Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been neuropathologically diagnosed in brain donors exposed to repetitive head impacts, including boxers and American ...football, soccer, ice hockey, and rugby players. CTE cannot yet be diagnosed during life. In December 2015, the National Institute of Neurological Disorders and Stroke awarded a seven-year grant (U01NS093334) to fund the "Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project." The objectives of this multicenter project are to: develop in vivo fluid and neuroimaging biomarkers for CTE; characterize its clinical presentation; refine and validate clinical research diagnostic criteria (i.e., traumatic encephalopathy syndrome TES); examine repetitive head impact exposure, genetic, and other risk factors; and provide shared resources of anonymized data and biological samples to the research community. In this paper, we provide a detailed overview of the rationale, design, and methods for the DIAGNOSE CTE Research Project.
The targeted sample and sample size was 240 male participants, ages 45-74, including 120 former professional football players, 60 former collegiate football players, and 60 asymptomatic participants without a history of head trauma or participation in organized contact sports. Participants were evaluated at one of four U.S. sites and underwent the following baseline procedures: neurological and neuropsychological examinations; tau and amyloid positron emission tomography; magnetic resonance imaging and spectroscopy; lumbar puncture; blood and saliva collection; and standardized self-report measures of neuropsychiatric, cognitive, and daily functioning. Study partners completed similar informant-report measures. Follow-up evaluations were intended to be in-person and at 3 years post-baseline. Multidisciplinary diagnostic consensus conferences are held, and the reliability and validity of TES diagnostic criteria are examined.
Participant enrollment and all baseline evaluations were completed in February 2020. Three-year follow-up evaluations began in October 2019. However, in-person evaluation ceased with the COVID-19 pandemic, and resumed as remote, 4-year follow-up evaluations (including telephone-, online-, and videoconference-based cognitive, neuropsychiatric, and neurologic examinations, as well as in-home blood draw) in February 2021.
Findings from the DIAGNOSE CTE Research Project should facilitate detection and diagnosis of CTE during life, and thereby accelerate research on risk factors, mechanisms, epidemiology, treatment, and prevention of CTE.
NCT02798185.
Introduction
This study examined plasma glial fibrillary acidic protein (GFAP) as a biomarker of cognitive impairment due to Alzheimer's disease (AD) with and against plasma neurofilament light chain ...(NfL), and phosphorylated tau (p‐tau)181+231.
Methods
Plasma samples were analyzed using Simoa platform for 567 participants spanning the AD continuum. Cognitive diagnosis, neuropsychological testing, and dementia severity were examined for cross‐sectional and longitudinal outcomes.
Results
Plasma GFAP discriminated AD dementia from normal cognition (adjusted mean difference = 0.90 standard deviation SD) and mild cognitive impairment (adjusted mean difference = 0.72 SD), and demonstrated superior discrimination compared to alternative plasma biomarkers. Higher GFAP was associated with worse dementia severity and worse performance on 11 of 12 neuropsychological tests. Longitudinally, GFAP predicted decline in memory, but did not predict conversion to mild cognitive impairment or dementia.
Discussion
Plasma GFAP was associated with clinical outcomes related to suspected AD and could be of assistance in a plasma biomarker panel to detect in vivo AD.
Exposure to repetitive head impacts from playing American football (including impacts resulting in symptomatic concussions and subconcussive trauma) is associated with increased risk for later-life ...health problems, including cognitive and neuropsychiatric decline and neurodegenerative disease. Most research on long-term health consequences of playing football has focused on former professional athletes, with limited studies of former college players.
To estimate the prevalence of self-reported health conditions among former college football players compared with a sample of men in the general population as well as standardized mortality ratios (SMRs) among former college football players.
This cohort study included data from 447 former University of Notre Dame (ND) football players aged 59 to 75 years who were seniors on the rosters from 1964 to 1980. A health outcomes survey was distributed to living players and next of kin of deceased players for whom contact information was available. The survey was completed from December 2018 to May 2019.
Participation in football at ND.
Prevalence of health outcomes was compared between living former players who completed the survey and propensity score-matched participants in the Health and Retirement Study (HRS). Standardized mortality ratios of all causes and specific causes of death among all former players were compared with those among men in the general US population.
