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Article: Repetitive head impacts induce neuronal loss and neuroinflammation in young athletes.

Butler, Morgane L M D / Pervaiz, Nida / Ypsilantis, Petra / Wang, Yichen / Cammasola Breda, Julia / Mazzilli, Sarah / Nicks, Raymond / Spurlock, Elizabeth / Hefti, Marco M / Huber, Bertrand R / Alvarez, Victor E / Stein, Thor D / Campbell, Joshua D / McKee, Ann C / Cherry, Jonathan D

bioRxiv : the preprint server for biology

2024

Abstract: Repetitive head impacts (RHI) sustained from contact sports are the largest risk factor for chronic traumatic encephalopathy (CTE). Currently, CTE can only be diagnosed after death and the multicellular cascade of events that trigger initial ... ...

Abstract	Repetitive head impacts (RHI) sustained from contact sports are the largest risk factor for chronic traumatic encephalopathy (CTE). Currently, CTE can only be diagnosed after death and the multicellular cascade of events that trigger initial hyperphosphorylated tau (p-tau) deposition remain unclear. Further, the symptoms endorsed by young individuals with early disease are not fully explained by the extent of p-tau deposition, severely hampering development of therapeutic interventions. Here, we show that RHI exposure associates with a multicellular response in young individuals (<51 years old) prior to the onset of CTE p-tau pathology that correlates with number of years of RHI exposure. Leveraging single nucleus RNA sequencing of tissue from 8 control, 9 RHI-exposed, and 11 low stage CTE individuals, we identify SPP1+ inflammatory microglia, angiogenic and inflamed endothelial cell profiles, reactive astrocytes, and altered synaptic gene expression in excitatory and inhibitory neurons in all individuals with exposure to RHI. Surprisingly, we also observe a significant loss of cortical sulcus layer 2/3 neurons in contact sport athletes compared to controls independent of p-tau pathology. These results provide robust evidence that multiple years of RHI exposure is sufficient to induce lasting cellular alterations that may underlie p-tau deposition and help explain the early clinical symptoms observed in young former contact sport athletes. Furthermore, these data identify specific cellular responses to repetitive head impacts that may direct future identification of diagnostic and therapeutic strategies for CTE.
Language	English
Publishing date	2024-03-28
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.26.586815
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Article ; Online: TDP43 pathology in chronic traumatic encephalopathy retinas.

Phansalkar, Ragini / Goodwill, Vanessa S / Nirschl, Jeffrey J / De Lillo, Chiara / Choi, Jihee / Spurlock, Elizabeth / Coughlin, David G / Pizzo, Donald / Sigurdson, Christina J / Hiniker, Annie / Alvarez, Victor E / Mckee, Ann C / Lin, Jonathan H

Acta neuropathologica communications

2023 Volume 11, Issue 1, Page(s) 152

Abstract: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head trauma. Brain pathology in CTE is characterized by neuronal loss, gliosis, and a distinctive pattern of neuronal accumulation of hyper-phosphorylated ... ...

Abstract	Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head trauma. Brain pathology in CTE is characterized by neuronal loss, gliosis, and a distinctive pattern of neuronal accumulation of hyper-phosphorylated tau (p-tau) and phospho-TDP43 (p-TDP43). Visual anomalies have been reported by patients with CTE, but the ocular pathology underlying these symptoms is unknown. We evaluated retinal pathology in post-mortem eyes collected from 8 contact sport athletes with brain autopsy-confirmed stage IV CTE and compared their findings to retinas from 8 control patients without CTE and with no known history of head injury. Pupil-optic nerve cross sections were prepared and stained with hematoxylin and eosin (H&E), p-tau, p-TDP43, and total TDP43 by immunohistochemistry. No significant retinal degeneration was observed in CTE eyes compared to control eyes by H&E. Strong cytoplasmic p-TDP43 and total TDP43 staining was found in 6/8 CTE eyes in a subset of inner nuclear layer interneurons (INL) of the retina, while only 1/8 control eyes showed similar p-TDP43 pathology. The morphology and location of these inner nuclear layer interneurons were most compatible with retinal horizontal cells, although other retinal cell types present in INL could not be ruled out. No p-tau pathology was observed in CTE or control retinas. These findings identify novel retinal TDP43 pathology in CTE retinas and support further investigation into the role of p-TDP43 in producing visual deficits in patients with CTE.
MeSH term(s)	Humans ; Chronic Traumatic Encephalopathy ; Neurodegenerative Diseases ; Retina ; Retinal Degeneration ; Brain ; Craniocerebral Trauma ; Eosine Yellowish-(YS)
Chemical Substances	Eosine Yellowish-(YS) (TDQ283MPCW)
Language	English
Publishing date	2023-09-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-023-01650-6
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Article ; Online: Vitreous Humor Biomarkers Reflect Pathological Changes in the Brain for Alzheimer's Disease and Chronic Traumatic Encephalopathy.

