Dataset Information

Tau Positron-Emission Tomography in Former National Football League Players.

ABSTRACT: BACKGROUND:Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been associated with a history of repetitive head impacts. The neuropathological diagnosis is based on a specific pattern of tau deposition with minimal amyloid-beta deposition that differs from other disorders, including Alzheimer's disease. The feasibility of detecting tau and amyloid deposition in the brains of living persons at risk for CTE has not been well studied. METHODS:We used flortaucipir positron-emission tomography (PET) and florbetapir PET to measure deposition of tau and amyloid-beta, respectively, in the brains of former National Football League (NFL) players with cognitive and neuropsychiatric symptoms and in asymptomatic men with no history of traumatic brain injury. Automated image-analysis algorithms were used to compare the regional tau standardized uptake value ratio (SUVR, the ratio of radioactivity in a cerebral region to that in the cerebellum as a reference) between the two groups and to explore the associations of SUVR with symptom severity and with years of football play in the former-player group. RESULTS:A total of 26 former players and 31 controls were included in the analysis. The mean flortaucipir SUVR was higher among former players than among controls in three regions of the brain: bilateral superior frontal (1.09 vs. 0.98; adjusted mean difference, 0.13; 95% confidence interval [CI], 0.06 to 0.20; P<0.001), bilateral medial temporal (1.23 vs. 1.12; adjusted mean difference, 0.13; 95% CI, 0.05 to 0.21; P<0.001), and left parietal (1.12 vs. 1.01; adjusted mean difference, 0.12; 95% CI, 0.05 to 0.20; P?=?0.002). In exploratory analyses, the correlation coefficients in these three regions between the SUVRs and years of play were 0.58 (95% CI, 0.25 to 0.79), 0.45 (95% CI, 0.07 to 0.71), and 0.50 (95% CI, 0.14 to 0.74), respectively. There was no association between tau deposition and scores on cognitive and neuropsychiatric tests. Only one former player had levels of amyloid-beta deposition similar to those in persons with Alzheimer's disease. CONCLUSIONS:A group of living former NFL players with cognitive and neuropsychiatric symptoms had higher tau levels measured by PET than controls in brain regions that are affected by CTE and did not have elevated amyloid-beta levels. Further studies are needed to determine whether elevated CTE-associated tau can be detected in individual persons. (Funded by Avid Radiopharmaceuticals and others.).

SUBMITTER: Stern RA

PROVIDER: S-EPMC6636818 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Tau Positron-Emission Tomography in Former National Football League Players.

Stern Robert A RA Adler Charles H CH Chen Kewei K Navitsky Michael M Luo Ji J Dodick David W DW Alosco Michael L ML Tripodis Yorghos Y Goradia Dhruman D DD Martin Brett B Mastroeni Diego D Fritts Nathan G NG Jarnagin Johnny J Devous Michael D MD Mintun Mark A MA Pontecorvo Michael J MJ Shenton Martha E ME Reiman Eric M EM

The New England journal of medicine 20190410 18

<h4>Background</h4>Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been associated with a history of repetitive head impacts. The neuropathological diagnosis is based on a specific pattern of tau deposition with minimal amyloid-beta deposition that differs from other disorders, including Alzheimer's disease. The feasibility of detecting tau and amyloid deposition in the brains of living persons at risk for CTE has not been well studied.<h4>Methods</h4>We used flort ...[more]

