All 14 retired footballers were male, 13 were professional, and 1 was a committed amateur (Case 4). They were all recognised as skilled headers of the ball, with half of them playing in centre-half or centre-forward positions, where heading of the ball is frequent (Table 2). They all began playing football regularly in their childhood or early teens for an average of 26 years. Concussion was only reported in six footballers, limited to a single episode in each during their careers. Two participants also boxed as amateurs, one of whom served in the military, but none reported any episodes of concussion during these activities.

Table 2 Summary of demographic and clinical data of 14 retired footballers with dementia (Cases 1–14) Full size table

All cases developed a progressive dementing illness in later life; ten of whom had coexisting motor impairments, including parkinsonism (N = 7), gait difficulties or postural instability with frequent falls (N = 6), and dysarthria (N = 3). Behavioural and mood changes were common features (N = 12). The average age at symptom onset was 63.6 years, and disease duration was 10 years. Twelve cases died from advanced neurodegenerative disease. Cases 5 and 10 died of myocardial infarction and ischaemic stroke, respectively. Substance or alcohol abuse and suicidal ideation were not reported in any cases. Twelve of the 14 cases had at least one CT or MR imaging of the brain following the onset of their neurological symptoms, and cortical atrophy was a consistent finding. Of the two earliest cases referred in the early 1980s, one had a normal air encephalogram and the other did not undergo neuroimaging. Cavum septi pellucidi was reported in one case (Case 11) on CT imaging of the brain performed 1 year after symptom onset, aged 68.

Neuropathological findings were available in six cases. While the mean age at symptom onset, age at death, and duration of football career did not differ between the post-mortem (Cases 1–6) and clinical (Cases 7–14) groups, the mean disease duration of the clinical group was relatively longer (11.8 years vs. 7.7 years, P = 0.01). Macroscopic brain examination revealed fenestration of the septum in all six cases and cavum septi pellucidi in one case (Case 1). Histological examination identified the pathognomonic features of CTE in four cases, fulfilling the mandatory diagnostic criteria of CTE [30], with Cases 2, 5, and 6 showing advanced CTE pathologies [32] (Fig. 2). Nevertheless, all six cases demonstrated some features supportive of CTE, including characteristic tau pathologies, dilatation of third ventricle, and septal abnormalities.

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) Full size image

All six cases had TDP-43 pathology with sparse to moderate TDP-43-positive dystrophic neurites and neuronal cytoplasmic inclusions (NCIs, Fig. 3). Occasional neuronal intranuclear inclusions (NIIs) were observed in Case 3. In Cases 2 and 3, TDP-43 pathology was restricted to the limbic regions, including the amygdala, entorhinal cortex, subiculum, and dentate gyrus, corresponding to Stage 3 of the staging scheme described for TDP-43 distribution in AD [18]. In the other four cases (Cases 1, 4, 5, and 6), TDP-43 pathology was more extensively distributed, involving regions, such as the striatum, substantia nigra, and cerebral cortices, corresponding to Stage 6 [18]. Features suggestive of diffuse axonal injury, such as axonal swellings (assessed by SMI31 immunohistochemistry), microglial nodules, or changes indicative of Wallerian degeneration (assessed by Iba-1 immunohistochemistry) were not observed in any of the six post-mortem cases [17].

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) Full size image

Table 3 summarises the characteristic neuropathological findings in the six cases applying the NIND diagnostic criteria for CTE [30].

Table 3 Characteristic neuropathological features observed in the six footballers according to the preliminary NINDS criteria for the diagnosis of CTE [30] Full size table

