Repetitive head impacts and chronic traumatic encephalopathy are associated with TDP-43 inclusions and hippocampal sclerosis

Nicks, Raymond; Clement, Nathan F.; Alvarez, Victor E.; Tripodis, Yorghos; Baucom, Zachery H.; Huber, Bertrand R.; Mez, Jesse; Alosco, Michael L.; Aytan, Nurgül; Cherry, Jonathan D.; Cormier, Kerry; Kubilius, Carol; Mathias, Rebecca; Svirsky, Sarah; Pothast, Morgan; Hildebrandt, Audrey M.; Chung, Jaeyoon; Han, Xudong; Crary, John F.; McKee, Ann C.; Frosch, Matthew P.; Stein, Thor D.

doi:10.1007/s00401-023-02539-3

Cited by 17 publications

(31 citation statements)

References 63 publications

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“…39 Pathologically, years of contact sport play, a proxy for RHI, has been associated with CTE, 13 neocortical LBD, 19 WMR, 15 more severe frontal and leptomeningeal CAA, 17 and HS and TDP-43 inclusions. 16 Here, we found that multiple neuropathologies were intercorrelated and that the number of unique pathology combinations was significantly less than predicted if they were independent in this RHI-exposed group. RHI may be one common cause of multiple neuropathologies.…”

Section: Intercorrelation Of Pathologies Secondary To Rhimentioning

confidence: 50%

“…Most TDP-43 inclusions were limbic predominant and indistinguishable from limbic-associated TDP-43 encephalopathy-neuropathologic change; however, TDP-43 deposition has been shown to occur at a younger age and is associated with RHI in CTE. 16 Brain tissue was also evaluated for the presence of vascular pathology, including gross infarcts, microinfarcts, moderate-severe atherosclerosis, and moderate-severe arteriolosclerosis. Pathologies were dichotomized as present or not (CTE stage III or IV, intermediate or high AD, neocortical LBD, HS, FTLD, TDP-43 inclusions, and gross and microinfarcts).…”

Section: Neuropathological Examinationmentioning

confidence: 99%

“…This has been previously reported in smaller groups of RHI-exposed individuals, including the common comorbidity of HS and TDP-43. 16,21,22 In CTE, TDP-43 inclusions can occur in a variety of regions, including at the sulcal depths in the frontal cortex, which may represent a CTE-specific form, but more commonly in limbic regions in the pattern described for limbic agerelated TDP-43 encephalopathy. 16 In addition, we found that CAA showed an association with dementia and cognitive impairment.…”

Section: Heterogeneity and Frequency Of Mixed Pathologiesmentioning

confidence: 99%

“…17,19 Betaamyloid deposition was found in 52% of brain donors with CTE as predominantly diffuse plaques, whereas neuritic plaques were less common. 20 In addition to CTE, RHI, as measured by years of play, has been associated with multiple neuropathologies, including neocortical LBD, 19 frontal CAA, 17 hippocampal TDP-43 inclusions, 16 and WMR. 15 Other studies in small numbers of soccer, rugby, and American football players have also shown frequent comorbid pathologies including AD, CTE, and TDP-43.…”

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confidence: 99%

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Relative Contributions of Mixed Pathologies to Cognitive and Functional Symptoms in Brain Donors Exposed to Repetitive Head Impacts

Saltiel,

Tripodis,

Menzin

et al. 2023

Annals of Neurology

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ObjectiveExposure to repetitive head impacts (RHI) is associated with later‐life cognitive symptoms and neuropathologies including chronic traumatic encephalopathy (CTE). Cognitive decline in community cohorts is often due to multiple pathologies; however, the frequency and contributions of these pathologies to cognitive impairment in people exposed to RHI is unknown. Here, we examined the relative contributions of 13 neuropathologies to cognitive symptoms and dementia in RHI‐exposed brain donors.MethodsNeuropathologists examined brain tissue from 571 RHI‐exposed donors and assessed for the presence of 13 neuropathologies, including CTE, Alzheimer disease (AD), Lewy body disease (LBD), and TDP‐43 inclusions. Cognitive status was assessed by presence of dementia, Functional Activities Questionnaire (FAQ), and Cognitive Difficulties Scale (CDS). Spearman's rho was calculated to assess intercorrelation of pathologies. Additionally, frequencies of pathological co‐occurrence were compared to a simulated distribution assuming no intercorrelation. Logistic and linear regressions tested associations between neuropathologies and dementia status and cognitive scale scores.ResultsThe sample age range was 18–97 (median: 65.0 [IQR 46.0–76.0]). 77.2% of donors had at least one moderate–severe neurodegenerative or cerebrovascular pathology. Stage III‐IV CTE was the most common neurodegenerative disease (43.1%), followed by TDP‐43 pathology, AD, and hippocampal sclerosis. Neuropathologies were intercorrelated and there were fewer unique combinations than expected if pathologies were independent (p < 0.001). The greatest contributors to dementia were AD, neocortical LBD, hippocampal sclerosis, CAA, and CTE.InterpretationIn this sample of RHI‐exposed brain donors with wide‐ranging ages, multiple neuropathologies were common and correlated. Mixed neuropathologies, including CTE, underlie cognitive impairment in contact sport athletes.This article is protected by copyright. All rights reserved.