Vig, Viha / Garg, Itika / Tuz-Zahra, Fatima / Xu, Jia / Tripodis, Yorghos / Nicks, Raymond / Xia, Weiming / Alvarez, Victor E / Alosco, Michael L / Stein, Thor D / Subramanian, Manju L

Journal of Alzheimer's disease : JAD

2023 Volume 93, Issue 3, Page(s) 1181–1193

Abstract: Background: Patients with eye disease have an increased risk for developing neurodegenerative disease. Neurodegenerative proteins can be measured in the eye; however, correlations between biomarker levels in eye fluid and neuropathological diagnoses ... ...

Abstract	Background: Patients with eye disease have an increased risk for developing neurodegenerative disease. Neurodegenerative proteins can be measured in the eye; however, correlations between biomarker levels in eye fluid and neuropathological diagnoses have not been established. Objective: This exploratory, retrospective study examined vitreous humor from 41 postmortem eyes and brain tissue with neuropathological diagnoses of Alzheimer's disease (AD, n = 7), chronic traumatic encephalopathy (CTE, n = 15), both AD + CTE (n = 10), and without significant neuropathology (controls, n = 9). Methods: Protein biomarkers i.e., amyloid-β (Aβ40,42), total tau (tTau), phosphorylated tau (pTau181,231), neurofilament light chain (NfL), and eotaxin-1 were quantitatively measured by immunoassay. Non-parametric tests were used to compare vitreous biomarker levels between groups. Spearman's rank correlation tests were used to correlate biomarker levels in vitreous and cortical tissue. The level of significance was set to α= 0.10. Results: In pairwise comparisons, tTau levels were significantly increased in AD and CTE groups versus controls (p = 0.08 for both) as well as AD versus AD+CTE group and CTE versus AD+CTE group (p = 0.049 for both). Vitreous NfL levels were significantly increased in low CTE (Stage I/II) versus no CTE (p = 0.096) and in low CTE versus high CTE stage (p = 0.03). Vitreous and cortical tissue levels of pTau 231 (p = 0.02, r = 0.38) and t-Tau (p = 0.04, r = -0.34) were significantly correlated. Conclusion: The postmortem vitreous humor biomarker levels significantly correlate with AD and CTE pathology in corresponding brains, while vitreous NfL was correlated with the CTE staging. This exploratory study indicates that biomarkers in the vitreous humor may serve as a proxy for neuropathological disease.
MeSH term(s)	Humans ; Alzheimer Disease/metabolism ; Chronic Traumatic Encephalopathy/pathology ; Neurodegenerative Diseases/metabolism ; Retrospective Studies ; Vitreous Body/metabolism ; Brain/pathology ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism
Chemical Substances	tau Proteins ; Amyloid beta-Peptides ; Biomarkers
Language	English
Publishing date	2023-05-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-230167
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Article ; Online: Cortical-sparing chronic traumatic encephalopathy (CSCTE): a distinct subtype of CTE.

Acta neuropathologica

2024 Volume 147, Issue 1, Page(s) 45

Abstract: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head impacts (RHI) and pathologically defined as neuronal phosphorylated tau aggregates around small blood vessels and concentrated at sulcal depths. Cross- ... ...