A total of 216 living players completed the health survey (median age, 67 years; IQR, 63-70 years) and were compared with 638 participants in the HRS (median age, 66 years; IQR, 63-70 years). Former players reported a higher prevalence of cognitive impairment (10 5% vs 8 1%; P = .02), headaches (22 10% vs 22 4%; P = .001), cardiovascular disease (70 33% vs 128 20%; P = .001), hypercholesterolemia (111 52% vs 182 29%; P = .001), and alcohol use (185 86% vs 489 77%; P = .02) and a lower prevalence of diabetes (24 11% vs 146 23%; P = .001). All-cause mortality (SMR, 0.54; 95% CI, 0.42-0.67) and mortality from heart (SMR, 0.64; 95% CI, 0.39-0.99), circulatory (SMR, 0.23; 95% CI, 0.03-0.83), respiratory (SMR, 0.13; 95% CI, 0.00-0.70), and digestive system (SMR, 0.13; 95% CI, 0.00-0.74) disorders; lung cancer (SMR, 0.26; 95% CI, 0.05-0.77); and violence (SMR, 0.10; 95% CI, 0.00-0.58) were significantly lower in the ND cohort than in the general population. Mortality from brain and other nervous system cancers was significantly higher in the ND cohort (SMR, 3.82; 95% CI, 1.04-9.77). Whereas point estimates were greater for all neurodegenerative causes (SMR, 1.42; 95% CI, 0.29-4.18), amyotrophic lateral sclerosis (SMR, 2.93; 95% CI, 0.36-10.59), and Parkinson disease (SMR, 2.07; 95% CI, 0.05-11.55), the difference did not reach statistical significance.
In this cohort study of former college football players, both positive and negative health outcomes were observed. With more than 800 000 former college players living in the US, additional research appears to be needed to provide stakeholders with guidance to maximize factors that improve health outcomes and minimize factors that may increase risk for later-life morbidity and mortality.
We examined the ability of plasma hyperphosphorylated tau (p-tau)
to detect cognitive impairment due to Alzheimer's disease (AD) independently and in combination with plasma total tau (t-tau) and ...neurofilament light (NfL).
Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables.
Plasma p-tau
discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau
had a direct association with cognitive diagnosis in a bootstrapped GGM.
These results support plasma p-tau
for the detection of AD dementia and the use of blood-based biomarkers for optimal disease detection.
The Framingham Stroke Risk Profile (FSRP) was created in 1991 to estimate 10-year risk of stroke. It was revised in 2017 (rFSRP) to reflect the modern data on vascular risk factors and stroke risk.
...This study examined the association between the rFSRP and cognitive and brain aging outcomes among participants from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS).
Cross-sectional rFSRP was computed at baseline for 19,309 participants (mean age = 72.84, SD = 8.48) from the NACC-UDS 9,697 (50.2%) normal cognition, 4,705 (24.4%) MCI, 4,907 (25.4%) dementia. Multivariable linear, logistic, or ordinal regressions examined the association between the rFSRP and diagnostic status, neuropsychological test performance, CDR® Sum of Boxes, as well as total brain volume (TBV), hippocampal volume (HCV), and log-transformed white matter hyperintensities (WMH) for an MRI subset (n = 1,196). Models controlled for age, sex, education, racial identity, APOEɛ4 status, and estimated intracranial volume for MRI models.
The mean rFSRP probability was 10.42% (min = 0.50%, max = 95.71%). Higher rFSRP scores corresponded to greater CDR Sum of Boxes (β= 0.02, p = 0.028) and worse performance on: Trail Making Test A (β= 0.05, p < 0.001) and B (β= 0.057, p < 0.001), and Digit Symbol (β= -0.058, p < 0.001). Higher rFSRP scores were associated with increased odds for a greater volume of log-transformed WMH (OR = 1.02 per quartile, p = 0.015). No associations were observed for diagnosis, episodic memory or language test scores, HCV, or TBV.
These results support the rFSRP as a useful metric to facilitate clinical research on the associations between cerebrovascular disease and cognitive and brain aging.
Trends in prescription for venous thromboembolism (VTE) prophylaxis following total hip (THR) and knee replacement (TKR) since the approval of direct oral anticoagulants (DOACs) and the 2012 ...guideline endorsement of aspirin are unknown, as are the risks of adverse events. We examined practice patterns in the prescription of prophylaxis agents and the risk of adverse events during the in-hospital period (the ‘in-hospital sample’) and 90 days following discharge (the ‘discharge sample’) among adults aged ⩾ 65 undergoing THR and TKR in community hospitals in the Institute for Health Metrics database over a 30-month period during 2011 to 2013. Eligible medications included fondaparinux, DOACs, low molecular weight heparin (LMWH), other heparin products, warfarin, and aspirin. Outcomes were validated by physician review of source documents: VTE, major hemorrhage, cardiovascular events, and death. The in-hospital and the discharge samples included 10,503 and 5722 adults from 65 hospitals nationwide, respectively (mean age 73, 74 years; 61%, 63% women). Pharmacologic prophylaxis was near universal during the in-hospital period (93%) and at discharge (99%). DOAC use increased substantially and was the prophylaxis of choice for nearly a quarter (in-hospital) and a third (discharge) of the patients. Aspirin was the sole discharge prophylactic agent for 17% and 19% of patients undergoing THR and TKR, respectively. Warfarin remained the prophylaxis agent of choice for patients aged 80 years and older. The overall risk of adverse events was low, at less than 1% for both the in-hospital and discharge outcomes. The low number of adverse events precluded statistical comparison of prophylaxis regimens.
