Keywords Soccer - Brain Injuries, Traumatic - Chronic Traumatic Encephalopathy - Positron-Emission
Tomography - Magnetic Resonance Imaging
Palavras-chave Futebol - Lesões Encefálicas Traumáticas - Encefalopatia Traumática Crônica - Tomografia
Por Emissão De Pósitrons - Imageamento Por Ressonância Magnética
INTRODUCTION
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease related to repetitive
head trauma[1 ] first described in boxers[2 ] and mostly studied in soldiers,[3 ]
[4 ] American football players,[5 ]
[6 ]
[7 ] and fighters.[8 ] The neuropathological hallmark of CTE is the deposition of phosphorylated Tau protein
(pTau) in neurons, and astroglia with perivascular distribution in the depth of sulci.[9 ] Deposition of TAR DNA-binding protein 43 kDa (TDP-43) and, less frequently, amyloid-β
can also be found.[9 ]
Neuroimaging studies of the long-term effects of traumatic brain injury have shown
that individuals exposed to repetitive head impacts have reduced cortical glucose
metabolism and gray matter volume with the regional distribution depending on the
mechanism, intensity, and frequency of the head impacts in the exposed subjects.[10 ]
[11 ]
Previous studies have shown that soccer players had worse cognitive performance on
neuropsychological tests than controls[12 ] and have mortality related to neurodegenerative diseases 3.45 times higher than
in the general population.[13 ] Moreover, recent post-mortem studies demonstrated CTE's neuropathology in demented
retired soccer players (RSPs).[14 ]
[15 ]
[16 ] These data suggest that soccer athletes, who are exposed to long-term, repetitive
head impacts are at risk of developing CTE.
Soccer is among the most practiced sports worldwide, and yet soccer players remain
an understudied population regarding the long-term effects of sport-related repeated
head impacts on the brains of these athletes. The main purpose of the present cross-sectional
observational study is to investigate multimodal neuroimaging findings ([18F]FDG-PET
and magnetic resonance imaging [MRI]) in RSPs.
METHODS
Selection of participants
Male RSPs and healthy age- and sex-matched controls were prospectively enrolled between
January/2017 and September/2019. The present study was approved by the Research Ethics
Committee of the São Paulo University Medical School (registry 1.561.037). All participants
provided informed consent.
The RSPs were randomly sampled among the athletes registered in a local sports association
(the syndicate of athletes of the state of São Paulo) or randomly referred by the
orthopedics department of our university hospital, irrespective of any cognitive complaints.
The inclusion criteria for the RSP group were: male sex, and previous professional
soccer practice. Inclusion criteria for controls were: male sex and lack of traumatic
brain injury (TBI) (control group). Common exclusion criteria for RSPs and controls
were: previous neurological disease (unrelated to neurodegeneration), contraindications
to MRI,[17 ] incidental intracranial lesions on MRI, or limiting imaging artifacts. Besides these
common exclusion criteria, it was considered not eligible for the study any RSP who
presented a history of TBI resulting in hospitalization and any control with regular
amateur/recreational soccer practice.
Controls were recruited from the families of the RSPs and as volunteers at our university
hospital's neurology department.
Neurological evaluation
Participants underwent neurological examination by a board-certified neurologist.
The standard neurological assessment included a physical examination and a clinical
interview which addressed the presence of any cognitive complaints, history of TBI,
TBI-related loss of consciousness, neurologic, cardiovascular, and endocrine diseases,
and a neuropsychological evaluation with the Mini-Mental State Examination (MMSE),[18 ] digit span (forward and backward),[19 ] figure memory test (naming, recognition, incidental memory, immediate memory, learning,
delayed recall),[20 ] verbal fluency (phonemic and semantic),[21 ]
[22 ] and clock drawing[23 ] tests.[24 ] Participants were screened for traumatic encephalopathy syndrome (TES) based on
Montenigro's criteria.[25 ] Lumbar puncture for the analysis of CSF biomarkers was proposed to all participants.
