Inverse relationship between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans
Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, et al.;
Commented by , 22 Mar 2006
Aim of the study
To compare in vivo brain amyloid load via positron emission tomography (PET) with cerebrospinal fluid (CSF) and plasma markers
Method
PET using the amyloid-binding agent Pittsburgh Compound-B (PIB) was performed in clinically characterized research subjects from the Alzheimer’s Disease (AD) Research Center at the Washington University School of Medicine, and CSF levels of Abeta42, tau, and phospho-tau181, plasma levels of Abeta40 and Abeta42 were measured within 2 years of the PET.
Results
Subjects fell into two non-overlapping groups: those with positive PIB binding (high amount of amyloid binding, predominantly in prefrontal cortex, precuneus, temporal cortex) had the lowest CSF Abeta42 level, those with negative PIB binding has the highest CSF Abeta42 levels. No relation was observed between PIB binding and the other biological CSF or blood measures.
PIB binding and CSF Abeta42 did not consistently correspond with clinical diagnosis, e.g. three cognitively normal subjects had abnormal PIB binding and low CSF Abeta42 suggesting a preclinical detection of Alzheimer’s disease.
Professor Gauthier's comments
These results expand on the original observations by Klunk et al. (ref. 1), that in vivo brain imaging of amyloid using PET could become an important tool for preclinical diagnosis of AD. The explanation proposed by the authors to explain the inverse relationship between high PIB binding and low CSF Abeta42 levels is a "sink" effect, where amyloid deposition in the brain in early stages of AD results in a new equilibrium between soluble and deposited Abeta42.
It is disappointing, but not unexpected, that plasma Abeta42 levels do not correlate with PIB binding. Follow-up of the three subjects with apparent preclinical diagnosis of AD is required to validate this observation.
There is also the possibility that this technology could be used as a proof of biological activity for amyloid-acting drugs in patients with mild AD, particularly for immunotherapy that has been shown to decrease brain amyloid load in animal models of AD.
Reference
1. Klunk WE et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Annals of Neurology 2004; 55 (3); 306-319