Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation

Daniel S. Albrecht, Anton Forsberg, Angelica Sandström, Courtney Bergan, Diana Kadetoff, Ekaterina Protsenko, Jon Lampa, Yvonne Claire Lee, Caroline Olgart Höglund, Ciprian Catana, Simon Cervenka, Oluwaseun Akeju, Mats Lekander, George Cohen, Christer Halldin, Norman Taylor, Minhae Kim, Jacob M. Hooker, Robert R. Edwards, Vitaly Napadow & 2 others Eva Kosek, Marco L. Loggia

Research output: Contribution to journalArticle

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 [11C]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 [11C]-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 [11C]PBR28 PET. 11 FM patients and 11 HC were scanned using [11C]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (VT) were computed from the [11C]PBR28 data. [11C]-L-deprenyl-D2 was quantified using λ k3. 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 [11C]PBR28 VT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [11C]-L-deprenyl-D2 signal, including those demonstrating elevated [11C]PBR28 signal in patients (p's ≥ 0.53, uncorrected). The elevations in [11C]PBR28 VT 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 [11C]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 [11C]PBR28 signal were not also accompanied by increased [11C]-L-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [11C]-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.

LanguageEnglish (US)
Pages72-83
Number of pages12
JournalBrain, Behavior, and Immunity
Volume75
DOIs
StatePublished - Jan 1 2019

Fingerprint

Fibromyalgia
Neuroglia
Positron-Emission Tomography
Selegiline
Brain
Microglia
Astrocytes
Fatigue
Musculoskeletal Pain
Occipital Lobe
Parietal Lobe
Proteins
(methyl-(11)C)N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine
Gyrus Cinguli
Frontal Lobe
General Hospitals

Keywords

  • Astrocytes
  • Chronic overlapping pain conditions
  • Deprenyl-D2
  • Fibromyalgia
  • Functional pain
  • MRI/PET
  • Microglia
  • Neuroimmunology
  • Neuroinflammation
  • Positron emission tomography
  • TSPO

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

Cite this

Albrecht, D. S., Forsberg, A., Sandström, A., Bergan, C., Kadetoff, D., Protsenko, E., ... Loggia, M. L. (2019). Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation. Brain, Behavior, and Immunity, 75, 72-83. https://doi.org/10.1016/j.bbi.2018.09.018
Albrecht, Daniel S. ; Forsberg, Anton ; Sandström, Angelica ; Bergan, Courtney ; Kadetoff, Diana ; Protsenko, Ekaterina ; Lampa, Jon ; Lee, Yvonne Claire ; Höglund, Caroline Olgart ; Catana, Ciprian ; Cervenka, Simon ; Akeju, Oluwaseun ; Lekander, Mats ; Cohen, George ; Halldin, Christer ; Taylor, Norman ; Kim, Minhae ; Hooker, Jacob M. ; Edwards, Robert R. ; Napadow, Vitaly ; Kosek, Eva ; Loggia, Marco L. / Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation. In: Brain, Behavior, and Immunity. 2019 ; Vol. 75. pp. 72-83.
@article{ae291c5a2cf64bcb9659c606c6b8a799,
title = "Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation",
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 [11C]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 [11C]-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 [11C]PBR28 PET. 11 FM patients and 11 HC were scanned using [11C]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (VT) were computed from the [11C]PBR28 data. [11C]-L-deprenyl-D2 was quantified using λ k3. 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 [11C]PBR28 VT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [11C]-L-deprenyl-D2 signal, including those demonstrating elevated [11C]PBR28 signal in patients (p's ≥ 0.53, uncorrected). The elevations in [11C]PBR28 VT 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 [11C]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 [11C]PBR28 signal were not also accompanied by increased [11C]-L-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [11C]-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.",
keywords = "Astrocytes, Chronic overlapping pain conditions, Deprenyl-D2, Fibromyalgia, Functional pain, MRI/PET, Microglia, Neuroimmunology, Neuroinflammation, Positron emission tomography, TSPO",
author = "Albrecht, {Daniel S.} and Anton Forsberg and Angelica Sandstr{\"o}m and Courtney Bergan and Diana Kadetoff and Ekaterina Protsenko and Jon Lampa and Lee, {Yvonne Claire} and H{\"o}glund, {Caroline Olgart} and Ciprian Catana and Simon Cervenka and Oluwaseun Akeju and Mats Lekander and George Cohen and Christer Halldin and Norman Taylor and Minhae Kim and Hooker, {Jacob M.} and Edwards, {Robert R.} and Vitaly Napadow and Eva Kosek and Loggia, {Marco L.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.bbi.2018.09.018",
language = "English (US)",
volume = "75",
pages = "72--83",
journal = "Brain, Behavior, and Immunity",
issn = "0889-1591",
publisher = "Academic Press Inc.",

}

Albrecht, DS, Forsberg, A, Sandström, A, Bergan, C, Kadetoff, D, Protsenko, E, Lampa, J, Lee, YC, Höglund, CO, Catana, C, Cervenka, S, Akeju, O, Lekander, M, Cohen, G, Halldin, C, Taylor, N, Kim, M, Hooker, JM, Edwards, RR, Napadow, V, Kosek, E & Loggia, ML 2019, 'Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation', Brain, Behavior, and Immunity, vol. 75, pp. 72-83. https://doi.org/10.1016/j.bbi.2018.09.018

Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation. / Albrecht, Daniel S.; Forsberg, Anton; Sandström, Angelica; Bergan, Courtney; Kadetoff, Diana; Protsenko, Ekaterina; Lampa, Jon; Lee, