Search terms and databases

Keywords were selected by agreement of all authors and then submitted to a librarian with expertise in systematic reviews who developed a draft MEDLINE search strategy. This was reviewed by a second expert health sciences librarian using the CADTH Peer Review Checklist for Search Strategies according to the PRESS 2015 Guideline Statement. The draft search strategy was revised based on suggestions from the PRESS review, and then tested to be sure known key studies were retrieved. The MEDLINE search (see online supplementary table 1) was adapted and translated for all other databases. The following 10 databases were searched: MEDLINE (Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R)), CINAHL Plus with Fulltext, EMBASE, PsycInfo, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, PsycARTICLES and SPORTDiscus. The search was limited to English-language and peer-reviewed publications, but had no date restriction. The search was conducted 10–11 September 2016.

Study selection criteria and data extraction

Studies were included if they (i) were original research; (ii) evaluated the incidence/prevalence, risk factors or causation related to neurodegenerative disease; (iii) included individuals who have suffered a sport-related concussion; (iv) evaluated athletes and/or retired athletes as the study subjects and (v) evaluated possible long-term sequelae defined as >10 years after sports-related injury. Studies were excluded from this review if they were published in a language other than English, animal studies, review articles, case reports, book chapters, conference abstracts, editorials/commentaries/expert opinion, theses or dissertations.

Citations were independently screened by pairs of authors. A third reviewer adjudicated disagreements between authors. Following the initial abstract and title screening process, full-text articles were retrieved and data were extracted using a standardised method. Results were extracted by one author and reviewed by a second author to ensure accuracy and completeness.

Subconcussive head impacts

Interest has been expressed in the concept of ‘subconcussive blows’ (ie, subconcussive head impacts) as an indicator of repetitive neurotrauma. Subconcussive impacts are typically defined as involving the transfer of mechanical energy to the brain at enough force to injure axonal or neuronal integrity, but not be expressed in clinical symptoms.^{14 15} These impacts have been proposed as a separate variable from concussion history by some researchers. We reviewed five subconcussive impact studies that (i) defined the concept or (ii) quantified the criteria (ie, years of exposure, estimated number of impacts). These studies are discussed, in part, in the sections below. They either discussed the concept of subconcussive impacts or added the estimated number of subconcussive impacts to the athletes’ concussion history.¹⁶ The majority of subjects were American football athletes or soccer players. Most studies identified significant group-level differences between ‘high exposure’ and ‘low/no exposure’ athletes,^{10 17 18} although there were some studies that did not support the notion that repetitive subconcussive impacts have a measurable, detrimental effect.^{19 20} Some studies have drawn inferences about subconcussive impacts based solely on a person’s participation in certain contact or collision sports. For example, Meehan and colleagues²⁰ surveyed >3702 college alumni between the ages of 40 and 70, 2121 of whom had no reported history of concussion. In those with no reported concussions (a proxy for studying subconcussive impacts), there were no differences in anxiety, depression, emotional dyscontrol, sleep disturbance or perceived cognitive functioning in those who participated in collision sports versus those who did not. There was greater use of alcohol in former collision sport athletes.

Neuroimaging

We reviewed 14 neuroimaging articles relating to the possible long-term sequelae of sports-related concussion. These included structural imaging, diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS) and positron emission tomography (PET). The majority of subjects were American football athletes and soccer players. Most studies identified significant group-level differences in these imaging modalities; however, lack of standardisation in imaging acquisition and analysis limits the generalisability of the findings. The average methodological quality rating using the Downs and Black criteria for these publications was 7.4, and the average level of evidence was 4.0.

Cognitive functioning and mental health

We reviewed 24 articles relating to possible long-term cognitive and mental health problems associated with concussion. The average methodological quality rating using the Downs and Black criteria for these publications was 9.7, and the average level of evidence was 3.8. Some of these studies are cross-sectional surveys.^{7 20 29–31} Some in-person clinical assessment studies have been conducted with^{8 10 17 18 21–24 26–28 32 33} and without^{7 19 34–37} neuroimaging. There are also studies that begin with a survey and then have a follow-up in-person assessment.³⁸ A number of cross-sectional studies have identified decrements on objective neuropsychological testing^{7 8 24 37} and subjectively experienced cognitive difficulties on self-report measures^{6 20} in former athletes. Some studies report a frequency–response relationship, with greater cognitive impairments in those with greater levels of exposure to head impacts or concussions.^{16 36} However, other studies have not found a frequency–response relationship when examining cognitive function.^{8 31 33} Guskiewicz and colleagures surveyed 2552 retired NFL players and found that 1.3% (n=33) reported a physician diagnosis of Alzheimer’s disease. Of the 758 who were aged ≥50, 2.9% (n=22) reported a physician diagnosis of mild cognitive impairment. Of the 641 former players who had a spouse or close relative complete a questionnaire, 12.0% (n=77) were identified as having significant memory problems. Former players with 3+ concussions during their playing career had a fivefold greater risk of mild cognitive impairment (MCI) diagnosis after age 50 compared with those with no prior concussions.⁶ Randolph and colleagues surveyed 513 retired NFL players aged ≥50 for whom their wives completed a questionnaire regarding memory. In this sample, 35.1% had a score on a scale completed by their spouses (AD8) that was suggestive of possible cognitive impairment.⁷ This is much higher than the 12.0% rate reported in the previous study,⁶ for unclear reasons. The rate of clinical diagnoses of MCI (vs survey screening) is unknown.

