Dataset Information

Imaging the brain's immune response to alcohol with [¹¹C]PBR28 TSPO Positron Emission Tomography.

ABSTRACT: In humans, the negative effects of alcohol are linked to immune dysfunction in both the periphery and the brain. Yet acute effects of alcohol on the neuroimmune system and its relationships with peripheral immune function are not fully understood. To address this gap, immune response to an alcohol challenge was measured with positron emission tomography (PET) using the radiotracer [¹¹C]PBR28, which targets the 18-kDa translocator protein, a marker sensitive to immune challenges. Participants (n = 12; 5 F; 25-45 years) who reported consuming binge levels of alcohol (>3 drinks for females; >4 drinks for males) 1-3 months before scan day were enrolled. Imaging featured a baseline [¹¹C]PBR28 scan followed by an oral laboratory alcohol challenge over 90 min. An hour later, a second [¹¹C]PBR28 scan was acquired. Dynamic PET data were acquired for at least 90 min with arterial blood sampling to measure the metabolite-corrected input function. [¹¹C]PBR28 volume of distributions (V_T) was estimated in the brain using multilinear analysis 1. Subjective effects, blood alcohol levels (BAL), and plasma cytokines were measured during the paradigm. Full completion of the alcohol challenge and data acquisition occurred for n = 8 (2 F) participants. Mean peak BAL was 101 ± 15 mg/dL. Alcohol significantly increased brain [¹¹C]PBR28 V_T (n = 8; F_(1,49) = 34.72, p > 0.0001; Cohen's d'=0.8-1.7) throughout brain by 9-16%. Alcohol significantly altered plasma cytokines TNF-α (F_(2,22) = 17.49, p < 0.0001), IL-6 (F_(2,22) = 18.00, p > 0.0001), and MCP-1 (F_(2,22) = 7.02, p = 0.004). Exploratory analyses identified a negative association between the subjective degree of alcohol intoxication and changes in [¹¹C]PBR28 V_T. These findings provide, to our knowledge, the first in vivo human evidence for an acute brain immune response to alcohol.

SUBMITTER: Raval NR

PROVIDER: S-EPMC10743097 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Imaging the brain's immune response to alcohol with [<sup>11</sup>C]PBR28 TSPO Positron Emission Tomography.

Raval Nakul R NR Angarita Gustavo G Matuskey David D Miller Rachel R Drake Lindsey R LR Kapinos Michael M Nabulsi Nabeel N Huang Yiyun Y Carson Richard E RE O'Malley Stephanie S SS Cosgrove Kelly P KP Hillmer Ansel T AT

Molecular psychiatry 20230802 8

In humans, the negative effects of alcohol are linked to immune dysfunction in both the periphery and the brain. Yet acute effects of alcohol on the neuroimmune system and its relationships with peripheral immune function are not fully understood. To address this gap, immune response to an alcohol challenge was measured with positron emission tomography (PET) using the radiotracer [<sup>11</sup>C]PBR28, which targets the 18-kDa translocator protein, a marker sensitive to immune challenges. Parti ...[more]

PMID: 37532797

Similar Datasets

Project description:Astrocytes and microglia become reactive under most brain pathological conditions, making this neuroinflammation process a surrogate marker of neuronal dysfunction. Neuroinflammation is associated with increased levels of translocator protein 18 kDa (TSPO) and binding sites for TSPO ligands. Positron emission tomography (PET) imaging of TSPO is thus commonly used to monitor neuroinflammation in preclinical and clinical studies. It is widely considered that TSPO PET signal reveals reactive microglia, although a few studies suggested a potential contribution of reactive astrocytes. Because astrocytes and microglia play very different roles, it is crucial to determine whether reactive astrocytes can also overexpress TSPO and yield to a detectable TSPO PET signal in vivo. We used a model of selective astrocyte activation through lentiviral gene transfer of the cytokine ciliary neurotrophic factor (CNTF) into the rat striatum, in the absence of neurodegeneration. CNTF induced an extensive activation of astrocytes, which overexpressed GFAP and become hypertrophic, whereas microglia displayed minimal increase in reactive markers. Two TSPO radioligands, [(18)F]DPA-714 [N,N-diethyl-2-(2-(4-(2-[(18)F]fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide] and [(11)C]SSR180575 (7-chloro-N,N-dimethyl-5-[(11)C]methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide), showed a significant binding in the lenti-CNTF-injected striatum that was saturated and displaced by PK11195 [N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)-isoquinoline-3-carboxamide]. The volume of radioligand binding matched the GFAP immunopositive volume. TSPO mRNA levels were significantly increased, and TSPO protein was overexpressed by CNTF-activated astrocytes. We show that reactive astrocytes overexpress TSPO, yielding to a significant and selective binding of TSPO radioligands. Therefore, caution must be used when interpreting TSPO PET imaging in animals or patients because reactive astrocytes can contribute to the signal in addition to reactive microglia.

Dataset Information

Imaging the brain's immune response to alcohol with [¹¹C]PBR28 TSPO Positron Emission Tomography.

Publications

Imaging the brain's immune response to alcohol with [<sup>11</sup>C]PBR28 TSPO Positron Emission Tomography.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Imaging the brain's immune response to alcohol with [11C]PBR28 TSPO Positron Emission Tomography.

Publications

Imaging the brain's immune response to alcohol with [<sup>11</sup>C]PBR28 TSPO Positron Emission Tomography.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Imaging the brain's immune response to alcohol with [¹¹C]PBR28 TSPO Positron Emission Tomography.