Plasma glial fibrillary acidic protein is elevated in cognitively normal older adults at risk of Alzheimer’s disease

© 2021, The Author(s). Glial fibrillary acidic protein (GFAP), an astrocytic cytoskeletal protein, can be measured in blood samples, and has been associated with Alzheimer’s disease (AD). However, plasma GFAP has not been investigated in cognitively normal older adults at risk of AD, based on brain amyloid-β (Aβ) load. Cross-sectional analyses were carried out for plasma GFAP and plasma Aβ1–42/Aβ1–40 ratio, a blood-based marker associated with brain Aβ load, in participants (65–90 years) categorised into low (Aβ−, n = 63) and high (Aβ+, n = 33) brain Aβ load groups via Aβ positron emission tomography. Plasma GFAP, Aβ1–42, and Aβ1–40 were measured using the Single molecule array (Simoa) platform. Plasma GFAP levels were significantly higher (p \u3c 0.00001), and plasma Aβ1–42/Aβ1–40 ratios were significantly lower (p \u3c 0.005), in Aβ+ participants compared to Aβ− participants, adjusted for covariates age, sex, and apolipoprotein E-ε4 carriage. A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished Aβ+ from Aβ− (area under the curve, AUC = 0.78), but was outperformed when plasma GFAP was added to the base model (AUC = 0.91) and further improved with plasma Aβ1–42/Aβ1–40 ratio (AUC = 0.92). The current findings demonstrate that plasma GFAP levels are elevated in cognitively normal older adults at risk of AD. These observations suggest that astrocytic damage or activation begins from the pre-symptomatic stage of AD and is associated with brain Aβ load. Observations from the present study highlight the potential of plasma GFAP to contribute to a diagnostic blood biomarker panel (along with plasma Aβ1–42/Aβ1–40 ratios) for cognitively normal older adults at risk of AD

Elevated plasma sclerostin is associated with high brain amyloid-b load in cognitively normal older adults

Osteoporosis and Alzheimer’s disease (AD) mainly affect older individuals, and the possibility of an underlying link contributing to their shared epidemiological features has rarely been investigated. In the current study, we investigated the association between levels of plasma sclerostin (SOST), a protein primarily produced by bone, and brain amyloid-beta (A ) load, a pathological hallmark of AD. The study enrolled participants meeting a set of screening inclusion and exclusion criteria and were stratified into A − (n = 65) and A + (n = 35) according to their brain A load assessed using A -PET (positron emission tomography) imaging. Plasma SOST levels, apolipoprotein E gene (APOE) genotype and several putative AD blood-biomarkers including A 40, A 42, A 42/A 40, neurofilament light (NFL), glial fibrillary acidic protein (GFAP), total tau (t-tau) and phosphorylated tau (p-tau181 and p-tau231) were detected and compared. It was found that plasma SOST levels were significantly higher in the A + group (71.49 ± 25.00 pmol/L) compared with the A − group (56.51 ± 22.14 pmol/L) (P \u3c 0.01). Moreover, Spearman’s correlation analysis showed that plasma SOST concentrations were positively correlated with brain A load (ρ = 0.321, P = 0.001). Importantly, plasma SOST combined with A 42/A 40 ratio significantly increased the area under the curve (AUC) when compared with using A 42/A 40 ratio alone (AUC = 0.768 vs 0.669, P = 0.027). In conclusion, plasma SOST levels are elevated in cognitively unimpaired older adults at high risk of AD and SOST could complement existing plasma biomarkers to assist in the detection of preclinical AD

Serum neurofilament light chain in genetic frontotemporal dementia: a longitudinal, multicentre cohort study

