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Introduction: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts (RHI) typically sustained by contact sport athletes. Post‐translation modifications to tau in CTE have not been well delineated or compared to Alzheimer's disease (AD). Methods: We measured phosphorylated tau epitopes within dorsolateral frontal cortex from post mortem brains with neither CTE nor AD (n = 108), CTE (n = 109), AD (n = 223), and both CTE and AD (n = 33). Results: Levels of hyperphosphorylated tau (p‐tau)202, p‐tau231, and p‐tau396 were significantly increased in CTE. Total years of RHI exposure was significantly associated with increased p‐tau202 levels (P =.001), but not p‐tau396. Instead, p‐tau396 was most closely related to amyloid beta (Aβ)1‐42 levels (P <.001). The p‐tau202:p‐tau396 ratio was significantly increased in early and late CTE compared to AD. Discussion: In frontal cortex, p‐tau202 is the most upregulated p‐tau species in CTE, while p‐tau396 is most increased in AD. p‐tau202 and p‐tau396 measurements may aid in developing biomarkers for disease. [ABSTRACT FROM AUTHOR]

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. We previously showed that duration of American football play is associated with risk and severity of CTE pathology. Helmet accelerometers have been used previously to examine frequency, linear acceleration, and rotational acceleration of hits sustained across youth, high school, and college football. Here we projected this data onto former American football playing brain donors to examine the relationship between cumulative frequency of hits, linear acceleration, and rotational acceleration during players' athletic careers and CTE pathology. Method: 656 former American football playing brain donors from the Veterans Affairs‐Boston University‐Concussion Legacy Foundation Brain Bank were examined for CTE pathology and severity. Years and position of play at each level (youth, high school, college, professional) were acquired through retrospective clinical interviews with brain donors next‐of‐kin. From a literature search of studies using helmet accelerometers, we calculated the mean frequency of hits, linear acceleration (g‐force), and rotational acceleration (rad/sec2) for one year of play at each level‐position combination. These values were projected onto brain donors' career exposure to derive cumulative frequency of head impacts (CHII), cumulative linear acceleration (CHII‐G), and cumulative rotational acceleration (CHII‐R). Separate logistic regression models examined the relationship of years of play, CHII, CHII‐G, and CHII‐R on CTE status and severity (low vs. high), adjusting for age at death. Result: The mean (SD) age at death was 59.7 (20.1) and 451 (68.8%) had CTE pathology. Each cumulative measure was significantly associated with presence of CTE (p's<.001) and severity of CTE (p's<.001). Based on ROC analyses, CHII‐R (AUC=0.765, p<.001) and CHII‐G (AUC= 0.758, p<.001) performed significantly better than years of play (AUC=0.716) in classifying CTE pathology, and there was no difference between years of play and CHII (AUC=0.698, p=0.25). Similar relationships were observed for CTE severity. Model fit and cross‐validation statistics were also consistent (Table 2). Conclusion: Among former American football playing brain donors, cumulative linear and rotational acceleration were better predictors of CTE pathology than duration of play or cumulative hits. The findings suggest head impact intensity is an important factor in developing CTE pathology. [ABSTRACT FROM AUTHOR]

Background: Exposure to repetitive head impacts (RHI) is the main risk‐factor for chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by perivascular hyperphosphorylated tau deposition. However, the occurrence and severity of CTE varies widely among those with similar RHI exposure, suggesting other factors, including genetics, may contribute. The MAPT gene, which codes for the tau protein, is implicated in other tauopathies, but has not been investigated in CTE. The 17q21.31 region, containing MAPT, includes a megabase‐long inversion (H1/H2; European ancestry only) and copy‐number variations, including α, β and γ segments, which can be characterized as nine segregating structural subhaplotypes. We investigated associations between these subhaplotypes, CTE, and related clinical and neuropathological outcomes. Method: 458 male brain donors of European ancestry from the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank with known RHI exposure from contact sports and/or military service were evaluated for CTE status, CTE stage (0 = absent; 4 = most severe), semiquantitative tau burden (0 = absent; 3 = most severe) across 11 brain regions and dementia based on informant report. Donors were genotyped on ∼5,000 SNPs across the 17q21.31 region in 2 batches. SHAPEIT and IMPUTE2 were used to phase and impute 12 biallelic surrogate markers and then SHAPEIT was