Cortical subpial aging-related tau astrogliopathy in older adult men who participated in youth amateur American-style football.

We examined postmortem brain tissue from men, over the age of 50, for chronic traumatic encephalopathy neuropathologic change (CTE-NC). We hypothesized that (i) a small percentage would have CTE-NC, (ii) those who played American football during their youth would be more likely to have CTE-NC than those who did not play contact or collision sports, and (iii) there would be no association between CTE-NC and suicide as a manner of death. Brain tissue from 186 men and accompanying clinical information were obtained from the Lieber Institute for Brain Development. Manner of death was determined by a board-certified forensic pathologist. Information was obtained from next of kin telephone interviews, including medical, social, demographic, family, and psychiatric history. The 2016 and 2021 consensus definitions were used for CTE-NC. Two authors screened all cases, using liberal criteria for identifying "possible" CTE-NC, and five authors examined the 15 selected cases. The median age at the time of death was 65 years (interquartile range = 57-75; range = 50-96). There were 25.8% with a history of playing American football and 36.0% who had suicide as their manner of death. No case was rated as definitively having "features" of CTE-NC by all five authors. Ten cases were rated as having features of CTE-NC by three or more authors (5.4% of the sample), including 8.3% of those with a personal history of playing American football and 3.9% of those who did not play contact or collision sports. Of those with mood disorders during life, 5.5% had features of CTE-NC compared to 6.0% of those who did not have a reported mood disorder. Of those with suicide as a manner of death, 6.0% had features of CTE-NC compared to 5.0% of those who did not have suicide as a manner of death. We did not identify a single definitive case of CTE-NC, from the perspective of all raters, and only 5.4% of cases were identified as having possible features of CTE-NC by some raters. CTE-NC was very uncommon in men who played amateur American football, those with mood disorders during life, and those with suicide as a manner of death.

A - 35 Tau in the CA2 Region of the Hippocampus in Older Adult Men Who Participated in High School Football

Editorial Commentary: Recurrence Rates Following Arthroscopic Bankart Repair Differ Among Contact and Collision Sports and Are Higher in Collision Sports

Exposure to traumatic brain injury (TBI) and/or repetitive head impacts (RHI) increase the risk of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy neuropathologic change (CTE-NC). Astrocytic tau pathology reminiscent of ageing-related tau astrogliopathy is a component feature of CTE-NC in many cases. Yet the relationship between TBI/RHI exposure and wider tau astrogliopathy, beyond that of CTE-NC, remains poorly characterized. Autopsy-derived material from 556 individuals was selected to include cases with a history of moderate or severe traumatic brain injury (survival >6 months, n = 77) or a history of participation in contact sports (n = 45), for comparison with uninjured controls with (n = 397) or without (n = 37) neuropathologically confirmed neurodegenerative disease. Representative tissue sections from multiple brain regions were then immunostained for hyperphosphorylated tau (p-tau; PHF-1) and assessed in accordance with the harmonized evaluation criteria for ageing-related tau astrogliopathy. PHF-1-immunoreactive thorn-shaped astrocytes were observed more frequently in contact sports participants (75.6%) versus controls with (32.5%; P < 0.001) and without (8.1%; P < 0.001) neurodegenerative disease. In addition, although the prevalence of thorn-shaped astrocytes following moderate/severe TBI (32.5%) was similar to neurodegenerative disease controls, regression analyses demonstrated increased odds of thorn-shaped astrocytes, when adjusting for age and sex (odds ratio 2.42, 95% confidence interval 1.29-4.54). These findings were observed regardless of whether the pathognomonic lesion of CTE-NC was present in the regions examined. Intriguingly, although subpial thorn-shaped astrocytes at sulcal depths were occasionally observed in aged controls with (3.6%) and without (2.8%) neurodegenerative disease, this pathology was considerably more common following RHI/TBI (42.2%; P < 0.001). These findings support a history of RHI or TBI as an independent risk factor for the development of thorn-shaped tau astrogliopathy, over and above ageing-related tau astrogliopathy observed in ageing and wider neurodegenerative disease. Moreover, trauma might be associated with thorn-shaped astrocytes within specific distributions, including the subpial region of the cortical sulcal depths. The clinical significance of these observations will be important to determine.

Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head trauma, including concussion and asymptomatic subconcussive impacts. CTE was first recognized in boxers almost a century ago and has been identified more recently in contact sports athletes, military veterans exposed to blast, and victims of domestic violence. Like most neurodegenerative diseases, CTE is diagnosed conclusively by a neuropathological examination of brain tissue. CTE is characterized by the buildup of hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs), neurites, and, sometimes, astrocytes, surrounding small blood vessels in a patchy distribution at the sulcal depths of the cerebral cortex. In 2015, using the McKee proposed criteria for the neuropathological diagnosis of CTE, a consensus panel of expert neuropathologists confirmed CTE as a unique neurodegenerative disease with a pathognomonic lesion and published the preliminary NINDS (National Institute of Neurological Disorders and Stroke) criteria for CTE. Since that time, the NINDS criteria for CTE have been implemented and validated in multiple international publications. Using the NINDS criteria, the largest clinicopathological series of CTE to date was reported that included 177 former American football players, including 110 (99%) of 111 former National Football League players, 48 (91%) of 53 former college football players, and 3 (21%) of 14 former high school players. Studies have also shown a significant association between cumulative exposure to repetitive head trauma, as judged by the length of American football playing career, and risk for and severity of CTE. There is also a significant relationship of the length of football playing career with p-tau pathology, inflammation, white matter rarefaction, and age at death in CTE. While p-tau pathology, inflammation, white matter rarefaction, and arteriolosclerosis contribute to dementia in CTE, whether they also influence the behavioral and mood symptoms in CTE has yet to be determined. There have been several instances of aging-related tau astrogliopathy (ARTAG), a common astrocytic pathology in the elderly, misdiagnosed as CTE in the recent literature, provoking claims that CTE pathology is present in people not known to have experienced repetitive head trauma. Although ARTAG is often found in CTE, the pathognomonic lesion of CTE is a neuronal lesion consisting of NFTs and neurites, with or without p-tau immunoreactive astrocytes. Some authors consider β-amyloid (Aβ) to be a primary feature of CTE, yet the data indicate that CTE is a primary tauopathy, with Aβ deposition a function of age and inheritance of the ApoEe4 allele. Some authors also question the progressive nature of CTE pathology, although there is clear evidence in most individuals that p-tau pathology increases in density and affects more brain regions with survival. This review is intended to outline the status of the evidence-based literature regarding CTE neuropathology and to address the misrepresentations and confusions that have arisen in recent reviews and a letter of correspondence.

This study examined the frequency of chronic traumatic encephalopathy-neuropathologic change (CTE-NC) and aging-related tau astrogliopathy (ARTAG) in community-dwelling older adults and tested the hypothesis that these tau pathologies are associated with a history of moderate-to-severe traumatic brain injury (msTBI), defined as a TBI with loss of consciousness >30 minutes. We evaluated CTE-NC, ARTAG, and Alzheimer disease pathologies in 94 participants with msTBI and 94 participants without TBI matched by age, sex, education, and dementia status TBI from the Rush community-based cohorts. Six (3%) of brains showed the pathognomonic lesion of CTE-NC; only 3 of these had a history of msTBI. In contrast, ARTAG was common in older brains (gray matter ARTAG = 77%; white matter ARTAG = 54%; subpial ARTAG = 51%); there were no differences in severity, type, or distribution of ARTAG pathology with respect to history of msTBI. Furthermore, those with msTBI did not have higher levels of PHF-tau tangles density but had higher levels of amyloid-β load (Estimate = 0.339, SE = 0.164, p = 0.040). These findings suggest that CTE-NC is infrequent while ARTAG is common in the community and that both pathologies are unrelated to msTBI. The association of msTBI with amyloid-β, rather than with tauopathies suggests differential mechanisms of neurodegeneration in msTBI.

Chronic traumatic encephalopathy neuropathologic change can only be definitively diagnosed post-mortem. It has been associated with repetitive mild neurotrauma sustained in amateur and professional contact, collision and combat sports, although it has also been documented in people with a single severe traumatic brain injury and in some people with no known history of brain injury. The characteristic neuropathology is an accumulation of perivascular neuronal and astrocytic phosphorylated tau in the depths of the cortical sulci. The tau-immunopositive neurons and astrocytes that are considered pathognomonic for chronic traumatic encephalopathy are morphologically indistinguishable from Alzheimer-related neurofibrillary tangles and ageing-related tau astrogliopathy, respectively, although they are found in different spatial distributions throughout the cortex. The Sydney Brain Bank collection consists of neurodegenerative diseases and neurologically normal controls. We screened 636 of these cases for chronic traumatic encephalopathy neuropathologic change. A subset of 109 cases had a known history of traumatic brain injury. Three cortical regions were screened for the presence of neuronal and astrocytic phosphorylated tau according to the current 2021 National Institute on Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering consensus criteria for chronic traumatic encephalopathy. Five cases (0.79%) showed pathological evidence of chronic traumatic encephalopathy and three of these had a history of traumatic brain injury. Three cases had coexisting Alzheimer’s and/or Lewy body disease pathology meeting criteria for neurodegenerative disease. Another eight cases almost met criteria for chronic traumatic encephalopathy neuropathological change except for an absence of neuronal tau or a strict perivascular arrangement. Ageing-related tau astrogliopathy was found in all eight cases as a coexisting neuropathology. Traumatic brain injury was associated with increased odds ratio [1.79, confidence interval 1.18–2.72] of having a higher neurofibrillary tangle stage and phosphorylated TAR DNA binding protein 43 (OR 2.48, confidence interval 1.35–4.54). Our study shows a very low rate of chronic traumatic encephalopathy neuropathological change in brains with or without neurodegenerative disease from the Sydney Brain Bank. Our evidence suggests that isolated traumatic brain injury in the general population is unlikely to cause chronic traumatic encephalopathy neuropathologic change but may be associated with increased brain ageing.

