Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts (RHI), but the components of RHI exposure underlying this relationship are unclear. We ...create a position exposure matrix (PEM), composed of American football helmet sensor data, summarized from literature review by player position and level of play. Using this PEM, we estimate measures of lifetime RHI exposure for a separate cohort of 631 football playing brain donors. Separate models examine the relationship between CTE pathology and players' concussion count, athletic positions, years of football, and PEM-derived measures, including estimated cumulative head impacts, linear accelerations, and rotational accelerations. Only duration of play and PEM-derived measures are significantly associated with CTE pathology. Models incorporating cumulative linear or rotational acceleration have better model fit and are better predictors of CTE pathology than duration of play or cumulative head impacts alone. These findings implicate cumulative head impact intensity in CTE pathogenesis.
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
Young contact sport athletes may be at risk for long-term neuropathologic disorders, including chronic traumatic encephalopathy (CTE).
To characterize the neuropathologic and clinical symptoms of ...young brain donors who were contact sport athletes.
This case series analyzes findings from 152 of 156 brain donors younger than 30 years identified through the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank who donated their brains from February 1, 2008, to September 31, 2022. Neuropathologic evaluations, retrospective telephone clinical assessments, and online questionnaires with informants were performed blinded. Data analysis was conducted between August 2021 and June 2023.
Repetitive head impacts from contact sports.
Gross and microscopic neuropathologic assessment, including diagnosis of CTE, based on defined diagnostic criteria; and informant-reported athletic history and informant-completed scales that assess cognitive symptoms, mood disturbances, and neurobehavioral dysregulation.
Among the 152 deceased contact sports participants (mean SD age, 22.97 4.31 years; 141 92.8% male) included in the study, CTE was diagnosed in 63 (41.4%; median IQR age, 26 24-27 years). Of the 63 brain donors diagnosed with CTE, 60 (95.2%) were diagnosed with mild CTE (stages I or II). Brain donors who had CTE were more likely to be older (mean difference, 3.92 years; 95% CI, 2.74-5.10 years) Of the 63 athletes with CTE, 45 (71.4%) were men who played amateur sports, including American football, ice hockey, soccer, rugby, and wrestling; 1 woman with CTE played collegiate soccer. For those who played football, duration of playing career was significantly longer in those with vs without CTE (mean difference, 2.81 years; 95% CI, 1.15-4.48 years). Athletes with CTE had more ventricular dilatation, cavum septum pellucidum, thalamic notching, and perivascular pigment-laden macrophages in the frontal white matter than those without CTE. Cognitive and neurobehavioral symptoms were frequent among all brain donors. Suicide was the most common cause of death, followed by unintentional overdose; there were no differences in cause of death or clinical symptoms based on CTE status.
This case series found that young brain donors exposed to repetitive head impacts were highly symptomatic regardless of CTE status, and the causes of symptoms in this sample are likely multifactorial. Future studies that include young brain donors unexposed to repetitive head impacts are needed to clarify the association among exposure, white matter and microvascular pathologic findings, CTE, and clinical symptoms.
Systolic blood pressure and pulse pressure are substantially higher in older adults. The relative contributions of increased forward versus reflected pressure wave amplitude or earlier arrival of the ...reflected wave to elevated pulse pressure remain controversial.
We measured proximal aortic pressure and flow, forward pressure wave amplitude, global wave reflection, reflected wave timing, and pulse wave velocity noninvasively in 6417 (age range, 19 to 90 years; 53 women) Framingham Heart Study Third Generation and Offspring participants. Variation in forward wave amplitude paralleled pulse pressure throughout adulthood. In contrast, wave reflection and pulse pressure were divergent across adulthood: In younger participants, pulse pressure was lower and wave reflection was higher with advancing age, whereas in older participants, pulse pressure was higher and wave reflection was lower with age. Reflected wave timing differed modestly across age groups despite considerable differences in pulse wave velocity. Forward wave amplitude explained 80 (central) and 66 (peripheral) of the variance in pulse pressure in younger participants (<50 years) and 90 and 84 in the older participants (≥ 50 years; all P<0.0001). In a stepwise model that evaluated age-pulse pressure relations in the full sample, the late accelerated increases in central and peripheral pulse pressure were markedly attenuated when variation in forward wave amplitude was considered.