Abstract	Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head impacts (RHI) and pathologically defined as neuronal phosphorylated tau aggregates around small blood vessels and concentrated at sulcal depths. Cross-sectional studies suggest that tau inclusions follow a stereotyped pattern that begins in the neocortex in low stage disease, followed by involvement of the medial temporal lobe and subcortical regions with significant neocortical burden in high stage CTE. Here, we define a subset of brain donors with high stage CTE and with a low overall cortical burden of tau inclusions (mean semiquantitative value ≤1) and classify them as cortical-sparing CTE (CSCTE). Of 620 brain donors with pathologically diagnosed CTE, 66 (11%) met criteria for CSCTE. Compared to typical high stage CTE, those with CSCTE had a similar age at death and years of contact sports participation and were less likely to carry apolipoprotein ε4 (p < 0.05). CSCTE had less overall tau pathology severity, but a proportional increase of disease burden in medial temporal lobe and brainstem regions compared to the neocortex (p's < 0.001). CSCTE also had lower prevalence of comorbid neurodegenerative disease. Clinically, CSCTE participants were less likely to have dementia (p = 0.023) and had less severe cognitive difficulties (as reported by informants using the Functional Activities Questionnaire (FAQ); p < 0.001, meta-cognitional index T score; p = 0.002 and Cognitive Difficulties Scale (CDS); p < 0.001,) but had an earlier onset age of behavioral (p = 0.006) and Parkinsonian motor (p = 0.013) symptoms when compared to typical high stage CTE. Other comorbid tauopathies likely contributed in part to these differences: when cases with concurrent Alzheimer dementia or frontal temporal lobar degeneration with tau pathology were excluded, differences were largely retained, but only remained significant for FAQ (p = 0.042), meta-cognition index T score (p = 0.014) and age of Parkinsonian motor symptom onset (p = 0.046). Overall, CSCTE appears to be a distinct subtype of high stage CTE with relatively greater involvement of subcortical and brainstem regions and less severe cognitive symptoms.
MeSH term(s)	Humans ; Chronic Traumatic Encephalopathy ; Neurodegenerative Diseases ; Cross-Sectional Studies ; Brain ; Alzheimer Disease
Language	English
Publishing date	2024-02-26
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-024-02690-5
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Article ; Online: Vascular injury is associated with repetitive head impacts and tau pathology in chronic traumatic encephalopathy.

Kirsch, Daniel / Shah, Arsal / Dixon, Erin / Kelley, Hunter / Cherry, Jonathan D / Xia, Weiming / Daley, Sarah / Aytan, Nurgul / Cormier, Kerry / Kubilus, Carol / Mathias, Rebecca / Alvarez, Victor E / Huber, Bertrand R / McKee, Ann C / Stein, Thor D

Journal of neuropathology and experimental neurology

2023 Volume 82, Issue 2, Page(s) 127–139

Abstract: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repetitive head impacts (RHI) and characterized by perivascular hyperphosphorylated tau (p-tau) deposits. The role of vascular injury, blood-brain barrier leakage, and ... ...

Abstract	Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repetitive head impacts (RHI) and characterized by perivascular hyperphosphorylated tau (p-tau) deposits. The role of vascular injury, blood-brain barrier leakage, and neuroinflammation in CTE pathogenesis is not well understood. We performed quantitative immunoassays for intercellular adhesion molecule 1 (ICAM1), vascular cellular adhesion molecule 1 (VCAM1), and C-reactive protein (CRP) within the postmortem dorsolateral frontal cortex of participants with and without a history of RHI and CTE (n = 156), and tested for associations with RHI, microgliosis, and tau pathology measures. Levels of vascular injury-associated markers ICAM1, VCAM1, and CRP were increased in CTE compared to RHI-exposed and -naïve controls. ICAM1 and CRP increased with RHI exposure duration (p < 0.01) and were associated with increased microglial density (p < 0.001) and tau pathology (AT8, p-tau396, p-tau202; p < 0.05). Histologically, there was significantly increased ICAM1 staining of the microvasculature, extracellular space, and astrocytes at the sulcal depths in high stage CTE compared to both low stage CTE and controls. Multifocal perivascular immunoreactivity for serum albumin was present in all RHI-exposed individuals. These findings demonstrate that vascular injury markers are associated with RHI exposure, duration, and microgliosis, are elevated in CTE, and increase with disease severity.
MeSH term(s)	Humans ; Chronic Traumatic Encephalopathy/pathology ; Neurodegenerative Diseases ; Vascular System Injuries/complications ; Frontal Lobe/metabolism ; Blood-Brain Barrier/pathology ; tau Proteins/metabolism
Chemical Substances	tau Proteins
Language	English
Publishing date	2023-01-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3088-0
ISSN	1554-6578 ; 0022-3069
ISSN (online)	1554-6578
ISSN	0022-3069
DOI	10.1093/jnen/nlac122
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Article ; Online: Risk of chronic traumatic encephalopathy in rugby union is associated with length of playing career.

Stewart, William / Buckland, Michael E / Abdolmohammadi, Bobak / Affleck, Andrew J / Alvarez, Victor E / Gilchrist, Shannon / Huber, Bertrand R / Lee, Edward B / Lyall, Donald M / Nowinski, Christopher J / Russell, Emma R / Stein, Thor D / Suter, Catherine M / McKee, Ann C

Acta neuropathologica

2023 Volume 146, Issue 6, Page(s) 829–832

MeSH term(s)	Humans ; Chronic Traumatic Encephalopathy ; Rugby ; Football ; Athletic Injuries/complications ; Athletic Injuries/epidemiology
Language	English
Publishing date	2023-10-24
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-023-02644-3
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Article ; Online: Chronic traumatic encephalopathy (CTE): criteria for neuropathological diagnosis and relationship to repetitive head impacts.

