Ashton, Nicholas J.

AbstractINTRODUCTIONBlood‐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.METHODSThe 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).RESULTSP‐tau181 and p‐tau231(padj = 0.016) were higher and Aβ42/p‐tau181 was lower(padj = 0.004) in football players compared to controls. Discrimination accuracy for p‐tau was modest (area under the curve [AUC] = 0.742). Effects were not attributable to AD‐related pathology. Younger age of first exposure (AFE) correlated with higher NfL (padj = 0.03) and GFAP (padj = 0.033). Plasma GFAP was higher in TES‐chronic traumatic encephalopathy (TES‐CTE) Possible/Probable (padj = 0.008).DISCUSSIONPlasma p‐tau181 and p‐tau231, GFAP, and NfL may offer some usefulness for the characterization of RHI‐related neuropathologies.Highlights 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.

AbstractBackgroundThe NINDS criteria define Traumatic Encephalopathy Syndrome (TES) as the clinical manifestation of the neuropathologically diagnosed chronic traumatic encephalopathy (CTE). The core clinical features of TES include both cognitive and neuropsychiatric symptoms, the latter termed neurobehavioral dysregulation (NBD). We explored potential biological correlates of NBD by investigating fluid biomarkers of neuronal damage, astrogliosis, phosphorylated tau (pTau), neuroinflammation, and catecholamines in former American football players.MethodOur cohort consisted of former professional (PRO) and college (COL) American football players from the DIAGNOSE CTE Research Project. NBD was measured by four subscales (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability) and a total NBD score, derived by factor analysis of multiple self‐report neuropsychiatric measures. Plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), CSF total tau and pTau181/231/217, as well as CSF biomarkers related to neuroinflammation (IL‐6, CRP, TNF‐α, VEGF‐A), were measured with various well‐validated immunoassay methods. Catecholamines in CSF (dopamine, 3,4‐dihydroxyphenylacetic acid, 3,4‐dihydroxyphenylalanine, noradrenaline, 3,4‐dihydroxyphenylglycol) were measured with HPLC. Multivariate linear regression models assessed the relationships between biomarkers and NBD scales, adjusted for age, BMI, race, and APOE e4, including stratification by exposure group, i.e., PRO, COL.ResultDemographics and biomarker levels are displayed in Table 1. High levels of IL‐6 were significantly associated with higher scores of all NBD subscales, independent of exposure group. Other significant relationships included plasma NfL with emotional dyscontrol and impulsivity. Within the college group, CSF pTau181 was significantly associated with emotional dyscontrol and CSF noradrenaline with explosivity, emotional dyscontrol, impulsivity, and total NBD score. (Table 2 & Figure 1). IL‐6 models were repeated with measures of cognitive dysfunction (another core feature of TES) added as covariates; these analyses again found significant relationships between IL‐6 and NBD, irrespective of cognitive functioning.ConclusionWe observed specific fluid biomarkers related to NBD in former American football players. Of note were the associations between IL‐6 and all NBD subscales (and not with cognitive functioning), suggesting that neuroinflammation may be a specific component in the expression of NBD symptoms. Future studies will investigate how these neuroinflammatory processes are related to other biomarkers, level of RHI exposure, and neuropathology.

AbstractBackgroundBlood phosphorylated tau (p‐tau) has proven to be the primary candidate as an accessible and scalable biomarker for Alzheimer’s disease (AD). Both p‐tau181 and p‐tau217 are highly accurate to detect AD within dementia cases. Our recent work in cerebrospinal fluid, however, indicates p‐tau231 to be associated to incipient AD pathology. In light of this, we developed a Single molecule array (Simoa) to detect plasma p‐tau231 and assessed its performance in multiple domains, specifically, its ability to detect preclinical AD.MethodIn all cohorts, plasma p‐tau231 was quantified using an in‐house Simoa method developed at the Clinical Neurochemistry Laboratory, Gothenburg University, Sweden. Data presented in this study are samples acquired from Translational Biomarkers of Aging and Dementia (TRIAD, n=503), King’s College London (n=55), Mayo Clinic Study of Aging (n=145), KARVIAH (n=140), Baltimore Longitudinal Study of Aging (n=430), University College London (n=70), Paris University (n=213), PREVENT‐AD (n=257), University of California (n=309) and ALFA+ (n=385).ResultIn the TRIAD cohort, plasma p‐tau231 demonstrated high accuracy in determining AD from young individuals (AUC=0.95), Aβ‐ elderly (AUC=0.92), Aβ‐ MCI (AUC=0.88) and other neurodegenerative disorders (AUC=0.92). In an autopsy study, plasma p‐tau231 could detect neuropathologically confirmed AD amongst dementia cases (AUC=0.99). In comparing healthy elderly Aβ‐ and Aβ+ individuals, p‐tau231 predicted preclinical Aβ pathology (AUC=0.83). Furthermore, inflection points of the weighted regression curves demonstrate that increases in plasma p‐tau231 occur before plasma p‐tau181 as a function of Aβ deposition load. Plasma p‐tau231 data from additional cohorts will focus on cross‐sectional and longitudinal preclinical datasets. In addition, further data will show the performance of p‐tau231 in symptomatic and presymptomatic PSEN1/APP mutation carriers, memory clinic cohorts, longitudinal neuropathology confirmed and acute neurological injury.ConclusionPlasma p‐tau231 is a new biomarker specific for AD pathology and at higher concentrations relative to p‐tau181 and p‐tau217. Our initial results indicate that plasma p‐tau231 is equivalent to p‐tau181 in diagnostic utility but has greater potential as a biomarker to monitor emerging Aβ pathology. This presentation will give an overview of novel cross‐sectional and longitudinal plasma p‐tau231 data, in more than 3000 individuals, that encompasses the AD continuum, familial AD and other neurological conditions.

Abstract Background Recent findings indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related neurological manifestations involve cytokine release syndrome along with endothelial activation, blood brain barrier dysfunction, and immune-mediated mechanisms. Very few studies have fully investigated the cerebrospinal fluid (CSF) correlates of SARS-CoV-2 encephalitis. Methods Patients with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection and encephalitis (COV-Enc), encephalitis without SARS-CoV-2 infection (ENC), and healthy controls (HC) underwent an extended panel of CSF neuronal (neurofilament light chain [NfL], T-tau), glial (glial fibrillary acidic protein [GFAP], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], chitinase-3-like protein 1 [YKL-40]) and inflammatory biomarkers (interleukin [IL]-1β, IL-6, Il-8, tumor necrosis factor [TNF] α, CXCL-13, and β2-microglobulin). Results Thirteen COV-Enc, 21 ENC, and 18 HC entered the study. In COV-Enc cases, CSF was negative for SARS-CoV-2 real-time PCR but exhibited increased IL-8 levels independently from presence of pleocytosis/hyperproteinorracchia. COV-Enc patients showed increased IL-6, TNF- α, and β2-microglobulin and glial markers (GFAP, sTREM2, YKL-40) levels similar to ENC but normal CXCL13 levels. Neuronal markers NfL and T-tau were abnormal only in severe cases. Conclusions SARS-CoV-2-related encephalitis were associated with prominent glial activation and neuroinflammatory markers, whereas neuronal markers were increased in severe cases only. The pattern of CSF alterations suggested a cytokine-release syndrome as the main inflammatory mechanism of SARS-CoV-2-related encephalitis.