Zetterberg, Henrik

Abstract Objectives Neurofilament light (NfL) is an established biofluid marker of neuroaxonal injury for neurological diseases. Several high-throughput and sensitive immunoassays have been developed to quantify NfL in blood and cerebrospinal fluid (CSF), facilitating the use of NfL as a biomarker in research and clinical practice. However, because of the lack of rigorous comparisons of assays, it has been difficult to determine whether data are comparable and whether assay performance differs. Here, we compared the performance of five NfL immunoassays. Methods To assess the five NfL immunoassays (Fujirebio, ProteinSimple, Quanterix, Roche and Siemens), we used pooled plasma or pooled CSF, as well as unique samples from 20 healthy controls and 20 individuals with El Escorial defined probable or definite amyotrophic lateral sclerosis (ALS), to evaluate precision, parallelism and/or bias. We also examined correlations between plasma and CSF NfL concentrations within and across assays and evaluated their ability to differentiate healthy controls from individuals with ALS. Results Four of the five assays demonstrated exemplary performance based on our analyses of precision and parallelism. Across the five assays, NfL concentrations were lower in plasma than in CSF, although they displayed a high degree of correlation. We noted bias across assays; plasma NfL concentrations were lowest for the Roche assay and highest for the ProteinSimple assay. In addition, all assays reliably distinguished healthy controls from individuals with ALS using plasma or CSF NfL. Conclusions Four NfL assays demonstrated similar analytic performance. Alongside performance, other factors such as costs, accessibility, usability, footprint, and intended use, should be considered.

AbstractBackgroundThe newly proposed criteria by the AA working group incorporates both biological and clinical stages to characterize the progression of AD. In this study, we aim to evaluate the agreement between these two complementary systems.MethodsUsing 188 participants from McGill TRIAD and 139 from the HEAD cohorts, we categorized participants into biological (0‐4) and clinical (0‐4) stages using amyloid PET, tau PET(MK‐6240), and clinical measures as described by the working group. Participants were then stratified into three categories: congruent (clinical = biological), higher in the biological stage (clinical < biological), and higher in the clinical stage (clinical > biological). In the TRIAD cohort, we further compared these groups for age, sex, years of education, vascular burden (WMH), microglial activation (PBR scan), Astrocyte reactivity (GFAP), amyloid load, tau load, and NPI‐Q scores using Welch two‐sided t‐test with FDR multiple comparison correction.ResultsIn the TRIAD cohort, 34% of participants were congruent, 24.5% had a higher clinical stage, and 41.5% had a higher biological stage. Meanwhile in the HEAD cohort 68.2% were congruent, 20.7% had a higher clinical stage, and 17% had a higher biological stage. TRIAD participants with a higher clinical stage had lower education (P = 0.02), more neuropsychiatric symptoms (P = 0.03), and a higher vascular burden (P = 0.03) (Table 1). As expected, people with higher biological stage had more amyloid(P<0.001), tau(P<0.001), and astrocyte reactivity(P<0.001) (Table 1, Figure 2).ConclusionsOur findings highlight important discordance between clinical and biological stages, which could be partially explained by cognitive reserve. This was supported by the protective effects of educational attainment in participants with a higher biological stage. Vascular burden played a major role in the cognitive impairment of individuals with higher clinical stages. Future studies should replicate these findings in larger more representative population‐based cohorts.

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.