McKee, Ann C / Stein, Thor D / Huber, Bertrand R / Crary, John F / Bieniek, Kevin / Dickson, Dennis / Alvarez, Victor E / Cherry, Jonathan D / Farrell, Kurt / Butler, Morgane / Uretsky, Madeline / Abdolmohammadi, Bobak / Alosco, Michael L / Tripodis, Yorghos / Mez, Jesse / Daneshvar, Daniel H

Acta neuropathologica

2023 Volume 145, Issue 4, Page(s) 371–394

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Cattle ; Humans ; Male ; Australia ; Brain/pathology ; Canada ; Chronic Traumatic Encephalopathy/pathology ; Football ; tau Proteins/metabolism ; Tauopathies
Chemical Substances	tau Proteins
Language	English
Publishing date	2023-02-10
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-023-02540-w
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Article ; Online: Interface astrogliosis in contact sport head impacts and military blast exposure.

Babcock, Katharine J / Abdolmohammadi, Bobak / Kiernan, Patrick T / Mahar, Ian / Cherry, Jonathan D / Alvarez, Victor E / Goldstein, Lee E / Stein, Thor D / McKee, Ann C / Huber, Bertrand R

Acta neuropathologica communications

2022 Volume 10, Issue 1, Page(s) 52

Abstract: Exposure to military blast and repetitive head impacts (RHI) in contact sports is associated with increased risk of long-term neurobehavioral sequelae and cognitive deficits, and the neurodegenerative disease chronic traumatic encephalopathy (CTE). At ... ...

Abstract	Exposure to military blast and repetitive head impacts (RHI) in contact sports is associated with increased risk of long-term neurobehavioral sequelae and cognitive deficits, and the neurodegenerative disease chronic traumatic encephalopathy (CTE). At present, the exact pathogenic mechanisms of RHI and CTE are unknown, and no targeted therapies are available. Astrocytes have recently emerged as key mediators of the multicellular response to head trauma. Here, we investigated interface astrogliosis in blast and impact neurotrauma, specifically in the context of RHI and early stage CTE. We compared postmortem brain tissue from former military veterans with a history of blast exposure with and without a neuropathological diagnosis of CTE, former American football players with a history of RHI with and without a neuropathological diagnosis of CTE, and control donors without a history of blast, RHI exposure or CTE diagnosis. Using quantitative immunofluorescence, we found that astrogliosis was higher at the grey-white matter interface in the dorsolateral frontal cortex, with mixed effects at the subpial surface and underlying cortex, in both blast and RHI donors with and without CTE, compared to controls. These results indicate that certain astrocytic alterations are associated with both impact and blast neurotrauma, and that different astroglial responses take place in distinct brain regions.
MeSH term(s)	Chronic Traumatic Encephalopathy/pathology ; Football/injuries ; Gliosis/complications ; Humans ; Neurodegenerative Diseases/complications ; Neuropathology
Language	English
Publishing date	2022-04-13
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-022-01358-z
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Article ; Online: Alzheimer's disease amyloid-β pathology in the lens of the eye.

Moncaster, Juliet A / Moir, Robert D / Burton, Mark A / Chadwick, Oliver / Minaeva, Olga / Alvarez, Victor E / Ericsson, Maria / Clark, John I / McKee, Ann C / Tanzi, Rudolph E / Goldstein, Lee E

Experimental eye research

2022 Volume 221, Page(s) 108974

Abstract: Neuropathological hallmarks of Alzheimer's disease (AD) include pathogenic accumulation of amyloid-β (Aβ) peptides and age-dependent formation of amyloid plaques in the brain. AD-associated Aβ neuropathology begins decades before onset of cognitive ... ...

