
scans were interpreted by an experienced neuroradiologist who was
blinded to the subject group.1H MR spectra were obtained from the
voxels localized in the bilateral MTL and bilateral prefrontal cortices
(PFC) (Fig. 1). All voxels contained a mixture of gray and white
matter, while avoiding potential signal artifacts from ventricles, fatty
tissues, and bones. Proton signal detection using the point-resolved
spectroscopy pulse sequence (PRESS) was performed after suppres-
sion of the water signal with the chemical shift-selective sequence.
PRESS spectra were also acquired without water suppression in order
to use the H2O signal as an internal reference (Christiansen et al.
1993). Acquisition parameters were the following: TR=1200 ms, TE=
30 ms, and 128 averages. Free induction decays were transferred to a
Silicon Graphics workstation and processed with the LCModel soft-
ware version 6.1 (Provencher 1993). The following metabolites were
quantified: N-acetylaspartate (NAA), myo-inositol (mI), choline-
containing compounds (Cho), as well as H2O for an internal
High-resolution T1-weighted images were analyzed with FSL-VBM,
a VBM style analysis (Good et al. 2001) carried out with FSL tools
(Smith et al. 2004). Modulated and segmented images were smoothed
with a 4-mm isotropic Gaussian kernel and fitted to the general linear
model using permutation-based non-parametric testing, correcting for
multiple comparisons across space. Additionally, brain tissue volumes
(including gray matter volume, white matter volume, and ventricular
cerebral spinal fluid), normalized for subject head size, were esti-
mated using SIENAX (Smith et al. 2002) from the FSL toolbox. Lastly,
cortical thickness analyses were executed using the CIVET pipeline of
the Brain Imaging Center (McGill University, Montreal, Canada) (Lyt-
telton et al. 2007). All of the above-mentioned tools for structural data
analysis are fully automated and user-independent.
All values are expressed as means (SDs). Data were analyzed with
SPSS 16 (SPSS, Chicago, IL, USA) unless otherwise specified. The sig-
nificance level was set at α=0.05, bilaterally. The effect sizes for
mean differences were estimated with Cohen’s d. MMSE and BDI-II
scores collected for screening purposes were not subjected to statisti-
cal analyses. The group mean differences for the TCFT, SDMT, RAVLT,
verbal fluency (phonemic and semantic), and Color trails test were
tested using Student’s t-tests for independent samples.
To limit the number of statistical comparisons, the group mean
only for metabolites known to be affected by aging, TBI, or MCI, in
our selected ROIs. These included NAA, mI, and Cho in the MTL, and
NAA and Cho in the PFC. Two-tailed Pearson correlations, corrected
for multiple comparisons with false discovery rate (FDR), were com-
puted between neuropsychological tests and1H MRS variables that
both significantly discriminated groups. Using the SurfStat toolbox
(http://www.math.mcgill.ca/keith/surfstat/), the cortical thickness
data were tested for the main effects of group, age, and their inter-
action, corrected with FDR. FDR correction was selected over more
conservative but less powerful methods because of the exploratory
nature of the current investigation (Perneger, 1998; Genovese et al.
1H MRS data were conducted with Student’s t-tests
All participants had MMSE scores ≥27 and BDI-II scores ≤9.
The demographic data and neuropsychological assessment
test results are summarized in Table 1. Neuroradiological
examination found no gross anatomical anomaly across
samples. Relative to controls, former athletes with concussion
(s) showed a reduced semantic verbal fluency (t(28) = 2.16,
Figure 1. Regions of interest for1H MRS examination. T1-weighted image of a brain showing approximate locations of the voxels used for MRS. (A) Medial temporal lobes
(hippocampus, part of subiculum, entorhinal cortex, and parahippocampal gyrus) (1.5×1.8×3.6 cm3). (B) PFC (3.5×3.5×2 cm3). PFC voxels were positioned to enclose the
maximal amount of gray matter.
Cerebral Cortex 3
at McGill University Libraries on August 8, 2012
P=0.040, d= 0.79) and altered episodic memory on both
delayed recall (t(27)= 2.36, P= 0.026, d= 0.86) and recog-
nition (t(27) =2.61, P =0.015, d= 0.95) conditions of the
TCFT, while performance on the copy trial was not different
across groups (t(27) =1.46, P >0.15). They also exhibited
higher retroactive interference on the RAVLT (t(28) =2.20,
1H MRS examination detected a significant elevation of
mI/H2O in the left MTL of formerly concussed participants
(t(23)= −2.54, P= 0.037, d= 0.89) that correlated strongly
with the TCFT delayed recall score (r =−0.72, P= 0.008), after
FDR correction for multiple comparisons. The same ROI
also exhibited an abnormal reduction in Cho (t(25) =2.15,
P=0.041, d= 0.84), while the right PFC presented a signifi-
cant increase in the same metabolite (t(26)= −2.54, P= 0.017,
d= 0.96), when referenced to H2O.
