Central pharmacodynamic activity of solanezumab in mild Alzheimer's disease dementia.

Introduction: Solanezumab treatment was previously shown to significantly increase total (bound + unbound) cerebrospinal fluid (CSF) levels of amyloid β (Aβ) and Aβ in patients with mild to moderate Alzheimer's disease dementia yet did not produce meaningful cognitive effects. This analysis assessed solanezumab's central nervous system target engagement by evaluating changes in CSF total and free Aβ isoforms and their relationship with solanezumab exposure.

Methods: CSF Aβ isoform concentrations were measured in patients with mild Alzheimer's disease dementia from a pooled EXPEDITION + EXPEDITION2 population and from EXPEDITION3.

Derivation of cutoffs for the Elecsys amyloid β (1-42) assay in Alzheimer's disease.

Introduction: An Elecsys® Amyloid β (Aβ [1-42]) immunoassay cutoff for classification of patients with Alzheimer's disease was investigated.

Methods: Cerebrospinal fluid samples collected from patients with mild-to-moderate Alzheimer's disease were analyzed by Elecsys® immunoassays: (1) Aβ (1-42), (2) total tau, and (3) phosphorylated tau. Cutoffs (Aβ [1-42] and ratios with tau) were estimated by method comparison between AlzBio3 ( = 206), mixture modeling ( = 216), and concordance with florbetapir F 18 imaging-based classification ( = 75).

A digital enzyme-linked immunosorbent assay for ultrasensitive measurement of amyloid-β 1-42 peptide in human plasma with utility for studies of Alzheimer's disease therapeutics.

Background: Amyloid-β 1-42 peptide (Aβ) is associated with plaque formation in the brain of patients with Alzheimer's disease (AD). Pharmacodynamic studies of AD therapeutics that lower the concentrations of Aβ in peripheral blood require highly sensitive assays for its measurement. A digital enzyme-linked immunosorbent assay (ELISA) using single molecule array (Simoa) technology has been developed that provides improved sensitivity compared with conventional ELISA methods using the same antibody reagents.

Dihydroxyphenylglycol as a Biomarker of Norepinephrine Transporter Inhibition by Atomoxetine: Human Model to Assess Central and Peripheral Effects of Dosing.

To assess the primary metabolite of norepinephrine, 3,4-dihydroxyphenylglycol (DHPG), as a sensitive biomarker for norepinephrine transporter (NET) function and the relationship of DHPG measured peripherally and centrally, NET was antagonized with 80 mg/d atomoxetine for 18 days. Twelve healthy subjects were treated with atomoxetine in an open-label, multiple-dose exploratory study. Plasma atomoxetine reached steady state by day 6, and the pharmacokinetic results demonstrated availability of atomoxetine to the central nervous system.

Recommendations for adaptation and validation of commercial kits for biomarker quantification in drug development.

Increasingly, commercial immunoassay kits are used to support drug discovery and development. Longitudinally consistent kit performance is crucial, but the degree to which kits and reagents are characterized by manufacturers is not standardized, nor are the approaches by users to adapt them and evaluate their performance through validation prior to use. These factors can negatively impact data quality.