Introduction
There is growing concern over the association between exposure to traumatic brain injury (TBI) and increased risk of a variety of neuropsychiatric and neurocognitive outcomes, in particular those linked to a specific neurodegenerative pathology known as chronic traumatic encephalopathy (CTE) [
11,
29,
31,
42,
50]. First recognized in the early part of the twentieth century as the punch drunk syndrome of boxers [
24], it was not until descriptions of CTE in autopsy studies of non-boxer athletes that the lifelong consequences of exposure to TBI attracted widespread attention [
27,
36]. Nevertheless, despite this increased attention, there remain comparatively few accounts of the neuropathology of late survival from TBI [
43]. As such, reflecting the relative paucity of cases described, consensus criteria for the neuropathological assessment of CTE remain preliminary [
26] and the associated clinical consequences of this pathology remain unclear [
48,
50].
In his report on the punch drunk syndrome, Harrison Martland provided the first, formal account of the chronic motor and neuropsychiatric consequences of exposure to repetitive mild TBI [
24]. Thereafter, autopsy studies on single cases and small case series described the neuropathology of dementia pugilistica (DP) as an apparently distinctive, perivascular deposition of hyperphosphorylated tau, in the form of neurofibrillary tangles [
3,
4,
11,
12]. In addition, widespread amyloid-β (Aβ) plaques were reported in a majority [
11,
40]. However, although isolated studies in non-boxer individuals exposed to repetitive TBI were reported [
6,
12], to the end of the twentieth century accounts of DP largely were restricted to observations in former boxers.
More recently, the pathology of DP, now termed CTE, has been documented in growing numbers of non-boxer athletes; the overwhelming majority from autopsy studies in former American footballers [
28,
31], in addition to isolated descriptions of former athletes from a wide and growing range of sports [
1,
9,
10,
22,
25,
37,
47], former military personnel [
8,
38] and individuals exposed to a single moderate or severe TBI [
15,
51]. Notably, many of these contemporary studies often describe more limited and localized pathology than historical case series of DP, with perhaps more attention on neuropsychiatric than cognitive symptomatology [
42,
46]. Further, recent reporting largely focuses on tau pathologies in CTE over the constellation of non-tau proteinopathies that develop in late survivors from TBI. Reflecting this, preliminary consensus criteria for the neuropathological identification of CTE define the disease solely on the pattern and distribution of tau [
26]. Finally, many reports often do not consider the clinical consequences of CTE pathology, particularly in patients with dementia where multiple neurodegenerative pathologies may co-exist.
There is, therefore, a continuing need to understand the complex neuropathology of late survival from exposure to TBI and its interaction with wider neurodegenerative pathologies. Herein, we report experience from a single institution on the neuropathological assessment of the largest series to date of former soccer (Association football) and rugby union (hereafter ‘rugby’) players with histories of dementia. Specifically, applying established and preliminary consensus criteria for neuropathological assessment of a range of neurodegenerative diseases, together with detailed review of the clinical histories, we provide insight into the integrated clinicopathological diagnoses of dementia in a cohort of former athletes exposed to repetitive head impacts and mild TBI. Our observations suggest that CTE neuropathologic change (CTE-NC) is present in a high proportion of former soccer and rugby players with dementia. However, considered together, the clinical features and neuropathologies support an integrated clinicopathologic diagnosis of CTE dementia (CTE-D) in only a small proportion of these cases.
Discussion
Herein, we present observations on neurodegenerative pathologies and their relationship to the final integrated, clinicopathological dementia diagnosis in a consecutive series of 11 brain donations from former soccer and rugby union players with dementia. In addition to ubiquitous tau pathologies, our cases invariably showed mixed, often multiple, co-existent neurodegenerative pathologies, including frequent Aβ pathologies as amyloid plaques and cerebral amyloid angiopathy. Further, although the pathognomonic neuropathology of CTE described within preliminary consensus criteria was present in a high proportion of brains in this series, in only three would CTE be regarded as the primary integrated dementia diagnosis following comprehensive review of the clinical histories and neuropathologies. In the remaining five cases with CTE neuropathologic change (CTE-NC), this appeared as co-morbid pathology in the setting of an alternative integrated dementia diagnosis. Thus, in context of dementia arising in athletes exposed to repetitive mild traumatic brain injury, three distinct clinicopathological groupings are suggested by this series defined by the presence of CTE-NC and its relationship to the final integrated dementia diagnosis. These observations support the need for comprehensive neuropathological evaluation and reporting in individuals exposed to TBI, with distinction between the autopsy finding of CTE-NC and the putative clinical consequences of this pathology, including CTE dementia (CTE-D).
