PARP1 Gene Variation and Microglial Activity on ~(11)CPBR28 PET in Older Adults at Risk for Alzheimer's Disease

摘要

Increasing evidence suggests that inflammation is one pathophysio-logical mechanism in Alzheimer's disease (AD). Recent studies have identified an 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 the PARP1 polymorphisms and brain microglial activity as indexed by [~(11)C]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 [~(11)C]PBR28 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 endopheno-types. Single nucleotide polymorphisms (SNPs) with 20% minor allele frequency that were within +/- 20 kb of the PARP1 gene 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 without APOE e4 status as a covariate. Associations with [~(11)C]PBR28 SUVs from thalamus and cingulate were significant at corrected p＜0.014 and ＜0.065, respectively. Subsequent multi-marker analysis with cingulate [~(11)C]PBR28 SUV showed that individuals with the "C" allele at rs6677172 and "A" allele at rs61835377 had higher [~(11)C]PBR28 SUV than individuals without these alleles (corrected P＜0.03), and individuals with the "G" allele at rs6677172 and "G" allele at rs61835377 displayed the opposite trend (corrected P＜0.065). A previous study with the same cohort showed an inverse relationship between [~(11)C]PBR28 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 [~(11)C]PBR28 SUV, suggesting that this gene variant warrants further investigation.