Unusual combinations of neurodegenerative pathologies with chronic traumatic encephalopathy (CTE) complicates clinical prediction of CTE

Abstract

Background and purpose: Chronic traumatic encephalopathy (CTE) has gained widespread attention due to its association with multiple concussions and contact sports. However, CTE remains a postmortem diagnosis, and the link between clinical symptoms and CTE pathology is poorly understood. This study aimed to investigate the presence of copathologies and their impact on symptoms in former contact sports athletes.

Methods: This was a retrospective case series design of 12 consecutive cases of former contact sports athletes referred for autopsy. Analyses are descriptive and include clinical history as well as the pathological findings of the autopsied brains.

Results: All participants had a history of multiple concussions, and all but one had documented progressive cognitive, psychiatric, and/or motor symptoms. The results showed that 11 of the 12 participants had evidence of CTE in the brain, but also other copathologies, including different combinations of tauopathies, and other rare entities.

Conclusions: The heterogeneity of symptoms after repetitive head injuries and the diverse pathological combinations accompanying CTE complicate the prediction of CTE in clinical practice. It is prudent to consider the possibility of multiple copathologies when clinically assessing patients with repetitive head injuries, especially as they age, and attributing neurological or cognitive symptoms solely to presumptive CTE in elderly patients should be discouraged.

Keywords: CTE; chronic traumatic encephalopathy; concussion; mixed pathology; tau.

FIGURE 1

Overview of the clinical symptoms, detailing the presenting symptoms and the severity of symptoms across different domains. STM, short‐term memory.

FIGURE 2

Overview of the neuropathological diagnosis in this cohort. AD, Alzheimer disease; AGD, argyrophilic grain disease; CAA, cerebral amyloid angiopathy; CBD, corticobasal degeneration; CTE, chronic traumatic encephalopathy; FTLD‐TDP, Frontotemporal lobar degeneration‐TAR DNA‐binding protein; GGT, globular glial tauopathy; LATE‐NC, limbic age‐related TDP‐43 encephalopathy neuropathological change; LBD, Lewy body disease; MND, motor neuron disease; NIHIBD, neuronal intranuclear hyaline inclusion body disease; Nr, number; PART, primary age‐related tauopathy; PSP, progressive supranuclear palsy.

FIGURE 3

Representative hyperphosphorylated tau (p‐tau) neuropathological changes detected in the frontal cortex in the examined cases. Immunostaining for the AT8 antibody. Case 1 (a), 2 (b), 3 (c), 4 (d), 5 (e), 6 (f), 7 (g), 8 (h), 9 (i), 10 (j), 11 (k), and 12 (l). Except for (a), which demonstrates tufted astrocytes, neuronal p‐tau deposits and occasional oligodendrocytic inclusions in the frontal cortex, (b) through (l) demonstrate various degrees of patchy p‐tau pathology in the depth of the cortical sulci accumulating around vessels and involving nerve cells and astrocytes. In Case 6 (f), the depth of the sulci p‐tau pathology was characterized by perivascular neurofibrillary tangles only. *Areas that are enlarged in (a) through (l). Bar in the right lower corner of image (a) represents 100 μm for (b) through (e) and (j) through (l), 200 μm for (a) and (f), and 40 μm for (a) through (l). Arrow in (f) points to the depth of the sulcus.