Chronic traumatic encephalopathy in a former Australian rules football player diagnosed with Alzheimer's disease.,Acta Neuropathologica Communications

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Chronic traumatic encephalopathy in a former Australian rules football player diagnosed with Alzheimer's disease.
Acta Neuropathologica Communications ( IF 6.2 ) Pub Date : 2020-02-26 , DOI: 10.1186/s40478-020-0895-z
Alan J Pearce ₁ , Joanne Sy ₂ , Maggie Lee _{2,

3} , Antony Harding _{2,

3} , Rowena Mobbs _{3,

4} , Jennifer Batchelor ₄ , Catherine M Suter ₂ , Michael E Buckland _{2,

3}

Affiliation

To the Editor:

The first case report of chronic traumatic encephalopathy (CTE) in a National Football League player in 2005 [9] opened the floodgates for the identification of CTE in American football. CTE is now reported in ex-players of other contact sports, including ice hockey, soccer, rugby union, and most recently in Australian rugby league [2]. To date, repetitive head injury remains the only known risk factor for the development of CTE [3]. Here we describe the first case of CTE in Australian rules football (ARF), the most popular contact sport in Australia.

The decedent was a male in his 9th decade who had played more than 350 first-grade matches of ARF over 19 years. At age 64 he was diagnosed with Alzheimer’s disease (AD), with accompanying personality change, depression and anger/aggression issues around this time. He had been diagnosed with REM sleep behaviour disorder several years prior to his presumptive AD diagnosis. His cognitive issues were dominated by memory loss, which was slowly progressive until a distinct acceleration in the last ~ 5 years of life. Mild Parkinsonian features of uncertain aetiology were identified several years after his AD diagnosis, possibly related to low-dose antipsychotic medication. He also had intercurrent ischaemic heart disease, hypercholesterolaemia, and hypertension, all of which were well managed. He did not use alcohol, tobacco, or illicit drugs.

Table 1 summarises the relevant neuropathology. There was mild-moderate frontal and temporal lobe atrophy with ex-vacuo ventriculomegaly (lateral and third ventricles), mild uncomplicated atheroma in the basal vasculature, and pallor of the substantia nigra. Phosphorylated Tau immunoreactivity (pTau) was present in many grey matter regions. Neocortical pTau was markedly concentrated in an irregular perivascular distribution at sulcal depths in the soma and processes of both neurons and astrocytes: this is the defining lesion of CTE [8] (Fig. 1a, b). Twelve CTE foci were present within nine frontal lobe blocks, and four foci in four temporal lobe blocks. In the temporal and insular cortices there was also dense involvement of superficial layers (layers II-III) (Fig. 1c), consisting of pretangle and tangle pTau, and some ghost tangles. This pattern of pTau deposition, commonly seen in severe CTE, is distinct from the typical pTau deposition in AD (Fig. 1d). Neuronal pTau was composed of both 3R and 4R isoforms, while astrocytic pTau was predominantly 4R.

Table 1 Summary of neuropathology findings

Full size table

Hippocampal sclerosis was present, with some ghost tangles, gliosis, and heavy pTau involvement. Widespread neuronal and neuritic pTau was also present in amygdala, medial hypothalamic nuclei, mammillary body, nucleus basalis, substantia nigra (Fig. 1e), raphe nuclei and colliculi. Subpial and subependymal pTau in thorn-shaped astrocytes was present, consistent with aging-related tau astrogliopathy (ARTAG), most prominent in the temporal lobe.

Phosphorylated TDP-43 was present as neuronal cytoplasmic inclusions and short neurites, and was colocalised with regions of severe CTE pathology (Fig. 1f), a common finding in CTE [8]. Beta-amyloid and neuritic plaques were seen, corresponding to Thaal phase 4 (A3; Fig. 1g), and CERAD score of C2. While pTau pathology was in the typical distribution of CTE rather than AD, assessing all neurofibrillary tangle pathology gave a Braak stage of IV (B2). Together this equated to intermediate AD-neuropathologic change (A3,B2,C2) [6]. Immunohistochemistry for alpha-synuclein was negative.

Severe arteriolosclerosis was present in basal ganglia and white matter. Rarefaction and gliosis in subcortical white matter was generally mild-moderate, while in the anterior commissure and external capsule it was severe. Axonal pTau was moderate in these above two tracts, and mild elsewhere, and was seen as immunoreactive neurites and axonal varicosities. Beta-amyloid precursor protein was absent from anterior commissure and external capsule, and present in internal capsule in a pattern consistent with agonal changes only.