used again to estimate 9 subhaplotypes. We tested the subhaplotype associations with CTE and the above outcomes in regression models adjusted for age at death and 10 principal components of population substructure. Results were meta‐analyzed across batches using the inverse variance method in METAL. Permutation testing was used to account for multiple testing and correlated data. Result: The imputation quality of the surrogate markers was good (info score:0.516‐0.797). There were no significant associations with CTE status. The H1β1γ1 subhaplotype (frequency = 0.39) was significantly associated with dementia (OR = 1.90; padj = 0.019) and semiquantitative tau burden in the amygdala (OR = 1.53; padj = 0.025), entorhinal cortex (OR = 1.50; padj = 0.047), inferior parietal cortex (OR = 1.51; padj = 0.039), middle frontal cortex (OR = 1.48; padj = 0.045), and superior temporal cortex (OR = 1.67; padj = 0.002). H1β1γ1 was nominally associated with CTE stage (OR = 1.35; p = 0.027). Conclusion: These findings suggest a relationship between MAPT region structural variation and CTE‐related outcomes. Extension in a richly characterized living cohort of elite American football players is ongoing. [ABSTRACT FROM AUTHOR]

Background: Although we have greatly increased our ability to identify the presence of neurodegenerative pathology during life, additional techniques and targets are still needed to increase diagnostic specificity. Recently, it has become evident that the neuroinflammatory response might be tailored towards distinct diseases resulting in disease specific "neuroinflammatory signatures". Therefore, a detailed comparison of neuroinflammatory molecules present among distinct neurodegenerative diseases could provide novel information of disease specific therapeutic targets or differential biomarkers. Method: To better examine potential neuroinflammatory signatures, a 71 immune‐related protein multiplex ELISA panel was utilized to analyze anterior cingulate grey matter from 127 individuals neuropathologically diagnosed with Alzheimer's disease (AD), but chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD). A partial least square regression analysis was used for unbiased clustering and identifying proteins that were distinctly correlated with each disease correcting for age and gender. Receiver operator characteristic and binary logistic regression analyses were then used to examine the ability of each candidate protein to distinguish diseases. Validation in postmortem cerebrospinal fluid (CSF) from 15 AD and 14 CTE cases was performed to determine if candidate proteins could act as possible biomarkers. Finally, histology was performed using candidate proteins to visualize cell type expression for better understanding of potential mechanistic pathways. Result: Five clusters of neuroimmune proteins were identified and compared to determine if clusters were specific to distinct disease. Each cluster was found to correlate with either CTE, AD, PSP, CBD, or AGD. When examining which proteins were the strongest driver of each cluster, it was observed the most distinctive protein for CTE was CCL21, AD was FLT3L, and PSP was IL13. Individual proteins that were specific to CBD and AGD were not observed. CCL21 was observed to be elevated in CTE CSF compared to AD, further validating the use as possible biomarkers. Conclusion: Overall, these results highlight that different neuroinflammatory responses might underlie unique mechanisms in related neurodegenerative pathologies. Additionally, the use of distinct neuroinflammatory signatures could help differentiate between neuropathologies and act as novel biomarker candidate to increase specificity for in‐life diagnoses. [ABSTRACT FROM AUTHOR]

Introduction: Validity of the 2014 traumatic encephalopathy syndrome (TES) criteria, proposed to diagnose chronic traumatic encephalopathy (CTE) in life, has not been assessed. Methods: A total of 336 consecutive brain donors exposed to repetitive head impacts from contact sports, military service, and/or physical violence were included. Blinded to clinical information, neuropathologists applied National Institute on Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering CTE criteria. Blinded to neuropathological information, clinicians interviewed informants and reviewed medical records. An expert panel adjudicated TES diagnoses. Results: A total of 309 donors were diagnosed with TES; 244 donors had CTE pathology. TES criteria demonstrated sensitivity and specificity of 0.97 and 0.21, respectively. Cognitive (odds ratio [OR] = 3.6; 95% confidence interval [CI]: 1.2–5.1), but not mood/behavior or motor symptoms, were significantly associated with CTE pathology. Having Alzheimer's disease (AD) pathology was significantly associated with reduced TES accuracy (OR = 0.27; 95% CI: 0.12–0.59). Discussion: TES criteria provided good evidence to rule out, but limited evidence to rule in, CTE pathology. Requiring cognitive symptoms in revised criteria and using AD biomarkers may improve CTE pathology prediction. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both the upper and lower motor neurons. Although ALS typically leads to death within 3 to 5 years after initial symptom onset, approximately 10% of patients with ALS live more than 10 years after symptom onset. We set out to determine similarities and differences in clinical presentation and neuropathology in persons with ALS with long vs. those with standard duration. Participants were United States military Veterans with a pathologically confirmed diagnosis of ALS (n = 179), dichotomized into standard duration (<10 years) and long‐duration (≥10 years). The ALS Functional Rating Scale‐Revised (ALSFRS‐R) was administered at study entry and semi‐annually thereafter until death. Microglial density was determined in a subset of participants. long‐duration ALS occurred in 76 participants (42%) with a mean disease duration of 16.3 years (min/max = 10.1/42.2). Participants with long‐duration ALS were younger at disease onset (P = 0.002), had a slower initial ALS symptom progression on the ALSFRS‐R (P < 0.001) and took longer to diagnose (P < 0.002) than standard duration ALS. Pathologically, long‐duration ALS was associated with less frequent TDP‐43 pathology (P < 0.001). Upper motor neuron degeneration was similar; however, long‐duration ALS participants had less severe lower motor neuron degeneration at death (P < 0.001). In addition, the density of microglia was decreased in the corticospinal tract (P = 0.017) and spinal cord anterior horn (P = 0.009) in long‐duration ALS. Notably, many neuropathological markers of ALS were similar between the standard and long‐duration groups and there was no difference in the frequency of known ALS genetic mutations. These findings suggest that the lower motor neuron system is relatively spared in long‐duration ALS and that pathological progression is likely slowed by as yet unknown genetic and environmental modifiers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to contact and collision sports, including American football. We hypothesized a dose-response relationship between duration of football played and CTE risk and severity.Methods: In a convenience sample of 266 deceased American football players from the Veterans Affairs-Boston University-Concussion Legacy Foundation and Framingham Heart Study Brain Banks, we estimated the association of years of football played with CTE pathological status and severity. We evaluated the ability of years played to classify CTE status using receiver operating characteristic curve analysis. Simulation analyses quantified conditions that might lead to selection bias.Results: In total, 223 of 266 participants met neuropathological diagnostic criteria for CTE. More years of football played were associated with having CTE (odds ratio [OR] = 1.30 per year played, 95% confidence interval [CI] = 1.19-1.41; p = 3.8 × 10-9 ) and with CTE severity (severe vs mild; OR = 1.14 per year played, 95% CI = 1.07-1.22; p = 3.1 × 10-4 ). Participants with CTE were 1/10th as likely to have played <4.5 years (negative likelihood ratio [LR] = 0.102, 95% CI = 0.100-0.105) and were 10 times as likely to have played >14.5 years (positive LR = 10.2, 95% CI = 9.8-10.7) compared with participants without CTE. Sensitivity and specificity were maximized at 11 years played. Simulation demonstrated that years played remained adversely associated with CTE status when years played and CTE status were both related to brain bank selection across widely ranging scenarios.Interpretation: The odds of CTE double every 2.6 years of football played. After accounting for brain bank selection, the magnitude of the relationship between years played and CTE status remained consistent. ANN NEUROL 2020;87:116-131. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) tau and beta‐amyloid levels in chronic traumatic encephalopathy (CTE), a disease which can be clinically indistinguishable from Alzheimer's disease (AD), are largely unknown. We examined postmortem CSF analytes among participants with autopsy confirmed CTE and AD. Method: A total of 192 participants from the Boston University AD Center and VA‐BU‐CLF Center had post‐mortem CSF collected at autopsy. Participants were divided into pathological groups based on consensus AD and CTE criteria, resulting in 61 participants with CTE (18 low, 43 high stage), 79 participants with AD (23 low, 56 intermediate to high pathological change), 11 participants with concurrent CTE and AD, and 41 participants lacking both CTE and AD neuropathology. The Meso Scale Discovery immunoassay system was utilized to measure amyloid‐beta (Ab1‐40, Ab1‐42), total tau (t‐tau), and phosphorylated tau (p‐tau181 and p‐tau231). Result: The low CTE group had higher levels of p‐tau231 compared no CTE/no AD (p=0.041), and compared to the low AD group (p=0.018). The low CTE group had lower levels of Aβ1‐42 compared to no CTE/no AD (p=0.016). The high CTE group had higher levels of p‐tau231 compared to AD (p=0.025) and lower levels of Aβ1‐42 compared to the AD group (p=0.015). Importantly, p‐tau231 and Aβ1‐42 were predictors of diagnosis of CTE vs. no CTE/no AD and CTE vs. AD (Figure 1). Conclusion: Increased CSF p‐tau231 is a promising potentially sensitive biomarkers of CTE and decreased CSF Aβ1‐42 in CTE warrants further investigation as to underlying mechanism and potential as an additional CTE biomarker. [ABSTRACT FROM AUTHOR]