Back ground Neurofilament light chain (NfL) is a promising blood biomarker in genetic frontotemporal dementia, with elevated concentrations in symptomatic carriers of mutations in GRN, C9orf72, and MAPT. A better understanding of NfL dynamics is essential for upcoming therapeutic trials. We aimed to study longitudinal NfL trajectories in people with presymptomatic and symptomatic genetic frontotemporal dementia. Methods We recruited participants from 14 centres collaborating in the Genetic Frontotemporal Dementia Initiative (GENFI), which is a multicentre cohort study of families with genetic frontotemporal dementia done across Europe and Canada. Eligible participants (aged >= 18 years) either had frontotemporal dementia due to a pathogenic mutation in GRN, C9orf72, or MAPT (symptomatic mutation carriers) or were healthy at-risk first-degree relatives (either presymptomatic mutation carriers or non-carriers), and had at least two serum samples with a time interval of 6 months or more. Participants were excluded if they had neurological comorbidities that were likely to affect NfL, including cerebrovascular events. We measured NfL longitudinally in serum samples collected between june 8, 2012, and Dec 8, 2017, through follow-up visits annually or every 2 years, which also included MRI and neuropsychological assessments. Using mixed-effects models, we analysed Nil changes over time and correlated them with longitudinal imaging and clinical parameters, controlling for age, sex, and study site. The primary outcome was the course of NfL over time in the various stages of genetic frontotemporal dementia. Findings We included 59 symptomatic carriers and 149 presymptomatic carriers of a mutation in GRN, C9orf72, or MAPT, and 127 non-carriers. Nine presymptomatic carriers became symptomatic during follow-up (so-called converters). Baseline NfL was elevated in symptomatic carriers (median 52 pg/mL [IQR 24-69]) compared with presymptomatic carriers (9 pg/mL [6-13];p<0.0001) and non-carriers (8 pg/mL [6-11];p<0.0001), and was higher in converters than in non-converting carriers (19 pg/mL [17-28] vs 8 pg/mL [6-11];p=0.0007;adjusted for age). During follow-up, NfL increased in converters (b=0.097 [S E 0. 018];p<0.0001). In symptomatic mutation carriers overall, NfL did not change during follow-up (b=0.017 [SE 0.010];p=0.101) and remained elevated. Rates of NfL change over time were associated with rate of decline in Mini Mental State Examination (b=-94.7 [SE 33.9];p=0.003) and atrophy rate in several grey matter regions, but not with change in Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale score (b=-3.46 [SE 46.3];p=0.941). Interpretation Our findings show the value of blood NfL as a disease progression biomarker in genetic frontotemporal dementia and suggest that longitudinal NfL measurements could identify mutation carriers approaching symptom onset and capture rates of brain atrophy. The characterisation of NfL over the course of disease provides valuable information for its use as a treatment effect marker. Copyright (C) 2019 Elsevier Ltd. All rights reserved

Pre-analytical stability of serum biomarkers for neurological disease: Neurofilament-light, glial fibrillary acidic protein and contactin-1

Objectives: Neurofilament-light (NfL), glial fibrillary acidic protein (GFAP) and contactin-1 (CNTN1) are blood-based biomarkers that could contribute to monitoring and prediction of disease and treatment outcomes in neurological diseases. Pre-analytical sample handling might affect results, which could be disease-dependent. We tested common handling variations in serum of volunteers as well as in a defined group of patients with multiple sclerosis (pwMS). Methods: Sample sets from 5 pwMS and 5 volunteers at the outpatient clinic were collected per experiment. We investigated the effect of the following variables: collection tube type, delayed centrifugation, centrifugation temperature, delayed storage after centrifugation and freeze-thawing. NfL and GFAP were measured by Simoa and CNTN1 by Luminex. A median recovery of 90-110% was considered stable. Results: For most pre-analytical variables, serum NfL and CNTN1 levels remained unaffected. In the total group, NfL levels increased (121%) after 6 h of delay at 2-8 °C until centrifugation, while no significant changes were observed after 24 h delay at room temperature (RT). In pwMS specifically, CNTN1 levels increased from additional freeze-thaw cycles number 2 to 4 (111%-141%), whereas volunteer levels remained stable. GFAP showed good stability for all pre-analytical variables. Conclusions: Overall, the serum biomarkers tested were relatively unaffected by variations in sample handling. For serum NfL, we recommend storage at RT before centrifugation at 2-8 °C up to 6 h or at RT up to 24 h. For serum CNTN1, we advise a maximum of two freeze-thaw cycles. Our results confirm and expand on recently launched consensus standardized operating procedures

Highly specific and ultrasensitive plasma test detects Abeta(1–42) and Abeta(1–40) in Alzheimer’s disease

