PARP1 gene variation and microglial activity on [11C]PBR28 PET in older adults at risk for Alzheimer's disease

Sungeun Kim, Kwangsik Nho, Shannon L. Risacher, Mark Inlow, Shanker Swaminathan, Karmen K. Yoder, Li Shen, John D. West, Brenna C. McDonald, Eileen F. Tallman, Gary D. Hutchins, James W. Fletcher, Martin R. Farlow, Bernardino Ghetti, Andrew J. Saykin

Research output: Chapter in Book/Report/Conference proceedingConference contribution

5 Scopus citations

Abstract

Increasing evidence suggests that inflammation is one pathophysiological 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 [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 [11C]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 endophenotypes. 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 ε4 status as a covariate. Associations with [11C]PBR28 SUVs from thalamus and cingulate were significant at corrected p<0.014 and <0.065, respectively. Subsequent multi-marker analysis with cingulate [11C]PBR28 SUV showed that individuals with the "C" allele at rs6677172 and "A" allele at rs61835377 had higher [11C]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 [11C]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 [ 11C]PBR28 SUV, suggesting that this gene variant warrants further investigation.

Original languageEnglish (US)
Title of host publicationMultimodal Brain Image Analysis - Third International Workshop, MBIA 2013, Held in Conjunction with MICCAI 2013, Proceedings
Pages150-158
Number of pages9
DOIs
StatePublished - Sep 5 2013
Event3rd International Workshop on Multimodal Brain Image Analysis, MBIA 2013, Held in Conjunction with the 16th International Conference on Medical Image Computing and Computer Assisted Intervention, MICCAI 2013 - Nagoya, Japan
Duration: Sep 22 2013Sep 22 2013

Publication series

NameLecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
Volume8159 LNCS
ISSN (Print)0302-9743
ISSN (Electronic)1611-3349

Other

Other3rd International Workshop on Multimodal Brain Image Analysis, MBIA 2013, Held in Conjunction with the 16th International Conference on Medical Image Computing and Computer Assisted Intervention, MICCAI 2013
CountryJapan
CityNagoya
Period9/22/139/22/13

ASJC Scopus subject areas

  • Theoretical Computer Science
  • Computer Science(all)

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    Kim, S., Nho, K., Risacher, S. L., Inlow, M., Swaminathan, S., Yoder, K. K., Shen, L., West, J. D., McDonald, B. C., Tallman, E. F., Hutchins, G. D., Fletcher, J. W., Farlow, M. R., Ghetti, B., & Saykin, A. J. (2013). PARP1 gene variation and microglial activity on [11C]PBR28 PET in older adults at risk for Alzheimer's disease. In Multimodal Brain Image Analysis - Third International Workshop, MBIA 2013, Held in Conjunction with MICCAI 2013, Proceedings (pp. 150-158). (Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics); Vol. 8159 LNCS). https://doi.org/10.1007/978-3-319-02126-3_15