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 (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 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.

Introduction

Sports-related concussions have received growing scientific and public attention over recent years. For one, the rapid increase 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 significant 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 (Cavanaugh et al. 2005; De Beaumont, Lassonde, et al. 2007; De Beaumont et al. 2011), regardless of time since injury. Attempts 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 impaired synaptic plasticity in the primary motor cortex that correlated with motor learning decline (De Beaumont et al. 2011), a finding suggesting that disrupted cellular mechanisms may relate to persistent brain function anomalies.

Sports-related concussions have also received a widespread media coverage because of the recent uncovering of important 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 characterized by an atrophy of the cerebral hemispheres, including the medial temporal lobes (MTLs), combined with the lateral ventricle 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 TBIs.

Further, the growing interest in the long-term effects of sports concussion is partly based on the observation of clinically 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 sustained 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 interaction between the aging process and the persistent subclinical effects of concussions is substantiated by an epidemiological study that reported a 5-fold increased prevalence 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 cognitive decline without showing any impairment on activities of daily living, which subsequently converts at an approximate rate of 10–20% annually into dementia (Petersen et al. 1999; Morris et al. 2001).

The recent emergence of these converging scientific findings on the long-term effects of sports concussion is currently fueling an important social debate regarding the safety of athletes and regulations over violent contact in sports, particularly 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 deleterious consequences on brain tissue. Since most structural evidence of brain tissue damage comes from postmortem neuropathological studies, the latter anomalies have not yet been directly related to cognitive symptoms documented in retired concussed athletes.

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 deceased American football athletes exhibit abnormal ventricular 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, although quantitatively lesser, on magnetic resonance imaging (MRI)-based measures of cerebral atrophy and cortical thickness. In addition, since former athletes with concussions were shown to exhibit decrements on episodic memory function, in which hippocampal structures are centrally implicated (De Beaumont et al. 2009), 1H MRS was used to quantify the neurometabolite concentration in this region of interest (ROI). Finally, knowing that former athletes with concussions exhibited a reduced performance on a selective attention/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 allocating attentional resources to novel stimuli (Comerchero and Polich, 1999; Kopp et al. 2006), frontal lobe neurochemical composition was also investigated using 1H MRS. This neuroimaging 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 neurochemical modifications of the brain parenchyma under all 3 conditions.

The second objective of the study was to establish neurocognitive links between hypothesized structural and neurometabolic anomalies in retired concussed athletes and their cognitive performance. Knowing that a previous study reported the episodic memory decline on standard neuropsychological examination in this population (De Beaumont et al. 2009), we attempted to replicate and detail those results using a neuropsychological test battery designed to preferentially 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 processing 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 significant cognitive decline in retired concussed athletes (Guskiewicz et al. 2005; De Beaumont et al. 2009), its effects on neurocognitive measures were modeled.

Materials and Methods

Participants

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 medication or radiotherapy (malignant cancers, diabetes, hypertension, and/or other cardiovascular diseases); no previous history of psychiatric 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, according 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 education of 16.67 years (SD 4.07) who sustained their last sports concussion in early adulthood (mean 24.00 and SD 4.55). A standardized concussion history questionnaire (Collins et al. 2002) was administered in an interview setting by a sports physician to obtain detailed information about the number of previous concussions, their approximate date, the description of the accident, and the nature and duration 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 diagnose concussions that might have gone unnoticed by some participants 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 injuries 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 education (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 committees and all participants provided written informed consent prior to testing in accordance with the Declaration of Helsinki.

Procedures

All participants underwent 2 testing sessions. Session 1 included the administration of the general health questionnaire to screen for 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 cognitive 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 symptoms (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 followed 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 "furniture" (semantic condition). Visual attention and inhibition was assessed with the symbol-digit modalities test (SDMT) and the color trails test (A and B). This neuropsychological test battery was administered by a trained neuropsychologist blinded to participants’ concussion history.

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 subsequently 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 (repetition time (TR) = 2300 ms; echo time (TE) = 2.91 ms; number of slices = 176) with a 1-mm3 resolution. T2-weighted images were obtained 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 suppression 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 software 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 reference.

Figure 1.

Regions of interest for 1H 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.

Figure 1.

Regions of interest for 1H 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.

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 estimated 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) (Lyttelton et al. 2007). All of the above-mentioned tools for structural data analysis are fully automated and user-independent.

Statistical analysis

All values are expressed as means (SDs). Data were analyzed with SPSS 16 (SPSS, Chicago, IL, USA) unless otherwise specified. The significance 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 statistical 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 differences for 1H MRS data were conducted with Student's t-tests 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 computed between neuropsychological tests and 1H 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 interaction, 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. 2002).

Results

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, 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 recognition (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, P = 0.039, d = 0.80).

