Abstract:

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-beta protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB-PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35-49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

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Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees

Ann Cohen+12 authors

Departments of ^Psychiatry,

^{Radiology, and}

^{Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261,}

^{Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01655,}

^{Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19219,}

^{Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, and}

^{Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115}

^{Corresponding author.}

Correspondence should be addressed to Dr. William E. Klunk, Western Psychiatric Institute and Clinic, Room 1422 Thomas Detre Hall, 3811 O'Hara Street, Pittsburgh, PA 15213-2593., ude.cmpu@ewknulk

Received 2007 Feb 16; Revised 2007 May 1; Accepted 2007 May 1.

Abstract

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-β protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB–PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35–49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

Keywords: Alzheimer's disease, positron emission tomography, amyloid-β, diagnosis, Pittsburgh Compound-B, striatum

Abstract

Footnotes

This work was supported by National Institutes of Health Grants R01 AG018402, P50 AG005133, K02 AG001039, R01 AG020226, R01 MH070729, K01 MH001976, R37 AG025516, and P01 AG025204; Alzheimer's Association Grant TLL-01-3381; and United States Department of Energy Grant DE-FD02-03 ER63590. These funding agencies had no role in the design or interpretation of results or preparation of this manuscript. We thank Dr. R. Nebes and E. Halligan and the staff at the University of Pittsburgh Alzheimer's Disease Research Center (C. McConaha, E. Eror, L. Macedonia, and M. Oakley) and PET facility (S. Hulland, J. Ruszkiewicz, P. McGeown, D. Ratica, K. Malone, S. Kendro, N. Flatt, and J. Gallo) for their efforts in conducting and analyzing these studies. We are indebted to our subjects and their families for the selfless contributions that made this work possible. GE Healthcare holds a license agreement with the University of Pittsburgh based on the technology described in this manuscript. Drs. Klunk and Mathis are coinventors of PiB and, as such, have a financial interest in this license agreement. GE Healthcare provided no grant support for this study and had no role in the design or interpretation of results or preparation of this manuscript. All other authors have no conflicts of interest with this work. Drs. Klunk, Mathis, Price and DeKosky had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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