Chronic traumatic encephalopathy (CTE) and aging-related tau astrogliopathy (ARTAG) are characterised by tau-immunopositive neuronal and/or astrocytic inclusions, with overlapping cortical involvement and astrocytic inclusion morphology. This study determined the prevalence of CTE and cortical ARTAG in a European community-based population (n=310) and explored overlap of both pathological entities. Frontal, parietal and temporal cortices were assessed. No case fulfilling CTE criteria was found. However, isolated astroglial or neuronal tau pathologies were recognized in sulcal depths (&lt;2%). One case without history of traumatic brain injury showed combined tau-immunoreactive features confined to frontal sulci without perivascular accumulation. Another 24 cases had single tau pathologies in cortical sulci. ARTAG was identified in 117 cases (38%), with a similar regional prevalence. Grey matter ARTAG was the most common followed by subpial, white matter and perivascular. The presence of any type of ARTAG was associated with having another type of ARTAG in the same region (P&lt;0.05). In summary, cortical ARTAG in this population is common and contrasts the high prevalence of CTE in individuals with repeated mild traumatic brain injury.LEARNING OBJECTIVESThis presentation will enable the learner to:Classify tau-immunopositive astrocytic inclusions characteristic of ARTAG1.Describe neuropathological components of CTE2.Identify CTE and cortical ARTAG in a case series

The etiology of major depression (MDD), a common and complex disorder, remains obscure. Gene expression profiling was conducted on post-mortem brain tissue samples from Brodmann Area 10 (BA10) in the prefrontal cortex from psychotropic drug-free persons with a history of MDD and age, gender, and post-mortem interval matched normal controls (n=14 pairs of subjects). Microarray analysis was conducted using the Affymetrix Exon 1.0 ST arrays. A list of differential expression changes were determined by dual fold change-probability criteria (|ALR|>0.585 [equivalent to a 1.5-fold difference in either direction], p<0.01), while molecular pathways of interest were evaluated using Gene Set Enrichment Analysis (GSEA) software. The results strongly implicate increased apoptotic stress in the samples from the MDD group. Three anti-apoptotic factors, Y-box binding protein 1 (YBX1), Caspase-1 dominant-negative inhibitor pseudo-ICE (COP1), and the putative apoptosis inhibitor FKGS2 were over-expressed. Gene set analysis suggested up-regulation of a variety of pro- and anti-inflammatory cytokines, including interleukin 1α (IL1α), IL2, IL3, IL5, IL8, IL9, IL10, IL12A, IL13, IL15, IL18, interferon gamma (IFNγ), and lymphotoxin alpha (LTA; TNF super family member 1). The genes showing reduced expression included metallothionein 1M (MT1M), a zinc binding protein with a significant role in the modulation of oxidative stress. The results of this study suggest that post-mortem brain tissue samples from BA10, a region which is involved in reward-related behavior, show evidence of local inflammatory, apoptotic, and oxidative stress in MDD.