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Section: Intercorrelation Of Pathologies Secondary To Rhimentioning

confidence: 50%

Section: Neuropathological Examinationmentioning

confidence: 99%

Section: Heterogeneity and Frequency Of Mixed Pathologiesmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Relative Contributions of Mixed Pathologies to Cognitive and Functional Symptoms in Brain Donors Exposed to Repetitive Head Impacts

Saltiel,

Tripodis,

Menzin

et al. 2023

Annals of Neurology

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“…5) [74]. A recent study by Nicks et al found TDP-43 inclusions in 87 of 307 CTE cases (30.5%) without hippocampal sclerosis (HS), most commonly in the frontal lobes and limbic regions or hippocampus alone and less often in amygdala or frontal regions alone [89]. Hippocampal sclerosis (HS) was reported in 90 of 401 CTE cases (23.4%), and of those, TDP-43 pathology was present in 95.7%.…”

Section: Relationship Between Rhi Cte Tdp-43 and Alsmentioning

confidence: 99%

Chronic traumatic encephalopathy (CTE): criteria for neuropathological diagnosis and relationship to repetitive head impacts

et al. 2023

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Over the last 17 years, there has been a remarkable increase in scientific research concerning chronic traumatic encephalopathy (CTE). Since the publication of NINDS–NIBIB criteria for the neuropathological diagnosis of CTE in 2016, and diagnostic refinements in 2021, hundreds of contact sport athletes and others have been diagnosed at postmortem examination with CTE. CTE has been reported in amateur and professional athletes, including a bull rider, boxers, wrestlers, and American, Canadian, and Australian rules football, rugby union, rugby league, soccer, and ice hockey players. The pathology of CTE is unique, characterized by a pathognomonic lesion consisting of a perivascular accumulation of neuronal phosphorylated tau (p-tau) variably alongside astrocytic aggregates at the depths of the cortical sulci, and a distinctive molecular structural configuration of p-tau fibrils that is unlike the changes observed with aging, Alzheimer’s disease, or any other tauopathy. Computational 3-D and finite element models predict the perivascular and sulcal location of p-tau pathology as these brain regions undergo the greatest mechanical deformation during head impact injury. Presently, CTE can be definitively diagnosed only by postmortem neuropathological examination; the corresponding clinical condition is known as traumatic encephalopathy syndrome (TES). Over 97% of CTE cases published have been reported in individuals with known exposure to repetitive head impacts (RHI), including concussions and nonconcussive impacts, most often experienced through participation in contact sports. While some suggest there is uncertainty whether a causal relationship exists between RHI and CTE, the preponderance of the evidence suggests a high likelihood of a causal relationship, a conclusion that is strengthened by the absence of any evidence for plausible alternative hypotheses. There is a robust dose–response relationship between CTE and years of American football play, a relationship that remains consistent even when rigorously accounting for selection bias. Furthermore, a recent study suggests that selection bias underestimates the observed risk. Here, we present the advances in the neuropathological diagnosis of CTE culminating with the development of the NINDS–NIBIB criteria, the multiple international studies that have used these criteria to report CTE in hundreds of contact sports players and others, and the evidence for a robust dose–response relationship between RHI and CTE.

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Cortical-sparing chronic traumatic encephalopathy (CSCTE): a distinct subtype of CTE

Alexander,

Alvarez,

Huber

et al. 2024

Acta Neuropathol

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Repetitive head impacts and chronic traumatic encephalopathy are associated with TDP-43 inclusions and hippocampal sclerosis

Cited by 17 publications

References 63 publications

Relative Contributions of Mixed Pathologies to Cognitive and Functional Symptoms in Brain Donors Exposed to Repetitive Head Impacts

Relative Contributions of Mixed Pathologies to Cognitive and Functional Symptoms in Brain Donors Exposed to Repetitive Head Impacts

Chronic traumatic encephalopathy (CTE): criteria for neuropathological diagnosis and relationship to repetitive head impacts

Cortical-sparing chronic traumatic encephalopathy (CSCTE): a distinct subtype of CTE

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