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The Journal of Neuroscience, June 6, 2007, 27(23):6174-6184; doi:10.1523/JNEUROSCI.0730-07.2007

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

William E. Klunk,^1,3 Julie C. Price,² Chester A. Mathis,² Nicholas D. Tsopelas,¹ Brian J. Lopresti,² Scott K. Ziolko,² Wenzhu Bi,² Jessica A. Hoge,² Ann D. Cohen,¹ Milos D. Ikonomovic,^1,3 Judith A. Saxton,³ Beth E. Snitz,³ Daniel A. Pollen,⁴ Majaz Moonis,⁴ Carol F. Lippa,⁵ Joan M. Swearer,⁴ Keith A. Johnson,⁶ Dorene M. Rentz,⁷ Alan J. Fischman,⁶ Howard J. Aizenstein,¹ and Steven T. DeKosky^1,3

Departments of ¹Psychiatry, ²Radiology, and ³Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, ⁴Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, ⁵Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19219, ⁶Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, and ⁷Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

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. Email: klunkwe{at}upmc.edu

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-ß 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.

Key words: Alzheimer's disease; positron emission tomography; amyloid-ß; diagnosis; Pittsburgh Compound-B; striatum

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Received Feb. 16, 2007; revised May 1, 2007; accepted May 1, 2007.

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. Email: klunkwe{at}upmc.edu

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