Faculty Bibliography

BACKGROUND:In vivo biomarkers that can detect long-term neuropathologies from repetitive head impact (RHI) exposure are needed, especially for the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). Here, we evaluated plasma p-tau217 as a potential biomarker for CTE p-tau pathology, and examined the concordance between plasma p-tau217 and Aβ pathology in an at-risk for CTE sample. METHOD/METHODS:The sample included 180 male former football players (120 professional, 60 college), and 56 asymptomatic men without RHI (i.e., controls). Participants completed blood draws, 18F-florbetapir (Aβ+=SUVR≥1.10), and 18F-flortaucipir PET. Traumatic encephalopathy syndrome (TES) diagnoses were made. Single molecule array for plasma p-tau217 (ALZpath) was performed (≥0.6 cutoff used to maximize sensitivity). Nine participants had post-mortem tissue. ANCOVA examined group differences in p-tau217 (football vs controls; TES-CTE no, TES-CTE suggestive, TES-CTE possible/probable). Multivariable regression models tested associations between p-tau217 and florbetapir/flortaucipir PET. Covariates included age, race and APOE e4. RESULT/RESULTS:Sample characteristics are in Table 1. p-tau217 concentrations were higher in former football players compared to controls (est. marginal mean difference=-0.217, p = 0.005). There were no group differences in Aβ-PET SUVR. No differences were found across TES-CTE certainty levels. In football players, higher p-tau217 was associated with higher Aβ-PET SUVR (B=1.380, 95%CI[0.597-2.155], p = 0.001) but not when Aβ+ (n = 17) participants and those with kidney/liver disease (n = 5) were excluded. Aβ+ participants had the highest p-tau217 (Figure 1). When compared against Aβ-PET, several false Aβ-positives (high p-tau217, Aβ-) were identified, including one extreme outlier (assay related) and a cluster of Aβ- participants with p-tau217 between 0.60-1.0. There were no associations with flortaucipir SUVR (frontal, mesial temporal, left parietal). Two extreme p-tau217 outliers had autopsy-confirmed CTE stage III (AD-, Table 2). Of the remaining donors, all were AD- and four had CTE (stages II-IV) with ptau217 between 0.125-0.449. CONCLUSION/CONCLUSIONS:Plasma p-tau217 has usefulness in quantifying Aβ pathology but restricted utility for detection of CTE. In this at-risk for CTE sample, p-tau217 and Aβ-PET were associated at the group level. At the individual level, false Aβ-positives (and negatives) existed, including Aβ- participants with high p-tau217. We will explore whether this discrepancy is due to disease or peripheral interference with the N-terminal binding in p-tau assays.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Disturbances in brain catecholamine activity may be associated with symptoms after exposure to repetitive head impacts (RHIs) or related chronic traumatic encephalopathy (CTE). In this article, we studied CSF catecholamines in former professional and college American football players and examined the relationship with football proxies of RHI exposure, CTE probability, cognitive performance, neuropsychiatric symptoms, and parkinsonism. METHODS:In this observational cross-sectional study, we examined male former American football players, professional ("PRO") or college ("COL") level, and asymptomatic unexposed male ("UE") individuals from the DIAGNOSE CTE Research Project. Catecholamines-norepinephrine (NE) and its metabolite, 3,4-dihydroxyphenylglycol (DHPG), and dopamine (DA) and its precursor, 3,4-dihydroxyphenylalanine (l-DOPA), and metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC)-were measured in CSF with high-performance liquid chromatography and compared across groups with analysis of covariance. Multivariable linear regression models tested the relationship between CSF catecholamines and proxies of RHI exposure (e.g., total years of playing American football), factor scores for cognition, and neurobehavioral dysregulation (explosivity, emotional dyscontrol, impulsivity, affective lability), as well as depressive/anxiety symptoms, measured with the Beck Depression/Anxiety Inventories. CTE probability and parkinsonism were assessed using the National Institute of Neurological Disorders and Stroke consensus diagnostic criteria for traumatic encephalopathy syndrome (TES), and biomarkers were compared among different diagnostic groups. RESULTS:The cohort consisted of 120 former American football players (85 PRO players, 35 COL players) and 35 UE participants (age 45-75). Former players had significantly lower levels of NE (mean difference = -0.114, 95% CI -0.190 to -0.038), l-DOPA (-0.121, 95% CI -0.109 to -0.027), and DOPAC (-0.116, 95% CI -0.177 to -0.054) than UE participants. For NE and DOPAC, these overall group differences were primarily due to differences between the PRO and UE cohorts. No significant differences were found across TES-CTE probability subgroups or TES-parkinsonism diagnostic groups. Within the COL cohort, tested as post hoc analyses, higher CSF NE and l-DOPA were associated with higher neurobehavioral dysregulation factor scores, BAI total score, and worse executive functioning and processing speed. CSF DHPG and DOPAC were associated with impulsivity only in this subgroup. DISCUSSION/CONCLUSIONS:We observed reduced CSF catecholamine concentrations in former elite American football players, although the relationship with degree of RHI exposure and the clinical impact needs further study.

