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-ß (Aß) and tau in Alzheimer's Disease (AD). However, its association with longitudinal cognition and comparative performance to PET Aß 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 Aß (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 Aß (A+) and tau (T+) with and without p217+tau pre-screening. DESIGN: A prospective observational cohort study. SETTING: Participants of the Australian Imaging, Biomarker and 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 Aß-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 (ß = -0.55, p < 0.001) and CDR-SB (ß =0.61, p < 0.001) with an effect size similar to Aß Centiloid (MMSE ß = -0.48, p = 0.002; CDR-SB ß = 0.43, p = 0.004) and meta-temporal (MetaT) tau SUVR (MMSE: ß = -0.62, p < 0.001; CDR-SB: ß = 0.65, p < 0.001). In CU, only MetaT tau SUVR was significantly associated with change in AIBL-PACC (ß = -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.

The Effect of Hydroethanol Extract of Achillea Millefolium on ß-adrenoceptors of Guinea Pig Tracheal Smooth Muscle.

Different pharmacological effects of Achillea millefolium including its relaxant effect on smooth muscle have been shown previously. In the present study the stimulatory effect of the plant extract on ß-adrenoceptor of tracheal muscle was examined in order to investigate one possible mechanism for its observed relaxant effect. Effect of three concentrations of hydroethanol extract, 10 nM propranolol, and saline on ß-adrenoceptor was tested in two experimental groups including; nonincubated tracheal smooth muscles (group 1) and incubated tracheal smooth muscle with chlorpheniramine (group 2). Concentration response curves to isoprenaline were performed in precontracted tracheal smooth muscle in the presence of the extract, propranolol and saline. Values of EC50 and CR-1 were measured. Leftward shifts in isoprenaline curves were observed in the presence of medium and high concentrations of the extract compared with saline in both groups. The values of EC50 obtained in the presence of medium and high concentrations of the extract only in group 1 were nonsignificantly lower than that of saline. The values of CR-1 obtained in the presence of all concentrations of the extract in both groups were negative and significantly different with that of propranolol. The results indicated a small stimulatory effect of the extract on ß2-adrenoceptors.