Plasma p217+tau versus NAV4694 amyloid and MK6240 tau PET across the Alzheimer's continuum

Introduction We evaluated a new Simoa plasma assay for phosphorylated tau (P-tau) at aa217 enhanced by additional p-tau sites (p217+tau). Methods Plasma p217+tau levels were compared to 18F-NAV4694 amyloid beta (Aβ) positron emission tomography (PET) and 18F-MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants. Results Compared to Aβ− CU, the plasma levels of p217+tau increased 2-fold in Aβ+ CU and 3.5-fold in Aβ+ CI. In Aβ− the p217+tau levels did not differ significantly between CU and CI. P217+tau correlated with Aβ centiloids P = .67 (CI, P = .64; CU, P = .45) and tau SUVRMT P = .63 (CI, P = .69; CU, P = .34). Area under curve (AUC) for Alzheimer's disease (AD) dementia versus Aβ− CU was 0.94, for AD dementia versus other dementia was 0.93, for Aβ+ versus Aβ− PET was 0.89, and for tau+ versus tau− PET was 0.89. Discussion Plasma p217+tau levels elevate early in the AD continuum and correlate well with Aβ and tau PET

Two-year prognostic utility of plasma p217+tau across the Alzheimer’s continuum

Background: Plasma p217+tau has shown high concordance with cerebrospinal fluid (CSF) and positron emission tomography (PET) measures of amyloid- (A ) and tau in Alzheimer’s Disease (AD). However, its association with longitudinal cognition and comparative performance to PET A and tau in predicting cognitive decline are unknown. Objectives: To evaluate whether p217+tau can predict the rate of cognitive decline observed over two-year average follow-up and compare this to prediction based on A (18F-NAV4694) and tau (18F-MK6240) PET. We also explored the sample size required to detect a 30% slowing in cognitive decline in a 2-year trial and selection test cost using p217+tau (pT+) as compared to PET A (A+) and tau (T+) with and without p217+tau pre-screening. Design: A prospective observational cohort study. Setting: Participants of the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) and Australian Dementia Network (ADNeT). Participants: 153 cognitively unimpaired (CU) and 50 cognitively impaired (CI) individuals. Measurements: Baseline p217+tau Simoa assay 18F-MK6240 tau-PET and 18F-NAV4694 A -PET with neuropsychological follow-up (MMSE, CDR-SB, AIBL-PACC) over 2.4 ± 0.8 years. Results: In CI, p217+tau was a significant predictor of change in MMSE ( = −0.55, p \u3c 0.001) and CDR-SB ( =0.61, p \u3c 0.001) with an effect size similar to A Centiloid (MMSE = −0.48, p = 0.002; CDR-SB = 0.43, p = 0.004) and meta-temporal (MetaT) tau SUVR (MMSE: = −0.62, p \u3c 0.001; CDR-SB: = 0.65, p \u3c 0.001). In CU, only MetaT tau SUVR was significantly associated with change in AIBL-PACC ( = −0.22, p = 0.008). Screening pT+ CI participants into a trial could lead to 24% reduction in sample size compared to screening with PET for A+ and 6–13% compared to screening with PET for T+ (different regions). This would translate to an 81–83% biomarker test cost-saving assuming the p217+tau test cost one-fifth of a PET scan. In a trial requiring PET A+ or T+, p217+tau pre-screening followed by PET in those who were pT+ would cost more in the CI group, compared to 26–38% biomarker test cost-saving in the CU. Conclusions: Substantial cost reduction can be achieved using p217+tau alone to select participants with MCI or mild dementia for a clinical trial designed to slow cognitive decline over two years, compared to participant selection by PET. In pre-clinical AD trials, p217+tau provides significant cost-saving if used as a pre-screening measure for PET A+ or T+ but in MCI/mild dementia trials this may add to cost both in testing and in the increased number of participants needed for testing

Plasma pTau-217 and N-terminal tau (NTA) enhance sensitivity to identify tau PET positivity in amyloid-β positive individuals