Image acquisition
[18F]FDG-PET and MRI images were simultaneously acquired in a 3.0-Tesla PET/MRI scanner
(Signa, GE Healthcare, Boston, MA, USA). The MRI protocol included volumetric T1-weighted
(T1WI), T2-weighted (T2WI), fluid-attenuated inversion recovery (FLAIR), and susceptibility-weighted
angiography (SWAN) images. Metabolic images were acquired 30 minutes after intravenous
[18F]FDG injection. The imaging acquisition protocol is detailed in the [Supplementary Material ] (online only).
Image processing
The GM volume was assessed with voxel-based analysis using Statistical Parametric
Mapping (SPM) 8 software (Wellcome Department of Human Neuroimaging). Initially, skull
and extracranial structures were manually extracted from T1WI using MRIcron software
(McCausland Center for Brain Imaging). Then, skull-striped T1WI were spatially normalized
into an anatomic template and segmented into CSF, GM, and WM using the Diffeomorphic Anatomical Registration using Exponentiated Lie algebra (DARTEL) algorithm. Images were then modulated by the Jacobian determinant and adjusted
to the Montreal Neurological Institute (MNI) coordinates. Besides quantifying GM volume,
this pipeline created the study-specific anatomic template for [18F]FDG-PET processing.
For [18F]FDG-PET group analysis, images were co-registered with their respective T1WI
(to correct for partial volume effects [PVEs], as described by Meltzer et al.[26 ]) and spatially normalized using SPM8 into the study-specific anatomic template previously
generated with DARTEL. Scans were smoothed with an 8.0-mm full width at half maximum
Gaussian filter to improve signal-to-noise ratio and mitigate misregistration into
the template space. A default threshold of 0.8 of the mean uptake inside the brain
was selected to ensure that the analysis included only voxels mapping cerebral tissue.
Global uptake differences between scans were adjusted using a proportional scaling
approach (global mean) at SPM8.
WMH in the FLAIR images were segmented automatically with the Lesion Growth Algorithm[27 ] as implemented in the Lesion Segmentation Tool toolbox (version 1.2.3 2013–03–12,
www.statisticalmodelling.de/lst.html ) for SPM, using a threshold of 0.3, as recommended by the developer.[27 ]
Visual analysis
[18F]FDG-PET images were evaluated by a neuroradiologist and a nuclear physician,
both experienced in neurologic [18F]FDG-PET and blinded to the participant's group.
Scans were rated as “normal,” “abnormal,” or “borderline” (nonspecific findings, possibly
within normal limits), based on visual interpretation assisted by the 3D-SSP semiquantitative
software (CortexID Suite, GE Healthcare, Boston, MA, USA) as previously proposed.[28 ] In addition to subjective visual analysis, readers considered a Z-score < 2.0 in
at least 2 cortical areas, after normalization for the pons and the cerebellum, as
a reference of abnormality.
To investigate typical patterns of Alzheimer disease (AD)[28 ] or other neurodegenerative diseases,[29 ] the regions of reduced rBGM in all abnormal scans were detailed.
T1WI was inspected by a neuroradiologist to detect structural neuroimaging abnormalities
related to repetitive head impacts, namely cavum septum pellucidum (CSP), cavum vergae (CV) and septum pellucidum fenestration (SPF). Also, brain atrophy was assessed on T1WI with the Global Cortical
Atrophy, Medial Temporal Lobe Atrophy, Posterior Atrophy, Anterior Cingulate Atrophy,
Orbitofrontal Atrophy, Anterior-Temporal Atrophy, and Fronto-Insular Atrophy scales.[30 ]
[31 ] The scales were rated separately for each hemisphere and averaged before statistical
analysis.
FLAIR and SWAN images were assessed for detection of WMH according to the Fazekas
scale,[32 ] and for detection of microbleeds and superficial siderosis, respectively.