Bariatric surgical weight loss is associated with reduced cardiovascular mortality; however, the mechanisms underlying this association are incompletely understood.
To identify variables associated ...with vascular remodeling after bariatric surgery and to examine how sex, race, and metabolic status are associated with microvascular and macrovascular outcomes.
This population-based longitudinal cohort included 307 individuals who underwent bariatric surgery. Participants were enrolled in the bariatric weight loss program at Boston Medical Center, a large, multi-ethnic urban hospital, with presurgical and postsurgical assessments. Data were collected from December 11, 2001 to August 27, 2019. Data were analyzed in September 2019.
Bariatric surgery.
Flow-mediated dilation (FMD) and reactive hyperemia (RH) (as measures of macrovascular and microvascular function, respectively) and clinical variables were measured preoperatively at baseline and at least once postoperatively within 12 months of the bariatric intervention.
A total of 307 participants with obesity (mean SD age, 42 12 years; 246 80% women; 199 65% White; mean SD body mass index, 46 8) were enrolled in this study. Bariatric surgery was associated with significant weight loss and improved macrovascular and microvascular function across subgroups of sex, race, and traditional metabolic syndrome (mean SD pre- vs postsurgery weight: 126 25 kg vs 104 25 kg; P < .001; mean SD pre- vs postsurgery FMD: 9.1% 5.3 vs 10.2% 5.1; P < .001; mean SD pre- vs postsurgery RH: 764% 400 vs 923% 412; P < .001). Factors associated with change in vascular phenotype correlated most strongly with adiposity markers and several metabolic variables depending on vascular territory (eg, association of weight change with change in RH: estimate, -3.2; 95% CI, -4.7 to -1.8; association of hemoglobin A1c with change in FMD: estimate, -0.5; 95% CI, -0.95 to -0.05). While changes in macrovascular function among individuals with metabolically healthy obesity were not observed, the addition of biomarker assessment using high-sensitivity C-reactive protein plasma levels greater than 2 mg/dL identified participants with seemingly metabolically healthy obesity who had low-grade inflammation and achieved microvascular benefit from weight loss surgery.
The findings of this study suggest that bariatric intervention is associated with weight loss and favorable remodeling of the vasculature among a wide range of individuals with cardiovascular risk. Moreover, differences in arterial responses to weight loss surgery by metabolic status were identified, underscoring heterogeneity in physiological responses to adiposity change and potential activation of distinct pathological pathways in clinical subgroups. As such, individuals with metabolically healthy obesity represent a mixed population that may benefit from more refined phenotypic classification.
The American Heart Association (AHA) introduced Life’s Simple 7 as a metric to define ideal cardiovascular health. We examined the association between cardiovascular health score (CHS) and prevalent ...nonalcoholic fatty liver disease (NAFLD) among Framingham Heart Study participants with varying genetic risk of NAFLD. Framingham Heart Study participants who underwent abdominal computed tomography scans were included (n = 2,773). We defined hepatic steatosis as the mean Hounsfield unit attenuation of the liver compared to a phantom control. We calculated CHS based on adherence to metrics from the AHA’s Life’s Simple 7 guidelines, including blood sugar, total cholesterol, blood pressure, body mass index (BMI), time spent on physical activity per week, and smoking status. We used multivariable‐adjusted regression models to evaluate the association between CHS and hepatic steatosis, accounting for covariates and stratifying by NAFLD genetic risk. Overall, 12% of the sample achieved 0‐1 goals and 25%, 27%, 21%, 13%, and 2.6% achieved 2, 3, 4, 5, or 6 goals, respectively. For each 1‐unit increase in CHS, there was a decrease in the odds ratio (OR) of prevalent hepatic steatosis (OR, 0.54; 95% confidence interval, 0.49‐0.59). Individually, BMI had the strongest association with NAFLD. Participants with high or intermediate genetic risk of NAFLD demonstrated higher relative decreases in hepatic steatosis with increased CHS compared to those at low genetic risk. Conclusion: Adhering to the AHA Life’s Simple 7 metrics was associated with reduced odds of prevalent NAFLD, particularly for those at high genetic risk. Additional longitudinal studies are needed.
