Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease

By M. Ikonomovic, William E. Klunk, E. Abrahamson, Chester A. Mathis, J. Price, N. Tsopelas, B. Lopresti, S. Ziolko, W. Bi, W. Paljug and 5 more. Brain : a journal of neurology, 2008

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The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PiB) binds with high affinity to β-pleated sheet aggregates of the amyloid-β (Aβ) peptide in vitro. The in vivo retention of PiB in brains of people with Alzheimer's disease shows a regional distribution that is very similar to distribution of Aβ deposits observed post-mortem. However, the basis for regional variations in PiB binding in vivo, and the extent to which it binds to different types of Aβ-containing plaques and tau-containing neurofibrillary tangles (NFT), has not been thoroughly investigated. The present study examined 28 clinically diagnosed and autopsy-confirmed Alzheimer's disease subjects, including one Alzheimer's disease subject who had undergone PiB-PET imaging 10 months prior to death, to evaluate region- and substrate-specific binding of the highly fluorescent PiB derivative 6-CN-PiB. These data were then correlated with region-matched Aβ plaque load and peptide levels, [3H]PiB binding in vitro, and in vivo PET retention levels. We found that in Alzheimer's disease brain tissue sections, the preponderance of 6-CN-PiB binding is in plaques immunoreactive to either Aβ42 or Aβ40, and to vascular Aβ deposits. 6-CN-PiB labelling was most robust in compact/cored plaques in the prefrontal and temporal cortices. While diffuse plaques, including those in caudate nucleus and presubiculum, were less prominently labelled, amorphous Aβ plaques in the cerebellum were not detectable with 6-CN-PiB. Only a small subset of NFT were 6-CN-PiB positive; these resembled extracellular ‘ghost’ NFT. In Alzheimer's disease brain tissue homogenates, there was a direct correlation between [3H]PiB binding and insoluble Aβ peptide levels. In the Alzheimer's disease subject who underwent PiB-PET prior to death, in vivo PiB retention levels correlated directly with region-matched post-mortem measures of [3H]PiB binding, insoluble Aβ peptide levels, 6-CN-PiB- and Aβ plaque load, but not with measures of NFT. These results demonstrate, in a typical Alzheimer's disease brain, that PiB binding is highly selective for insoluble (fibrillar) Aβ deposits, and not for neurofibrillary pathology. The strong direct correlation of in vivo PiB retention with region-matched quantitative analyses of Aβ plaques in the same subject supports the validity of PiB-PET imaging as a method for in vivo evaluation of Aβ plaque burden.

Subfields: Cognitive Neuroscience, Psychiatry and Mental health, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/4771df1ee9656f9ad79564764eccf8f4ece689ed

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Citations in the corpus

Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease (2009, background): “11C-labeled Pittsburgh Compound B (PiB) is a PET radioligand that selectively binds to fibrillar aggregates of the A peptide (6, 7).”
Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease (2009, positive): “…as 11 C Pittsburgh compound B (PIB) primarily measure brain amyloid plaque load (Klunk et al ., 2004; Rowe et al ., 2007; Drzezga et al ., 2008; Ikonomovic et al ., 2008; Leinonen et al ., 2008) but also localize in cerebral vascular amyloid (Bacskai et al ., 2007; Johnson et al ., 2007;…”
Brain imaging in Alzheimer disease. (2012, background): “…to be equivalent as screening tools for clinical trials, but the more dynamic nature of amyloid PET and the fact that amyloid tracer retention correlates directly with Ab load (Ikonomovic et al. 2008) makes this a more suitable outcome measure when the goal is to detect changes in brain Ab load.”
Human apoE isoforms differentially regulate brain amyloid-β peptide clearance (2011, neutral): “Interaction of nascent ApoE2, ApoE3, and ApoE4 isoforms expressed in mammalian cells with amyloid peptide beta (1-40).”
Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade (2010, positive): “PiB specifically binds to fibrillar A β , and not to soluble A β or to diffuse plaques.26 35 The evidence therefore strongly supports the notion that both amyloid imaging and low CSF A β 42 are valid biomarkers of brain A β -plaque load.”
Frequent Amyloid Deposition Without Significant Cognitive Impairment Among the Elderly (2008, neutral): “cerebellum.(8,9) The aim of the present study was to characterize the relationship of amyloid deposition with cognition among elderly persons using PiB positron emission tomography (PET) imaging.”
Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases. (2018, background): “PET studies that use tracers that specifically bind amyloid (C11PiB [Klunk et al. 2004; Ikonomovic et al. 2008], F18-florbetapir [Wong et al. 2010; Clark et al. 2011, 2012], F18-flutemetamol [Vandenberghe et al. 2010; Wolk et al. 2011], and F18-florbetaben [Rowe et al. 2008]) can noninvasively…”
18F‐flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: A phase 2 trial (2010, background): “The fraction of (11)C-PIB binding to hyperphosphorylated tau and -synuclein is negligible at the nanomolar concentrations administered for in vivo imaging.(1,3,4,6) In recent years, (11)C-PIB studies have been conducted in clinically probable AD,(2,4,5,7,8) various other types of cognitive disorders”