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.

Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre [11C]PBR28 HRRT PET study

“…Obese subjects often have higher levels of serum cholesterol [49], which could induce competition between TSPO ligand and cholesterol between available TSPO binding sites. This hypothesis is supported by a previous study, where higher plasma cholesterol levels were shown to be associated with lower whole brain [ 11 C]PBR28 VT in healthy control subjects and alcohol use disorder patients [50]. Cholesterol medication such as statins are expected to affect serum cholesterol level.…”

Imaging Biomarkers of the Neuroimmune System among Substance Use Disorders: A Systematic Review

“…However, no TSPO PET studies of cannabis users were identified. In the case of alcohol, the MRS literature is mixed, while 3 independent TSPO PET studies reported alcohol-dependent individuals reliably exhibited suppressed or impaired neuroimmune system relative to controls [142, 143, 146]. Alcohol’s osmotic effects and/or overlapping resonance with myo- inositol may contribute to the discordant MRS and PET findings.…”

“…Benzodiazepines are known to bind TSPO [144] and thus could influence TSPO availability [145]. However, the author’s reported [ 11 C]PBR28 binding was unaffected among those subjects [143]. In the third study, Kalk et al[146] imaged 9 alcohol-dependent subjects approximately three weeks since their last drink (ad libitum cigarette smoking prior to scanning) and healthy controls.…”

“…First, preclinical research indicates acute alcohol exposure increases proinflammatory markers systemically [151, 152] and in the brain [153, 154]. Second, human studies of long-term alcohol consumption observe significantly lower TSPO levels [142, 143, 146], which remain lower than controls 3 weeks since last drink [146]. Third, in vivo gray matter volume is lower among alcohol-dependent subjects versus healthy controls [155].…”

“…Peripheral monocytes from alcohol-dependent subjects exhibited blunted proinflammatory cytokine production (IL-6 and IL-8) following LPS incubation, compared to controls. In the second study, Kim et al[143] imaged 19 alcohol-dependent individuals ~3 days since last drink (range: 0–7 days) and 17 healthy controls using [ 11 C]PBR28. Control subjects were well-matched for demographic characteristics, but not cigarette smoking.…”