Taken together, these findings demonstrate severe (Stage III) CTE. This is the first confirmed case in ARF. CTE was associated with early-onset dementia, with neuropsychological features commonly described in pathologically confirmed CTE cases from other sports. Typical CTE pathology in this case was accompanied by intermediate AD-neuropathologic change, and severe small vessel disease.

ARF is the most popular contact sport in Australia, with a player base of more than 1.5 million, and a significant (30%) female representation. ARF is characterized by its fast-paced physicality: it involves running at speed, frequent jumping, and high-impact landing. With 18 players per side high-force collisions are commonplace, and can occur in any direction, on the ground or in the air. Thus unsurprisingly, ARF has a high injury and concussion rate [7], and the unique nature of the game places players at risk of head injury from multiple and complex mechanisms, distinct from those of the rugby codes. The limited available evidence on long-term neurological outcomes of ARF players suggests that, like ex-athletes of other contact sports, they too are predisposed to develop persisting deficits in motor control and cognition [4, 10].

There are no criteria for distinguishing AD-associated from CTE-associated pTau pathology when there is intercurrent disease. The identification of conformational differences in the β-helix region of pTau in CTE versus AD [5] suggests that these are two distinct pathologies, but currently all neurofibrillary tangle pathology in a CTE case is assessed to derive a Braak stage for AD. This ‘double-counting’ of pTau is likely to overestimate the severity of co-occurring AD in CTE, particularly in older individuals such as described here. Development of conformation-specific antibodies specific for CTE-pTau would greatly assist in distinguishing these two diseases.

This case represents only the second ARF player brain donated to the recently established Australian Sports Brain Bank [1], and the first to be diagnosed with CTE. While we can make no claims of CTE incidence in ARF based on this index case, the distinctive and severe pTau pathology is something we have not encountered in our busy clinical practice outside of ex-contact sports players [2]. That it exists at all should serve as a call to action to recognise and research CTE, and the very clear association with repetitive head injury. Claims of a lack of demonstrated ‘causality’ are unhelpful, and arguably irrelevant when assessing a public and occupational health issue such as CTE.

N/A

AD:: Alzheimer’s disease
ARF:: Australian Rules football
ARTAG:: aging-related tau astrogliopathy
CTE:: chronic traumatic encephalopathy

1.
Australian Sports Brain Bank www.brainbank.org.au.
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We thank the donors and their families. We gratefully acknowledge the expert technical assistance of Diana van Beek and Karina Hammond. We also thank PathWest Neuropathology Department, Royal Perth Hospital, for their assistance with the Australian Sports Brain Bank.

Funding for the Australian Sports Brain Bank has been provided by the Sydney Local Health District, Northern Sydney Local Health District, Concussion Legacy Foundation and StopConcussions.com.

Affiliations

College of Science, Health and Engineering, La Trobe University, Bundoora, VIC, 3086, Australia
- Alan J. Pearce
Department of Neuropathology, Royal Prince Alfred Hospital, Camperdown, NSW, 2050, Australia
- Joanne Sy
- , Maggie Lee
- , Antony Harding
- , Catherine M. Suter
- & Michael E. Buckland
Brain & Mind Centre, University of Sydney, Camperdown, NSW, 2006, Australia
- Maggie Lee
- , Antony Harding
- , Rowena Mobbs
- & Michael E. Buckland
Macquarie University, Macquarie Park, NSW, 2109, Australia
- Rowena Mobbs
- & Jennifer Batchelor

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Contributions

MEB, AH, ML, JS were involved in pathological assessment. RM and JB synthesized clinical data. AJP, CS, MEB drafted the manuscript and all authors reviewed and revised the manuscript.

Corresponding author

Correspondence to Michael E. Buckland.

Ethics approval and consent to participate

Ethical approval is granted by the Sydney Local Health District HREC, Approval# X19–0010. Written informed consent for brain donation was provided by senior next of kin and executor of the estate.

Consent for publication

Consent for publication has been provided by the family of the decedents.

Competing interests

AJP currently receives partial research salary funding from Sports Health Check charity. AJP has previously received partial research funding from the Australian Football League, Impact Technologies Inc., and Samsung Corporation. The remaining authors declare that they have no competing interests.