Table 1

Demographic and neuropsychological data

Measures Controls, mean (SD) Concussed, mean (SD) P-values 
N 15 15  
Age 58.13 (5.28) 60.87 (7.51) 0.26 
Hockey players (%) 70 70  
Education (years) 17.27 (3.45) 16.67 (4.06) 0.67 
APOE ɛ-4 (% positive) 2 (13.33) 2 (13.33) 1.00a 
MMSE 29.40 (1.12) 29.20 (0.86) 0.31b 
BDI-II 2.93 (3.08) 3.43 (3.29) 0.67b 
TCFT (# of items drawn) 
 Copy 35.86 (0.36) 35.33 (1.29) 0.16 
 Immediate recall 30.14 (2.58) 27.80 (3.95) 0.07 
 Delayed recall 30.18 (2.47) 27.33 (3.83) 0.03 
 Recognition 20.36 (1.28) 18.60 (2.19) 0.02 
RAVLT (# of words) 
 Trials 1–5 total 54.87 (7.83) 52.33 (5.79) 0.32 
 Delayed recall 12.20 (2.01) 11.00 (2.67) 0.18 
 Recognition 13.07 (1.91) 12.67 (1.99) 0.58 
 Proactive interference 1.00 (1.36) 0.93 (1.44) 0.90 
 Retroactive interference 0.93 (1.03) 2.13 (1.85) 0.04 
 SDMT (# of correct digits) 54.00 (8.60) 49.53 (7.43) 0.14 
Color trails test (s) 
 Form A 35.13 (10.61) 32.43 (6.43) 0.42 
 Form B 74.13 (26.86) 73.00 (16.58) 0.89 
Verbal fluency (words) 
 Phonemic 46.00 (7.80) 49.67 (11.31) 0.31 
 Semantic 52.93 (8.67) 46.40 (7.69) 0.04 
Measures Controls, mean (SD) Concussed, mean (SD) P-values 
N 15 15  
Age 58.13 (5.28) 60.87 (7.51) 0.26 
Hockey players (%) 70 70  
Education (years) 17.27 (3.45) 16.67 (4.06) 0.67 
APOE ɛ-4 (% positive) 2 (13.33) 2 (13.33) 1.00a 
MMSE 29.40 (1.12) 29.20 (0.86) 0.31b 
BDI-II 2.93 (3.08) 3.43 (3.29) 0.67b 
TCFT (# of items drawn) 
 Copy 35.86 (0.36) 35.33 (1.29) 0.16 
 Immediate recall 30.14 (2.58) 27.80 (3.95) 0.07 
 Delayed recall 30.18 (2.47) 27.33 (3.83) 0.03 
 Recognition 20.36 (1.28) 18.60 (2.19) 0.02 
RAVLT (# of words) 
 Trials 1–5 total 54.87 (7.83) 52.33 (5.79) 0.32 
 Delayed recall 12.20 (2.01) 11.00 (2.67) 0.18 
 Recognition 13.07 (1.91) 12.67 (1.99) 0.58 
 Proactive interference 1.00 (1.36) 0.93 (1.44) 0.90 
 Retroactive interference 0.93 (1.03) 2.13 (1.85) 0.04 
 SDMT (# of correct digits) 54.00 (8.60) 49.53 (7.43) 0.14 
Color trails test (s) 
 Form A 35.13 (10.61) 32.43 (6.43) 0.42 
 Form B 74.13 (26.86) 73.00 (16.58) 0.89 
Verbal fluency (words) 
 Phonemic 46.00 (7.80) 49.67 (11.31) 0.31 
 Semantic 52.93 (8.67) 46.40 (7.69) 0.04 

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.

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 significant 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 optimized VBM revealed no gray matter density differences between groups after correction with permutation-based statistics. 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 expansion 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 detrimental 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 detected in formerly concussed participants at the TCFT delayed recall condition (Fig. 3).

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.

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.

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.

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.

Discussion

The present study investigated the effects of sports concussion and aging using multimodal neuroimaging in conjunction with the cognitive assessment. This research reveals: 1) the episodic memory decline in former athletes with concussion; 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 combined effect of age and concussion on cortical thickness measures in various ROIs that correlates with the episodic memory decline; 5) abnormally elevated mI relative concentration 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 participants relative to unconcussed counterparts are particularly salient neuroanatomical findings. The lateral ventricle enlargement 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. 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 predictive 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 preferentially 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 concussions, 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 substantiated 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 cortical 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 accentuated 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 technical 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 neuroanatomical studies need to address the cellular underpinnings 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 concussed participants. Taken together, these findings are indicative of abnormal aging in the former concussed athletes group not only affecting cognitive functions but also cortical tissue integrity.

Further evidence of the long-term effects of concussions on brain integrity was found using in vivo 1H-MRS. Indeed, Cho, for which the 1H-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 alterations, 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 population (Chantal et al. 2004) found choline alterations similar to those uncovered in concussed athletes from the current study. Although various explanations have been proposed to account for this neurometabolic imbalance, increased membrane 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 deposition 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 football 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 novel finding.

Finally, this study replicates previous findings of the episodic memory decline in formerly concussed athletes (De Beaumont et al. 2009) in addition to uncovering increased retroactive interference as well as semantic verbal fluency decrements 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 population of very mildly impaired individuals (MMSE ≥24) (Salmon et al. 2002). Further, evidence of executive function decline in our sample comes from significantly increased retroactive interference on verbal memory examination. When combined with recognition memory scores, which are abnormally low in our concussed group, retroactive interference scores have been reported to distinguish MCI patients from normal elderly individuals with great sensitivity and specificity (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 neurocognitive 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 activities 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 characterized in a larger sample with a more exhaustive neuropsychological examination, preferentially using a prospective approach.

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 unconcussed counterparts. This notion is supported by an episodic memory decline being related to the ventricular enlargement, cortical thinning, and hippocampal neurochemical 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 neurometabolic 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 correlated with cognitive decline, preferentially affecting episodic memory, which is the first clinical symptom of both amnestic MCI and CTE. Despite these similarities, motor system alterations 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 involved 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 sustained on average 2 concussions, and who took on a successful 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 physically and mentally active, and was on average 10 years younger than the typical MCI age of onset, this neurobiological 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 minimized 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 athletes 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 athletic career. Nevertheless, this study highlights disquieting 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 implications 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 longitudinal 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.

Funding

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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