Higher pulse pressure at any age and higher pulse pressure with advancing age is associated predominantly with a larger forward pressure wave. The influence of wave reflection on age-related differences in pulse pressure was minor.
Background Electronic cigarettes (e-cigarettes) have been proposed as a potential harm reduction tool for combustible cigarette smokers. The majority of adult e-cigarette users continue to smoke ...combustible cigarettes and are considered dual users. The vascular impact of e-cigarettes remains incompletely defined. Methods and Results We examined the association of e-cigarette use with measures of vascular function and tonometry, preclinical measures of cardiovascular injury. As part of the CITU (Cardiovascular Injury due to Tobacco Use) study, we performed noninvasive vascular function testing in individuals without known cardiovascular disease or cardiovascular disease risk factors who were nonsmokers (n=94), users of combustible cigarettes (n=285), users of e-cigarettes (n=36), or dual users (n=52). In unadjusted analyses, measures of arterial stiffness including carotid-femoral pulse wave velocity, augmentation index, carotid-radial pulse wave velocity, and central blood pressures differed across the use groups. In multivariable models adjusted for age, sex, race, and study site, combustible cigarette smokers had higher augmentation index compared with nonusers (129.8±1.5 versus 118.8±2.7,
=0.003). The augmentation index was similar between combustible cigarette smokers compared with sole e-cigarette users (129.8±1.5 versus 126.2±5.9,
=1.0) and dual users (129.8±1.5 versus 134.9±4.0,
=1.0). Endothelial cells from combustible cigarette smokers and sole e-cigarette users produced less nitric oxide in response to A23187 stimulation compared with nonsmokers, suggestive of impaired endothelial nitric oxide synthase signaling. Conclusions Our findings suggest that e-cigarette use is not associated with a more favorable vascular profile. Future longitudinal studies are needed to evaluate the long-term risks of sustained e-cigarette use.
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.
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.
Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive head impacts (RHI) that has been neuropathologically diagnosed in American football players and other contact sport ...athletes. In 2013, McKee and colleagues proposed a staging scheme for characterizing the severity of the hyperphosphorylated tau (p-tau) pathology, the McKee CTE staging scheme. The staging scheme defined four pathological stages of CTE, stages I(mild)–IV(severe), based on the density and regional deposition of p-tau. The objective of this study was to test the utility of the McKee CTE staging scheme, and provide a detailed examination of the regional distribution of p-tau in CTE. We examined the relationship between the McKee CTE staging scheme and semi-quantitative and quantitative assessments of regional p-tau pathology, age at death, dementia, and years of American football play among 366 male brain donors neuropathologically diagnosed with CTE (mean age 61.86, SD 18.90). Spearman’s rho correlations showed that higher CTE stage was associated with higher scores on all semi-quantitative and quantitative assessments of p-tau severity and density (
p
’s < 0.001). The severity and distribution of CTE p-tau followed an age-dependent progression: older age was associated with increased odds for having a higher CTE stage (
p
< 0.001). CTE stage was independently associated with increased odds for dementia (
p
< 0.001). K-medoids cluster analysis of the semi-quantitative scales of p-tau across 14 regions identified 5 clusters of p-tau that conformed to increasing CTE stage (stage IV had 2 slightly different clusters), age at death, dementia, and years of American football play. There was a predilection for p-tau pathology in five regions: dorsolateral frontal cortex (DLF), superior temporal cortex, entorhinal cortex, amygdala, and locus coeruleus (LC), with CTE in the youngest brain donors and lowest CTE stage restricted to DLF and LC. These findings support the usefulness of the McKee CTE staging scheme and demonstrate the regional distribution of p-tau in CTE.
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.
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