Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology

Abstract

Background: Chronic traumatic encephalopathy (CTE) is the term coined for the neurodegenerative disease often suspected in athletes with histories of repeated concussion and progressive dementia. Histologically, CTE is defined as a tauopathy with a distribution of tau-positive neurofibrillary tangles (NFTs) that is distinct from other tauopathies, and usually shows an absence of beta-amyloid deposits, in contrast to Alzheimer's disease (AD). Although the connection between repeated concussions and CTE-type neurodegeneration has been recently proposed, this causal relationship has not yet been firmly established. Also, the prevalence of CTE among athletes with multiple concussions is unknown.

Methods: We performed a consecutive case series brain autopsy study on six retired professional football players from the Canadian Football League (CFL) with histories of multiple concussions and significant neurological decline.

Results: All participants had progressive neurocognitive decline prior to death; however, only 3 cases had post-mortem neuropathological findings consistent with CTE. The other 3 participants had pathological diagnoses of AD, amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Moreover, the CTE cases showed co-morbid pathology of cancer, vascular disease, and AD.

Discussion: Our case studies highlight that not all athletes with history of repeated concussions and neurological symptomology present neuropathological changes of CTE. These preliminary findings support the need for further research into the link between concussion and CTE as well as the need to expand the research to other possible causes of taupathy in athletes. They point to a critical need for prospective studies with good sampling methods to allow us to understand the relationship between multiple concussions and the development of CTE.

Keywords: chronic traumatic encephalopathy; dementia; neurodegenerative disease; professional athletes; repetitive brain injury.

Figure 1

Gross macroscopic findings on neuropathological examination. Selected examples from each case are presented as three vertical panels with lateral views of the unsectioned brain (upper panel), coronal sections through various parts of the cerebrum (middle panel), and axial sections through the brainstem (lower panel). (A) Case 1: There is mild-to-moderate atrophy with ventricular enlargement and cavum septi pellucidi. Thinning of the corpus callosum and mild depigmentation of the substantia nigra is also evident. (B) Case 2: Unsectioned brain, ventricles, and sections of the midbrain and substantia nigra appear within normal limits with no apparent evidence of neurodegeneration. (C) Case 3: Preferential mild-to-moderate atrophy of frontal and temporal lobes with significant enlargement of ventricles seen on coronal sections. A fenestrated septum pellucidum and atrophied amygdala and hippocampus are also seen on this section. The substantia nigra of this patient shows significant loss of pigmentation. (D) Case 4: There is mild frontal and temporal lobe atrophy with enlarged ventricles and cavum septi pellucidi. Axial sections of the brainstem show normal appearing substantia nigra and a metastatic lesion in the pons. (E) Case 5: Atrophic brain is seen with moderately enlarged ventricles and a normally pigmented substantia nigra. (F) Case 6: Minimal atrophy and ventricular enlargement are seen, and there is mild loss in the substantia nigra.

Figure 2

Selected microscopic findings on neuropathological examination. (A) Case 1: High power view of sample of cerebral cortex stained for hyperphosphorylated-tau shows concentration of neurofibrillary tangles predominantly in the superficial layers of the gray matter and in the depths of sulci, which is characteristic of CTE. (B) Case 2: Magnified motor neuron in ventral horn of spinal cord shows a representative intracytoplasmic TDP-43 inclusion. Inset shows a hyalin inclusion. (C) Case 3: Alpha-synuclein staining showing Lewy bodies and neurites which are seen throughout the cortex, substantia nigra, and locus ceruleus. This patient also had features of CTE (not shown). Inset shows higher power view of cytoplasmic Lewy body. (D) Case 4: Immunohistochemisty showing widespread reactivity against tau-positive neurofibrillary and astrocytic tangles in multiple layers. (E) Case 5: Bielschowsky silver stain showing numerous neurofibrillary tombstones in the hippocampus. (F) Case 6: HandE/LFB and alpha-synuclein staining of representative cortical section showing diffuse Lewy bodies and Lewy neurites. Inset shows Lewy body.