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.
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
Objective: Sports-related concussions are associated with both acute and long-term consequences. Past work has identified novel risk factors and modifiers for concussions, including mood and ...neuropsychiatric disorders. Attention Deficit Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder that may also contribute to concussion risk, although no study has examined this possibility.
Methods: One hundred and thirty-nine NCAA Division-I athletes at Kent State University (KSU) self-reported a history of prior concussion and diagnostic history of ADHD as part of a larger concussion management programme at KSU.
Results: ADHD was prevalent (10.1%) and 18.0% of the sample reported a prior history of at least one concussion injury. 50.4% of athletes with ADHD reported a history of at least one prior concussion vs 14.4% of athletes without ADHD, which represented a significant difference (p < 0.01). Analyses showed that athletes with ADHD were more likely to report a past history of concussions than those without ADHD (F (1,133) = 4.31, p = 0.04).
Conclusion: ADHD is prevalent in NCAA Division-I athletes and associated with history of past concussions. If replicated, these findings could have important implications in the prevention and management of concussions in athletes with ADHD.
We examined baseline and longitudinal associations between plasma neurofilament light (NfL) and total tau (t-tau), and the clinical presentation of Alzheimer's disease (AD). A total of 579 ...participants (238, normal cognition NC; 185, mild cognitive impairment MCI; 156, AD dementia) had baseline blood draws; 82% had follow-up evaluations. Plasma samples were analyzed for NfL and t-tau using Simoa technology. Baseline plasma NfL was higher in AD dementia than MCI (standardized mean difference = 0.55, 95% CI: 0.37–0.73) and NC (standardized mean difference = 0.68, 95% CI: 0.49–0.88), corresponded to Clinical Dementia Rating scores (OR = 1.94, 95% CI: 1.35–2.79), and correlated with all neuropsychological tests (r's = 0.13–0.42). Longitudinally, NfL did not predict diagnostic conversion but predicted decline on 3/10 neuropsychological tests. Baseline plasma t-tau was higher in AD dementia than NC with a small effect (standardized mean difference = 0.33, 95% CI: 0.10–0.57) but not MCI. t-tau did not statistically significant predict any longitudinal outcomes. Plasma NfL may be useful for the detection of AD dementia and monitoring of disease progression. In contrast, there was minimal evidence in support of plasma t-tau.
•Baseline plasma neurofilament light was higher in Alzheimer's disease dementia than mild cognitive impairment and normal cognition.•Baseline plasma neurofilament light was associated with baseline cognitive test score and predicted subsequent decline but did not predict diagnostic conversion.•Baseline plasma total tau was higher in Alzheimer's disease dementia than mild cognitive impairment and normal cognition.•There were no statistically significant effects for baseline plasma total tau on cognitive decline or diagnostic conversion.
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.
Introduction
The relationship between persistent loneliness and Alzheimer's disease (AD) is unclear. We examined the relationship between different types of mid‐life loneliness and the development of ...dementia and AD.
Methods
Loneliness was assessed in cognitively normal adults using one item from the Center for Epidemiologic Studies Depression Scale. We defined loneliness as no loneliness, transient loneliness, incident loneliness,or persistent loneliness, and applied Cox regression models and Kaplan‐Meier plots with dementia and AD as outcomes (n = 2880).
Results
After adjusting for demographics, social network, physical health, and apolipoprotein E ε4, persistent loneliness was associated with higher (hazard ratio HR, 1.91; 95% confidence interval CI 1.25–2.90; P < .01), and transient loneliness with lower (HR, 0.34; 95% CI 0.14–0.84; P < .05), risk of dementia onset, compared to no loneliness. Results were similar for AD risk.
Discussion
Persistent loneliness in mid‐life is an independent risk factor for dementia and AD, whereas recovery from loneliness suggests resilience to dementia risk.
Longitudinal investigations are needed to improve understanding of the contributions of cerebral small vessel disease to the clinical manifestation of Alzheimer's disease, particularly in the early ...disease stages. This study leveraged the National Alzheimer's Coordinating Center Uniform Data Set to longitudinally examine the association between white matter hyperintensities and neuropsychological, neuropsychiatric, and functional decline among participants with normal cognition.
The sample included 465 participants from the National Alzheimer's Coordinating Center Uniform Data Set who had quantitated volume of white matter hyperintensities from fluid-attenuated inversion recovery MRI, had normal cognition at the time of their MRI, and were administered the National Alzheimer's Coordinating Center Uniform Data Set neuropsychological test battery within 1 year of study evaluation and had at least two post-MRI time points of clinical data. Neuropsychiatric status was assessed by the Geriatric Depression Scale-15 and Neuropsychiatric Inventory-Questionnaire. Clinical Dementia Rating Sum of Boxes defined functional status. For participants subsequently diagnosed with mild cognitive impairment (MCI) or dementia, their impairment must have been attributed to Alzheimer's disease (AD) to evaluate the relationships between WMH and the clinical presentation of AD.
Of the 465 participants, 56 converted to MCI or AD dementia (average follow-up = 5 years). Among the 465 participants, generalized estimating equations controlling for age, sex, race, education, APOE ε4, and total brain and hippocampal volume showed that higher baseline log-white matter hyperintensities predicted accelerated decline on the following neuropsychological tests in rank order of effect size: Trails B (p < 0.01), Digit Symbol Coding (p < 0.01), Logical Memory Immediate Recall (p = 0.02), Trail Making A (p < 0.01), and Semantic Fluency (p < 0.01). White matter hyperintensities predicted increases in Clinical Dementia Rating Sum of Boxes (p < 0.01) and Geriatric Depression Scale-15 scores (p = 0.01). Effect sizes were comparable to total brain and hippocampal volume. White matter hyperintensities did not predict diagnostic conversion. All effects also remained after including individuals with non-AD suspected etiologies for those who converted to MCI or dementia.