Regarding mental health, depression has been most frequently studied. Five studies report a frequency–response relationship between concussions or head impact exposure and depression symptom reporting.^{16 30 35 39 40} Didehbani and colleagues studied cognitively intact former NFL athletes and found greater depression symptoms compared with age and intelligence quotient (IQ)-matched subjects.³⁵ In a sample of 797 former collegiate athletes (all sports), approximately 39% of whom reported one or more prior concussions, their rates of self-reported mental health and cognitive problems were as follows: depression=10.4%, anxiety=16.2%, alcohol dependence=5.8%, substance use=2.9% and cognitive problems=3.8%.³⁰ This sample also completed the Patient Health Questionnaire-9 (PHQ-9) to screen for depression. The rate of screening positively for depression (ie, PHQ-9≥10) stratified by concussion history was as follows: 0=2.8%, 1=5.6%, 2=10.4% and 3+=8.9%.³¹ The rate of self-reported depression in retired NFL players (n=1044), stratified by concussion history, was as follows: 0=3.0%, 1–2=8.2%, 3–4=13.7%, 5–9=19.3% and 10+=26.8%.²⁹

The link between soccer heading, cognitive functioning and psychological health is unclear. No association between cognitive function and length of career or position played was found in older (mean age=67 years) retired professional soccer players.¹⁹ Similarly, former professional soccer players who still play recreationally were found to have largely similar performance on a variety of cognitive assessments compared with matched non-contact sport athlete controls.¹⁸ In this study, however, the soccer players had a greater decrease in cortical thickness with age—and cortical thickness in parietal and occipital areas of the brain were negatively correlated with lifetime estimates of heading.

Five long-term effects cohort studies using medical record linkage or death certificates^41–45 have been published, one after the cut-off date for this systematic review.⁴⁵ The results of these studies are summarised in online supplementary table 1. Three studies of causes of death in former NFL players have been published.^41–43 Two of these studies examined the death certificates of those who died between 1960 and 2007 (334 deaths from a cohort of 3439 former players). All cause and specific mortality rates (eg, cancer, cardiovascular disease, pulmonary disease and other health problems) were lower in former players than in men from the general population.^{42 43} Baron and colleagues reported that the rates of psychiatric illness and suicide were significantly lower in the former athletes than in men from the general population.⁴² They also reported that diseases of the nervous system and sense organs were somewhat higher than men in the general population, but the difference was not statistically significant. Of the 334 former players who had died, 12 (3.6%) had one of these latter diseases listed on his death certificate when it would have been expected, from population estimates, that the number should be 9.7 people (ie, 2.9%). There was no autopsy confirmation of the diseases listed on the death certificate and no analysis of genetic susceptibility (eg, apolipoprotein E). In a reanalysis of the same data set, Lehman and colleagues⁴³ reported that the rates of Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) were higher in former NFL football players compared with men in the general population. Of the 334 death certificates reviewed, the number of times neurodegenerative diseases were listed as an underlying or contributing cause of death was as follows: Alzheimer’s disease/dementia=7 (2.1%), Parkinson’s disease=3 (0.9%) and ALS=7 (2.1%). In two medical record linkage studies of former high school football players,^{44 45} the rates of dementia, mild cognitive impairment and parkinsonism did not differ in comparison to control subjects (see table 2).