PMID: 30969506

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Project description:American-style football (ASF) players experience repetitive head impacts that may result in chronic traumatic encephalopathy neuropathological change (CTE-NC). At present, a definitive diagnosis of CTE-NC requires the identification of localized hyperphosphorylated Tau (p-Tau) after death via immunohistochemistry. Some studies suggest that positron emission tomography (PET) with the radiotracer [18F]-Flortaucipir (FTP) may be capable of detecting p-Tau and thus establishing a diagnosis of CTE-NC among living former ASF players. To assess associations between FTP, football exposure, and objective neuropsychological measures among former professional ASF players, we conducted a study that compared former professional ASF players with age-matched male control participants without repetitive head impact exposure. Former ASF players and male controls underwent structural magnetic resonance imaging and PET using FTP for p-Tau and [11C]-PiB for amyloid-β. Former players underwent neuropsychological testing. The ASF exposure was quantified as age at first exposure, professional career duration, concussion signs and symptoms burden, and total years of any football play. Neuropsychological testing included measures of memory, executive functioning, and depression symptom severity. P-Tau was quantified as FTP standardized uptake value ratios (SUVR) and [11C]-PiB by distribution volume ratios (DVR) using cerebellar grey matter as the reference region. There were no significant differences in [18F]-FTP uptake among former ASF players (n = 27, age = 50 ± 7 years) compared with control participants (n = 11, age = 55 ± 4 years), nor did any participant have significant amyloid-β burden. Among ASF participants, there were no associations between objective measures of neurocognitive functioning and [18F]-FTP uptake. There was a marginally significant difference, however, between [18F]-FTP uptake isolated to the entorhinal cortex among players in age-, position-, and race-adjusted models (p = 0.05) that may represent an area of future investigation. The absence of increased [18F]-FTP uptake in brain regions previously implicated in CTE among former professional ASF players compared with controls questions the utility of [18F]-FTP PET for clinical evaluation in this population.

Project description:ImportancePilot studies that involved early imaging of the 18 kDa translocator protein (TSPO) using positron emission tomography (PET) indicated high levels of TSPO in the brains of active or former National Football League (NFL) players. If validated further in larger studies, those findings may have implications for athletes involved in collision sport.ObjectiveTo test for higher TSPO that marks brain injury and repair in a relatively large, unique cohort of former NFL players compared with former elite, noncollision sport athletes.Design, setting, and participantsThis cross-sectional study used carbon 11-labeled N,N-diethyl-2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide positron emission tomography ([11C]DPA-713 PET) data from former NFL players within 12 years of last participation in the NFL and elite noncollision sport athletes from across the US. Participants were enrolled between April 2018 and February 2023.Main outcomes and measuresRegional [11C]DPA-713 total distribution volume from [11C]DPA-713 PET that is a measure of regional brain TSPO; regional brain volumes on magnetic resonance imaging; neuropsychological performance, including attention, executive function, and memory domains.ResultsThis study included 27 former NFL players and 27 former elite, noncollision sport athletes. Regional TSPO levels were higher in former NFL players compared with former elite, noncollision sport athletes (unstandardized β coefficient, 1.08; SE, 0.22; 95% CI, 0.65 to 1.52; P < .001). The magnitude of the group difference depended on region, with largest group differences in TSPO in cingulate and frontal cortices as well as hippocampus. Compared with noncollision sport athletes, former NFL players performed worse in learning (mean difference [MD], -0.70; 95% CI, -1.14 to -0.25; P = .003) and memory (MD, -0.77; 95% CI, -1.24 to -0.30; P = .002), with no correlation between total gray matter TSPO and these cognitive domains.Conclusions and relevanceIn this cross-sectional study using [11C]DPA-713 PET, higher brain TSPO was found in former NFL players compared with noncollision sport athletes. This finding is consistent with neuroimmune activation even after cessation of NFL play. Future longitudinal [11C]DPA-713 PET and neuropsychological testing promises to inform whether neuroimmune-modulating therapy may be warranted.

