TY - JOUR
T1 - Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease
AU - Ikonomovic, Milos D.
AU - Klunk, William E.
AU - Abrahamson, Eric E.
AU - Mathis, Chester A.
AU - Price, Julie C.
AU - Tsopelas, Nicholas D.
AU - Lopresti, Brian J.
AU - Ziolko, Scott
AU - Bi, Wenzhu
AU - Paljug, William R.
AU - Debnath, Manik L.
AU - Hope, Caroline E.
AU - Isanski, Barbara A.
AU - Hamilton, Ronald L.
AU - DeKosky, Steven T.
N1 - Funding Information:
This work was funded by National Institutes of Health (R01 AG018402 to C.A.M., P50 AG05133 to S.T.DeK., P01 AG14449 to S.T.DeK., K02 AG001039 to W.E.K., R01 AG020226 to W.E.K., R01 MH070729 to J.C.P., K01 MH001976 to J.C.P., R37 AG025516 to W.E.K., P01 AG025204 to S.T.DeK.); The Alzheimer’s Association (TLL-01-3381 to W.E.K.); The U.S. Department of Energy (DE-FD02-03 ER63590 to C.A.M.); The Dana Foundation (to J.C.P. and C.A.M.). We thank the staff at the University of Pittsburgh Alzheimer’s Disease Research Center and PET facility for their efforts in conducting and analysing these studies. We are indebted to our subjects and their families for the selfless contributions that made this work possible. Funding to pay the Open Access publication charges for this article was provided by NIH grants AG05133 and AG025516.
PY - 2008/6
Y1 - 2008/6
N2 - 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.
AB - 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.
KW - Amyloid imaging
KW - PET imaging
KW - PiB
KW - Pittsburgh Compound-B
KW - Plaques
UR - http://www.scopus.com/inward/record.url?scp=43849083580&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=43849083580&partnerID=8YFLogxK
U2 - 10.1093/brain/awn016
DO - 10.1093/brain/awn016
M3 - Article
C2 - 18339640
AN - SCOPUS:43849083580
SN - 0006-8950
VL - 131
SP - 1630
EP - 1645
JO - Brain
JF - Brain
IS - 6
ER -