PARP1gene variation and microglial activity on [11C]PBR28 PET in older adults at risk for Alzheimer's disease.
Increasing evidence suggests that inflammation is one pathophysio-logical mechanism in Alzheimer's disease (AD). Recent studies have identifiedan association between the poly (ADP-ribose) polymerase 1 (PARP1) gene and AD. This gene encodes a protein that is involved in many biological functions, including DNA repair and chromatin remodeling, and is a mediator of inflammation. Therefore, we performed a targeted genetic association analysis to investigate the relationship between thePARP1polymorphisms and brain micro-glial activity as indexed by [11C]PBR28 positron emission tomography (PET). Participants were 26 non-Hispanic Caucasians in the Indiana Memory and Aging Study (IMAS). PET data were intensity-normalized by injected dose/total body weight. Average PBR standardized uptake values (SUV) from 6 bilateral regions of interest (thalamus, frontal, parietal, temporal, and cingulate cortices, and whole brain gray matter) were used as endophenotypes. Single nucleotide polymorphisms (SNPs) with 20% minor allele frequency that were within +/- 20 kb of thePARP1gene were included in the analyses. Gene-level association analyses were performed using a dominant genetic model with translocator protein (18-kDa) (TSPO) genotype, age at PET scan, and gender as covariates. Analyses were performed with and withoutAPOEε4 status as a covariate. Associations with PBR SUVs from thalamus and cingulate were significant at correctedp<0.014 and <0.065, respectively. Subsequent multi-marker analysis with cingulate PBR SUV showed that individuals with the "C" allele at rs6677172 and "A" allele at rs61835377 had higher PBR SUV than individuals without these alleles (correctedP<0.03), and individuals with the "G" allele at rs6677172 and "G" allele at rs61835377 displayed the opposite trend (correctedP<0.065). A previous study with the same cohort showed an inverse relationship between PBR SUV and brain atrophy at a follow-up visit, suggesting possible protective effect of microglial activity against cortical atrophy. Interestingly, all 6 AD and 2 of 3 LMCI participants in the current analysis had one or more copies of the "GG" allele combination, associated with lower cingulate PBR SUV, suggesting that this gene variant warrants further investigation.
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
Sungeun
S
Kim
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
Kwangsik
K
Nho
Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
Shannon L
SL
Risacher
Department of Mathematics, Rose-Hulman Institute of Technology, Terre Haute, IN, USA.
Mark
M
Inlow
Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
Shanker
S
Swaminathan
Indiana Institute for Biomedical Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
Karmen K
KK
Yoder
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Li
L
Shen
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
John D
JD
West
Brenna C
BC
McDonald
Eileen F
EF
Tallman
Gary D
GD
Hutchins
James W
JW
Fletcher
Martin R
MR
Farlow
Bernardino
B
Ghetti
Andrew J
AJ
Saykin