Statistical analysis
Demographic, clinical data, and MRI findings on visual analysis were statistically
analyzed using R (https://www.r-project.org/ ). For group comparison, categorical data were assessed with the chi-squared test
and numerical data with the t -test for independent sample or the Mann-Whitney U-test, according to data distribution
assessed with the Shapiro-Wilk test. Data with a normal distribution are expressed
as mean ± standard deviation (SD), and data with a nonnormal distribution are expressed
as median; interquartile range (IQR). The threshold for significance was set at p = 0.05.
For the initial exploratory analyses of [18F]FDG-PET and T1WI, statistical parametric
maps of [18F]FDG uptake and GM volume were generated using SPM8 with the threshold
for significance at the voxel level set at p
uncorrected = 0.001 (Z-score = 3.09) with a minimum extension of 10 voxels in the corresponding
cluster. Results were considered valid when surviving correction for multiple comparisons
with the false discovery rate (FDR) method (pFDR ≤ 0.05).[33 ]
Relevant peak voxels from the statistical parametric maps were initially identified
in the Montreal Neurological Institute (MNI) coordinate system and then converted
to the Talairach and Tournoux coordinates with the MNI2Tal web application (Legacy
BioImage Suite).[34 ]
Numeric values (measured in kBq/ml) representing the mean [18F]FDG uptake for each
participant (a proxy for regional brain glucose metabolism [rBGM] in the clusters
with statistically significant results in the SPM group analysis) were obtained with
the MarsBar toolbox for SPM (http://marsbar.sourceforge.net/).35
These values were used to investigate correlations of [18F]FDG uptake with the time
of soccer practice and the scores of neuropsychological tests in the RSPs using linear
regressions.
RESULTS
Participant characteristics
Nineteen male RSPs and 20 healthy and age-matched male controls were included ([Supplementary Figure S1 ] [online only]).
The median age was 62 (50–64.5) and 60 (48–73) years old, and the duration of formal
education was 14 (11–15) and 15 (11.8–16) years in the RSP and control groups, respectively.
No significant age differences were found between groups; however, controls had higher
educational levels ([Table 1 ]). The RSPs had a total soccer practice time of 19.7 ± 6.2 years. Regarding playing
position, 10/19 (52.7%) RSPs played in defense, 4/19 (21.0%) in midfield, and 5/19
(26.3%) in offensive roles.
Table 1
Demographics, MRI visual analysis, clinical and neuropsychological data, and burden
of white matter FLAIR hyperintensities in both groups
Retired soccer players (19, male)
Controls (20, male)
p -value
Demographics (years, median; IQR)
Age (years old)
62; 50–64.5
60; 48–73
0.527a
Education
14; 11–15
15; 11.8–16
0.035a
Septum pellucidum abnormalities (% of participants)
Cavum Septum Pellucidum
68
15
0.001b
Cavum Vergae
37
20
0.243b
Fenestration of Cavum Septum Pellucidum
32
0
0.006b
Brain atrophy (visual rating) (median; IQR)
Global cortical atrophy (Pasquier) scale
1; 0–1
1; 0–2
0.136a
Medial temporal lobe atrophy (Scheltens) scale
0; 0–1
0;0–0.125
0.446a
Posterior atrophy (Koedam) scale
0; 0–1
0; 0–1
0.543a
Anterior cingulate atrophy scale
0; 0–0.5
0; 0–1
0.414a
Orbitofrontal atrophy scale
0; 0–0
0; 0–0
0.964a
Anterior-temporal atrophy scale
0; 0–0
0; 0–1
0.471a
Frontoinsular atrophy scale
0; 0–0
0; 0–0.25
0.730a
White matter FLAIR hyperintensities (visual rating and quantification) (median; IQR)
Fazekas scale
1; 0–1
1; 0–1
0.666a
Volume of white matter FLAIR hyperintensitiesd
5.7; 2.4–32.5
2.7; 1.5–18.1
0.224a
Neuropsychological evaluation
MMSE total score (median; IQR)