Neuropathology

Autopsy studies have revealed multiple forms of neuropathology, both macroscopic and microscopic, in former contact and collision sport athletes. Macroscopic findings include (i) frontal and temporal atrophy, thinning of the hypothalamic floor, shrinkage of the mammillary bodies, pallor of the substantia nigra, hippocampal sclerosis and reduction in brain mass; (ii) enlarged ventricles and (iii) CSP with or without septal fenestrations.^46–48 Microscopic features include (i) localised neuronal and glial accumulations of p-tau with varying microscopic morphologies, involving perivascular areas of the cerebral cortex and sulcal depths, and with a preference for neurons within superficial cortical laminae; (ii) multifocal axonal varicosities involving deep cortex and subcortical white matter; (iii) variable and often absent Aβ deposits and (iv) TDP-43-positive inclusions and neurites.^46–48

We reviewed nine neuropathology studies that included five or more subjects. These reports focused on the pathology associated with CTE. The average methodological quality rating using the Downs and Black criteria for these publications was 5.2, and the average level of evidence was 4.2. In 2010, McKee et al described the neuropathology of 12 former athletes (7 football players, 3 boxers and 1 hockey player) whose brains and spinal cords had been donated to the Center for the Study of Traumatic Encephalopathy at Boston University School of Medicine.⁴⁹ Subjects ranged in age from 42 to 85 years (average age 65) and all had a history of cognitive and behavioural changes associated with CTE. Three of the athletes also had signs and symptoms of motor neuron disease (MND). P-tau immunoreactivity in neurons and astroglia in the depth of sulci was noted in all subjects. Seven of the nine cases without MND also had TDP-43 immunoreactive inclusions.

In 2011, Omalu et al reported autopsy findings in 17 athletes (14 professional, 3 high school).⁵⁰ Selected brain samples or whole-brain specimens were examined by routine histopathology, special stains and immunohistochemistry. CTE pathology was based on the presence of topographically distributed neurofibrillary tangles and neuritic threads, with or without amyloid plaques, and the absence of features indicative of another tauopathy. The authors found CTE changes in 10 of the 14 professional athletes and 1 of 3 high school athletes (71% overall). The authors noted four histological phenotypes, based on relative abundance of p-tau in cerebral cortex, subcortical structures and brainstem, and presence or absence of diffuse β-amyloid plaques.

In 2013, McKee et al described the neuropathology in 85 subjects with a history of mild TBI, 64 of which were former athletes.¹¹ The brains of 18 cognitively intact controls with no history of repetitive mild TBI were also examined. The diagnosis of CTE was based on p-tau immunoreactivity around small blood vessels at the depths of cortical sulci, clusters of p-tau-positive subpial and periventricular astrocytes, and neurofibrillary tangles in the superficial layers of the cerebral cortex—this pathology was identified in 80% of the cases and none of the control subjects. Other abnormalities included TDP-43 immunoreactivity (85% of cases) and comorbid neurodegenerative disease including MND (12%), Parkinson’s or Lewy body disease (16%), Alzheimer’s disease (11%) and frontotemporal lobar degeneration (6%). A neuropathological staging system for CTE (stages I–IV) was also proposed.

In 2013, Hazrati described a series of six retired professional Canadian football players whose ages ranged from 61 to 87 years.⁵¹ The subjects had a history of multiple concussions and medically or family member documented cognitive, behavioural and/or motor symptoms. Three of the six subjects had neuropathological findings consistent with CTE. The other three subjects were diagnosed with Alzheimer’s disease, Parkinson’s disease and MND. In addition, the CTE cases showed comorbid pathology of Alzheimer’s disease, vascular disease and cancer.

Bieniek and colleagues studied a range of neurodegenerative disease cases along with a small number of normal controls.⁵² Review of available medical records from 1721 men identified 66 cases with a history of contacts sports. The authors found that 21 of the 66 cases (32%) had cortical p-tau staining consistent with CTE. None of the 162 control brains, and none of the 33 cases with a history of a single TBI, had CTE pathology. This study was conducted using a neurodegenerative disease brain bank, so there were comorbid neurodegenerative conditions (Alzheimer’s disease, Lewy body disease, frontotemporal lobar degeneration) in 20 of the 21 cases with CTE.

Ling and colleagues⁵³ conducted a large-scale postmortem study of CTE in the UK using the McKee et al¹¹ criteria. They screened 268 cases and found histological evidence of CTE in 32 (11.9%), including cases of women with this pathology. The mean age at death was 81 years. The majority of the positive cases met neuropathological criteria for other neurodegenerative diseases and had prior exposure to at least one TBI.

Until 2015, there was no consensus regarding the neuropathological criteria for the diagnosis of CTE. The National Institutes of Neurological Disease and Stroke and National Institute of Biomedical Imaging and Bioengineering (NINDS/NIBIB) funded a panel of neuropathologists to establish criteria. The consensus panel defined the pathognomonic lesion of CTE as an accumulation of p-tau in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern.⁵⁴ In addition to p-tau-related supportive criteria, TDP-43 immunoreactive inclusions and macroscopic features (ventricular enlargement and CSP) were identified as supportive of CTE.