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Pearce, A.J., Sy, J., Lee, M. et al. Chronic traumatic encephalopathy in a former Australian rules football player diagnosed with Alzheimer’s disease. acta neuropathol commun 8, 23 (2020). https://doi.org/10.1186/s40478-020-0895-z

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Received: 06 January 2020
Accepted: 05 February 2020
Published: 26 February 2020
DOI: https://doi.org/10.1186/s40478-020-0895-z

Keywords

Chronic traumatic encephalopathy
Traumatic brain injury
Australian football league
Concussion
Repetitive head injury
Dementia
Neurodegeneration
Tau
Public health
Occupational health

中文翻译：

一名前澳大利亚橄榄球运动员被诊断患有阿尔茨海默病，患有慢性创伤性脑病。

致编辑：

2005 年，第一个国家橄榄球联盟球员慢性创伤性脑病 (CTE) 病例报告 [9] 为美式足球中 CTE 的识别打开了大门。目前，其他接触性运动的前运动员也有 CTE 的报道，包括冰球、足球、橄榄球联盟，以及最近在澳大利亚橄榄球联赛中 [2]。迄今为止，重复性头部损伤仍然是发生 CTE 的唯一已知危险因素 [3]。在这里，我们描述了澳大利亚最受欢迎的接触性运动——澳式橄榄球 (ARF) 中的首例 CTE 病例。

死者是一名9岁的男性，19年来参加了350多场ARF一级比赛。 64 岁时，他被诊断出患有阿尔茨海默病 (AD)，并伴随着性格改变、抑郁和愤怒/攻击性问题。在他被推定为 AD 的几年前，他就被诊断出患有 REM 睡眠行为障碍。他的认知问题主要是记忆丧失，这种情况缓慢进展，直到生命的最后 5 年明显加速。在诊断出 AD 几年后，他发现了病因不明的轻度帕金森病特征，可能与低剂量抗精神病药物有关。他还患有并发缺血性心脏病、高胆固醇血症和高血压，所有这些疾病都得到了很好的控制。他不酗酒、不吸烟或服用违禁药物。

表 1 总结了相关的神经病理学。存在轻度至中度的额叶和颞叶萎缩，伴有空泡前脑室扩大（侧脑室和第三脑室），基底血管系统有轻度无并发症的动脉粥样硬化，黑质苍白。磷酸化 Tau 免疫反应性 (pTau) 存在于许多灰质区域。新皮质 pTau 明显集中在神经元和星形胶质细胞的胞体和突起的脑沟深处，不规则地分布在血管周围：这是 CTE 的典型病变[8]（图 1a，b）。 9 个额叶块内存在 12 个 CTE 病灶，4 个颞叶块内存在 4 个病灶。在颞叶和岛叶皮质中，浅层（II-III层）也有密集受累（图1c），由预缠结和缠结pTau以及一些鬼缠结组成。这种 pTau 沉积模式常见于严重的 CTE 中，与 AD 中典型的 pTau 沉积不同（图 1d）。神经元 pTau 由 3R 和 4R 亚型组成，而星形细胞 pTau 主要由 4R 亚型组成。

表 1 神经病理学结果总结

全尺寸桌子

存在海马硬化，伴有一些鬼影缠结、神经胶质增生和严重的 pTau 受累。广泛的神经元和神经炎性 pTau 也存在于杏仁核、下丘脑内侧核、乳头体、基底核、黑质（图 1e）、中缝核和丘中。软膜下和室管膜下 pTau 存在于刺状星形胶质细胞中，与衰老相关 tau 星形胶质细胞病 (ARTAG) 一致，在颞叶最为突出。

磷酸化的TDP-43以神经元细胞质内含物和短神经突的形式存在，并且与严重CTE病理区域共定位（图1f），这是CTE中的常见发现[8]。可见 β-淀粉样蛋白和神经炎斑块，对应于 Thaal 4 期（A3；图 1g），CERAD 评分为 C2。虽然 pTau 病理学属于 CTE 而不是 AD 的典型分布，但评估所有神经原纤维缠结病理学得出的 Braak 分期为 IV (B2)。这相当于中间 AD 神经病理学变化 (A3、B2、C2) [6]。 α-突触核蛋白的免疫组织化学结果呈阴性。

基底节和白质存在严重的动脉硬化。皮质下白质稀疏和神经胶质增生一般为轻度至中度，而前连合和外囊则为严重。轴突 pTau 在上述两个束中为中度，而在其他地方为轻度，并且被视为免疫反应性神经突和轴突静脉曲张。 β-淀粉样蛋白前体蛋白不存在于前连合和外囊中，并且以仅与临终变化一致的模式存在于内囊中。

总而言之，这些发现表明存在严重的（第三阶段）CTE。这是ARF的首例确诊病例。 CTE 与早发性痴呆相关，其神经心理学特征常见于其他运动领域经病理证实的 CTE 病例中。该病例中典型的 CTE 病理伴随着中期 AD 神经病理改变和严重的小血管疾病。