OBJECTIVE:This study aimed to externally validate the Memory Assessment Clinics Scale for Epilepsy (MAC-E), a brief self-report measure of subjective memory complaints in adults with epilepsy. METHODS:A cross-sectional study was conducted including adults with focal pharmacoresistant epilepsy from three Level 4 epilepsy centers in the U.S., who completed the MAC-E as part of a clinical neuropsychological evaluation. Confirmatory factor analysis was conducted, and goodness-of-fit criteria were calculated to assess model fit: comparative fit index (CFI), root mean square error of approximation (RMSEA), and standardized root mean residual (SRMR). Item response theory models were constructed, and Mokken analysis was used to assess discrimination and unidimensionality. Internal consistency was evaluated with McDonald's Omega. RESULTS:values for each of the 5 factors (0.58-0.91 and 0.34-0.82, respectively). MAC-E items demonstrated high levels of discrimination as well as the ability to evaluate across the entirety of each latent trait. Score responses were uniformly distributed across latent traits, and unidimensionality was established by factor (all H coefficients > 0.4). Internal consistency was high across factors (omega range: 0.77-0.88). CONCLUSIONS:Results of this study demonstrate good external validation of the MAC-E in an independent, multicenter cohort of adults with epilepsy. These findings provide further support that the MAC-E is a psychometrically valid, self-report instrument to assess every-day memory abilities in adults with epilepsy in both clinical and research settings.

OBJECTIVE/UNASSIGNED:The long-recognized association of brain injury with increased risk of dementia has undergone significant refinement and more detailed study in recent decades. Chronic traumatic encephalopathy (CTE) is a specific neurodegenerative tauopathy related to prior exposure to repetitive head impacts (RHI). We aim to contextualize CTE within a historical perspective and among emerging data which highlights the scientific and conceptual evolution of CTE-related research in parallel with the broader field of neurodegenerative disease and dementia. METHODS/UNASSIGNED:We provide a narrative state-of-the-science update on CTE neuropathology, clinical manifestations, biomarkers, different types and patterns of head impact exposure relevant for CTE, and the complicated influence of neurodegenerative co-pathology on symptoms. CONCLUSIONS/UNASSIGNED:Now almost 20 years since the initial case report of CTE in a former American football player, the field of CTE continues evolving with increasing clarity but also several ongoing controversies. Our understanding of CTE neuropathology outpaces that of disease-specific clinical correlates or the development of in-vivo biomarkers. Diagnostic criteria for symptoms attributable to CTE are still being validated, but leveraging increasingly available biomarkers for other conditions like Alzheimer's disease may be helpful for informing the CTE differential diagnosis. As diagnostic refinement efforts advance, clinicians should provide care and/or referrals to providers best suited to treat an individual patient's clinical symptoms, many of which have evidence-based behavioral treatment options that are etiologically agnostic. Several ongoing research initiatives and the gradual accrual of gold standard clinico-pathological data will pay dividends for advancing the many existing gaps in the field of CTE.

INTRODUCTION/BACKGROUND:Blood-based biomarkers offer a promising approach for the detection of neuropathologies from repetitive head impacts (RHI). We evaluated plasma biomarkers of amyloid, tau, neurodegeneration, and inflammation in former football players. METHODS:The sample included 180 former football players and 60 asymptomatic, unexposed male participants (aged 45-74). Plasma assays were conducted for beta-amyloid (Aβ) 40, Aβ42, hyper-phosphorylated tau (p-tau) 181+231, total tau (t-tau), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), Aβ42/p-tau181 and Aβ42/Aβ40 ratios. We evaluated their ability to differentiate the groups and associations with RHI proxies and traumatic encephalopathy syndrome (TES). RESULTS:= 0.008). DISCUSSION/CONCLUSIONS:Plasma p-tau181 and p-tau231, GFAP, and NfL may offer some usefulness for the characterization of RHI-related neuropathologies. HIGHLIGHTS/CONCLUSIONS:Former football players had higher plasma p-tau181 and p-tau231 and lower Aβ42/ptau-181 compared to asymptomatic, unexposed men. Younger age of first exposure was associated with increased plasma NfL and GFAP in older but not younger participants. Plasma GFAP was higher in participants with TES-CTE possible/probable compared to TES-CTE no/suggestive.

BACKGROUND AND OBJECTIVES/UNASSIGNED:Obstructive sleep apnea (SA) is common in older men and a contributor to negative cognitive, psychiatric, and brain health outcomes. Little is known about SA in those who played contact sports and are at increased risk of neurodegenerative disease(s) and other neuropathologies associated with repetitive head impacts (RHI). In this study, we investigated the frequency of diagnosed and witnessed SA and its contribution to clinical symptoms and tau pathology using PET imaging among male former college and former professional American football players. METHODS/UNASSIGNED:The sample included 120 former National Football League (NFL) players, 60 former college players, and 60 asymptomatic men without exposure to RHI (i.e., controls). Diagnosed SA was self-reported, and all participants completed the Mayo Sleep Questionnaire (MSQ, informant version), the Epworth Sleepiness Scale (ESS), neuropsychological testing, and tau (flortaucipir) PET imaging. Associations between sleep indices (diagnosed SA, MSQ items, and the ESS) and derived neuropsychological factor scores, self-reported depression (Beck Depression Inventory-II [BDI-II]), informant-reported neurobehavioral dysregulation (Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A] Behavioral Regulation Index [BRI]), and tau PET uptake, were tested. RESULTS/UNASSIGNED:gene carrier status. Higher ESS scores correlated with higher BDI-II and BRIEF-A BRI scores. Continuous positive airway pressure use mitigated all of the abovementioned associations. Among the former college football players, witnessed apnea and higher ESS scores were associated with higher BRIEF-A BRI and BDI-II scores, respectively. No other associations were observed in this subgroup. DISCUSSION/UNASSIGNED:Former elite American football players are at risk of SA. Our findings suggest that SA might contribute to cognitive, neuropsychiatric, and tau outcomes in this population. Like all neurodegenerative diseases, this study emphasizes the multifactorial contributions to negative brain health outcomes and the importance of sleep for optimal brain health.

INTRODUCTION/BACKGROUND:Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project. METHOD/METHODS:We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same-age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES). RESULTS:Significantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups. DISCUSSION/CONCLUSIONS:Additional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.