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P2‐076: A NOVEL ALTERNATIVE MODEL TO MMRM AS THE PRIMARY MODEL FOR SPORADIC AD CLINICAL TRIALS: THE PROPORTIONAL MMRM
Author(s) -
Wang Guoqiao,
Xiong Chengjie,
McDade Eric,
Li Yan,
Aschenbrenner Andrew J.,
Hassenstab Jason,
Berry Scott,
Bateman Randall J.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.761
Subject(s) - repeated measures design , type i and type ii errors , statistics , analysis of variance , analysis of covariance , mathematics , statistical power , covariance , parametric statistics , econometrics
imaging probes that can distinguish these forms from fibrils. We have synthesised a luminescent conjugated oligopolythiophene (pTP-TFE) which is considered to bind to oligomer forms of beta-amyloid based on an aggregation assay. Hence it was of interest to characterise the binding profile of this compound in greater detail, to assess the relative binding to range of aggregated protein size, including oligomers. Methods: Compound pFTAA (another oligopolythiophene), pTP-TFE and Thioflavin T (ThT) were first used to monitor Ab fibrillation conducted on a POLARstar Omega plated reader. Transmission Electron Microscopy (TEM) was used to characterize the morphology of both Ab oligomers and fibrils species.To determine this profile of binding we also used the novel technique of QIAD (Quantitative determination of interference with Ab aggregate size distribution) 2 which can purify and quantify different sizes of Ab species Abmonomers, oligomers and fibrils. Subquently we applied QIAD on our compound, pTP-TFE, to separated and fractionated Ab species. Fluorescent intensity values were measured after these three compounds mixed with all sizes of the Ab aggregates. Results: For fibrillation kinetics of Ab aggregates, pTP-TFE reacted earlier than pFTAA, whereas ThT was the slowest. TEM micrographs showed small amount of smaller oligomeric species were present at 90 min while both pFTAA and ThT showed no fluorescence change. QIAD assay produced high amount of oligomers. Compared to binding fibrils Ab protein (Fractions 10-14) pTP-TFE has higher fluorescence intensity towards the oligomeric fractions (Fraction 3-6) which indicates a greater binding to these forms. Conclusions: The novel compound pTP-TFE showed greater binding to Ab oligomers compared to fibril. Therefore this compound has potential for further development as an imaging probe for characterising oligomer pathology. References: 1.Aslund et al, ACS Chem. Biol. 2009, 4, 673-684. 2. Brener et al, Sci. Rep. 2015, 5, 13222.