All cases had concomitant AD pathology (Fig. 3; Table 4) and some features of ARTAG (Table 3), which are currently not regarded as supportive of the diagnosis of CTE [30]. Histological features of CTE can be distinguished from coexisting AD pathology by patchy involvement of the superficial cortical layers, focal NFTs, and neuronal and astrocytic tau pathology adjacent to penetrating blood vessels with predilection of the depths of cortical sulci [4, 18, 30]. These specific histological features of CTE contrast with the uniform distribution of AD-tau pathology (neurofibrillary tangles) predominant in the deep cortical layers (Fig. 3e). Nevertheless, confluent tau pathology with high burden of AD-related changes in some cases can preclude the definitive diagnosis of CTE, as observed in Case 4 of the present series (Tables 3, 4). Cerebral amyloid angiopathy (CAA) and hippocampal sclerosis were observed in five and two cases, respectively. Argyrophilic grains were absent in the hippocampus and amygdala of all cases. Other concomitant diagnoses were CBD (Case 1) and LBD (Case 4). Case 3 had mild hyaline arteriosclerosis in the parietal and occipital cortices and basal ganglia. Case 6 had a small focal ischaemic infarct in the cingulate white matter and mild small vessel disease in the striatum.

Table 4 Neuropathological features of the six footballers included in this study Full size table

Table 4 summarises the main neuropathological diagnoses of these cases.

Case summaries

Case 1

This man was a centre-forward. At 56, he became anxious and depressed. He gradually slowed up, his speech became slurred, and he was unsteady on his feet resulting in falls. Examination revealed rigidity and bradykinesia. At 60, he developed progressive non-fluent aphasia. He was irritable and aggressive. The clinical picture was a combination of FTD with parkinsonism.

The brain was mildly atrophic with dilatation of the fourth ventricle, cavum septi pellucidi with septal fenestration.

Histological examination of the neocortex showed superficial spongiosis and occasional swollen neurons. Tau immunohistochemistry revealed a combination of pre-tangles, neurofibrillary tangles (NFTs), threads, and astrocytic plaques, involving the neocortices, deep grey nuclei, hippocampal formation, brainstem, and the cerebellum, with threads and coiled bodies in the subcortical white matter, indicative of a diagnosis of CBD [11]. There was severe loss of pigmented neurons and gliosis in the substantia nigra.

The distribution of neuritic and Aβ-positive plaques and NFTs corresponded to ‘intermediate’ AD neuropathological changes (A3B2C2).

The superficial cortical layers displayed a high burden of neuronal and glial inclusions, positive for both 3-repeat and 4-repeat tau immunohistochemistry, supporting CTE-related pathology. Foci of perivascular astrocytic tangles (ATs) and NFTs in the sulcal depths of the frontal and parietal cortices were consistent with CTE [30]. There were occasional ghost tangles in CA1 and CA2.

Case 2

This man turned professional in his teens. He reported a head-to-head collision with loss of consciousness and skull fracture in a football match.

At 69, he had progressive episodic memory impairment and became eccentric. His MMSE score was 22/30 at age 71 and 17/30 at age 74. Past history included transient ischaemic attacks and hypertension. He developed impulsivity, grandiose ideation, and explosive rage attacks. In his last year, aged 78 with advanced dementia, a malignant abdominal mass was identified.

Examination of the brain showed moderate atrophy of the temporal lobes and hippocampi and fenestration of the septum pellucidum, with no evidence of metastatic tumour. Pigmentation in the substantia nigra was preserved.

The findings of multiple foci of tau-positive ATs and NFTs with more intense in the sulcal depths of the frontal and temporal cortices with a perivascular distribution were diagnostic of CTE [30]. In addition, there was widespread tau pathology supportive of CTE with neuronal and glial inclusions in the superficial cortical layers. CTE-tau pathology was widespread throughout the limbic structures, subcortical nuclei, and brainstem, in association with other supportive features (Table 3).

Neuritic and Aβ plaques were present in the neocortices, hippocampus, and striatum, corresponding to ‘intermediate’ AD neuropathological changes (A2B2C2). There was hippocampal sclerosis. Ghost tangles were observed in CA1, 3, and 4.

Case 3

This man played centre-half for over 20 years and was also an amateur cricketer. He reported a head-to-head collision with loss of consciousness during a football match.

At 66, he developed progressive episodic memory impairment, disorientation and became irritable and aggressive; gradually, he progressed to advanced dementia with occasional seizures. He died aged 74. Past history included hypertension and ischaemic heart disease.