Background: Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. The clinical presentation of CTE can be progressive, leading to cognitive and functional impairment. CTE presence and severity varies among those with similar RHI exposure, suggesting a role for other factors, genetics among them. Family history (FH) of dementia is a proxy of genetic risk of neurodegenerative disease, but its relationship with CTE is unknown. This study aimed to analyze the relationships between FH of dementia, quantitative tau pathology and functional impairment in brain donors at risk for CTE. Method: 558 brain donors from the Veterans Affairs‐Boston University‐Concussion Legacy Foundation Brain Bank with known RHI exposure through contact sports or military service were examined for CTE pathology. We performed digital quantification of AT8 immunostaining for tau pathology in the CA4 hippocampal subfield, a region disproportionately affected in CTE. First‐degree FH of dementia and the Functional Assessment Questionnaire (FAQ; 30 point scale), a validated measure of instrumental activities of daily living, were collected through telephone interviews with brain donors' next‐of‐kin. Using a regression framework, we examined the direct and indirect relationships between FH of dementia, CA4 quantitative tau burden and FAQ score, adjusting for age and race. Result: The mean (SD) age at death was 59.9 (20.4) and 362 (65%) had CTE pathology. In separate models, first‐degree FH of dementia was significantly associated with increased CA4 tau burden (β=0.27, p=0.01) and with increased FAQ score (β=2.11, p=0.02). Additionally, CA4 tau burden was associated with increased FAQ score (β=2.58, p=0.001). After adjusting for CA4 tau burden, the effect of first‐degree FH of dementia was reduced and no longer significant (β=.598, p=.663). Conclusion: Among brain donors with RHI exposure, hippocampal CA4 tau burden may mediate the relationship between first‐degree FH of dementia and functional impairment. The findings suggest that the risk of CTE may be heritable and share etiologic mechanisms with other dementing illnesses. [ABSTRACT FROM AUTHOR]

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). CTE has distinct neuropathology defined by perivascular hyperphosphorylated tau (ptau) deposition. The presence and severity of CTE pathology varies among those with similar RHI exposure, suggesting a role for non‐RHI risk factors, including genetics. Here we conducted the first genome‐wide association study (GWAS) of neuropathologically‐confirmed CTE. Method: 175 brain donors from the Veterans Affairs‐Boston University‐Concussion Legacy Foundation Brain Bank with known exposure to RHI in the form of contact sports and/or military service were assessed for CTE pathology. CTE pathology was staged on a semiquantitative scale from 0 to 4 (0 = absent; 4 = most severe). Ptau burden was also assessed across 11 brain regions commonly affected in CTE on a semiquantitative scale from 0 to 3 (0 = absent; 3 = most severe). We tested the association of genome‐wide genotyped and imputed single nucleotide polymorphisms (SNPs) with CTE stage in a linear regression model adjusted for 10 principal components of population substructure. We tested the association of top hits with ptau burden in each of the 11 brain regions. Result: Two loci achieved genome‐wide significance: top SNP rs63565460 [minor allele frequency (MAF) = 0.08; beta = ‐1.64; p = 2.4 × 10−8] is an intronic SNP in PIP5K1B on chromosome 9; and top SNP rs12447028 (MAF = 0.07; beta = ‐1.84, p = 2.6 × 10−8) is an intronic SNP in ABAT on chromosome 16. The PIP5K1B locus had the largest effects in cortical regions. PIP5K1B is expressed in brain and has been associated with intelligence in GWAS. The ABAT locus had the largest effects in the inferior orbital gyrus and the locus coeruleus. ABAT is expressed in brain and has been associated in GWAS with anger proclivity, a symptom of CTE. The ABAT protein functions in GABA catabolism. Conclusion: In the first GWAS of CTE, two promising loci in PIP5K1B and ABAT achieved genome‐wide significance. Both loci had the largest effects in brain regions affected early in CTE. Efforts to enlarge the sample size, incorporate measures of RHI exposure and test additional endophenotypes are underway. Identified loci may implicate disease mechanisms, provide targets for therapies, and guide counseling of athletes regarding risk of play. [ABSTRACT FROM AUTHOR]