Dataset Information

Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study.

ABSTRACT: Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition associated with repetitive traumatic brain injury (rTBI) seen in contact-sport athletes and military personnel. The medial temporal lobe (MTL; i.e., hippocampus, subiculum, and entorhinal and perirhinal cortices) memory circuit displays tau lesions during the pathological progression of CTE. We examined MTL tissue obtained from 40 male Caucasian and African American athletes who received a postmortem CTE neuropathological diagnosis defined as stage II, III, or IV. Sections were immunolabeled using an early (AT8) or a late (TauC3) marker for pathological tau and for amyloid beta (A?) species (6E10, A?1-42 and thioflavin S). Stereological analysis revealed that stage III had significantly less AT8-positive neurons and dystrophic neurites than stage IV in all MTL regions except hippocampal subfield CA3, whereas significantly more AT8-positive neurons, dystrophic neurites, and neurite clusters were found in the perirhinal cortex, entorhinal cortex, hippocampal CA1, and subiculum of CTE stage III compared with stage II. TauC3-positive pathology was significantly higher in the perirhinal and subicular cortex of stage IV compared to stage III and the perirhinal cortex of stage III compared to stage II. AT8-positive neurite clusters were observed in stages III and IV, but virtually absent in stage II. When observed, A? pathology appeared as amyloid precursor protein (APP)/A? (6E10)-positive diffuse plaques independent of region. Thioflavine S labeling, did not reveal evidence for fibril or neuritic pathology associated with plaques, confirming a diffuse, non-cored plaque phenotype in CTE. Total number of AT8-positive profiles correlated with age at death, age at symptom onset, and time from retirement to death. There was no association between AT8-positive tau pathology and age sport began, years played, or retirement age, and no difference between CTE stage and the highest level of sport played. In summary, our findings demonstrate different tau profiles in the MTL across CTE stages, proffering CA3 tau pathology and MTL dystrophic neurite clusters as possible markers for the transition between early (II) and late (III/IV) stages, while highlighting CTE as a progressive noncommunicative tauopathy.

SUBMITTER: Kelley CM

PROVIDER: S-EPMC6909582 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study.

Kelley Christy M CM Perez Sylvia E SE Mufson Elliott J EJ

Acta neuropathologica communications 20191212 1

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition associated with repetitive traumatic brain injury (rTBI) seen in contact-sport athletes and military personnel. The medial temporal lobe (MTL; i.e., hippocampus, subiculum, and entorhinal and perirhinal cortices) memory circuit displays tau lesions during the pathological progression of CTE. We examined MTL tissue obtained from 40 male Caucasian and African American athletes who received a postmortem CTE neuropat ...[more]

PMID: 31831066

Similar Datasets

Project description:Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive traumatic brain injury (TBI) and characterized by deposition of hyperphosphorylated tau at the depths of sulci. We sought to determine the presence of CTE pathology in a brain bank for neurodegenerative disorders for individuals with and without a history of contact sports participation. Available medical records of 1721 men were reviewed for evidence of past history of injury or participation in contact sports. Subsequently, cerebral cortical samples were processed for tau immunohistochemistry in cases with a documented history of sports exposure as well as age- and disease-matched men and women without such exposure. For cases with available frozen tissue, genetic analysis was performed for variants in APOE, MAPT, and TMEM106B. Immunohistochemistry revealed 21 of 66 former athletes had cortical tau pathology consistent with CTE. CTE pathology was not detected in 198 individuals without exposure to contact sports, including 33 individuals with documented single-incident TBI sustained from falls, motor vehicle accidents, domestic violence, or assaults. Among those exposed to contact sports, those with CTE pathology did not differ from those without CTE pathology with respect to noted clinicopathologic features. There were no significant differences in genetic variants for those with CTE pathology, but we observed a slight increase in MAPT H1 haplotype, and there tended to be fewer homozygous carriers of the protective TMEM106B rs3173615 minor allele in those with sports exposure and CTE pathology compared to those without CTE pathology. In conclusion, this study has identified a small, yet significant, subset of individuals with neurodegenerative disorders and concomitant CTE pathology. CTE pathology was only detected in individuals with documented participation in contact sports. Exposure to contact sports was the greatest risk factor for CTE pathology. Future studies addressing clinical correlates of CTE pathology are needed.

Project description:Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy characterized by accumulation of hyperphosphorylated tau (p-tau) in perivascular aggregates in neurons and glia at the depths of neocortical sulci and progresses to diffuse neocortical, allocortical and brainstem structures. The strongest risk factor is exposure to repetitive head impacts acquired most commonly through contact sports and military service. Given that CTE can only be definitively diagnosed after death, a better understanding of the cellular and molecular changes in CTE brains may lead to identification of mechanisms that could be used for novel biomarkers, monitoring progression or therapeutic development. Disruption of alternative pre-mRNA splicing of tau mRNA plays a pathogenic role in tauopathy, with multiple characteristic patterns of isoform accumulation varying among tauopathies. Limited data are available on CTE, particularly at early stages. Using biochemical and histological approaches, we performed a detailed characterization of tau isoform signatures in post-mortem human brain tissue from individuals with a range of CTE stages (n = 99). In immunoblot analyses, severity was associated with decreased total monomeric tau and increased total oligomeric tau. Immunoblot with isoform-specific antisera revealed that oligomeric tau with three and four microtubule binding domain repeats (3R and 4R) also increased with CTE severity. Similarly, immunohistochemical studies revealed p-tau accumulation consisting of both 3R and 4R in perivascular lesions. When the ratio of 4R:3R was analyzed, there was mixed expression throughout CTE stages, although 4R predominated in early CTE stages (I-II), a 3R shift was observed in later stages (III-IV). While neurons were found to contain both 3R and 4R, astrocytes only contained 4R. These 4R-positive cells were exclusively neuronal at early stages. Overall, these findings demonstrate that CTE is a mixed 4R/3R tauopathy. Furthermore, histologic analysis reveals a progressive shift in tau isoforms that correlates with CTE stage and extent of neuronal pathology.

Project description:Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers1-3, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse4-7. No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels8,9. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer's disease and other tauopathies10,11. However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer's and Pick's diseases, and from those formed in vitro12-15. Similar to Alzheimer's disease12,14,16-18, all six brain tau isoforms assemble into filaments in CTE, and residues K274-R379 of three-repeat tau and S305-R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer's disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer's disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases.

Dataset Information

Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study.

Publications

Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets