Dataset Information

Influence of alcoholism and cholesterol on TSPO binding in brain: PET [11C]PBR28 studies in humans and rodents.

ABSTRACT: Neuroinflammation appears to contribute to neurotoxicity observed with heavy alcohol consumption. To assess whether chronic alcohol results in neuroinflammation we used PET and [11C]PBR28, a ligand that binds to the 18-kDa translocator protein (TSPO), to compare participants with an alcohol use disorder (AUD: n?=?19) with healthy controls (HC: n?=?17), and alcohol-dependent (n?=?9) with -nondependent rats (n?=?10). Because TSPO is implicated in cholesterol's transport for steroidogenesis, we investigated whether plasma cholesterol levels influenced [11C]PBR28 binding. [11C]PBR28 binding did not differ between AUD and HC. However, when separating by TSPO genotype rs6971, we showed that medium-affinity binders AUD participants showed lower [11C]PBR28 binding than HC in regions of interest (whole brain, gray and white matter, hippocampus, and thalamus), but no group differences were observed in high-affinity binders. Cholesterol levels inversely correlated with brain [11C]PBR28 binding in combined groups, due to a correlation in AUD participants. In rodents, we observed no differences in brain [11C]PBR28 uptake between alcohol-dependent and -nondependent rats. These findings, which are consistent with two previous [11C]PBR28 PET studies, may indicate lower activation of microglia in AUD, whereas failure to observe alcohol effects in the rodent model indicate that species differences do not explain the discrepancy with prior rodent autoradiographic studies reporting increases in TSPO binding with chronic alcohol. However, reduced binding in AUD participants could also reflect competition from endogenous TSPO ligands such as cholesterol; and since the rs6971 polymorphism affects the cholesterol-binding domain of TSPO this could explain why differences were observed only in medium-affinity binders.

SUBMITTER: Kim SW

PROVIDER: S-EPMC6046047 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Influence of alcoholism and cholesterol on TSPO binding in brain: PET [<sup>11</sup>C]PBR28 studies in humans and rodents.

Kim Sung Won SW Wiers Corinde E CE Tyler Ryan R Shokri-Kojori Ehsan E Jang Yeon Joo YJ Zehra Amna A Freeman Clara C Ramirez Veronica V Lindgren Elsa E Miller Gregg G Cabrera Elizabeth A EA Stodden Tyler T Guo Min M Demiral Şükrü B ŞB Diazgranados Nancy N Park Luke L Liow Jeih-San JS Pike Victor V Morse Cheryl C Vendruscolo Leandro F LF Innis Robert B RB Koob George F GF Tomasi Dardo D Wang Gene-Jack GJ Volkow Nora D ND

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20180503 9

Neuroinflammation appears to contribute to neurotoxicity observed with heavy alcohol consumption. To assess whether chronic alcohol results in neuroinflammation we used PET and [<sup>11</sup>C]PBR28, a ligand that binds to the 18-kDa translocator protein (TSPO), to compare participants with an alcohol use disorder (AUD: n = 19) with healthy controls (HC: n = 17), and alcohol-dependent (n = 9) with -nondependent rats (n = 10). Because TSPO is implicated in cholesterol's transport for steroidogene ...[more]

PMID: 29777199

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Project description: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 the PARP1 polymorphisms 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 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 ?4 status as a covariate. Associations with PBR SUVs from thalamus and cingulate were significant at corrected p<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 (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 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.

Dataset Information

Influence of alcoholism and cholesterol on TSPO binding in brain: PET [11C]PBR28 studies in humans and rodents.

Publications

Influence of alcoholism and cholesterol on TSPO binding in brain: PET [<sup>11</sup>C]PBR28 studies in humans and rodents.

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