The structural images of the brain processed by an opti-
mized VBM revealed no gray matter density differences
between groups after correction with permutation-based stat-
istics. In contrast, SIENAX analysis revealed a significant
enlargement of the lateral ventricles of concussed participants
(t(28)= −2.44, P=0.023, d= 0.89) that correlated positively
with episodic memory performance deficits at the TCFT
delayed recall condition (r= 0.55, P =0.033). In the same
analysis, when the age variable was introduced in addition to
the group, lateral ventricular volume presented a significant
age×group interaction, suggesting that ventricular volume ex-
pansion was further exacerbated with the advancing age in
the concussed group (F(1, 28)=9.20, P =0.005).
As expected, cortical thickness analysis revealed a detri-
mental main effect of age when the 2 groups were combined
(Fig. 2). Indeed, MRI-based cortical thickness of the frontal,
temporal, and parietal lobes presented a diffuse thinning with
the advancing age. However, this adverse age effect was
again exacerbated in the former concussed athletes group, as
revealed by the significant age ×group interaction in various
ROIs (Fig. 3). In addition, these clusters of abnormal thinning
correlated markedly with the episodic memory decline de-
tected in formerly concussed participants at the TCFT delayed
recall condition (Fig. 3).
The present study investigated the effects of sports concus-
sion and aging using multimodal neuroimaging in conjunc-
tion with the cognitive assessment. This research reveals: 1)
the episodic memory decline in former athletes with concus-
sion; 2) a significant decline on measures of semantic verbal
fluency; 3) a significant enlargement of the lateral ventricles
that correlates with episodic memory decrements; 4) a com-
bined effect of age and concussion on cortical thickness
measures in various ROIs that correlates with the episodic
memory decline; 5) abnormally elevated mI relative concen-
tration in the left MTL that correlates with the episodic
memory decline; and 6) perturbations of Cho concentrations
in both the left MTL and right PFC.
The enlarged ventricles found in retired concussed partici-
pants relative to unconcussed counterparts are particularly
salient neuroanatomical findings. The lateral ventricle enlarge-
ment has consistently been found in deceased athletes with
pathologically verified CTE (McKee et al. 2009; Omalu et al.
2011). The lateral ventricle expansion is also reported in
various neurological conditions, including AD and, to a lesser
extent, MCI (Jack et al. 2005; Fleisher et al. 2008; Chou et al.
Demographic and neuropsychological data
MeasuresControls, mean (SD)Concussed, mean (SD)P-values
Hockey players (%)
APOE ɛ-4 (% positive)
TCFT (# of items drawn)
RAVLT (# of words)
Trials 1–5 total
SDMT (# of correct digits)
Color trails test (s)
Verbal fluency (words)
Note: APOE ɛ-4, proportion of participants with a ɛ-4 allele; MMSE, mini-mental state
examination; BDI-II, Beck depression inventory II; TCFT, Taylor complex figure test; RAVLT, Rey
auditory verbal learning test; SDMT, symbol-digit modalities test.
aFisher’s exact test.
bMann–Whitney U test.
Figure 2. Age effect on cortical thickness. The main effect of age on cortical thickness over the entire sample. Colors encode the P-value, FDR corrected.
Sports Concussions and Aging
• Tremblay et al.
at McGill University Libraries on August 8, 2012
2010). Aside from being considered a significant predictor of
conversion from amnestic MCI to AD (Fleisher et al. 2008),
the annual ventricular enlargement rate is found to be predic-
tive of conversion from normal aging to an MCI (Jack et al.
2005). In agreement with the majority of previous quantitative
MRI studies conducted with TBI patients, the ventricular
enlargement found in concussed athletes may predominantly
reflect white matter losses consequent to diffuse axonal injury
(Bigler 2001; Bendlin et al. 2008). Diffuse axonal injury pre-
ferentially affecting the corpus callosum in addition to other
major fiber bundles is reported in TBI patients with or even
without gross anatomical lesions (Gale et al. 1995; Nakayama
et al. 2006). This is consistent with recent diffusion tensor
imaging studies conducted with concussed athletes (Cubon
et al. 2011; Henry et al. 2011) and military personnel with a
blast-related mild traumatic brain injury (Mac Donald et al.
2011) reporting evidence of diffuse white matter injury in this
population of young adults. It remains to be seen, using
diffusion-weighted imaging in retired athletes with concus-
sions, whether these white matter anomalies are still present
with the advancing age and if they relate to the ventricular
enlargement and/or cognitive decline. Although the cause of
this ventricular enlargement in our sample remains uncertain
with regards to diffuse axonal injury, the clinical significance
of this finding in former athletes with concussion is substan-
tiated by the significant relation found with episodic visual
memory decline, a correlation also observed in patients with
remote TBI of much greater severity (Himanen et al. 2005).
