Functional TSPO polymorphism predicts variance in the diurnal cortisol rhythm in bipolar disorder

Prossin, Alan R.; Chandler, Matthew; Ryan, Kelly A.; Saunders, Erika F.H.; Kamali, Masoud; Papadopoulos, Vassilios; Zöllner, Sebastian; Dantzer, Robert; McInnis, Melvin G.

doi:10.1016/j.psyneuen.2018.01.013

Cited by 24 publications

(17 citation statements)

References 49 publications

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“…We also observed a significant inverse association between [ 11 C]PBR28 binding in brain and levels of cortisol in plasma of medium-affinity binders only. This is consistent with findings that TSPO deletion in rodents [ 46 ] and its corresponding rs6971 polymorphism in humans has recently been associated with diurnal variation (morning versus evening in cortisol levels in saliva in patients with bipolar disorder and AUD [ 47 ]. In our sample, all blood draws for plasma cortisol, cholesterol, and ACTH analyses were drawn in the morning, thus investigating effects of rs6971 on diurnal variance in cortisol was not possible; and tracer injection time (ranging from 10 a.m. to 2:30 p.m.) did not correlate with whole brain [ 11 C]PBR28 binding in groups pooled together.…”

Section: Discussionsupporting

confidence: 92%

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

Kim

Wiers

Tyler

et al. 2018

Neuropsychopharmacol

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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.

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Section: Discussionsupporting

confidence: 92%

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

Kim

Wiers

Tyler

et al. 2018

Neuropsychopharmacol

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“…The presence of this TSPO polymorphism has been linked to the function of the hypothalamicpituitary-adrenal axis, predisposing carriers to psychiatric disorders [124][125][126][127], and potentially impairing the response of patients to anxiolytic TSPO drug ligands [128,129]. The presence of this TSPO polymorphism was linked to reduced pregnenolone [130] and adrenocorticotropic hormone (ACTH)-induced corticosteroid levels [110] and shown to be associated with dysregulated cortisol rhythms and consequent clinical exacerbations in bipolar disorders [131]. This finding provides clear evidence of the link between TSPO, cholesterol binding, and steroid formation under normal and stress conditions.…”

Section: Genetics and Genetic Modelsmentioning

confidence: 99%

Cellular sources of TSPO expression in healthy and diseased brain

Nutma

Ceyzériat

Amor

et al. 2021

Eur J Nucl Med Mol Imaging

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The 18 kDa translocator protein (TSPO) is a highly conserved protein located in the outer mitochondrial membrane. TSPO binding, as measured with positron emission tomography (PET), is considered an in vivo marker of neuroinflammation. Indeed, TSPO expression is altered in neurodegenerative, neuroinflammatory, and neuropsychiatric diseases. In PET studies, the TSPO signal is often viewed as a marker of microglial cell activity. However, there is little evidence in support of a microglia-specific TSPO expression. This review describes the cellular sources and functions of TSPO in animal models of disease and human studies, in health, and in central nervous system diseases. A discussion of methods of analysis and of quantification of TSPO is also presented. Overall, it appears that the alterations of TSPO binding, their cellular underpinnings, and the functional significance of such alterations depend on many factors, notably the pathology or the animal model under study, the disease stage, and the involved brain regions. Thus, further studies are needed to fully determine how changes in TSPO binding occur at the cellular level with the ultimate goal of revealing potential therapeutic pathways.

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“…Upon microglial activation in the disease pathogenesis, TSPO may experience polymerization leading to the formation of multiple possible binding sites [ 51 ]. TSPO functional polymorphisms (AG and AA genotypes) may contribute to neuroprotective mechanisms and reduce immune function [ 52 ]. Further investigation into understanding the association of TSPO gene SNPs and TSPO expression, and these results need to be replicated in a larger population.…”

Section: Discussionmentioning

confidence: 99%

Microglia Implicated in Tauopathy in the Striatum of Neurodegenerative Disease Patients from Genotype to Phenotype

Knight

Yang

et al. 2020

IJMS

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We found interactions between dopamine and oxidative damage in the striatum involved in advanced neurodegeneration, which probably change the microglial phenotype. We observed possible microglia dystrophy in the striatum of neurodegenerative brains. To investigate the interactions between oxidative damage and microglial phenotype, we quantified myeloperoxidase (MPO), poly (ADP-Ribose) (PAR), and triggering receptors expressed on myeloid cell 2 (TREM2) using enzyme-linked immunosorbent assay (ELISA). To test the correlations of microglia dystrophy and tauopathy, we quantified translocator protein (TSPO) and tau fibrils using autoradiography. We chose the caudate and putamen of Lewy body diseases (LBDs) (Parkinson’s disease, Parkinson’s disease dementia, and Dementia with Lewy body), Alzheimer’s disease (AD), and control brains and genotyped for TSPO, TREM2, and bridging integrator 1 (BIN1) genes using single nucleotide polymorphisms (SNP) assays. TREM2 gene variants were absent across all samples. However, associations between TSPO and BIN1 gene polymorphisms and TSPO, MPO, TREM2, and PAR level variations were found. PAR levels reduced significantly in the caudate of LBDs. TSPO density and tau fibrils decreased remarkably in the striatum of LBDs but increased in AD. Oxidative damage, induced by misfolded tau proteins and dopamine metabolism, causes microglia dystrophy or senescence during the late stage of LBDs. Consequently, microglia dysfunction conversely reduces tau propagation. The G allele of the BIN1 gene is a potential risk factor for tauopathy.

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Functional TSPO polymorphism predicts variance in the diurnal cortisol rhythm in bipolar disorder

Abstract: We identified differences in diurnal cortisol rhythm depending on presence/absence of common TSPO polymorphism in BD volunteers with or without AUD and healthy volunteers. These results have wide ranging implications but further validation is needed prior to optimal clinical translation.

Cited by 24 publications

References 49 publications

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

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

Cellular sources of TSPO expression in healthy and diseased brain

Microglia Implicated in Tauopathy in the Striatum of Neurodegenerative Disease Patients from Genotype to Phenotype

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