Notably, mixed neurodegenerative pathologies were present in nine of our series, even in relatively younger aged patients. Mixed pathologies increasingly are recognized in studies of neurodegenerative disease [
18,
41,
44], with prevalence estimates ranging up to 80% of dementias at autopsy and directly correlated with age [
41]. In contrast to our experience, previous series report mixed neurodegenerative pathologies in just 45% of former athletes [
31]. In this respect, mixed pathologies appear more frequent in our patients than in similar studies in former athletes, perhaps reflecting an older patient cohort. Conceivably, such mixed neurodegenerative pathologies might contribute to clinically ‘atypical’ presentations, leading to challenges in establishing accurate clinical diagnoses. There is undoubtedly a need for continued autopsy brain examination in individuals surviving TBI, with accurate and comprehensive documentation of the full spectrum of pathologies encountered in each examination.
Reporting in CTE largely focuses on p-tau pathologies. Indeed, preliminary consensus criteria define pathognomonic CTE neuropathology solely by the pattern and distribution of p-tau [
26]. While pathognomonic p-tau pathologies were common in our current series, Aβ pathology as plaque and/or CAA was as frequent and present in all but one case with CTE-NC. In contrast, studies on former American footballers with CTE document Aβ pathology in just 61% [
45]. However, incidence of dementia was reported higher in those older American footballers in which there were high burdens of CTE and Aβ. In this context, our data support these observations and might suggest that few post-TBI dementias arise in context of a pure tauopathy (pure CTE-NC), the majority arising in context of mixed proteinopathies, including frequent Aβ pathologies. As such, dementia-associated neurodegenerative pathology in former athletes might be more reminiscent of AD.
Since the first description of CTE in a former American football player [
36], there has been a proliferation in autopsy series reporting its presence in individuals surviving a spectrum of TBI exposures (for review, see Hay et al. [
11]). Nevertheless, the published case experience in CTE remains low [
43], with reports typically documenting CTE pathology, but including little interpretation of its clinical implications. By example, an autopsy series documenting 110 of 111 former National Football League (NFL) American footballers with CTE pathology offered no insights into final integrated clinicopathological diagnoses [
31]. Similarly, no opinion on final, integrated clinicopathological diagnoses after neuropathological evaluation was provided in a study of six former soccer players with dementia, four of whom had CTE neuropathology [
22]. We identified CTE-NC in eight of our 11 former athletes with dementia. However, in just three of these cases was the integrated, primary dementia diagnosis consistent with CTE dementia (CTE-D) after consideration of the comprehensive clinical information. As such, while CTE-NC is a common pathology in former contact sports athletes with dementia, CTE-D appears a less common primary dementia diagnosis.
In this series of former soccer and rugby players with dementia, CTE-NC was present in 73% of cases. Adding this experience to observations in previous, isolated case reports in rugby and soccer, where sought, autopsy confirmed CTE pathology is reported in 75% of former athletes from these sports: 13/18 (seven from this study) soccer [
1,
6,
9,
10,
22,
25] and 5/6 (four from this study) rugby [
25,
45]. Elsewhere, CTE neuropathology has been reported ranging from 50% (7/14) of former boxers [
7] to 99% (110/111) of former NFL footballers examined [
31]. Although such studies are subject to numerous biases and limitations, rendering them uninformative regarding true disease prevalence, the apparent variation in reported prevalence of CTE neuropathology between these autopsy series might suggest between sports’ differences in risk and/or variability in methodologies of specimen accrual and neuropathology assessment between laboratories.
In summary, our observations suggest that while CTE-NC may be a common pathology in former soccer and rugby players with dementia, CTE dementia appears a less common primary dementia diagnosis. Current criteria for AD distinguish neurodegenerative pathologies, defined as AD neuropathologic changes (ADNC) [
13,
33], from the clinical syndrome of dementia of Alzheimer’s disease type [
14]. Reflecting this approach, we propose that there should be a similar distinction between CTE neuropathologic change and the clinical consequences of this pathology, including CTE dementia. As experience grows, CTE-NC conceivably might echo experience in AD, where the neuropathologic change can represent incidental pathology without clinical effect, or the major pathology driving clinical dementia phenotypes, or a co-morbid pathology within mixed neurodegenerative disease. In other words, in the absence of clinical correlation, CTE neuropathologic change should perhaps be regarded as a pattern of pathology, rather than diagnostic of a specific disease.
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