In this baseline cognitively normal sample, greater white matter hyperintensities were associated with accelerated cognitive, neuropsychiatric, and functional decline independent of traditional risk factors and MRI biomarkers for Alzheimer's disease.
To test the hypothesis that repetitive head impacts (RHIs), like those from contact sport play and traumatic brain injury (TBI) have long-term neuropsychiatric and cognitive consequences, we compared ...middle-age and older adult participants who reported a history of RHI and/or TBI with those without this history on measures of depression and cognition.
This cross-sectional study included 13,323 individuals (mean age, 61.95; 72.5% female) from the Brain Health Registry who completed online assessments, including the Ohio State University TBI Identification Method, the Geriatric Depression Scale (GDS-15), and the CogState Brief Battery and Lumos Labs NeuroCognitive Performance Tests. Inverse propensity-weighted linear regressions accounting for age, sex, race/ethnicity, and education tested the effects of RHI and TBI compared to a non-RHI/TBI group.
A total of 725 participants reported RHI exposure (mostly contact sport play and abuse) and 7,277 reported TBI (n = 2,604 with loss of consciousness LOC). RHI (β, 1.24; 95% CI, 0.36-2.12), TBI without LOC (β, 0.43; 95% CI, 0.31-0.54), and TBI with LOC (β, 0.75; 95% CI, 0.59-0.91) corresponded to higher GDS-15 scores. While TBI with LOC had the most neuropsychological associations, TBI without LOC had a negative effect on CogState Identification (β, 0.004; 95% CI, 0.001-0.01) and CogState One Back Test (β, 0.004; 95% CI, 0.0002-0.01). RHI predicted worse CogState One Back Test scores (β, 0.02; 95% CI, -0.01 to 0.05). There were RHI × TBI interaction effects on several neuropsychological subtests, and participants who had a history of both RHI and TBI with LOC had the greatest depression symptoms and worse cognition.
RHI and TBI independently contributed to worse mid- to later-life neuropsychiatric and cognitive functioning.
Blood-based biomarkers such as tau phosphorylated at threonine 181 (phosphorylated-tau181) represent an accessible, cost-effective and scalable approach for the in vivo detection of Alzheimer's ...disease pathophysiology. Plasma-pathological correlation studies are needed to validate plasma phosphorylated-tau181 as an accurate and reliable biomarker of Alzheimer's disease neuropathological changes. This plasma-to-autopsy correlation study included participants from the Boston University Alzheimer's Disease Research Center who had a plasma sample analysed for phosphorylated-tau181 between 2008 and 2018 and donated their brain for neuropathological examination. Plasma phosphorelated-tau181 was measured with single molecule array technology. Of 103 participants, 62 (60.2%) had autopsy-confirmed Alzheimer's disease. Average time between blood draw and death was 5.6 years (standard deviation = 3.1 years). Multivariable analyses showed higher plasma phosphorylated-tau181 concentrations were associated with increased odds for having autopsy-confirmed Alzheimer's disease AUC = 0.82, OR = 1.07, 95% CI = 1.03-1.11, P < 0.01; phosphorylated-tau standardized (z-transformed): OR = 2.98, 95% CI = 1.50-5.93, P < 0.01. Higher plasma phosphorylated-tau181 levels were associated with increased odds for having a higher Braak stage (OR = 1.06, 95% CI = 1.02-1.09, P < 0.01) and more severe phosphorylated-tau across six cortical and subcortical brain regions (ORs = 1.03-1.06, P < 0.05). The association between plasma phosphorylated-tau181 and Alzheimer's disease was strongest in those who were demented at time of blood draw (OR = 1.25, 95%CI = 1.02-1.53), but an effect existed among the non-demented (OR = 1.05, 95% CI = 1.01-1.10). There was higher discrimination accuracy for Alzheimer's disease when blood draw occurred in years closer to death; however, higher plasma phosphorylated-tau181 levels were associated with Alzheimer's disease even when blood draw occurred >5 years from death. Ante-mortem plasma phosphorylated-tau181 concentrations were associated with Alzheimer's disease neuropathology and accurately differentiated brain donors with and without autopsy-confirmed Alzheimer's disease. These findings support plasma phosphorylated-tau181 as a scalable biomarker for the detection of Alzheimer's disease.
Youth participation in contact and collision sports, particularly tackle football, is associated with exposure to repetitive head impacts during a time period when tremendous brain maturation is ...occurring. Accumulating evidence suggests that exposure to repetitive head impacts from youth tackle football may increase vulnerability to long-term cognitive, neuropsychiatric, and neurologic disturbances. There are limitations to the current literature and conflicting findings exist. Nonetheless, participation in youth football has become a cause of concern to clinicians, scientists, politicians, coaches, parents, and children. The objective of this paper is to review the literature on the long-term cognitive, neuropsychiatric, and neurologic outcomes associated with participation in youth contact and collision sports, with a focus on tackle football. We provide an overview of the empirically derived framework that has served as the foundation for the investigation of youth tackle football and neurologic outcomes. The extant research studies on age of first exposure to tackle football and later-life cognitive and neuropsychiatric functioning, as well as structural brain changes are reviewed. We discuss the limitations of the current evidence, suggest future directions, and conclude with our opinions on societal and clinical implications.
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