Widespread τ and amyloid-β pathology many years after a single traumatic brain injury in humans

Abstract

While a history of a single traumatic brain injury (TBI) is associated with the later development of syndromes of cognitive impairment such as Alzheimer's disease, the long-term pathology evolving after single TBI is poorly understood. However, a progressive tauopathy, chronic traumatic encephalopathy, is described in selected cohorts with a history of repetitive concussive/mild head injury. Here, post-mortem brains from long-term survivors of just a single TBI (1-47 years survival; n=39) vs. uninjured, age-matched controls (n=47) were examined for neurofibrillary tangles (NFTs) and amyloid-β (Aβ) plaques using immunohistochemistry and thioflavine-S staining. Detailed maps of findings permitted classification of pathology using semiquantitative scoring systems. NFTs were exceptionally rare in young, uninjured controls, yet were abundant and widely distributed in approximately one-third of TBI cases. In addition, Aβ-plaques were found in a greater density following TBI vs. controls. Moreover, thioflavine-S staining revealed that while all plaque-positive control cases displayed predominantly diffuse plaques, 64% of plaque-positive TBI cases displayed predominantly thioflavine-S-positive plaques or a mixed thioflavine-S-positive/diffuse pattern. These data demonstrate that widespread NFT and Aβ plaque pathologies are present in up to a third of patients following survival of a year or more from a single TBI. This suggests that a single TBI induces long-term neuropathological changes akin to those found in neurodegenerative disease.

Figure 1

Representative immunohistochemical and thioflavine‐S staining for neurofibrillary tangles (NFTs). A. NFTs in the parahippocampal gyrus of a 49‐year‐old male 1 year post‐traumatic brain injury (TBI). B. Representative thioflavine‐S‐positive staining in the same case as A. C. NFTs in the fusiform gyrus of a 27‐year‐old male 1.5 years after TBI. D. NFTs in the frontal lobe of a case of advanced Alzheimer's disease (positive control). E, G. Representative images showing prevalent NFTs in the superficial layers of the cortex of the medial temporal lobe. F. Extensive neuropil threads and occasional NFTs in a 53‐year‐old individual who died 8 years following TBI. H, I. Representative images showing isolated clusters of NFTs within the depth of sulci. J. Uninjured control case displaying no neurons positive for tau immunostaining in the hippocampal region CA1. All scale bars approximately 100 µm.

Figure 2

Graphical representation of findings regarding neurofibrillary tangles (NFTs). A. Percentage of cases with NFTs in entire cohort/cohort with those aged >60 excluded: traumatic brain injury (TBI) vs. controls. B. Extent and distribution of NFTs in TBI positive cases vs. controls by pathological group. Group 1 (minimal pathology): NFTs of sparse to moderate density in the transentorhinal cortex with or without small numbers in the CA1 sector of the hippocampus. Group 2 (moderate pathology): as described in Group 1, together with NFTs extending into the fusiform gyrus (lateral to entorhinal cortex) and sparse tangles in the isocortex (cingulate/insular blocks). Group 3 (extensive pathology): NFTs in more widespread sectors of the hippocampus and subiculum and with extensive isocortical involvement.

Figure 3

Representative immunohistochemical and thioflavine‐S staining for amyloid‐beta (Aβ) plaques. A. Plaques in the inferior temporal gyrus of a 55‐year‐old female 47 years post‐ traumatic brain injury. B. Representative thioflavine‐S‐positive staining in the same cases as A. C. Plaques in the frontal lobe of a case of advanced Alzheimer's disease. D. Uninjured control displaying no Aβ immunostaining. All scale bars approximately 50 µm.

Figure 4

Graphical representation of findings regarding amyloid‐beta plaques. A. Age‐adjusted plaque density in plaque‐positive traumatic brain injury (TBI) cases (11 of 39; 28%) vs. controls (13 of 47; 28%). B. Percentage of plaque‐positive cases displaying thioflavine‐S‐positive staining in TBI cases vs. controls.