Background: A growing body of evidence has suggested that repetitive head impacts (RHIs) in collision sports produce changes in white matter tracts of athletes as detected by diffusion tensor imaging (DTI). Few studies have examined DTI in 8-12 year old collision sport (CS) athletes, compared them to non-collision sports (NCS) athletes, and correlated findings to accelerometry data. We sought to explore whether, after a single season of participation in youth football, 8-12 year old male CS athletes will: 1) have change in DTI fractional anisotropy (FA) of commonly injured brain regions, 2) have FA differences when compared to an age-matched NCS cohort, and 3) whether there is a correlation between FA and number, magnitude, and location of impacts. Methods: Thirty five 8-12 year old male participants in an organized youth tackle football league were recruited (CS) and matched with twelve 8-12 year old male participants in a local swim team (NCS). Each cohort underwent brain MRI with FA at 5 regions of interest (ROIs) before the youth football season and again immediately following the football season. CS participants’ helmets were instrumented with a force switch sensor to record number, magnitude, and direction of head impacts throughout a single season. Descriptive statistics were calculated for age, height, weight, FA values in all DTI ROIs (Anterior Corona Radiata (ACR), Cingulate Cortex (CgC), Genu of the Corpus Collosum (gCC), Posterior Limb of the Internal Capsule (pllC) and Splenium of the Corpus Collosum (SCC)), magnitude of head impact recorded by accelerometry by season, game and practice, number of hits by season, game and practice and by direction (top, side and rear). A mixed model (group by time) repeated measures MANOVA was conducted to determine if there were any differences in FA between the CS group and the NCS group from pre- to post-season. Correlation and regression analyses were carried out to determine if there was a relationship between the changes of FA from pre- to post-season and number and magnitude of head impacts in the CS group. Results: The average age of participants was: CS: 10.11 years, NCS: 10.17 years. The average height of participants was: CS: 56.89±4.06 inches; NCS: 59.92±5.00 inches (p=0.04). The average weight was: CS: 84.23±21.51 lbs; NCS: 84.75±24.04 lbs, (p&gt;0.05). A total of 1905 hits were recorded for 34 participants in the CS group for the season, 341 (17.9% of total) collected during 7 games and 1564 (82.1% of total) observed during 31 practices. A total of 301 impacts (15.8% of total) with magnitude &gt;= 80 g were collected. For brain ROIs investigated with FA, no significant interaction between group (CS and NCS) and time (pre to post season) was observed (p&gt;0.05). Correlation analysis revealed a significantly positive and moderate relationship between increase of left CgC FA from pre to post season and the total magnitude of lateral head impacts (r=0.40, p=0.03). Conclusion: Our cohort of 8-12 year old male football players sustained fewer impacts when compared to prior accelerometry studies on youth football, although there was a larger number of higher force impacts recorded. There was no significant change in FA measurement of white matter integrity in our youth football players after a single football season, nor was there any difference detected in FA between youth football players and an age-matched cohort of swimmers. There was a significant correlation between total magnitude of hits sustained by youth football players during the season and an increase in FA in the left CgC. Whether this finding is adaptive or pathologic remains unclear. Significance: There is no evidence that 8-12 year old male football players sustain significant white matter changes after a single season of tackle football, although there is positive correlation of FA of the left cingulate gyrus to total magnitude of head impacts over the season.

This study determined the prevalence of chronic traumatic encephalopathy (CTE) and cortical aging-related tau astrogliopathy (ARTAG) in a European community-based population (n = 310). The frontal, parietal, and temporal cortices, representing initial stages of CTE were assessed. No case fulfilling CTE consensus criteria was found. However, isolated astroglial or neuronal tau pathologies were recognized in the depths of cortical sulci (<2%). A single case (female, 85 years) without a history of traumatic brain injury (TBI) showed combined tau-immunoreactive features confined to frontal sulci without perivascular accumulation. Another 24 cases had single tau pathologies in cortical sulci. ARTAG was identified in 117 cases (38%), with a similar regional prevalence. Gray matter ARTAG was the most common followed by subpial, white matter, and perivascular. The presence of any type of ARTAG was strongly associated with having another type of ARTAG in the same region (p < 0.05). In summary, although isolated tau pathologies in the depths of cortical sulci were identified, no case fulfilled diagnostic criteria of CTE. Cortical ARTAG in this population is common and contrasts the high prevalence of CTE in individuals with repeated mild TBI. ARTAG in isolation might not be indicative of CTE although commonalities in pathogenesis should be considered.

