Early AD pathology in a C-PIB-negative case: a PIB-amyloid imaging, biochemical, and immunohistochemical study

Department of Neurology, University of Pittsburgh School of Medicine, 200 Lothrop Street BST S521, Pittsburgh, PA 15213. USA,
Acta Neuropathologica (Impact Factor: 10.76). 03/2012; 123(3):433-47. DOI: 10.1007/s00401-012-0943-2
Source: PubMed


Amyloid-β (Aβ) deposits are detectable in the brain in vivo using positron emission tomography (PET) and [C-11]-labeled Pittsburgh Compound B ([C-11]PiB); however, the sensitivity of this technique is not well understood. In this study, we examined Aβ pathology in an individual who had clinical diagnoses of probable dementia with Lewy bodies and possible Alzheimer's disease (AD) but with no detectable [C-11]PiB PET retention ([C-11]PiB(-)) when imaged 17 months prior to death. Brain samples were processed in parallel with region-matched samples from an individual with a clinical diagnosis of probable AD and a positive [C-11]PiB PET scan ([C-11]PiB(+)) when imaged 10 months prior to death. In the [C-11]PiB(-) case, Aβ plaques were sparse, occupying less than 2% cortical area, and were weakly labeled with 6-CN-PiB, a highly fluorescent derivative of PiB. In contrast, Aβ plaques occupied up to 12% cortical area in the [C-11]PiB(+) case, and were intensely labeled with 6-CN-PIB. The [C-11]PiB(-) case had low levels of [H-3]PiB binding (< 100 pmol/g) and Aβ1-42 (< 500 pmol/g) concentration except in the frontal cortex where Aβ1-42 values (788 pmol/g) approached cortical values in the [C-11]PiB(+) case (800-1, 700 pmol/g). In several cortical regions of the [C-11]PiB(-) case, Aβ1-40 levels were within the range of cortical Aβ1-40 values in the [C-11]PiB(+) case. Antemortem [C-11]PiB DVR values correlated well with region-matched postmortem measures of Aβ1-42 and Aβ1-40 in the [C-11]PiB(+), and with Aβ1-42 only in the [C-11]PiB(-) case. The low ratios of [H-3]PiB binding levels to Aβ concentrations and 6-CN-PiB to Aβ plaque loads in the [C-11]PiB(-) case indicate that Aβ pathology in the brain may be associated with low or undetectable levels of [C-11]PiB retention. Studies in greater numbers of [C-11]PiB PET autopsy cases are needed to define the Aβ concentration and [H-3]PiB binding levels required to produce a positive [C-11]PiB PET signal.

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    • "The problems facing conventional [ 11 C]PIB quantification are manifest when [ 11 C]PIB retention is evaluated in healthy subjects and patients with AD with different degrees of Aβ deposition. For example, it has been reported that PIB may bind differentially to polymorphic Aβ aggregates in some humans as well as in animals (Rosen et al., 2010; Ikonomovic et al., 2012). Additionally, apparent retention of PIB is evident in cerebral white matter both in vivo by PET (Fodero-Tavoletti et al., 2009) and in vitro by postmortem auto-radiography (Klunk et al., 2004; Svedberg et al., 2009). "
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    ABSTRACT: Rapid clearance and disappearance of a tracer from the circulation challenges the determination of the tracer's binding potentials in brain (BP ND) by positron emission tomography (PET). This is the case for the analysis of the binding of radiolabeled [(11)C]Pittsburgh Compound B ([(11)C]PIB) to amyloid-β (Aβ) plaques in brain of patients with Alzheimer's disease (AD). To resolve the issue of rapid clearance from the circulation, we here introduce the flow-independent Washout Allometric Reference Method (WARM) for the analysis of washout and binding of [(11)C]PIB in two groups of human subjects, healthy aged control subjects (HC), and patients suffering from AD, and we compare the results to the outcome of two conventional analysis methods. We also use the rapid initial clearance to obtain a surrogate measure of the rate of cerebral blood flow (CBF), as well as a method of identifying a suitable reference region directly from the [(11)C]PIB signal. The difference of average absolute CBF values between the AD and HC groups was highly significant (P < 0.003). The CBF measures were not significantly different between the groups when normalized to cerebellar gray matter flow. Thus, when flow differences confound conventional measures of [(11)C]PIB binding, the separate estimates of CBF and BP ND provide additional information about possible AD. The results demonstrate the importance of data-driven estimation of CBF and BP ND, as well as reference region detection from the [(11)C]PIB signal. We conclude that the WARM method yields stable measures of BP ND with relative ease, using only integration for noise reduction and no model regression. The method accounts for relative flow differences in the brain tissue and yields a calibrated measure of absolute CBF directly from the [(11)C]PIB signal. Compared to conventional methods, WARM optimizes the Aβ plaque load discrimination between patients with AD and healthy controls (P = 0.009).
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    • "Amyloid-PET imaging provides information regarding the Ab plaque burden that is independent from structural changes in brain anatomy (Jack et al., 2008). Amyloid-PET imaging has shown very high postmortem validation (Clark et al., 2011; Ikonomovic et al., 2012), good predictability for progression to AD dementia (Koivunen et al., 2011) but low sensitivity to change in the clinical stages (Ossenkoppele et al., 2012). Several issues remain to be resolved concerning the method of scan assessment and interpretation and the significance of the frequent cases of biomarker positive asymptomatic individuals (Wolk et al., 2011). "
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    • "Similarly, while structural MRI provides exquisite anatomical contrast due to its high spatial resolution, functional and volumetric MRI have also been utilized to predict AD onset with nearly 80% accuracy (Jack et al., 1999; Kerchner, 2011; Koffie et al., 2011; Wang et al., 2006; Yanagisawa et al., 2011). Nevertheless, despite the potential advantages offered by MRI and other optical-based methodologies, PET/CT imaging is still considered the most practical approach because of its sensitivity, detection depth and the ability of PET probes to retain binding affinity for neuroimaging of Aβ plaques (Cohen et al., 2012; Ikonomovic et al., 2012). Despite the real-world availability of PET/CT, amyloid imaging facilitated by this technique is currently limited by the scarcity of specific molecular probes capable of binding to Aβ plaques. "
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