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  • 1
    Online-Ressource
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    Developing methods to detect and diagnose chronic traumatic encephalopathy during life: rationale, design, and methodology for the DIAGNOSE CTE Research Project
    Springer Science and Business Media LLC ; 2021
    In:  Alzheimer's Research & Therapy Vol. 13, No. 1 ( 2021-12)
    Details
    In: Alzheimer's Research & Therapy, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2021-12)
    Kurzfassung: 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. Methods 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. Results 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. Conclusions 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. Trial registration NCT02798185
    Materialart: Online-Ressource
    ISSN: 1758-9193
    URL: Article
    DOI: 10.1186/s13195-021-00872-x
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2021
    ZDB Id: 2506521-X
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  • 2
    Online-Ressource
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    Associations between near end-of-life flortaucipir PET and postmortem CTE-related tau neuropathology in six former American football players
    Springer Science and Business Media LLC ; 2023
    In:  European Journal of Nuclear Medicine and Molecular Imaging Vol. 50, No. 2 ( 2023-01), p. 435-452
    Details
    In: European Journal of Nuclear Medicine and Molecular Imaging, Springer Science and Business Media LLC, Vol. 50, No. 2 ( 2023-01), p. 435-452
    Kurzfassung: Flourine-18-flortaucipir tau positron emission tomography (PET) was developed for the detection for Alzheimer’s disease. Human imaging studies have begun to investigate its use in chronic traumatic encephalopathy (CTE). Flortaucipir-PET to autopsy correlation studies in CTE are needed for diagnostic validation. We examined the association between end-of-life flortaucipir PET and postmortem neuropathological measurements of CTE-related tau in six former American football players. Methods Three former National Football League players and three former college football players who were part of the DIAGNOSE CTE Research Project died and agreed to have their brains donated. The six players had flortaucipir (tau) and florbetapir (amyloid) PET prior to death. All brains from the deceased participants were neuropathologically evaluated for the presence of CTE. On average, the participants were 59.0 (SD = 9.32) years of age at time of PET. PET scans were acquired 20.33 (SD = 13.08) months before their death. Using Spearman correlation analyses, we compared flortaucipir standard uptake value ratios (SUVRs) to digital slide-based AT8 phosphorylated tau (p-tau) density in a priori selected composite cortical, composite limbic, and thalamic regions-of-interest (ROIs). Results Four brain donors had autopsy-confirmed CTE, all with high stage disease ( n  = 3 stage III, n  = 1 stage IV). Three of these four met criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES). Two did not have CTE at autopsy and one of these met criteria for TES. Concomitant pathology was only present in one of the non-CTE cases (Lewy body) and one of the CTE cases (motor neuron disease). There was a strong association between flortaucipir SUVRs and p-tau density in the composite cortical ( ρ  = 0.71) and limbic ( ρ  = 0.77) ROIs. Although there was a strong association in the thalamic ROI ( ρ  = 0.83), this is a region with known off-target binding. SUVRs were modest and CTE and non-CTE cases had overlapping SUVRs and discordant p-tau density for some regions. Conclusions Flortaucipir-PET could be useful for detecting high stage CTE neuropathology, but specificity to CTE p-tau is uncertain. Off-target flortaucipir binding in the hippocampus and thalamus complicates interpretation of these associations. In vivo biomarkers that can detect the specific p-tau of CTE across the disease continuum are needed.
    Materialart: Online-Ressource
    ISSN: 1619-7070 , 1619-7089
    URL: Article
    DOI: 10.1007/s00259-022-05963-x
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2023
    ZDB Id: 2098375-X
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  • 3
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    Abstract 133: Prognostic Utility of the GDF-15/FSTL-1 Axis for Adverse Cardiac and Limb Events in Patients With Peripheral Artery Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 34, No. suppl_1 ( 2014-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. suppl_1 ( 2014-05)
    Kurzfassung: Background: Peripheral artery disease (PAD) confers greater vulnerability to cardiovascular events. Inflammatory activation and tissue ischemia induce expression of a vasoprotective cytokine network including GDF15 and FSTL1. We sought to evaluate the clinical utility of novel vascular stress biomarkers for risk stratification in PAD. Methods and Results: We followed 245 PAD patients prospectively over two years for adverse cardiac events (n=40, myocardial infarction, unstable angina, coronary revascularization, transient ischemic event, stroke, congestive heart failure, cardiac death) and adverse limb events (n=52, worsening claudication, peripheral revascularization, critical limb ischemia, amputation, graft or stent failure). At baseline, we measured serum GDF15 and FSTL-1 and disease severity by the ankle-brachial index (ABI). In survival analyses, higher GDF15 was associated with both adverse cardiac and limb events (P 〈 0.0001, P 〈 0.01). FSTL-1 was associated with adverse limb (P=0.03) but not cardiac events. In multivariable models adjusting for relevant covariates including ABI, higher GDF15 remained associated with higher risk of limb events (HR 1.83, 95% CI 1.10, 3.06, P=0.02) and cardiac events (HR 1.92, 95% CI 1.09, 3.32, P=0.02). There was a trend for an association of higher FSTL1 with limb events (HR 2.34, 95% CI 0.93, 5.75, P=0.07). Addition of GDF15 to clinical variables led to an increase in the c statistic (P 〈 0.05) and net reclassification improvement (P 〈 0.01) for both cardiac and limb events. Conclusions: Our findings show that vascular stress markers involving the GDF15-FSTL1 axis provide additional prognostic value over clinical factors and disease severity for predicting adverse cardiac and limb events in patients with PAD.