BackgroundRepetitive head impacts (RHI) from American style football (ASF) and other contact sports are a known risk factor for the neurodegenerative disease chronic traumatic encephalopathy (CTE). RHI can also lead to mixed neuropathologies that uniquely contribute to clinical symptoms. Here, we compared various types of vascular and white matter pathologies between brain donors with and without exposure to RHI from different types of contact and collision sports (CCS).MethodsThe sample included 79 deceased male ASF players (RHI‐ASF) and 49 deceased male non‐ASF CCS athletes (RHI‐CCS) from the UNITE brain bank. Each RHI group had a comparison group that included similar aged (+/‐ 5 years) male brain donors without RHI from the Boston University Alzheimer’s Disease Research Center and Framingham Heart Study brain banks. The modified Ischemic Injury Scale (mIIS) served as a global indicator of vascular and white matter pathologies and is a sum of hippocampal sclerosis, infarct/lacune, microinfarct, microbleeds, laminar necrosis, arteriolosclerosis, atherosclerosis of Circle of Willis, cerebral amyloid angiopathy, and white matter rarefaction. Dementia diagnoses were made during consensus conferences. Linear or logistic regression compared the RHI vs non‐RHI groups on the mIIS and its subcomponents. Logistic regression models examined the association between mIIS and dementia. Models were adjusted for age.Results Table 1 shows sample characteristics. The RHI‐CCS group was comprised of boxers, amateur wrestlers, and ice hockey, soccer, rugby, and lacrosse players. 94 decedents had CTE, all of whom were in an RHI exposed group. Of the mIIS components, arteriolosclerosis was the most common across all groups. White matter rarefaction was also the most frequent mIIS component for both RHI groups, but not for non‐RHI groups. Compared to their respective controls, RHI‐ASF and RHI‐CCS were associated with higher mIIS scores (Table 2). Higher mIIS scores corresponded to increased odds for having dementia in both the RHI‐ASF and RHI‐CCS groups (Table 2). White matter rarefaction best discriminated both RHI groups from non‐RHI; atherosclerosis also discriminated RHI‐CCS group (Table 3).ConclusionThese results support vascular and white matter pathologies, specifically white matter rarefaction, as prominent and clinically relevant sequelae of RHI from CCS.

Adolescents who participate in collision and heavy contact sports are at risk for several mechanisms of spinal injury, including hyperflexion, hyperextension, and rotational and axial loading forces. This chapter reviews spinal injuries and injury mechanisms that are common to adolescent collision sport athletes. The incidence of catastrophic spinal injury is reviewed, as well as measures aimed at decreasing this incidence in sports such as American football, rugby, and hockey. A wide range of non-catastrophic injuries to the adolescent spine can also occur during participation in collision sports, including sprains and strains, acute fractures, disc injuries, apophyseal injuries, overuse/stress injuries, and transient neurological injury. The physician who cares for adolescent athletes should be familiar with the differences in the patterns and presentations of spinal injuries between adolescents and adults. Return-to-play decisions should be considered individually based on injury type, severity, and symptoms. The presence of underlying developmental or acquired abnormalities of the spine should be considered when making decisions about participation in collision sports.

Background:Several risk factors for the postoperative recurrence of instability after arthroscopic Bankart repair have been reported, but there have been few detailed investigations of the specific risk factors in relation to the type of sport.Purpose:This study investigated the postoperative recurrence of instability after arthroscopic Bankart repair without additional reinforcement procedures in competitive athletes, including athletes with a large glenoid defect. The purpose of this study was to investigate risk factors related to the postoperative recurrence of instability in athletes.Study Design:Case-control study; Level of evidence, 3.Methods:A total of 115 athletes (123 shoulders) were classified into 5 groups according to type of sport: rugby (41 shoulders), American football (32 shoulders), other collision sports (18 shoulders), contact sports (15 shoulders), and overhead sports (17 shoulders). First, the recurrence rate in each sporting category was investigated, with 113 shoulders followed up for a minimum of 2 years. Then, factors related to postoperative recurrence were investigated in relation to the type of sport.Results:Postoperative recurrence of instability was noted in 23 of 113 shoulders (20.4%). The recurrence rate was 33.3% in rugby, 17.2% in American football, 11.1% in other collision sports, 14.3% in contact sports, and 12.5% in overhead sports. The most frequent cause of recurrence was tackling, and recurrence occurred with tackling in 12 of 16 athletes playing rugby or American football. Reoperation was completed in 11 shoulders. By univariate analysis, significant risk factors for postoperative recurrence of instability included playing rugby, age between 10 and 19 years at surgery, preoperative glenoid defect, small bone fragment of bony Bankart lesion, and capsular tear. However, by multivariate analysis, the most significant factor was not the type of sport but younger age at operation and a preoperative glenoid defect with small or no bone fragment. Compared with the other sports, there was a significantly greater recurrence rate among rugby players without the aforementioned significant risk factors (small glenoid defect, ≤10%; medium or large bone fragment, >5%; and no capsular tear).Conclusion:Younger age at operation and preoperative glenoid defect with small or no bone fragment significantly influenced recurrent instability among competitive athletes.

Youth Exposure to Repetitive Head Impacts From Tackle Football and Long-term Neurologic Outcomes: A Review of the Literature, Knowledge Gaps and Future Directions, and Societal and Clinical Implications