Deficient high-affinity binding of Pittsburgh compound B in a case of Alzheimer’s disease (original) (raw)

Abstract

Radiolabeled Pittsburgh compound B (PIB) is a benzothiazole imaging agent that usually binds with high affinity, specificity, and stoichiometry to cerebral β-amyloid (Aβ) in patients with Alzheimer’s disease. Among a cohort of ten AD subjects examined postmortem, we describe a case of idiopathic, end-stage Alzheimer’s disease with heavy Aβ deposition yet substantially diminished high-affinity binding of 3H-PIB to cortical homogenates and unfixed cryosections. Cortical tissue samples were analyzed by immunohistochemistry, electron microscopy, ELISA, immunoblotting, MALDI-TOF mass spectrometry, in vitro 3H-PIB binding and 3H-PIB autoradiography. The PIB-refractory subject met the histopathological criteria for AD. However, cortical tissue from this case contained more vascular β-amyloidosis, higher levels of insoluble Aβ40 and Aβ42, and a higher ratio of Aβ40:Aβ42 than did tissue from the nine comparison AD cases. Furthermore, cerebral Aβ from the PIB-refractory subject displayed an unusual distribution of low- and high-molecular weight Aβ oligomers, as well as a distinct pattern of N- and C-terminally truncated Aβ peptides in both the soluble and insoluble cortical extracts. Genetically, the patient was apolipoprotein-E3/4 heterozygous, and exhibited no known AD-associated mutations in the genes for the β-amyloid precursor protein, presenilin1 or presenilin2. Our findings suggest that PIB may differentially recognize polymorphic forms of multimeric Aβ in humans with Alzheimer’s disease. In addition, while the prevalence of PIB-refractory cases in the general AD population remains to be determined, the paucity of high-affinity binding sites in this AD case cautions that minimal PIB retention in positron-emission tomography scans of demented patients may not always rule out the presence of Alzheimer-type Aβ pathology.

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Acknowledgments

This work was supported by RR-00165, PO1AG026423, P50AG025688, AG030539, the Woodruff Foundation and the Emory University Research Committee. We thank M. Paul Murphy for helpful discussions, and Jean-Francois Paré, Carolyn Suwyn, Elaine Pranski, Emiliya Mezhericher, and Aaron Farberg for excellent technical assistance.

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Authors and Affiliations

1. Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA, 30329, USA
   Rebecca F. Rosen, Jeromy Dooyema & Lary C. Walker
2. Department of Neurology, Emory University, Atlanta, GA, 30322, USA
   Brian J. Ciliax, Thomas S. Wingo, James J. Lah & Lary C. Walker
3. Center for Neurodegenerative Disease, Emory University, Atlanta, GA, 30322, USA
   Brian J. Ciliax, Marla Gearing, James J. Lah & Lary C. Walker
4. Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, 30322, USA
   Marla Gearing
5. Department of Pathology, New York University School of Medicine, New York, NY, 10016, USA
   Jorge A. Ghiso
6. Department of Molecular and Cellular Biochemistry, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA
   Harry LeVine III

Authors

1. Rebecca F. Rosen
2. Brian J. Ciliax
3. Thomas S. Wingo
4. Marla Gearing
5. Jeromy Dooyema
6. James J. Lah
7. Jorge A. Ghiso
8. Harry LeVine III
9. Lary C. Walker

Corresponding authors

Correspondence toRebecca F. Rosen or Lary C. Walker.

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Rosen, R.F., Ciliax, B.J., Wingo, T.S. et al. Deficient high-affinity binding of Pittsburgh compound B in a case of Alzheimer’s disease.Acta Neuropathol 119, 221–233 (2010). https://doi.org/10.1007/s00401-009-0583-3

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• Received: 28 May 2009
• Revised: 03 August 2009
• Accepted: 05 August 2009
• Published: 19 August 2009
• Issue date: February 2010
• DOI: https://doi.org/10.1007/s00401-009-0583-3

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