Koga et al⁵⁵ examined 139 cases of multiple system atrophy (MSA) using NINDS/NIBIB CTE criteria. CTE pathology was found in 8 (6%) of the 139 MSA cases, all of which were male, and 4 with a history of contact sports. The authors also noted that 7.2% were identified as having ageing-related tau astrogliopathy (ARTAG), a pathology that should be differentiated from CTE pathology. The authors speculated that falls secondary to the movement disorder may cause CTE pathology.

Subconcussive impacts

A small number of studies examined the possible long-term effects of subconcussive head impacts. There are significant methodological challenges associated with the study of subconcussive impacts.¹⁵ The challenge researchers face at this time is that (i) there is no established definition of a subconcussive impact or a subconcussive injury, (ii) a impact may or may not cause an injury, and it is difficult to determine if an injury has occurred, and (iii) the biomechanical features and thresholds for quantifying a impact and identifying an injury have not been agreed upon. Therefore, the hypothesis that subconcussive impacts cause long-term neurological injury requires more research before conclusions can be drawn.

Neuroimaging

Imaging studies have been conducted mostly with former American professional football players,^{8 21–24 27 28 32 33} but also with former soccer players^{10 18 21} and boxers.²⁶ Imaging studies of retired professional football players reveal structural changes in the brain such as cortical thinning^{18 23} and CSP,^{21 22 62} functional changes in brain metabolism,³² as measured by functional MRI, microstructural differences in white matter,^{8 9} as measured by DTI, and accumulations of tau on PET imaging²⁸ in some former athletes. The literature to date has significant methodological limitations that lower the overall level of evidence and temper confidence in conclusions that can be drawn. The imaging literature includes studies that likely are not representative of the broader population of former athletes. In reviewing the methodology and results of some imaging studies, it is sometimes unclear the extent to which positive findings were based on a priori hypotheses, exploratory post hoc analyses or both. A significant methodological weaknesses in the literature is lack of replication. Although positive findings have been reported in studies within an imaging modality, such as DTI or MRS, the specific findings within those studies differ.

Clinical studies

In total, 18 of the 24 studies relating to possible cognitive and mental health problems associated with exposure to collision sports and concussions have been published in the past five years, reflecting the interest in this topic and rapid growth of the knowledge base. These cross-sectional clinical studies and survey studies reveal that some of the former athletes have cognitive deficits or decrements^{6 7 36 37} and psychological health problems.^{16 29 35} Survey studies have revealed that a substantial minority of former NFL players have mental health problems,^63–65 and current depression is more likely in those with a history of concussions.²⁹ It is also important to appreciate that chronic pain and opioid use is relatively common in former NFL players,⁶⁶ and those with depression and chronic pain also have greater life stress and financial difficulties.⁶⁴ There are at least three unanswered questions relating to these studies. First, the contribution of repetitive subconcussive head impacts to these clinical features is poorly characterised and understood. Second, a frequency–response relationship between concussions, head impact exposures and the severity of future clinical symptoms is unknown. Finally, modifying factors for the development of clinical symptoms and problems in association with repetitive neurotrauma are largely unknown.

Neuropathology

Nine neuropathology studies were included in this review, seven of which were published between 2010 and 2016. Autopsy studies have revealed diverse forms of macroscopic and microscopic neuropathology in former athletes.^{11 48 50 51} Prior to 2015, there were no agreed upon neuropathological criteria for identifying CTE. The new consensus criteria provide a preliminary standardised approach to describe the neuropathology of CTE.⁵⁴ The new consensus criteria differ from the criteria for CTE used in past studies, particularly by excluding tau pathology that is associated with ageing: primary age-related tauopathy⁶⁷ and ARTAG.⁶⁸ Importantly, tau pathology and the accumulation of other altered proteins such as Aβ, α-synuclein and TDP-43-positive immunoreactivity occurs with human ageing and several neurodegenerative diseases, and can also be found in people who are cognitively normal⁶⁹; thus, it would be incorrect to assume that all such pathology is unique to, or caused by, CTE. To date, a cause and effect relationship between CTE and concussions or exposure to contact sports has not been established. More research on CTE is needed to better understand the incidence and prevalence of CTE pathology, the extent to which the neuropathological findings cause specific clinical symptoms, the extent to which the neuropathology is progressive, the clinical diagnostic criteria and other risk or protective factors. Well-designed case–control and cohort studies can begin to answer these important questions. Longitudinal studies are needed.