Project description:ImportanceThe recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-β plaques and tau neurofibrillary tangles.ObjectiveTo determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflect cerebral β-amyloidosis or neurofibrillary tangle aggregation measured with positron emission tomography (PET).Design, setting, and participantsThis was a cross-sectional study of 2 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) study, with data collected between October 2017 and August 2021, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), with data collected between September 2015 and November 2019. TRIAD was a single-center study, and ADNI was a multicenter study. Two independent subsamples were derived from TRIAD. The first TRIAD subsample comprised individuals assessed with CSF p-tau (p-tau181, p-tau217, p-tau231, p-tau235), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. The second TRIAD subsample included individuals assessed with plasma p-tau (p-tau181, p-tau217, p-tau231), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. An independent cohort from ADNI comprised individuals assessed with CSF p-tau181, [18F]florbetapir PET, and [18F]flortaucipir PET. Participants were included based on the availability of p-tau and PET biomarker assessments collected within 9 months of each other. Exclusion criteria were a history of head trauma or magnetic resonance imaging/PET safety contraindications. No participants who met eligibility criteria were excluded.ExposuresAmyloid PET, tau PET, and CSF and plasma assessments of p-tau measured with single molecule array (Simoa) assay or enzyme-linked immunosorbent assay.Main outcomes and measuresAssociations between p-tau biomarkers with amyloid PET and tau PET.ResultsA total of 609 participants (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) were included in the study. For all 4 phosphorylation sites assessed in CSF, p-tau was significantly more closely associated with amyloid-PET values than tau-PET values (p-tau181 difference, 13%; 95% CI, 3%-22%; P = .006; p-tau217 difference, 11%; 95% CI, 3%-20%; P = .003; p-tau231 difference, 15%; 95% CI, 5%-22%; P < .001; p-tau235 difference, 9%; 95% CI, 1%-19%; P = .02) . These results were replicated with plasma p-tau181 (difference, 11%; 95% CI, 1%-22%; P = .02), p-tau217 (difference, 9%; 95% CI, 1%-19%; P = .02), p-tau231 (difference, 13%; 95% CI, 3%-24%; P = .009), and CSF p-tau181 (difference, 9%; 95% CI, 1%-21%; P = .02) in independent cohorts.Conclusions and relevanceResults of this cross-sectional study of 2 observational cohorts suggest that the p-tau abnormality as an early event in AD pathogenesis was associated with amyloid-β accumulation and highlights the need for careful interpretation of p-tau biomarkers in the context of the amyloid/tau/neurodegeneration, or A/T/(N), framework.

Project description:ImportanceBiomarkers for chronic traumatic encephalopathy (CTE) are currently lacking. The radiotracer fluorine F 18-labeled (18F)-flortaucipir (FTP) detects tau pathology in Alzheimer disease, and positron emission tomography (PET) with FTP shows elevated binding in individuals at risk for CTE. No study, however, has assessed the correlation between in vivo FTP PET and postmortem tau in CTE.ObjectiveTo assess the regional association between in vivo FTP binding and postmortem tau pathology in a patient with pathologically confirmed CTE.Design, setting, and participantsA white male former National Football League player with 17 years of US football exposure was clinically diagnosed with traumatic encephalopathy syndrome at a neurology tertiary referral center. 18F-Fludeoxyglucose, carbon 11-labeled Pittsburgh compound B, and FTP PET were performed 52 months prior to death, and magnetic resonance imaging, 50 months prior to death. Brain images were assessed qualitatively for abnormalities blinded to autopsy data. Autopsy was performed using a neurodegenerative research protocol. The FTP standardized uptake value ratios (inferior cerebellar gray reference region) and W-score (age-adjusted z-score) maps were compared with phosphorylated tau immunohistochemical analysis with monoclonal antibody CP13.Main outcomes and measuresQualitative and quantitative comparisons between antemortem FTP PET and tau pathology at autopsy.ResultsFlortaucipir uptake was distributed in a patchy, frontotemporal-predominant pattern that overlapped with regions showing neurodegeneration on magnetic resonance imaging and hypometabolism on 18F-fludeoxyglucose PET. Pathological assessment revealed stage 4 CTE; limbic argyrophilic grain disease; stage 2 limbic-predominant, age-related transactive response DNA-binding protein 43 encephalopathy; and Braak neurofibrillary tangle stage 3. 18F-Flortaucipir W-maps matched areas of high postmortem tau burden in left fusiform and inferior temporal gyri and juxtacortical frontal white matter. High FTP W-scores with low tau burden were found in the basal ganglia, thalamus, motor cortex, and calcarine cortex. No regions with low FTP W-scores corresponded to areas with high pathological tau burden. A modest correlation, which did not reach statistical significance (ρ = 0.35, P = .17), was found between FTP standardized uptake value ratio and tau area fraction at the regional level.Conclusions and relevanceIn this patient, FTP PET findings during life showed a modest correspondence with postmortem pathology in CTE. These findings suggest that FTP may have limited utility as a tau biomarker in CTE.

Dataset Information

Tau Positron-Emission Tomography in Former National Football League Players.

Publications

Tau Positron-Emission Tomography in Former National Football League Players.

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