Plasma biomarkers that reflect specific amyloid beta (Abeta) proteoforms provide an insight in the treatment effects of Alzheimer’s disease (AD) therapies. Our aim was to develop and validate ready-to-use Simoa ‘Amyblood’ assays that measure full length Abeta 1-42 and Abeta 1-40 and compare their performance with two commercial assays. Linearity, intra- and inter-assay %CV were compared between Amyblood, Quanterix Simoa triplex, and Euroimmun ELISA. Sensitivity and selectivity were assessed for Amyblood and the Quanterix triplex. Clinical performance was assessed in CSF biomarker confirmed AD (n = 43, 68 ± 6 years) and controls (n = 42, 62 ± 5 years). Prototype and Amyblood showed similar calibrator curves and differentiation (20 AD vs 20 controls, p < 0.001). Amyblood, Quanterix triplex, and ELISA showed similar linearity (96%-122%) and intra-assay %CVs (≤ 3.1%). A minor non-specific signal was measured with Amyblood of + 2.4 pg/mL Abeta 1-42 when incubated with 60 pg/mL Abeta 1-40. A substantial non-specific signal of + 24.7 pg/mL Abeta x-42 was obtained when 40 pg/mL Abeta 3-42 was measured with the Quanterix triplex. Selectivity for Abeta 1-42 at physiological Abeta 1-42 and Abeta 1-40 concentrations was 125% for Amyblood and 163% for Quanterix. Amyblood and Quanterix ratios (p < 0.001) and ELISA Abeta 1-42 concentration (p = 0.025) could differentiate AD from controls. We successfully developed and upscaled a prototype to the Amyblood assays with similar technical and clinical performance as the Quanterix triplex and ELISA, but better specificity and selectivity than the Quanterix triplex assay. These results suggest leverage of this specific assay for monitoring treatment response in trials

Amyloid-β misfolding as a plasma biomarker indicates risk for future clinical Alzheimer’s disease in individuals with subjective cognitive decline

Background: We evaluated Aβ misfolding in combination with Aβ42/40 ratio as a prognostic tool for future clinical progression to mild cognitive impairment (MCI) or dementia due to Alzheimer’s disease (AD) in individuals with subjective cognitive decline (SCD). Methods: Baseline plasma samples (n = 203) from SCD subjects in the SCIENCe project and Amsterdam Dementia Cohort (age 61 ± 9 years; 57% male, mean follow-up time 2.7 years) were analyzed using immuno-infrared-sensor technology. Within 6 years of follow-up, 22 (11%) individuals progressed to MCI or dementia due to AD. Sensor readout values > 1646 cm− 1 reflected normal Aβ folding; readouts at ≤ 1646 cm− 1 reflected low and at < 1644 cm− 1 high misfolding. We used Cox proportional hazard models to quantify Aβ misfolding as a prognostic biomarker for progression to MCI and dementia due to AD. The accuracy of the predicted development of MCI/AD was determined by time-dependent receiver operating characteristic (t-ROC) curve analyses that take individual follow-up and conversion times into account. Statistical models were adjusted for age, sex, and APOEε4 status. Additionally, plasma Aβ42/40 data measured by SIMOA were statistically analyzed and compared. Results: All 22 patients who converted to MCI or AD-dementia within 6 years exhibited Aβ misfolding at baseline. Cox analyses revealed a hazard ratio (HR) of 19 (95% confidence interval [CI] 2.2–157.8) for future conversion of SCD subjects with high misfolding and of 11 (95% CI 1.0–110.1) for those with low misfolding. T-ROC curve analyses yielded an area under the curve (AUC) of 0.94 (95% CI 0.86–1.00; 6-year follow-up) for Aβ misfolding in an age, sex, and APOEε4 model. A similar model with plasma Aβ42/40 ratio yielded an AUC of 0.92 (95% CI, 0.82–1.00). The AUC increased to 0.99 (95% CI, 0.99–1.00) after inclusion of both Aβ misfolding and the Aβ42/40 ratio. Conclusions: A panel of structure- and concentration-based plasma amyloid biomarkers may predict conversion to clinical MCI and dementia due to AD in cognitively unimpaired subjects. These plasma biomarkers provide a noninvasive and cost-effective alternative for screening early AD pathological changes. Follow-up studies and external validation in larger cohorts are in progress for further validation of our findings

Correction to: Amyloid-β misfolding as a plasma biomarker indicates risk for future clinical Alzheimer’s disease in individuals with subjective cognitive decline (Alzheimer's Research & Therapy, (2020), 12, 1, (169), 10.1186/s13195-020-00738-8): Amyloid-β misfolding as a plasma biomarker indicates risk for future clinical Alzheimer’s disease in individuals with subjective cognitive decline (Alzheimer's Research & Therapy, (2020), 12, 1, (169), 10.1186/s13195-020-00738-8)

Following publication of the original article [1], the authors noticed that the published figures have errors which was occurred during processing of the figures in production team. 1) fonts are shifted (Figure 1) 2) colors are not displayed (Figure 2, open circles should be colored) 3) labelling is incorrect (Figure 4, "Afl" should be "Aß", Supplementary Figures "D Absorbance" should be "? absorbance" (Δ = delta)) The correct Figures 1, 2 and 4 are shown below. The original article [1] has been updated. (Figure presented.)