IC-P-054: Relationship between in vivo amyloid imaging with 11C-PIB and CSF Aβ42

Abstract

Abundant evidence supports a central role for amyloid–β (Aβ) and its conversion from soluble to insoluble forms (e.g., fibrils or oligomers) in the pathogenesis of Alzheimer's disease (AD). Potential disease–modifying therapies targeting Aβ and its metabolism are currently being developed and will ultimately provide the definitive test of this hypothesis. In order for therapies to have the greatest clinical impact, it will be necessary to identify individuals with AD pathology prior to marked cognitive symptoms and neuronal cell loss (i.e., ‘preclinical’ or very early stage DAT). We recently investigated the relationship between the in vivo amyloid load (via PET imaging of the amyloid–binding compound, 11C–PIB) and various CSF measures in a small (n=24) research cohort (age 48–83 years) that included both cognitively normal individuals and those diagnosed with very mild or mild DAT (Fagan et al., 2006, Ann. Neurol.). We observed a striking inverse relation between mean cortical amyloid load and CSF Aβ42 (but not other CSF markers); those with positive PIB–binding had low CSF Aβ42 levels and those with negative PIB–binding had high CSF Aβ42 levels, with no overlap between the two groups. Importantly, this pattern was observed in a subset of subjects who were cognitively normal, suggesting the presence of amyloid pathology in the absence of cognitive symptoms (“preclinical AD”). These findings suggest that brain amyloid deposition results in low CSF Aβ42, and that amyloid imaging and CSF Aβ42 may potentially be useful as antecedent biomarkers of (preclinical) AD. We have since expanded our cohort size and will provide an update of our findings, including the consistency of this pattern in this larger sample, the degree to which it is maintained in individuals exhibiting a relatively low level of brain amyloid, and whether analyses of regional PIB binding offer additional discriminatory power. These additional analyses will provide important information regarding the potential utility of these measures as diagnostic and/or antecedent biomarkers of AD and may also offer insights into possible mechanism(s) of amyloid deposition in the AD brain.