| 1. |
- Albrecht, Daniel S., et al.
(author)
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Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation
- 2019
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In: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 75, s. 72-83
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Journal article (peer-reviewed)abstract
- Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [C-11]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [C-11]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [C-11]PBR28 PET. 11 FM patients and 11 HC were scanned using [C-11]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (V-T) were computed from the [C-11]PBR28 data. [C-11]-L-deprenyl-D2 was quantified using lambda k(3). PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [C-11]PBR28 ITT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [C-11]-L-deprenyl-Ds signal, including those demonstrating elevated [C-11] PBR28 signal in patients (p's >= 0.53, uncorrected). The elevations in [C-11]PBR28 V-T and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [C-11] PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [C-11]PBR28 signal were not also accompanied by increased [C-11]-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [C-11]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.
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| 2. |
- Kanegawa, Naoki, et al.
(author)
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In vivo evidence of a functional association between immune cells in blood and brain in healthy human subjects
- 2016
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In: Brain, behavior, and immunity. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0889-1591 .- 1090-2139. ; 54, s. 149-157
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Journal article (peer-reviewed)abstract
- Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood. We examined 32 healthy individuals using positron emission tomography (PET) and [C-11]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells. In 26 individuals, two measurements were performed with varying time intervals. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. All individuals were genotyped for TSPO polymorphism and categorized as high, mixed, and low affinity binders. We assessed TSPO binding expressed as total distribution volume of [C-11]PBR28 in brain and in blood cells. TSPO binding in brain was strongly and positively correlated to binding in blood cells both at baseline and when analyzing change between two PET examinations. Furthermore, there was a significant correlation between change of leukocyte numbers and change in TSPO binding in brain, and a trend level correlation to change in TSPO binding in blood cells. These in vivo findings indicate an association between immunological cells in blood and brain via intact BBB, suggesting a functional interaction between these two compartments, such as interchange of peripherally derived cells or a common regulatory mechanism. Measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies using TSPO as a marker of brain immune activation. (C) 2016 Elsevier Inc. All rights reserved.
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| 3. |
- Tamm, Sandra, et al.
(author)
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Evidence of fatigue, disordered sleep and peripheral inflammation, but not increased brain TSPO expression, in seasonal allergy : A [11C]PBR28 PET study
- 2018
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In: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 68, s. 146-157
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Journal article (peer-reviewed)abstract
- Allergy is associated with non-specific symptoms such as fatigue, sleep problems and impaired cognition. One explanation could be that the allergic inflammatory state includes activation of immune cells in the brain, but this hypothesis has not been tested in humans. The aim of the present study was therefore to investigate seasonal changes in the glial cell marker translocator protein (TSPO), and to relate this to peripheral inflammation, fatigue and sleep, in allergy. We examined 18 patients with severe seasonal allergy, and 13 healthy subjects in and out-of pollen season using positron emission tomography (n = 15/13) and the TSPO radioligand [11C]PBR28. In addition, TNF-α, IL-5, IL-6, IL-8 and IFN-γ were measured in peripheral blood, and subjective ratings of fatigue and sleepiness as well as objective and subjective sleep were investigated. No difference in levels of TSPO was seen between patients and healthy subjects, nor in relation to pollen season. However, allergic subjects displayed both increased fatigue, sleepiness and increased percentage of deep sleep, as well as increased levels of IL-5 and TNF-α during pollen season, compared to healthy subjects. Allergic subjects also had shorter total sleep time, regardless of season. In conclusion, allergic subjects are indicated to respond to allergen exposure during pollen season with a clear pattern of behavioral disruption and peripheral inflammatory activation, but not with changes in brain TSPO levels. This underscores a need for development and use of more specific markers to understand brain consequences of peripheral inflammation that will be applicable in human subjects.
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| 4. |
- Tuisku, Jouni, et al.
(author)
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Effects of age, BMI and sex on the glial cell marker TSPO : a multicentre [11C]PBR28 HRRT PET study
- 2019
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In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer. - 1619-7070 .- 1619-7089. ; 46:11, s. 2329-2338
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Journal article (peer-reviewed)abstract
- Purpose The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [C-11]PBR28. Methods [C-11]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19-80 years; BMI range 17.6-36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (V-T) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. Results There were significant positive correlations between age and V-T in the frontal and temporal cortex. BMI showed a significant negative correlation with V-T in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher V-T. A subgroup analysis revealed a positive correlation between V-T and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. Conclusion These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.
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