27; 25.5–29
29; 28.8–30
0.003a
Clock drawing test (median; IQR)
9; 9–10
10; 9–10
0.036a
Semantic verbal fluency test (animals) (mean ± SD)
15.7 ± 4.4
20.8 ± 4.8
0.002c
Phonemic verbal fluency test total score* (mean ± SD)
35.3 ± 11.5
42.6 ± 9.6
0.040c
Digit span test total score* (mean ± SD)
8.3 ± 2.1
11.5 ± 3.9
0.005c
Figure memory test
Naming (median; IQR)
10; 10–10
10; 10–10
1.000a
Incidental memory (mean ± SD)
6.5 ± 2.4
6.0 ± 2.1
0.467c
Immediate memory (median; IQR)
8; 7–9
8; 7–9
1.000a
Learning (median; IQR)
9; 8–10
9; 8–10
0.609a
Delayed recall (median; IQR)
9; 7–9
9; 8–9.3
0.437a
Recognition (median; IQR)
10; 9.5–10
10; 10–10
0.094a
Clinical evaluation
History of traumatic brain injury
11 (58%)
0
<0.001c
Psychiatric symptoms
6 (31%)
2 (10%)
0.171b
Subjective cognitive complaints
2 (10%)
5 (25%)
0.447b
Arterial systemic hypertension
4 (21%)
6 (30%)
0.562b
Type 2 diabetes
2 (10%)
2 (10%)
0.920b
Abbreviations: IQR, interquartile range; MMSE, Mini-Mental State Examination; SD,
standard deviation.
Notes: a Mann-Whitney U test. b Chi-squared test. c t-test for independent samples. d Volume of WM FLAIR hyperintensities measured with Lesion Segmentation Tool toolbox
for SPM 8 software (threshold = 0.30). Data with normal distribution are expressed
as mean ± SD and data with non-normal distribution are expressed as median; IQR. *One
control (with normal MMSE, naming, incidental memory, immediate memory, learning,
delayed recall, and recognition scores) had missing values on the Digits Span and
Phonemic Verbal Fluency Tests.
History of head trauma
All RSPs were exposed to frequent heading. However, 11/19 (58%) reported TBI related
to head-to-head (9/11, 82%), head-to-ground (1/11, 9%), and head-to-elbow (1/11, 9%)
impacts. Loss of consciousness was reported by 3/19 (16%) players. Traumatic brain
injury was reported by 4/10 (40%) defenders, 2/4 (50%) midfielders, and ⅗ (60%) offenders
(p = 0.689).
Neurological evaluation
Compared with controls, RSPs had significantly lower MMSE scores, performed significantly
worse on semantic verbal fluency, clock drawing, phonemic verbal fluency, and digit
span tests ([Table 1 ]). The figure memory test showed no significant differences between groups.
Among RSPs, 6/19 (31%) reported anxiety, depression, attention deficits, or alcohol
abuse, while 2/20 (10%) of controls reported anxiety or depressive symptoms. Cognitive
decline, defined as an impairment in sporadic memory, spatial orientation, or verbal
fluency (after ruling out non-neurodegenerative causes), was clinically confirmed
in 2/19 (10%) RSPs, diagnosed with TES and further classified as probable CTE according
to Montenigro's criteria.[25 ] Among controls, 4/20 (20%) had subjective cognitive complaints that were not confirmed
as cognitive decline in the neurological evaluation ([Table 1 ]).
[18F]FDG-PET group analysis
The RSPs exhibited reduced [18F]FDG uptake in the left temporal pole (pFDR = 0.008)
and in the anterior left middle temporal gyrus (pFDR = 0.043). Smaller clusters of
glucose hypometabolism were observed in the right hippocampus, the posterior left
fusiform/inferior temporal gyrus, the left insula, and the right parahippocampal gyrus
but did not survive correction for multiple comparisons ([Figure 1 ], [Supplementary Table S1 ] [online only]). These findings were observed after correction for PVE and persisted
when age and education were covariates. The FDG uptake in the right hippocampus was
negatively correlated with the soccer practice time (p = 0.039; rPearson = - 0.48). No correlation between soccer practice time and [18F]FDG uptake was observed
in the remaining clusters of hypometabolism.
