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Cited by 252Traumatic Brain Injury ResearchDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

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Mixed pathologies including chronic traumatic encephalopathy account for dementia in retired association football (soccer) players

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Ling, Helen, Morris, Huw R., Neal, James W., Lees, Andrew J., Hardy, John, Holton, Janice L., Revesz, Tamas, Williams, David D. R.·2017·Acta Neuropathologica
DOI 10.1007/s00401-017-1680-3PMC PMC5325836
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Abstract

In retired professional association football (soccer) players with a past history of repetitive head impacts, chronic traumatic encephalopathy (CTE) is a potential neurodegenerative cause of dementia and motor impairments. From 1980 to 2010, 14 retired footballers with dementia were followed up regularly until death. Their clinical data, playing career, and concussion history were prospectively collected. Next-of-kin provided consent for six to have post-mortem brain examination. Of the 14 male participants, 13 were professional and 1 was a committed amateur. All were skilled headers of the ball and had played football for an average of 26 years. Concussion rate was limited in six cases to one episode each during their careers. All cases developed progressive cognitive impairment with an average age at onset of 63.6 years and disease duration of 10 years. Neuropathological examination revealed septal abnormalities in all six post-mortem cases, supportive of a history of chronic repetitive head impacts. Four cases had pathologically confirmed CTE; concomitant pathologies included Alzheimer's disease (N = 6), TDP-43 (N = 6), cerebral amyloid angiopathy (N = 5), hippocampal sclerosis (N = 2), corticobasal degeneration (N = 1), dementia with Lewy bodies (N = 1), and vascular pathology (N = 1); and all would have contributed synergistically to the clinical manifestations. The pathological diagnosis of CTE was established in four individuals according to the latest consensus diagnostic criteria. This finding is probably related to their past prolonged exposure to repetitive head impacts from head-to-player collisions and heading the ball thousands of time throughout their careers. Alzheimer's disease and TDP-43 pathologies are common concomitant findings in CTE, both of which are increasingly considered as part of the CTE pathological entity in older individuals. Association football is the most popular sport in the world and the potential link between repetitive head impacts from playing football and CTE as indicated from our findings is of considerable public health interest. Clearly, a definitive link cannot be established in this clinico-pathological series, but our findings support the need for further systematic investigation, including large-scale case-control studies to identify at risk groups of footballers which will justify for the implementation of protective strategies.

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Crossref · 10.1007/s00401-017-1680-3