INTRODUCTION: We set out to identify tau PET-positive (A+T+) individuals among amyloid-beta (Aβ) positive participants using plasma biomarkers. METHODS: In this cross-sectional study we assessed 234 participants across the AD continuum who were evaluated by amyloid PET with [18F]AZD4694 and tau-PET with [18F]MK6240 and measured plasma levels of total tau, pTau-181, pTau-217, pTau-231, and N-terminal tau (NTA-tau). We evaluated the performances of plasma biomarkers to predict tau positivity in Aβ+ individuals. RESULTS: Highest associations with tau positivity in Aβ+ individuals were found for plasma pTau-217 (AUC [CI95%] = 0.89 [0.82, 0.96]) and NTA-tau (AUC [CI95%] = 0.88 [0.91, 0.95]). Combining pTau-217 and NTA-tau resulted in the strongest agreement (Cohen's Kappa = 0.74, CI95% = 0.57/0.90, sensitivity = 92%, specificity = 81%) with PET for classifying tau positivity. DISCUSSION: The potential for identifying tau accumulation in later Braak stages will be useful for patient stratification and prognostication in treatment trials and in clinical practice. Highlights: We found that in a cohort without pre-selection pTau-181, pTau-217, and NTA-tau showed the highest association with tau PET positivity. We found that in Aβ+ individuals pTau-217 and NTA-tau showed the highest association with tau PET positivity. Combining pTau-217 and NTA-tau resulted in the strongest agreement with the tau PET-based classification

Equivalence of plasma p-tau217 with cerebrospinal fluid in the diagnosis of Alzheimer's disease

INTRODUCTION: Plasma biomarkers are promising tools for Alzheimer's disease (AD) diagnosis, but comparisons with more established biomarkers are needed. METHODS: We assessed the diagnostic performance of p-tau181, p-tau217, and p-tau231 in plasma and CSF in 174 individuals evaluated by dementia specialists and assessed with amyloid-PET and tau-PET. Receiver operating characteristic (ROC) analyses assessed the performance of plasma and CSF biomarkers to identify amyloid-PET and tau-PET positivity. RESULTS: Plasma p-tau biomarkers had lower dynamic ranges and effect sizes compared to CSF p-tau. Plasma p-tau181 (AUC = 76%) and p-tau231 (AUC = 82%) assessments performed inferior to CSF p-tau181 (AUC = 87%) and p-tau231 (AUC = 95%) for amyloid-PET positivity. However, plasma p-tau217 (AUC = 91%) had diagnostic performance indistinguishable from CSF (AUC = 94%) for amyloid-PET positivity. DISCUSSION: Plasma and CSF p-tau217 had equivalent diagnostic performance for biomarker-defined AD. Our results suggest that plasma p-tau217 may help reduce the need for invasive lumbar punctures without compromising accuracy in the identification of AD. Highlights: p-tau217 in plasma performed equivalent to p-tau217 in CSF for the diagnosis of AD, suggesting the increased accessibility of plasma p-tau217 is not offset by lower accuracy. p-tau biomarkers in plasma had lower mean fold-changes between amyloid-PET negative and positive groups than p-tau biomarkers in CSF. CSF p-tau biomarkers had greater effect sizes than plasma p-tau biomarkers when differentiating between amyloid-PET positive and negative groups. Plasma p-tau181 and plasma p-tau231 performed worse than p-tau181 and p-tau231 in CSF for AD diagnosis

Two Birds with One Stone? Possible Dual-Targeting H1N1 Inhibitors from Traditional Chinese Medicine

The H1N1 influenza pandemic of 2009 has claimed over 18,000 lives. During this pandemic, development of drug resistance further complicated efforts to control and treat the widespread illness. This research utilizes traditional Chinese medicine Database@Taiwan (TCM Database@Taiwan) to screen for compounds that simultaneously target H1 and N1 to overcome current difficulties with virus mutations. The top three candidates were de novo derivatives of xylopine and rosmaricine. Bioactivity of the de novo derivatives against N1 were validated by multiple machine learning prediction models. Ability of the de novo compounds to maintain CoMFA/CoMSIA contour and form key interactions implied bioactivity within H1 as well. Addition of a pyridinium fragment was critical to form stable interactions in H1 and N1 as supported by molecular dynamics (MD) simulation. Results from MD, hydrophobic interactions, and torsion angles are consistent and support the findings of docking. Multiple anchors and lack of binding to residues prone to mutation suggest that the TCM de novo derivatives may be resistant to drug resistance and are advantageous over conventional H1N1 treatments such as oseltamivir. These results suggest that the TCM de novo derivatives may be suitable candidates of dual-targeting drugs for influenza.National Science Council of Taiwan (NSC 99-2221-E-039-013-)Committee on Chinese Medicine and Pharmacy (CCMP100-RD-030)China Medical University and Asia University (CMU98-TCM)China Medical University and Asia University (CMU99-TCM)China Medical University and Asia University (CMU99-S-02)China Medical University and Asia University (CMU99-ASIA-25)China Medical University and Asia University (CMU99-ASIA-26)China Medical University and Asia University (CMU99-ASIA-27)China Medical University and Asia University (CMU99-ASIA-28)Taiwan Department of Health. Clinical Trial and Research Center of Excellence (DOH100-TD-B-111-004)Taiwan Department of Health. Cancer Research Center of Excellence (DOH100-TD-C-111-005

Plasma p217+tau concordance with 18F-NAV4694 beta-amyloid and 18F-MK6240 tau PET in mild Alzheimer’s disease and cognitively unimpaired participants in the AIBL/ADNeT cohort

Abstract Background Beta‐amyloid (Aß) PET assists diagnosis of Alzheimer’s disease (AD) and has an important role in selection for trials. Aß PET is costly. Reports suggest that plasma measures of phospho‐tau have high concordance with both Aß and tau PET. We compared a new assay, plasma p217+tau to Aß and tau PET. Method 181 MCI/mild AD and 222 cognitively unimpaired (CU) participants in AIBL and the Australian Dementia Network (ADNeT) trial screening program were studied. Aß PET threshold was set at 25 centiloids (CL) as the standard for defining a positive scan and also at 50 CL which best correlates with NIA/AA AD neuropathologic change criteria. In CU we also evaluated a 20 CL PET threshold as this may be used in preclinical trial selection. Tau PET threshold was set at the SUVR (normalised to cerebellar cortex) for a meta‐temporal ROI (entorhinal cortex, amygdala, parahippocampus, and fusiform, inferior and middle temporal gyri) at the 95th percentile of Aß PET negative CU. Plasma p217+tau was measured with SIMOA using a Janssen in‐house assay. ROC area under the curve (AUC) was generated with Youden Index defined sensitivity (sens) and specificity (spec). Result Rank‐order correlation between p217+tau and Aß CL was significant in MCI/AD: ρ=0.65, p<10‐22 and CU: ρ=0.45, p<10‐12 and with tau SUVR for MCI/AD:ρ=0.68, p<10‐25 and CU:ρ=0.32, p<10‐7. In MCI/AD the AUC for p217+tau to predict Aß >25CL was 0.91 (sens 83%, spec 85%) and at >50CL was 0.90 (sens 73%, spec 93%). For tau+ PET the AUC was 0.86 (sens 73%, spec 90%). In the CU, the AUC vs Aß >25CL was 0.84 (sens 81%, spec 81%) dropping to 0.79 (sens 72%, spec 82%) for the 20CL PET threshold. The AUC vs tau+ PET in CU was 0.87 (sens 90%, spec 76%). Conclusion Plasma p217+tau showed good concordance with PET defined Aß and tau positivity in both MCI/AD and CU indicating potential to support the diagnosis of AD and to screen for preclinical AD trials. Early triage with p217+tau may reduce the number of screening Aß PET needed to identify Aß+ PET CU for preclinical trials by 50%