Notes: Maps generated by Surf Ice software (http://www.nitrc.org/projects/surfice/ .) with p <0.05, uncorrected. Bars on the right: Zscores ranging from p = 0.05 (Z-score = 2.0) to p = 0.001 (Z-score = 3.0). Reduced [18 F]FDG uptake is observed in the left temporal pole, the anterior left middle temporal
gyrus, the right hippocampus, the posterior left fusiform/inferior temporal gyrus,
the left insula, and the right parahippocampal gyrus. Reduced GM volume is observed
in the right parahippocampal gyrus, the posterior left middle temporal gyrus, and
the posterior left fusiform/inferior temporal gyrus.
Figure 1 Illustrative anatomic localization of the peak clusters of reduced rGBM and reduced
GMvolume in retired soccer players compared with controls.
The individual rBGM in all clusters of reduced [18F]FDG uptake was consistently lower
in RSPs than in controls, mostly evident in the left temporal pole, the anterior left
middle temporal gyrus, the posterior left fusiform/inferior temporal gyrus, and the
right hippocampus ([Figure 2A ]). However, no significant differences in rBGM were observed among playing positions
([Figure 2B ]).
Note: Plots generated with Prism 6 software (www.graphpad.com/scientific-software/prism/ ).
Figure 2 Scatter plot of individual [18 F]FDG uptake in the clusters of reduced rBGM for each participant (A ) and for each retired soccer player, compared regarding their playing position (B ). (A ). Individual [18 F]FDG uptake in all clusters is consistently lower in retired soccer players than
in controls, with statistically significant differences between groups in the left
temporal pole and the anterior leftmiddle temporal gyrus(*). The three individuals
with the lowest uptake in the left temporal pole were defensive players (participants
A , B , and C ). Participants A and B were clinically classified as possible and probable CTE, respectively.
(B ). No significant differences were observed among defenders, midfielders, and offenders
regarding [18 F]FDG uptake in these areas (p < 0.216).
Scores of the Semantic Verbal Fluency (animals) test correlated positively with [18F]FDG
uptake in the right hippocampus (p = 0.006; r2
Pearson = 0.61), left temporal pole (p = 0.042; r2
Pearson = 0.47), and in the posterior left middle temporal gyrus (p = 0.041; r2
Pearson = 0.47). No significant correlation was observed between the remaining neuropsychological
test scores and the [18F]FDG uptake.
[18F]FDG-PET visual analysis
Abnormal [18F]FDG-PET scans were observed in 16/19 (84%) RSPs and in only 4/20 (20%)
controls (p < 0.001). Clearly abnormal exams were found in 7/19 (36%) RSPs (participants A-G,
[Figure 3 ]), while 9/19 (47%) had borderline scans. Only 1/20 (5%) controls had an abnormal
exam, and 3/20 (15%) had borderline alterations. None of the RSP who reported a loss
of consciousness presented with abnormal scans.
Abbreviation: SUV, Standard Uptake Value.
Figure 3 Individual 3D-SSP of the [18 F]FDG-PET metabolic images from all seven retired soccer players with definitely abnormal
scans in the visual analysis. All seven retired soccer players classified as abnormal
presented with reduced [18F]FDG-PET uptake in the lateral temporal lobes, with some
individual variation. Participants A and E have also reduced rBGM in the frontal lobes,
and participant C in the left temporal-parietal-occipital region and the left precuneus.