    Materialart: Online-Ressource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.34.suppl_1.133
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2014
    ZDB Id: 1494427-3
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  • 4
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    Abstract 278: Vascular Anatomic and Physiologic Relationships with Local Adipose Phenotype in Chronic Kidney Disease Patients
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 35, No. suppl_1 ( 2015-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. suppl_1 ( 2015-05)
    Kurzfassung: Introduction: Local adipose biomarkers have recently been shown to correlate with outward remodeling (adiponectin, IL-8, MCP-1, resistin and TNF) and flow volume (adiponectin, MCP-1) after human hemodialysis AVF creation. As a potential mechanism underlying this observation, we hypothesized that vascular anatomy and physiologic function is dependent on local adipose phenotype. Methods: During AVF creation surgery, adipose tissue contiguous to the proximal anastomosis was obtained from patients at two institutions participating in the NIDDK Hemodialysis Fistula Maturation (HFM) Study (n=112). Nine adipose-associated biologic mediators (adiponectin, IL-1 beta, IL-6, IL-8, leptin, MCP-1, PAI-1, resistin, and TNF) were quantified. Levels of adipose biomarkers were correlated to measurements obtained from comprehensive pre-operative non-invasive vascular anatomic and functional studies performed as part of the HFM Study protocol using Spearman correlation (before logarithmic transformation) and Pearson correlation (after transformation). Bonferroni correction was performed for multiple testing (alpha/9=0.006) Results: Smaller brachial arterial diameter correlated with higher IL-8 (r=-0.23, 95% CI -0.41 to -0.03, p=0.02), MCP-1 (r=-0.24, 95% CI -0.42 to -0.05, p=0.01), and PAI-1 (r=-0.25, 95% CI -0.42 to -0.05, p=0.01) levels and lower brachial arterial flow velocity correlated with higher MCP-1 (r=-0.22, 95% CI -0.40 to -0.02, p =0.03), but the associations were not significant after Bonferroni adjustment. Brachial artery flow- and nitroglycerin-mediated dilation (FMD and NMD), carotid-radial and -femoral pulse wave velocity (PWV), augmentation index, and the slope of the venous volume-pressure relationship did not correlate with adipose mediator levels. Conclusions: While there was suggestion of a relationship between local adipose mediator levels and baseline brachial artery characteristics, relationships with vascular function as assessed by FMD, NMD, PWV and venous capacitance slope were not evident using tests of monotonic associations. Processes not reflected in these measures of vascular characteristics and function may underlie relationships between adipose phenotype and vascular remodeling in human AVFs.
    Materialart: Online-Ressource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.35.suppl_1.278
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2015
    ZDB Id: 1494427-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
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    Hemodynamic Correlates of Blood Pressure Across the Adult Age Spectrum : Noninvasive Evaluation in the Framingham Heart Study
    Ovid Technologies (Wolters Kluwer Health) ; 2010
    In:  Circulation Vol. 122, No. 14 ( 2010-10-05), p. 1379-1386
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 122, No. 14 ( 2010-10-05), p. 1379-1386
    Kurzfassung: 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. Methods and Results— 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. Conclusions— 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.
