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 Yoder, Li Shen, John D. West, Brenna McDonald, Eileen F. Tallman, Gary Hutchins, James Fletcher, Martin Farlow, Bernardino Ghetti, Andrew Saykin

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

5 Citations (Scopus)

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
Title of host publicationLecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
Pages150-158
Number of pages9
Volume8159 LNCS
DOIs
StatePublished - 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)03029743
ISSN (Electronic)16113349

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

Fingerprint

Administrative data processing
Positron Emission Tomography
Positron emission tomography
Alzheimer's Disease
Genes
Gene
Brain
Inflammation
Polymorphism
Covariates
Proteins
Protein
Genetic Association
Remodeling
Single nucleotide Polymorphism
Mediator
Chromatin
Cortex
Nucleotides
Region of Interest

ASJC Scopus subject areas

  • Computer Science(all)
  • Theoretical Computer Science

Cite this

Kim, S., Nho, K., Risacher, S. L., Inlow, M., Swaminathan, S., Yoder, K., ... Saykin, A. (2013). PARP1 gene variation and microglial activity on [11C]PBR28 PET in older adults at risk for Alzheimer's disease. In Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) (Vol. 8159 LNCS, 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

PARP1 gene variation and microglial activity on [11C]PBR28 PET in older adults at risk for Alzheimer's disease. / Kim, Sungeun; Nho, Kwangsik; Risacher, Shannon L.; Inlow, Mark; Swaminathan, Shanker; Yoder, Karmen; Shen, Li; West, John D.; McDonald, Brenna; Tallman, Eileen F.; Hutchins, Gary; Fletcher, James; Farlow, Martin; Ghetti, Bernardino; Saykin, Andrew.

Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics). Vol. 8159 LNCS 2013. p. 150-158 (Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics); Vol. 8159 LNCS).

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

Kim, S, Nho, K, Risacher, SL, Inlow, M, Swaminathan, S, Yoder, K, Shen, L, West, JD, McDonald, B, Tallman, EF, Hutchins, G, Fletcher, J, Farlow, M, Ghetti, B & Saykin, A 2013, PARP1 gene variation and microglial activity on [11C]PBR28 PET in older adults at risk for Alzheimer's disease. in Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics). vol. 8159 LNCS, Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), vol. 8159 LNCS, pp. 150-158, 3rd 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, 9/22/13. https://doi.org/10.1007/978-3-319-02126-3_15
Kim S, Nho K, Risacher SL, Inlow M, Swaminathan S, Yoder K et al. PARP1 gene variation and microglial activity on [11C]PBR28 PET in older adults at risk for Alzheimer's disease. In Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics). Vol. 8159 LNCS. 2013. p. 150-158. (Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)). https://doi.org/10.1007/978-3-319-02126-3_15
Kim, Sungeun ; Nho, Kwangsik ; Risacher, Shannon L. ; Inlow, Mark ; Swaminathan, Shanker ; Yoder, Karmen ; Shen, Li ; West, John D. ; McDonald, Brenna ; Tallman, Eileen F. ; Hutchins, Gary ; Fletcher, James ; Farlow, Martin ; Ghetti, Bernardino ; Saykin, Andrew. / PARP1 gene variation and microglial activity on [11C]PBR28 PET in older adults at risk for Alzheimer's disease. Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics). Vol. 8159 LNCS 2013. pp. 150-158 (Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)).
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AU - Yoder, Karmen

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