All RSPs with abnormal scans showed hypometabolism in the medial and lateral temporal
lobes. Additionally, participants A and E had reduced rBGM in the frontal lobes, and
participant C in the left temporal-parietal-occipital region, extending to the ipsilateral
precuneus. Participants C, D, and G had temporoparietal hypometabolism that could
be visually interpreted as AD. However, given the extension to occipital regions or
the lack of clear involvement of the posterior cingulate gyrus and precuneus, these
findings did not fit the typical AD pattern (Figure 3 and [Supplementary Table S2 ] [online only]). The only control with abnormal [18F]FDG-PET had reduced rBGM in
both cerebellar hemispheres.
The RSPs with abnormal [18F]FDG-PET were not significantly different from those with
borderline and normal scans (analyzed together) regarding age (63.1 ± 3.8 versus 54.4 ± 12.7
years old, p = 0.098), education (11.6 ± 3.8 versus 13.3 ± 2.3 years, p = 0.245), and time of soccer practice (19.3 ± 7.6 versus 20 ± 5.6 years, p = 0.817).
The RSPs with abnormal [18F]FDG-PET on visual analysis presented with lower MMSE scores
than RSPs with normal or borderline scans (pMann-Whitney = 0.045). No differences between RSPs with abnormal and normal or borderline [18F]FDG-PET
scans were observed regarding the remaining neuropsychological tests.
MRI visual analysis
Cavum septum pellucidus and SPF were significantly more frequent in RSPs (68%) than
in controls (15%). No differences between groups were observed regarding the frequency
of CV ([Table 1 ]).
Regarding scores of brain atrophy and Fazekas scales, no differences between RSPs
and controls were observed ([Table 1 ]). Visual analysis of SWAN images was unremarkable in all participants.
GM volume analysis
The RSPs exhibited reduced GM volume in similar brain regions as those with reduced
[18F]FDG uptake, including the right parahippocampal gyrus (pFDR = 0.544), the posterior
left middle temporal gyrus (pFDR = 0.085), and the posterior left fusiform/inferior
temporal gyrus (pFDR = 0.085) (Figure 1, [Supplementary Table S1 ] [online only]). None of these clusters survived correction for multiple comparisons.
Quantitative assessment of WMH
The quantitative analysis revealed no significant differences in the volume of WMH
between RSPs (5.7; 2.4–32.5) and controls (2.7; 1.5–18.1) (p = 0.224).
DISCUSSION
The present cross-sectional observational study investigated multimodal neuroimaging
findings in retired professional soccer players (RSPs). We found that RSPs exhibited
reduced glucose metabolism in the temporal lobes, with clusters in the left temporal
pole and the anterior left middle temporal gyrus surviving correction for multiple
comparisons. They also presented smaller clusters of reduced GM volume in similar
anatomic regions that did not survive correction for multiple comparisons. The areas
of hypometabolism were also detected in a visual analysis by experts. Ultimately,
these findings point to neurodegeneration in the temporal lobes, with a slight predominance
on the left side, and could be related to long-term repetitive head impacts.
These results agree with the previous neuroimaging and neuropathological features
observed by Grinberg et al. in an RSP with a clinical diagnosis of late-onset AD.[14 ] In a post-mortem 3T MRI, these authors found atrophy in the anterior and medial
structures of the temporal lobes (greater on the left) and CSP. Also, the neuropathological
examination showed phospho-tau CTE pathology in the temporal lobes and limbic structures,
as well as TDP-43-related hippocampal sclerosis.[14 ] Therefore, signs of neurodegeneration in the temporal lobes were expected in our
study.
Several studies with military personnel, boxers, and American football players,[4 ]
[8 ]
[10 ]
[36 ]
[37 ]
[38 ]
[39 ] have shown mild TBI-related hypometabolism in the cerebellum, the pons, the temporal
and frontal regions, the posterior cingulate, and the thalamus. In RSPs, however,
the clusters of cortical hypometabolism are less extensive and widespread than reported
in those populations. These imaging findings likely reflect differences in the type,
intensity, and frequency of head impacts to which soccer players are exposed.