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Fig. 1 Flow diagram illustrating the number of cases included in the clinical and post-mortem groups of ex-footballers with dementia
Fig. 1 Flow diagram illustrating the number of cases included in the clinical and post-mortem groups of ex-footballers with dementiaCC BY · PubMed Central
Fig. 2 CTE pathology. a, b Case 1, parietal cortex, c, d Case 2, temporal cortex, e, f Case 5, temporal cortex, g, h Case 5, posterior frontal cortex (including the motor cortex), and i–l Case 6, temporal cortex. b, d, f, h, j, and l are images at high magnifications of the boxed regions on (a), (c), (e), (g), (i), and (k), respectively. a–l Patchy tau aggregates in neurons, astrocytes, and cell processes found preferentially at the depths of the cortical sulci with multiple perivascular foci. Cortical sulci are marked by asterisks. m Neuronal tau aggregates preferentially affecting superficial cortical layers (layers II–III) in CTE (Case 6, temporal cortex), which contrasts with the involvement of the deep cortical layers in Alzheimer’s disease (see Fig. 3). n Prominent proximal dendritic swellings in CA4 hippocampal subregion (Case 5). o Dot-like structures in the neuropils (Case 6, temporal cortex). All sections immunostained for AT8. Bar represents 100 µm in (a), (c), (e), (g), (i), and (m), 40 µm in (b), (j), and (k), 20 µm in (d), (f), (h), (l), and (n), and 10 µm in (o)
Fig. 2 CTE pathology. a, b Case 1, parietal cortex, c, d Case 2, temporal cortex, e, f Case 5, temporal cortex, g, h Case 5, posterior frontal cortex (including the motor cortex), and i–l Case 6, temporal cortex. b, d, f, h, j, and l are images at high magnifications of the boxed regions on (a), (c), (e), (g), (i), and (k), respectively. a–l Patchy tau aggregates in neurons, astrocytes, and cell processes found preferentially at the depths of the cortical sulci with multiple perivascular foci. Cortical sulci are marked by asterisks. m Neuronal tau aggregates preferentially affecting superficial cortical layers (layers II–III) in CTE (Case 6, temporal cortex), which contrasts with the involvement of the deep cortical layers in Alzheimer’s disease (see Fig. 3). n Prominent proximal dendritic swellings in CA4 hippocampal subregion (Case 5). o Dot-like structures in the neuropils (Case 6, temporal cortex). All sections immunostained for AT8. Bar represents 100 µm in (a), (c), (e), (g), (i), and (m), 40 µm in (b), (j), and (k), 20 µm in (d), (f), (h), (l), and (n), and 10 µm in (o)CC BY · PubMed Central
Fig. 3 Mixed pathologies. a Hippocampal sclerosis (Case 2). b TDP-43-positive neuronal cytoplasmic inclusions in granule cells of the dentate gyrus (arrowheads; Case 2). c Astrocytic plaque in CBD (Case 1, temporal cortex). d Lewy body (Case 4, substantia nigra). e Uniform laminar distribution of Alzheimer-tau pathology which is particularly numerous in the deep cortical layers (red arrows, layer V), which contrasts with the patchy CTE-tau pathology observed in sulcal depths (see Fig. 2); tau-immunoreactive white matter astrocytes (blue arrows) are non-specific features of CTE (Case 3, frontal cortex). f Cerebral amyloid angiopathy of a cortical penetrating vessel (Case 1, frontal cortex). Bar represents 800 µm in (a), 600 µm in (e), 20 µm in (c) and (f), and 10 µm in (b) and (d)
Fig. 3 Mixed pathologies. a Hippocampal sclerosis (Case 2). b TDP-43-positive neuronal cytoplasmic inclusions in granule cells of the dentate gyrus (arrowheads; Case 2). c Astrocytic plaque in CBD (Case 1, temporal cortex). d Lewy body (Case 4, substantia nigra). e Uniform laminar distribution of Alzheimer-tau pathology which is particularly numerous in the deep cortical layers (red arrows, layer V), which contrasts with the patchy CTE-tau pathology observed in sulcal depths (see Fig. 2); tau-immunoreactive white matter astrocytes (blue arrows) are non-specific features of CTE (Case 3, frontal cortex). f Cerebral amyloid angiopathy of a cortical penetrating vessel (Case 1, frontal cortex). Bar represents 800 µm in (a), 600 µm in (e), 20 µm in (c) and (f), and 10 µm in (b) and (d)CC BY · PubMed Central

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Metadata

Authors
Ling, H., Morris, H. R., Neal, J. W., Lees, A. J., Hardy, J., Holton, J. L., Revesz, T., & Williams, D. D. R.
Affiliations
  • National Hospital for Neurology and Neurosurgery (GB)
  • UCL Queen Square Institute of Neurology (GB)
  • Cardiff University (GB)
  • Cefn Coed Hospital (GB)
Corresponding author
Holton, Janice L.
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2017-02-15
Volume
133
Issue
3
Pages
337-352
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-017-1680-3
PMC
PMC5325836
OpenAlex
W2588072485
Cited by
252
References
45
Citations by year
2026: 10 · 2025: 22 · 2024: 20 · 2023: 31 · 2022: 28 · 2021: 30 · 2020: 51 · 2019: 28 · 2018: 16 · 2017: 16
FWCI
23.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
Funders
The Drake Foundation
Topics
  • Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords
chronic traumatic encephalopathy, soccer, dementia, repetitive head impacts, Alzheimer's disease, TDP-43, cerebral amyloid angiopathy, hippocampal sclerosis, corticobasal degeneration, dementia with Lewy bodies, neuropathology, concussion
MeSH terms
Chronic Traumatic Encephalopathy, Sequestosome-1 Protein, Aged, Aged, 80 and over, Autopsy, Brain, Calcium-Binding Proteins, Dementia, DNA-Binding Proteins, Humans, Male, Microfilament Proteins, Middle Aged, Retirement, Retrospective Studies, Soccer, Amyloid beta-Peptides, tau Proteins, alpha-Synuclein

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