ARF 是澳大利亚最受欢迎的接触运动，拥有超过 150 万玩家，其中女性比例很高（30%）。 ARF的特点是快节奏的身体素质：包括快速奔跑、频繁跳跃和高冲击力着陆。每方有 18 名球员，强力碰撞很常见，并且可能发生在任何方向，无论是在地面还是在空中。因此，毫不奇怪，ARF 具有很高的受伤和脑震荡发生率 [7]，并且该游戏的独特性质使运动员面临多种复杂机制导致头部受伤的风险，这与橄榄球规则不同。关于 ARF 运动员长期神经系统结果的有限证据表明，与其他接触运动的前运动员一样，他们也容易出现运动控制和认知方面的持续缺陷 [4, 10]。

当并发疾病时，没有区分 AD 相关性和 CTE 相关性 pTau 病理的标准。 CTE 与 AD 中 pTau β 螺旋区域构象差异的识别表明，这是两种不同的病理，但目前对 CTE 病例中的所有神经原纤维缠结病理进行评估，以得出 AD 的 Braak 阶段。 pTau 的这种“重复计算”可能会高估 CTE 中同时发生的 AD 的严重程度，尤其是在老年人中，如此处所述。开发针对 CTE-pTau 的构象特异性抗体将极大地有助于区分这两种疾病。

该病例是第二例捐赠给最近成立的澳大利亚运动脑库[1]的 ARF 运动员大脑，也是第一例被诊断患有 CTE 的病例。虽然我们不能根据这个指标病例断言 ARF 中 CTE 的发生率，但在我们忙碌的临床实践中，除了前接触运动员之外，还没有遇到过独特且严重的 pTau 病理学 [2]。它的存在应该成为人们认识和研究 CTE 的行动号召，以及它与重复性头部损伤的明确关联。在评估 CTE 等公共和职业健康问题时，声称缺乏证明的“因果关系”是没有帮助的，而且可以说是无关紧要的。

不适用

广告：: 阿尔茨海默氏病
ARF：: 澳式足球
阿尔塔格：: 衰老相关的 tau 星形胶质细胞病
热膨胀系数：: 慢性创伤性脑病

1.

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2.

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下载参考资料

我们感谢捐赠者及其家人。我们非常感谢 Diana van Beek 和 Karina Hammond 的专家技术援助。我们还感谢皇家珀斯医院 PathWest 神经病理科对澳大利亚运动脑库的协助。

澳大利亚运动脑库的资金由悉尼地方卫生区、北悉尼地方卫生区、脑震荡遗产基金会和 StopConcussions.com 提供。

隶属关系

拉筹伯大学科学、健康与工程学院，邦多拉，维多利亚州，3086，澳大利亚
- 艾伦·皮尔斯
皇家阿尔弗雷德王子医院神经病理科，坎珀当，新南威尔士州，2050，澳大利亚
- 施乔安妮
- , 玛吉·李
- , 安东尼·哈丁
- , 凯瑟琳·苏特
- 和迈克尔·E·巴克兰
悉尼大学大脑与思维中心，坎珀当，新南威尔士州，2006 年，澳大利亚
- 李玛吉
- , 安东尼·哈丁
- , 罗伊娜·莫布斯
- 和迈克尔·E·巴克兰
麦考瑞大学，麦考瑞公园，新南威尔士州，2109，澳大利亚
- 罗伊娜·莫布斯
- 和詹妮弗·巴彻勒

作者

在以下位置搜索艾伦·J·皮尔斯：
- 考研医学•
- 谷歌学术
搜索 Joanne Sy：
- 考研医学•
- 谷歌学术
搜索 Maggie Lee：
- 考研医学•
- 谷歌学术
在以下位置搜索安东尼·哈丁：
- 考研医学•
- 谷歌学术
在以下位置搜索 Rowena Mobbs：
- 考研医学•
- 谷歌学术
在以下位置搜索詹妮弗·巴彻勒：
- 考研医学•
- 谷歌学术
在以下位置搜索 Catherine M. Suter：
- 考研医学•
- 谷歌学术
在以下位置搜索迈克尔·E·巴克兰：
- 考研医学•
- 谷歌学术

贡献

MEB、AH、ML、JS参与病理评估。 RM 和 JB 综合了临床数据。 AJP、CS、MEB 起草了手稿，所有作者均审阅并修改了手稿。

通讯作者

通讯作者：迈克尔·E·巴克兰。

道德批准并同意参与

道德批准由悉尼地方卫生区 HREC 授予，批准号 X19-0010。大脑捐赠的书面知情同意书由高级近亲和遗产执行人提供。

同意发表

已获得死者家属同意发表。

利益争夺

AJP 目前从运动健康检查慈善机构获得部分研究工资资助。 AJP 此前曾获得澳大利亚橄榄球联盟、Impact Technologies Inc. 和三星公司的部分研究资助。其余作者声明他们没有竞争利益。

出版商备注

施普林格·自然对于已出版的地图和机构隶属关系中的管辖权主张保持中立。

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