The American Heart Association (AHA) introduced Life's Simple 7 as a metric to define ideal cardiovascular health. We examined the association between cardiovascular health score (CHS) and prevalent nonalcoholic fatty liver disease (NAFLD) among Framingham Heart Study participants with varying genetic risk of NAFLD. Adhering to the AHA Life's Simple 7 metrics was associated with reduced odds of prevalent NAFLD, particularly for those at high genetic risk.
Abstract Objective Several bone marrow-derived cell populations have been identified that may possess angiogenic activity and contribute to vascular homeostasis in experimental studies. We examined ...the extent to which lower quantities of these circulating angiogenic cell phenotypes may be related to impaired vascular function and greater arterial stiffness. Methods We studied 1948 Framingham Heart Study participants (mean age, 66 ± 9 years; 54% women) who were phenotyped for circulating angiogenic cells: CD34+, CD34+/KDR+, and early outgrowth colony forming units (CFU). Participants underwent non-invasive assessments of vascular function including peripheral arterial tone (PAT), arterial tonometry, and brachial reactivity testing. Results In unadjusted analyses, higher CD34+ and CD34+/KDR+ concentrations were modestly associated with lower PAT ratio ( β = −0.052 ± 0.011, P < 0.001 and β = −0.030 ± 0.011, P = 0.008, respectively) and with higher carotid-brachial pulse wave velocity ( β = 0.144 ± 0.043, P = 0.001 and β = 0.112 ± 0.043, P = 0.009), but not with flow-mediated dilation; higher CD34+ was also associated with lower carotid-femoral pulse wave velocity ( β = −0.229 ± 0.094, P = 0.015). However, only the association of lower CD34+ concentration with higher PAT ratio persisted in multivariable analyses that adjusted for standard cardiovascular risk factors. In all analyses, CFU was not associated with measures of vascular function or arterial stiffness. Conclusions In our large, community-based sample of men and women, circulating angiogenic cell phenotypes largely were not associated with measures of vascular function or arterial stiffness in analyses adjusting for traditional risk factors.
Abstract
Background
Chronic traumatic encephalopathy (CTE) is neurodegenerative disease associated with a history of repetitive head impacts (RHI). The majority of CTE cases have been reported in ...former contact sport athletes, including American football players. In 2017, a case series from the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank reported that 48 of the first 53 donors with college football as their highest level of play had CTE. Here we present updated numbers of former college football players with CTE in the UNITE Brain Bank and compare them to former college football players without CTE. We hypothesized that increasing CTE stage would be associated with dementia and increasing scores on clinical scales of informant reported symptoms.
Method
Brain donors from the UNITE Brain Bank with college football as their highest level of play were included. CTE neuropathological diagnosis and staging (0‐IV; 0 = no CTE, IV = most severe) were assessed using validated criteria. Informants completed standardized scales of cognition (Cognitive Difficulties Scale, CDS), activities of daily living (Functional Activities Questionnaire, FAQ), and neurobehavioral dysregulation (BRIEF‐A Behavioral Regulation Index, BRI). Consensus dementia diagnoses were made by expert clinicians. Multivariable regression models examined associations between CTE stage, dementia, and each clinical scale, controlling for age at death, racial identity, education, and duration of football play in years.
Result
Among 319 donors with college football as their highest level of play (median age at death = 64.0; IQR = 47‐77), 222 (69.5%) had CTE. Among those with CTE, 44 (19.8%) were stage I, 47 (21.2%) were stage II, 79 (35.6%) were stage III and 52 (23.4%) were stage IV. Among those with CTE, 122 (55.0%) were demented and 123 (61.5%) and 131 (70.8%) had clinically meaningful elevations on the FAQ and BRI respectively. CTE stage was significantly associated with having dementia (OR = 1.37; 95%CI:1.08‐1.72) and with more symptoms on the CDS (beta = 5.04; 95%CI:1.41‐8.66) and FAQ (beta = 1.12; 95%CI:0.38‐1.86), but not the BRI. Effect estimates were larger after removing donors with non‐CTE neurodegenerative pathology.
Conclusion
Among former college football playing brain donors, CTE pathology was very common. CTE stage was significant associated with dementia history and symptoms on clinical scales.
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