Deficient high-affinity binding of Pittsburgh compound B in a case of Alzheimer's disease.
Radiolabeled Pittsburgh compound B (PIB) is a benzothiazole imaging agent that usually binds with high affinity, specificity, and stoichiometry to cerebral beta-amyloid (Abeta) 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 Abeta deposition yet substantially diminished high-affinity binding of (3)H-PIB to cortical homogenates and unfixed cryosections. Cortical tissue samples were analyzed by immunohistochemistry, electron microscopy, ELISA, immunoblotting, MALDI-TOF mass spectrometry, in vitro (3)H-PIB binding and (3)H-PIB autoradiography. The PIB-refractory subject met the histopathological criteria for AD. However, cortical tissue from this case contained more vascular beta-amyloidosis, higher levels of insoluble Abeta40 and Abeta42, and a higher ratio of Abeta40:Abeta42 than did tissue from the nine comparison AD cases. Furthermore, cerebral Abeta from the PIB-refractory subject displayed an unusual distribution of low- and high-molecular weight Abeta oligomers, as well as a distinct pattern of N- and C-terminally truncated Abeta 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 beta-amyloid precursor protein, presenilin1 or presenilin2. Our findings suggest that PIB may differentially recognize polymorphic forms of multimeric Abeta 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 Abeta pathology.
Rosen
Rebecca F
RF
Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA. rfrosen@emory.edu
Ciliax
Brian J
BJ
Wingo
Thomas S
TS
Gearing
Marla
M
Dooyema
Jeromy
J
Lah
James J
JJ
Ghiso
Jorge A
JA
LeVine
Harry
H
Walker
Lary C
LC
D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds; D001345:Autoradiography; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D046529:Microscopy, Electron, Transmission; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013844:Thiazoles; D014316:Tritium
C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D019275:Radiopharmaceuticals; D013844:Thiazoles; D014316:Tritium
Brain. 2007 Aug;130(Pt 8):2055-69
17586869
Eur J Nucl Med Mol Imaging. 2008 Mar;35 Suppl 1:S46-50
18188557
Neurobiol Aging. 2011 Feb;32(2):223-34
19329226
J Neurosci. 2007 Oct 10;27(41):10957-68
17928437
Ann Neurol. 1995 Aug;38(2):254-9
7654074
J Comp Neurol. 2008 Jul 20;509(3):259-70
18481275
Neurology. 2006 Aug 8;67(3):446-52
16894106
Arch Neurol. 2007 Mar;64(3):431-4
17353389
Neurology. 2007 May 15;68(20):1718-25
17502554
Eur J Nucl Med Mol Imaging. 2008 Dec;35(12):2169-81
18566819
J Neurosci. 2005 Nov 16;25(46):10598-606
16291932
Neurochem Int. 2009 May-Jun;54(5-6):347-57
19162107
Neurobiol Aging. 2010 Apr;31(4):542-8
18619711
Ann Neurol. 2007 Sep;62(3):229-34
17683091
Acta Neuropathol. 2009 Jul;118(1):115-30
19225789
Neuroimaging Clin N Am. 2003 Nov;13(4):781-9, ix
15024961
Genes Brain Behav. 2008 Feb;7 Suppl 1:67-82
18184371
J Biol Chem. 2005 Nov 4;280(44):36883-94
16091362
Brain. 2008 Jun;131(Pt 6):1630-45
18339640
Lancet. 1993 Sep 18;342(8873):697-9
8103819
Brain. 2007 Oct;130(Pt 10):2607-15
17698496
Science. 1993 Aug 13;261(5123):921-3
8346443
Ann Neurol. 2008 Jun;63(6):697-708
18571782
Curr Alzheimer Res. 2009 Apr;6(2):137-43
19355848
Arch Neurol. 2008 Oct;65(10):1304-9
18695050
Science. 2007 Nov 9;318(5852):930-6
17991853
Neurology. 2007 Feb 13;68(7):501-8
17065593
Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3586-90
7724603
Brain. 2007 Nov;130(Pt 11):2837-44
17928318
Acta Neuropathol. 2000 Jul;100(1):36-42
10912918
Alzheimer Dis Assoc Disord. 1998 Mar;12(1):33-9
9539408
Am J Pathol. 1996 Jun;148(6):2083-95
8669492
Acta Neuropathol. 2004 Feb;107(2):83-90
14655019
Ann Neurol. 2004 Mar;55(3):306-19
14991808