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P1‐124: VALIDATION OF WEIGHTED TWO‐POINT CORRELATION ANALYSIS ON TAU PET WITHOUT IMAGE INTENSITY NORMALIZATION
Author(s) -
Shokouhi Sepideh,
Kang Hakmook,
Gwirtsman Harry E.,
Newhouse Paul A.
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.2018.06.127
Subject(s) - normalization (sociology) , voxel , correlation , mathematics , linear regression , nuclear medicine , intensity (physics) , spatial normalization , statistics , pattern recognition (psychology) , medicine , artificial intelligence , physics , radiology , computer science , geometry , sociology , anthropology , quantum mechanics
Background:Recent preclinical mouse models and imaging studies using specific tau PET tracers suggest that tau pathology follows a clear trajectory in the human brain. This has inspired a wave of therapeutic approaches using vaccination or antibodies against tau protein. However, it is unclear under what form tau is secreted and how binding to proteins at the postsynaptic membrane affects the dynamics of clearing. Methods:We use a Quantitative Systems Pharmacology (QSP) approach, essentially a mechanism-based advanced computer model of human biology and pathology to integrate available knowledge about tau spreading in a temporal model. Four different tau forms are modeled together with capture by antibodies based on their respective affinities. Biological processes such as binding to heparin sulfate proteoglycans and subsequent absorption/internalization are modeled based on existing literature data. Results: We recapitulate the dose-dependent decrease in steady-state intrasynaptic tau concentration as a function of antibody concentration and affinity. The presence of microglia and subsequent antibodymediated tau uptake complicates the dose-response. Interestingly when considering a very long absorption/internalization step, there exists a dose-range for the antibody (0-30nM)where the internalization rate of the tau species with the lowest affinity is shown to increase, due to altered competition at the binding sites. Sensitivity analysis suggest that even small differences in affinity can result in such negative effects. Given the fact that extracellular tau is present in different forms (i.e., exosomes) with different accessibility for the antibody, this suggests that further experimental elucidation of the absorption/internalization step is necessary for optimizing clinical trial design. Conclusions: Formalizing the knowledge about specific and critical biological processes in a mathematical computer model can help identifying key processes that drive disease outcomes and can help prioritized experimental studies. Quantitative Systems Pharmacology is at the core of MAPTA, a precompetitive and multidisciplinary alliance and is a powerful tool to understand better the complex biology of tau and downstream mechanisms that are the most relevant to the development of new therapeutics for neurodegenerative diseases.