The detrimental effect of normal aging on MRI-based corti-
cal thickness measurement is well documented (Allen et al.
2005; Fotenos et al. 2005; Walhovd et al. 2005; Fjell et al.
2009). The presence of this same relation over the entire
study sample is in agreement with this notion (Fig. 2). More
importantly, when concussion history was included as an
additional factor to aging, a significant interaction indicated
accentuated cortical thinning in concussed athletes over
various ROIs known to be particularly vulnerable to the aging
process (Fig. 3) (Fjell et al. 2009). These clusters of accentu-
ated thinning also relate to the cortical regions subjected to
neuronal loss in former contact sports athletes posthumously
diagnosed with CTE (McKee et al. 2009). However, one tech-
nical limitation is that MRI-based cortical thickness reduction
does not necessarily imply neuronal loss in our concussed
sample; the MRI measurement being insensitive to the variety
of cellular types constituting the cerebral cortex. Further neu-
roanatomical studies need to address the cellular underpin-
nings of cortical thinning specific to older former concussed
athletes. Of clinical relevance, clusters of cortical thinning
resulting from the interaction of aging and concussion were
found to correlate with the episodic memory decline in con-
cussed participants. Taken together, these findings are indica-
tive of abnormal aging in the former concussed athletes
group not only affecting cognitive functions but also cortical
Further evidence of the long-term effects of concussions on
brain integrity was found using in vivo1H-MRS. Indeed, Cho,
for which the1H-MRS signal is mainly composed of cytosolic
glycerophosphocholine and phosphocholine (Miller et al.
1996; Klein 2000), were found to be imbalanced in the left
MTL and right PFC of concussed participants. In the MCI and
AD literature, Cho present an inconsistent pattern of altera-
tions, partly explained by a moderate test–retest reliability
across different methodologies (Valenzuela and Sachdev
2001). However, using precisely the same methodology, a
previous study from our group conducted with an MCI popu-
lation (Chantal et al. 2004) found choline alterations similar to
Figure 3. Synergistic effect of concussion and aging. Clusters of significant interaction between concussion history (groups) and aging effect on cortical thickness. Concussed
participants exhibited a pronounced detrimental effect of aging in 4 clusters: Left frontal, right frontal, right temporo-parietal, and right temporal cortices. Colors encode P-value,
FDR corrected. In concussed participants, abnormal cortical thinning in all clusters but the right temporal one correlates with the episodic memory decline on TCFT.
Cerebral Cortex 5
at McGill University Libraries on August 8, 2012
those uncovered in concussed athletes from the current study.
Although various explanations have been proposed to
account for this neurometabolic imbalance, increased mem-
brane turnover due to neuronal degeneration is perhaps most
consistently reported in the TBI and AD literature (Garnett
et al. 2000; Klein 2000). In parallel, the left MTL mI increase
found in concussed athletes is compellingly supported by the
MCI literature (Kantarci et al. 2008; Wang et al. 2009; Chao
et al. 2010) and is also found to correlate with neurofibrillary
tangle count (NFT) in postmortem AD brains (Klunk et al.
1996). Converging evidence indicates that early NFT depo-
sition over the perirhinal cortex seems to be linked to early
visual memory impairments in MCI patients (Barbeau et al.
2004), a finding also consistent with the chronic effects of
concussions reported herein. This excess of mI, which is
known as a marker of glial proliferation (Fisher et al. 2002), is
also in line with the recent neuropathological uncovering of
hippocampal NFT deposition in deceased professional foot-
ball players with pathologically verified CTE (Omalu et al.
