IC‐P‐137: Gene‐based analyses of microglial activation on [11C] PBR28 PET in older adults at risk for Alzheimer's disease
Year: 2013
Type: article
Study design: Observational Study
Abstract: Neuroinflammation plays a role in Alzheimer's disease (AD) pathogenesis. The translocator protein (18-kDa) (TSPO) is a marker of inflammation that is associated with the presence of activated microglia. Positron emission tomography (PET) radioligands for TSPO have been developed, including [11 C]PBR28, a second generation PET tracer that permits investigation of in vivo brain inflammation (Kreisl, Neuroimage, 2010). To determine whether key AD and proinflammatory candidate gene variants were associated with [11 C]PBR28 uptake, we conducted gene-based analyses using recently reported AD risk genes (ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A, PICALM, TREM2) (Hollingworth, NatGenet, 2011; Guerreiro, NEngJMed, 2013) and genes coding for several major proinflammatory cytokines (IL1A, IL1B, IL6, TNF). 26 Caucasian participants with genetic and [11 C]PBR28 data (Yoder, submitted) were analyzed in the present study. Gene-based analyses of the above mentioned genes was carried out using bilateral mean [11 C]PBR28 standardized uptake values (SUV) in the a) thalamus, b) cortical grey matter (GM), c) whole brain GM, and d) whole brain GM and white matter (GM+WM) as quantitative phenotypes, with TSPO genotype as a covariate. Genes included single nucleotide polymorphisms (SNPs) having a minor allele frequency≥20% within or +/- 50 kilobases of the gene. 100,000 permutations were performed. Among established AD risk genes, two significant SNPs of EPHA1 (rs4595035 and rs11771145, located upstream of the gene, not in linkage disequilibrium) were associated with mean [11 C]PBR28 SUV in whole brain GM+WM (empirical gene-based p =0.0477). The minor allele of each SNP was associated with higher mean SUV (Fig.1a-b). Among inflammatory genes, a trend-level association was found for TNF (rs3135041, a SNP located downstream of the gene), with mean SUV in whole brain GM (empirical gene-based p =0.1043). The minor allele of this SNP was associated with lower mean SUV (Fig.1c). EPHA1 codes for ephrin A1 receptor, which is associated with neurodevelopment (axon guidance, adhesion, stem cells, etc.), and is upregulated after CNS injury. TNF codes for a key proinflammatory cytokine. The finding that these two immune pathways and AD risk-related genes are associated with [11 C]PBR28 brain uptake suggests that [11 C]PBR28 SUV may be a useful quantitative phenotype for studying genetic underpinnings of AD. Comparison of mean [C]PBR28 SUV adjusted for TSPO genotype in the three genotype groups: (a) rs4595035 (minor allele T), (b) rs11771145 (minor allele A), and (c) rs3135041 (minor allele G).
Source: Alzheimer s & Dementia
Institution: Indiana University School of Medicine
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2138113453