Relationship of Cerebrospinal Fluid Markers to¹¹C-PiB and¹⁸F-FDDNP Binding

Abstract

The purpose of this study was to investigate the potential relationships between cerebrospinal fluid (CSF) measurements of b-amyloid-1-42 (Ab ) and total tau to 11 C-Pittsburgh compound B ( 11 C-PiB) and 2-(1-f6-[(2-18 F-fluoroethyl)(methyl)amino]-2-naphthylgethylidene) malononitrile ( 18 F-FDDNP) binding as measured using PET. Methods: A total of 37 subjects were included, consisting of 15 patients with Alzheimer disease (AD), 12 patients with mild cognitive impairment, and 10 healthy controls. All subjects underwent a lumbar puncture and PET using both 11 C-PiB and 18 F-FDDNP. For both PET tracers, parametric images of binding potential were generated. Potential associations of CSF levels of Ab 1-42 and tau with 11 C-PiB and 18 F-FDDNP binding were assessed using Pearson correlation coefficients and linear regression analyses. Results: For both global 11 C-PiB and 18 F-FDDNP binding, significant correlations with CSF levels of Ab 1-42 (r 5 20.72 and 20.37, respectively) and tau (r 5 0.58 and 0.56, respectively) were found across groups (all P , 0.001, except P , 0.05 for correlation between 18 F-FDDNP and Ab 1-42 ). Linear regression analyses showed that, adjusted for regional volume, age, sex, and diagnosis, global 11 C-PiB uptake had an inverse association with Ab 1-42 CSF levels (standardized b 5 20.50, P , 0.001), whereas there was a positive association between global 18 F-FDDNP binding and tau CSF levels (standardized b 5 0.62, P , 0.01). Conclusion: The good agreement between these 2 different types of biomarkers (i.e., CSF and PET) provides converging evidence for their validity. The inverse association between 11 C-PiB and CSF tau Ab 1-42 confirms that 11 C-PiB measures amyloid load in the brain. The positive association between 18 F-FDDNP and CSF tau suggests that at least part of the specific signal of 18 F-FDDNP in AD patients is due to tangle formation.

Fluid Biomarkers in Alzheimer Disease

“…However, one study found that CSF Ttau correlates with postmortem tangle load (Tapiola et al 2009), suggesting that the release of tau specifically from degenerating tanglebearing neurons may contribute to the CSF level of T-tau. Consistent with this idea, binding of 18F FDDNP, an agent that is reported to label both plaques and tangles, positively correlates with CSF T-tau levels (Tolboom et al 2009).…”

“…The development of Ab ligands suitable for positron emission tomography (PET) has enabled direct visualization of fibrillar Ab load in the brain in living individuals. Studies have consistently found a relationship between in vivo amyloid load as assessed by Pittsburgh Compound B (PIB)-PET binding and CSF Ab42, with higher 11C PIB binding correlating with lower CSF Ab42 levels (Fagan et al 2006;Forsberg et al 2008;Grimmer et al 2009;Tolboom et al 2009). A similar relationship has been found between CSF Ab42 and binding of 18F FDDNP, a PET ligand believed to label both plaques and tangles (Tolboom et al 2009).…”

Brain Imaging in Alzheimer Disease

“…4; Forsberg et al 2008;Koivunen et al 2008;Lowe et al 2009;Okello et al 2009;Tolboom et al 2009;Wolk et al 2009;Devanand et al 2010;Jagust et al 2010;Rowe et al 2010). Five of these studies included longitudinal clinical follow-up for 1-3 years on 155 MCI patients and showed that 57 of these 155 progressed to clinical AD (37%) and 53 of these 57 were amyloid positive at baseline (93%); only four of 54 amyloid-negative MCI patients progressed to clinical AD in these studies (7%) Koivunen et al 2008;Okello et al 2009;Wolk et al 2009;Jagust et al 2010).…”

Currently Available Neuroimaging Approaches in Alzheimer Disease (AD) Early Diagnosis

“…Approximately 88.9% of the patients with progressive mild cognitive impairment were considered affected by 18 F-FDG PET, whereas 84.9% of stable patients had negative 18 F-FDG PET (Yuan et al, 2008). Another method for in vivo assessment of the extent of AD is the use of new radiotracers including the amyloid PET tracer Pittsburgh Compound B ( 11 C-PIB) for visualizing fibers Aβ (Morris et al, 2009, Kadir et al, 2011 or 2-(1-{6-[( 18 F-fluoroethyl)(methyl)amino]-2naphthyl}ethylidene) malononitrile ( 18 F-FDDNP) that has been reported to label not only amyloid but also neurofibrillary tangles (Tolboom et al, 2009), and these methods have generated new possibilities for early diagnosis of brain impairments. The first attempt to image brain Aβ accumulation in AD was reported by Friedland et al in 1997 using a monoclonal antibody fragment labelled with 99m Tc for single SPECT.…”