Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees.
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.
Klunk
William E
WE
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. klunkwe@upmc.edu
Price
Julie C
JC
Mathis
Chester A
CA
Tsopelas
Nicholas D
ND
Lopresti
Brian J
BJ
Ziolko
Scott K
SK
Bi
Wenzhu
W
Hoge
Jessica A
JA
Cohen
Ann D
AD
Ikonomovic
Milos D
MD
Saxton
Judith A
JA
Snitz
Beth E
BE
Pollen
Daniel A
DA
Moonis
Majaz
M
Lippa
Carol F
CF
Swearer
Joan M
JM
Johnson
Keith A
KA
Rentz
Dorene M
DM
Fischman
Alan J
AJ
Aizenstein
Howard J
HJ
DeKosky
Steven T
ST
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D000682:Amyloid / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D049268:Positron-Emission Tomography / Q000379:methods; D053764:Presenilin-1 / Q000235:genetics*
D000682:Amyloid; D053764:Presenilin-1