2006; McKee et al. 2009). The strong correlation between the
elevated mI and episodic memory decline found in former
concussed athletes emphasizes the clinical relevance of this
Finally, this study replicates previous findings of the episo-
dic memory decline in formerly concussed athletes (De Beau-
mont et al. 2009) in addition to uncovering increased
retroactive interference as well as semantic verbal fluency de-
crements for the first time in this population. Semantic verbal
fluency tests have proven to be more sensitive to the early
effects of AD on executive functions than their phonemic
counterparts (Monsch et al. 1992), a peculiarity also reported
in our concussed group. Interestingly, a concomitant decline
in semantic verbal fluency and non-verbal episodic memory
was identified as a key predictor of AD conversion in a popu-
lation of very mildly impaired individuals (MMSE ≥24)
(Salmon et al. 2002). Further, evidence of executive function
decline in our sample comes from significantly increased ret-
roactive interference on verbal memory examination. When
combined with recognition memory scores, which are abnor-
mally low in our concussed group, retroactive interference
scores have been reported to distinguish MCI patients from
normal elderly individuals with great sensitivity and speci-
ficity (both >85%) (Loewenstein et al. 2004). Although no
neuropsychological studies have been conducted in patients
who were posthumously diagnosed with CTE, memory loss is
the most frequently reported initial symptoms in the literature
(McKee et al. 2009). In spite of the fact that these neurocogni-
tive measures statistically differentiated the groups, it is
important to mention that none of the concussed participants
exhibited clinically significant cognitive deficits, and that all
participants were well functioning in their daily living activi-
ties at the time of testing. These positive results should not
overshadow the other cognitive domains where concussed
participants performed at the control group level. The clinical
cognitive profile of this population has yet to be fully charac-
terized in a larger sample with a more exhaustive neuropsy-
chological examination, preferentially using a prospective
Anatomo-functional correlations found in this study by no
means reflect a direct relationship between structural damage
and a specific cognitive function decline. Results from this
study rather point to a wider neuropathology involving
multiple brain regions to account for cognitive performance
decrements found in former concussed athletes relative to un-
concussed counterparts. This notion is supported by an episo-
dic memory declinebeing
enlargement, cortical thinning, and hippocampal neurochemi-
cal anomalies in our concussed samples. As documented in
both the CTE and amnestic MCI literatures (Petersen et al.
1999; McKee et al. 2009), episodic memory decrements might
be the first cognitive function to be affected by the underlying
neuropathology in the current sample, which may explain
why the above-mentioned neurocognitive correlations have
yet to implicate other cognitive functions.
In conclusion, the current study unveils multifaceted brain
anomalies in retired athletes who sustained sports-related
concussions in early adulthood. Anatomical and neurometa-
bolic findings resemble the patterns of abnormal aging
reflected in pathological conditions such as MCI and CTE. Of
clinical significance, the anatomical findings uncovered in
otherwise healthy former athletes with concussions were cor-
related with cognitive decline, preferentially affecting episodic
memory, which is the first clinical symptom of both amnestic
MCI and CTE. Despite these similarities, motor system altera-
tions specifically affecting young athletes with concussions
that persist up to their late adulthood (De Beaumont et al.
2009, 2011) distinguish the natural history of MCI from one of
the current syndromes. The present study also raises alarming
concerns regarding the minimal severity of brain injury in-
volved to induce long-term brain tissue damage. Indeed, this
study was conducted with participants who played for their
university athletic team in their young adulthood, who sus-
tained on average 2 concussions, and who took on a success-
ful professional career outside the world of contact sports
after their graduation. This study shows that uncomplicated
concussion history is related to the abnormal aging pattern in
otherwise healthy former concussed athletes. Considering
that this study sample was also highly educated, both phys-
ically and mentally active, and was on average 10 years
younger than the typical MCI age of onset, this neurobiologi-
cal and cognitive profile may well underestimate the more
typical pattern of brain decline to be found in the general
population aging with a prior history of sports concussions.
For similar reasons, the neuropsychological test performance
of the concussed sample should not be interpreted with
respect to the normative data, which would otherwise suggest
that its performance is more or less normal, but should rather
be compared with the performance of the control group that
presents the exact same life profile as the concussed group,
except for the concussion history.
The limitations of this study include small sample size and
retrospective classification based on self-reported information.
The impact of these 2 methodological limitations were mini-
mized by assuring a stringent equivalency between samples
on biologically and psychologically relevant variables, and by
combining a standardized concussion diagnostic procedure
with a conservative classification strategy. Having to include
such a stringent set of inclusion criteria also compromises the
generalizability of our findings to a small subset of former ath-
letes with a history of concussions. Despite our efforts to
reliably reconstruct concussion histories according to modern
guidelines, our sample probably underrepresents athletes
who exclusively sustained very mild concussions in their ath-
letic career. Nevertheless, this study highlights disquieting
Sports Concussions and Aging
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at McGill University Libraries on August 8, 2012
information about the chronic effects of remote concussions
on late-life cognitive decline and calls for replication studies
conducted with a broader sample of former athletes that
present with more diverse medical history characteristics. The
current findings, if replicated, could have practical impli-
cations with regard to the enforcement of safety measures
and regulations that should not be restricted to professional
sports associations but should rather apply to all individuals,
including children, playing contact sports. Large-scale longi-
tudinal studies are urgently needed to validate these novel
findings and to investigate the incidence of MCI or CTE in the
general population with remote sports-related concussions.
This work was supported by the Canadian Institutes of Health
Research, the Fonds de la Recherche en Sante du Quebec, the
Canadian Foundation for Innovation, the Natural Sciences and
Engineering Research Council of Canada, and the Canada
Research Chair program. Conflict of Interest: none declared.
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