Imaging beta-amyloid fibrils in Alzheimer's disease: a critical analysis through simulation of amyloid fibril polymerization.
The polymerization of beta-amyloid (A beta) peptides into fibrillary plaques is implicated, in part, in the pathogenesis of Alzheimer's disease. A beta molecular imaging probes (A beta-MIPs) have been introduced in an effort to quantify amyloid burden or load, in subjects afflicted with AD by invoking the classic PET receptor model for the quantitation of neuronal receptor density. In this communication, we explore conceptual differences between imaging the density of amyloid fibril polymers and neuronal receptors. We formulate a mathematical model for the polymerization of A beta with parameters that are mapped to biological modulators of fibrillogenesis and introduce a universal measure for amyloid load to accommodate various interactions of A beta-MIPs with fibrils. Subsequently, we hypothesize four A beta-MIPs and utilize the fibrillogenesis model to simulate PET tissue time activity curves (TACs). Given the unique nature of polymer growth and resulting PET TAC, the four probes report differing amyloid burdens for a given brain pathology, thus complicating the interpretation of PET images. In addition, we introduce the notion of an MIP's resolution, apparent maximal binding site concentration, optimal kinetic topology and its resolving power in characterizing the pathological progression of AD and the effectiveness of drug therapy. The concepts introduced in this work call for a new paradigm that goes beyond the classic parameters B(max) and K(D) to include binding characteristics to polymeric peptide aggregates such as amyloid fibrils, neurofibrillary tangles and prions.
Shoghi-Jadid
Kooresh
K
Department of Biomathematics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1766, USA. kshogi@mednet.ucla.edu
Barrio
Jorge R
JR
Kepe
Vladimir
V
Wu
Hsiao-Ming
HM
Small
Gary W
GW
Phelps
Michael E
ME
Huang
Sung-Cheng
SC
D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D003198:Computer Simulation; D006801:Humans; D007090:Image Interpretation, Computer-Assisted / Q000379:methods*; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D008956:Models, Chemical; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging* / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D012720:Severity of Illness Index
D016229:Amyloid beta-Peptides; D019275:Radiopharmaceuticals