    Materialart: Online-Ressource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.109.914507
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2010
    ZDB Id: 1466401-X
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  • 6
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    Circulating angiogenic cell populations, vascular function, and arterial stiffness
    Elsevier BV ; 2012
    In:  Atherosclerosis Vol. 220, No. 1 ( 2012-01), p. 145-150
    Details
    In: Atherosclerosis, Elsevier BV, Vol. 220, No. 1 ( 2012-01), p. 145-150
    Materialart: Online-Ressource
    ISSN: 0021-9150
    URL: Article
    DOI: 10.1016/j.atherosclerosis.2011.10.015
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2012
    ZDB Id: 1499887-7
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  • 7
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    Amyloid PET across the cognitive spectrum in former professional and college American football players: findings from the DIAGNOSE CTE Research Project
    Springer Science and Business Media LLC ; 2023
    In:  Alzheimer's Research & Therapy Vol. 15, No. 1 ( 2023-10-05)
    Details
    In: Alzheimer's Research & Therapy, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2023-10-05)
    Kurzfassung: Exposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical sulci. However, it is unclear whether exposure to RHI accelerates amyloid-β (Aβ) plaque formation and increases the risk for Alzheimer’s disease (AD). Although the Aβ neuritic plaques characteristic of AD are observed in a minority of later-stage CTE cases, diffuse plaques are more common. This study examined whether former professional and college American football players, including those with cognitive impairment and dementia, have elevated neuritic Aβ plaque density, as measured by florbetapir PET. Regardless of cognitive and functional status, elevated levels of florbetapir uptake were not expected. Methods We examined 237 men ages 45–74, including 119 former professional (PRO) and 60 former college (COL) football players, with and without cognitive impairment and dementia, and 58 same-age men without a history of contact sports or TBI (unexposed; UE) and who denied cognitive or behavioral symptoms at telephone screening. Former players were categorized into four diagnostic groups: normal cognition, subjective memory impairment, mild cognitive impairment, and dementia. Positive florbetapir PET was defined by cortical-cerebellar average SUVR of ≥ 1.10. Multivariable linear regression and analysis of covariance (ANCOVA) compared florbetapir average SUVR across diagnostic and exposure groups. Multivariable logistic regression compared florbetapir positivity. Race, education, age, and APOE4 were covariates. Results There were no diagnostic group differences either in florbetapir average SUVR or the proportion of elevated florbetapir uptake. Average SUVR means also did not differ between exposure groups: PRO-COL ( p  = 0.94, 95% C.I. = [− 0.033, 0.025]), PRO-UE ( p  = 0.40, 95% C.I. = [− 0.010, 0.029]), COL-UE ( p  = 0.36, 95% CI = [0.0004, 0.039]). Florbetapir was not significantly associated with years of football exposure, cognition, or daily functioning. Conclusions Cognitive impairment in former American football players is not associated with PET imaging of neuritic Aβ plaque deposition. These findings are inconsistent with a neuropathological diagnosis of AD in individuals with substantial RHI exposure and have both clinical and medico-legal implications. Trial registration NCT02798185.
    Materialart: Online-Ressource
    ISSN: 1758-9193
    URL: Article
    DOI: 10.1186/s13195-023-01315-5
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2023
    ZDB Id: 2506521-X
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  • 8
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    Ante-mortem plasma phosphorylated tau (181) predicts Alzheimer’s disease neuropathology and regional tau at autopsy
    Oxford University Press (OUP) ; 2022
    In:  Brain Vol. 145, No. 10 ( 2022-10-21), p. 3546-3557
    Details
    In: Brain, Oxford University Press (OUP), Vol. 145, No. 10 ( 2022-10-21), p. 3546-3557
    Kurzfassung: 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 & lt; 0.01; phosphorylated-tau standardized (z-transformed): OR = 2.98, 95% CI = 1.50–5.93, P & lt; 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 & lt; 0.01) and more severe phosphorylated-tau across six cortical and subcortical brain regions (ORs = 1.03–1.06, P & lt; 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 & gt;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.
    Materialart: Online-Ressource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awac175
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2022
    ZDB Id: 1474117-9
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
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    Online-Ressource
    Plasma p‐tau 181 shows stronger network association to Alzheimer's disease dementia than neurofilament light and total tau
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. 8 ( 2022-08), p. 1523-1536
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. 8 ( 2022-08), p. 1523-1536
    Kurzfassung: We examined the ability of plasma hyperphosphorylated tau (p‐tau) 181 to detect cognitive impairment due to Alzheimer's disease (AD) independently and in combination with plasma total tau (t‐tau) and neurofilament light (NfL). Methods 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. Results Plasma p‐tau 181 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 181 had a direct association with cognitive diagnosis in a bootstrapped GGM. Discussion These results support plasma p‐tau 181 for the detection of AD dementia and the use of blood‐based biomarkers for optimal disease detection.
    Materialart: Online-Ressource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.8
    DOI: 10.1002/alz.12508
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2022
    ZDB Id: 2201940-6
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
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    A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer’s Disease Neuropathology
    IOS Press ; 2018
    In:  Journal of Alzheimer's Disease Vol. 63, No. 4 ( 2018-05-30), p. 1347-1360
    Details
    In: Journal of Alzheimer's Disease, IOS Press, Vol. 63, No. 4 ( 2018-05-30), p. 1347-1360
    Materialart: Online-Ressource
    ISSN: 1387-2877 , 1875-8908
    URL: Article
    DOI: 10.3233/JAD-180017
    Sprache: Unbekannt
    Verlag: IOS Press
    Publikationsdatum: 2018
    ZDB Id: 2070772-1
    Standort Signatur Einschränkungen Verfügbarkeit
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