Abstract	Neuropathological hallmarks of Alzheimer's disease (AD) include pathogenic accumulation of amyloid-β (Aβ) peptides and age-dependent formation of amyloid plaques in the brain. AD-associated Aβ neuropathology begins decades before onset of cognitive symptoms and slowly progresses over the course of the disease. We previously reported discovery of Aβ deposition, β-amyloidopathy, and co-localizing supranuclear cataracts (SNC) in lenses from people with AD, but not other neurodegenerative disorders or normal aging. We confirmed AD-associated Aβ molecular pathology in the lens by immunohistopathology, amyloid histochemistry, immunoblot analysis, epitope mapping, immunogold electron microscopy, quantitative immunoassays, and tryptic digest mass spectrometry peptide sequencing. Ultrastructural analysis revealed that AD-associated Aβ deposits in AD lenses localize as electron-dense microaggregates in the cytoplasm of supranuclear (deep cortex) fiber cells. These Aβ microaggregates also contain αB-crystallin and scatter light, thus linking Aβ pathology and SNC phenotype expression in the lenses of people with AD. Subsequent research identified Aβ lens pathology as the molecular origin of the distinctive cataracts associated with Down syndrome (DS, trisomy 21), a chromosomal disorder invariantly associated with early-onset Aβ accumulation and Aβ amyloidopathy in the brain. Investigation of 1249 participants in the Framingham Eye Study found that AD-associated quantitative traits in brain and lens are co-heritable. Moreover, AD-associated lens traits preceded MRI brain traits and cognitive deficits by a decade or more and predicted future AD. A genome-wide association study of bivariate outcomes in the same subjects identified a new AD risk factor locus in the CTNND2 gene encoding δ-catenin, a protein that modulates Aβ production in brain and lens. Here we report identification of AD-related human Aβ (hAβ) lens pathology and age-dependent SNC phenotype expression in the Tg2576 transgenic mouse model of AD. Tg2576 mice express Swedish mutant human amyloid precursor protein (APP-Swe), accumulate hAβ peptides and amyloid pathology in the brain, and exhibit cognitive deficits that slowly progress with increasing age. We found that Tg2576 trangenic (Tg
MeSH term(s)	Alzheimer Disease/genetics ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Brain/pathology ; Cataract/pathology ; Disease Models, Animal ; Genome-Wide Association Study ; Humans ; Mice ; Mice, Transgenic ; Neurodegenerative Diseases/pathology
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor
Language	English
Publishing date	2022-02-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80122-7
ISSN	1096-0007 ; 0014-4835
ISSN (online)	1096-0007
ISSN	0014-4835
DOI	10.1016/j.exer.2022.108974
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Article ; Online: Tau Pathology in Chronic Traumatic Encephalopathy is Primarily Neuronal.

Butler, Morgane L M D / Dixon, Erin / Stein, Thor D / Alvarez, Victor E / Huber, Bertrand / Buckland, Michael E / McKee, Ann C / Cherry, Jonathan D

Journal of neuropathology and experimental neurology

2022 Volume 81, Issue 10, Page(s) 773–780

Abstract: Millions of individuals are exposed to repetitive head impacts (RHI) each year through contact sports, military blast, and interpersonal violence. RHI is the major risk factor for developing chronic traumatic encephalopathy (CTE), a neurodegenerative ... ...

Abstract	Millions of individuals are exposed to repetitive head impacts (RHI) each year through contact sports, military blast, and interpersonal violence. RHI is the major risk factor for developing chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy. Recent consensus criteria defined the pathognomonic lesion in CTE as perivascular, hyperphosphorylated tau (p-tau) in neuronal aggregates. Astroglial p-tau is an inconsistent supporting feature and not in itself diagnostic of CTE. This study quantitated the spatial and cellular distribution of p-tau pathology in postmortem dorsolateral frontal cortex of 150 individuals with CTE, from ages 21 to 80 years old, without comorbid pathology. p-Tau-immunoreactive cells were quantitated in the gray matter sulcus, crest, subpial region, and within pathognomonic CTE lesions. Significantly more neuronal p-tau than astrocytic p-tau was found across all cortical regions (p < 0.0001). Sulcal astrocytic p-tau was primarily (75%, p < 0.0001) localized to subpial regions as thorn-shaped astrocytes, a form of age-related tau astrogliopathy. Neuronal p-tau was significantly associated with age, years of RHI exposure, and CTE severity; astrocytic p-tau pathology was only significantly associated with age. These findings strongly support neuronal degeneration as a driving feature of CTE and will help inform future research and the development of fluid biomarkers for the detection of neuronal degeneration in CTE.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Astrocytes/pathology ; Chronic Traumatic Encephalopathy/pathology ; Frontal Lobe/pathology ; Humans ; Middle Aged ; Neurons/pathology ; Tauopathies/pathology ; Young Adult
Language	English
Publishing date	2022-07-29
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	3088-0
ISSN	1554-6578 ; 0022-3069
ISSN (online)	1554-6578
ISSN	0022-3069
DOI	10.1093/jnen/nlac065
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