Examination of the brain revealed mild focal atrophy of the cerebral cortex and hippocampi, marked dilatation of the third and lateral ventricles, and fenestration of the septum pellucidum. Tau immunohistochemistry demonstrated NFTs and threads in the deep cortical layers, hippocampal formation, amygdala, mammillary body and striatum, widespread neritic and Aβ mature, and diffuse plaques in the neocortices and hippocampus, consistent with ‘intermediate’ AD neuropathological change (A3B2C3). There was severe CAA in the neocortices, gliosis in the hippocampus (CA1, 4), and mild loss of pigmented neurons in the substantia nigra.

Case 4

This man was a dedicated amateur footballer and played either centre-half or centre-forward every season from the age of 10 for more than 20 years. He had one mid-air collision in a match which rendered him unconscious. He also boxed as an amateur but did not report any knockout or post-concussion symptoms.

He had a 5-year history of memory loss, irritability, aggressive behaviour, and visual hallucination which rapidly progressed to advanced dementia with parkinsonism, gait difficulties, and dysphagia. He died aged 60.

The brain was moderately atrophic especially in the medial temporal lobe and hippocampi. The septum pellucidum was fenestrated.

Tau immunohistochemistry revealed frequent NFTs and neuritic plaques with predilection for the deep cortical laminae. The extensive distribution of Aβ plaques and NFTs corresponded to a diagnosis of ‘high’ AD neuropathological change (A3B3C3).

Frequent α-synuclein immunoreactive Lewy bodies were observed in the cortices, cingulate gyrus, hippocampus, substantia nigra, and locus coeruleus with severe loss of pigmented neurons in the substantia nigra and locus coeruleus, compatible with advanced LBD (Braak stage 6 [7] and ‘diffuse neocortical’ category [33]).

Case 5

This man had a professional football career that spanned two decades. He reported one episode of head collision in a match which resulted in fractured jaw but no loss of consciousness.

At 63, he developed progressive memory loss, anomia, aggressive behaviour, and impulsivity. In his last year of life, he developed dysarthria and had moderately advanced dementia. He died at 72 of myocardial infarction.

The brain was moderately atrophic, predominantly affecting the medial temporal lobe and hippocampi, with dilatation of the lateral ventricles and fenestration of the septum pellucidum.

Tau immunohistochemistry showed foci of ATs, NFTs, and threads in the sulcal depths in the frontal and temporal cortices with a clear perivascular predilection, consistent with the diagnosis of CTE [30]. The predilection of tau aggregates in the superficial cortical layers and other supportive features of CTE were observed (Table 3) [32].

Neuritic and Aβ plaques were observed in the neocortices. The distribution of AD-related pathologies corresponded to ‘intermediate’ AD neuropathological change (A2B2C2). There was hippocampal sclerosis, frequent ghost tangles in CA1 and mild loss of pigmented neurons in the substantia nigra.

Case 6

This man reported one head-to-player collision with loss of consciousness while playing at an English football league match.

He had a 6-year history of memory impairment, intermittent disorientation, disinhibition, and aggressive behaviour, which progressed to dementia. Examination revealed hypomimia, hand tremor, limb rigidity, and bradykinesia. He died at 83.

Examination of the brain showed mild focal atrophy of the frontal and medial temporal lobes and hippocampi, dilatation of the lateral and third ventricles, and fenestration of the septum pellucidum. There was a small focal ischaemic infarct in the white matter underlying the cingulate cortex.

The widespread tau pathologies were consistent with a diagnosis of advanced CTE [32], which included tau-positive neuronal and astrocytic lesions with predilection for the sulcal depths of the temporal cortex in a perivascular distribution and other supportive features (Table 3) [30].

There were neuritic and Aβ plaques in the neocortices and hippocampus. The distribution of Aβ plaques and NFTs corresponded to a diagnosis of ‘intermediate’ AD neuropathological change (A3B2C2). Mild nigral cell loss was observed. There was mild small vessel disease in the striatum.