Lesman-Segev et al.[10 ] showed that, when compared with controls, American football players with TES and
negative amyloid-PET have clusters of reduced FDG uptake in the medial temporal lobe
structures and frontal cortex (with minor involvement of the lateral left temporal
and parietal lobes) and clusters of reduced GM volume in frontal regions, the insula,
and anterior temporal lobes. We did not observe hypometabolism or reduced GM volume
in frontal areas; however, the involvement of lateral and medial temporal lobe structures
in RSPs without involving areas typically affected in AD (precuneus and posterior
cingulate gyrus) is in agreement with those findings in American football athletes.
A study by Meabon et al.[39 ] demonstrated a dose-response relationship between blast-related concussion and cerebellar
hypometabolism in veteran soldiers (subjects exposed to more blast-related head impacts
had lower cerebellar glucose uptake). Despite differences in the spatial distribution
of glucose hypometabolism clusters (likely related to different trauma mechanisms,
intensity, and frequency in different populations), we observed that lower rBGM in
the right hippocampus is related to longer careers among RSPs, pointing to a possible
dose-response relationship between sports-related mild TBI and brain hypometabolism
in these athletes.
On the MRI visual analysis, we found a higher prevalence of CSP and SPF in RSPs than
in controls. Similarly, Koerte et al.[40 ] and Lesman-Segev et al.[10 ] found a higher frequency of CSP in American football athletes. These findings have
been reported as a CTE feature[40 ]
[41 ] and are likely related to the thinning and detachment of the septum pellucidum layers
caused by the impact of cerebrospinal fluid (CSF) waves generated during the head
trauma.[41 ]
Regarding WMH, a study by Berginström et al.,[42 ] using an automated segmentation method to quantify these lesions, demonstrated that
the burden of WMH increases with the TBI severity but that no differences are observed
between mild TBI patients and healthy controls. In our work, we used the same approach
as Berginström et al.[42 ] to segment WMH, and we found no differences in the load of WMH between RSPs and
controls, which was expected since RSP were exposed to mild, but not moderate or severe,
TBI.
The main limitation of our study is the lack of Tau-PET imaging (regionally unavailable)
and CSF biomarkers since all participants refused lumbar puncture. In the absence
of CSF biomarkers, tau, and amyloid-PET, we could not exclude other causes of neurodegeneration/neurodegenerative
diseases, namely AD.
However, the regional pattern of hypometabolism observed in RSPs was not suggestive
of AD pathology. Besides, the neuropsychological evaluation showed that RSPs had lower
global cognitive performance, with impaired attention and executive functions. No
impairment of episodic memory was observed in this group. This neuropsychological
profile would be expected in CTE,[25 ] but not in AD.[43 ]
[44 ] Also, given the mean age of RSP (62 years old, IQR: 50–64.5), if the hypometabolism
in RSPs were related to AD pathology, it would be of the pre-senile AD, which is rarer
than the sporadic form. We believe it unlikely that our random recruitment resulted
in a cohort of RSPs with a predominance of pre-senile AD or even frontotemporal lobar
degeneration.
Although, to our knowledge, this is the largest sample of RSPs with multimodal brain
PET/MRI to date, the relatively small number of RSPs limited the sub-analysis regarding
the different playing positions and risk of CTE.
The present paper shows that [18F]FDG-PET/MRI can be used to investigate athletes
with suspected CTE, including using a visual clinically-based approach at the individual
level. Additionally, we demonstrated that RSPs have brain metabolic and structural
changes in the temporal lobes and a higher prevalence of CSP and SPF, findings similar
to those reported in other athletes and possibly related to long-term repetitive head
impacts. Further studies with larger samples, CSF biomarkers, tau, and amyloid-PET
will deepen our understanding of this condition.
In conclusion, RSPs have reduced regional brain glucose metabolism in the temporal
lobes and a higher prevalence of CSP and SPF than age and sex-matched controls. Also,
the cerebral glucose hypometabolism in RSP may present a dose-response relationship
with the career length of the RSP. These findings might be related to chronic brain
damage due to repetitive head impacts related to sportive practice.
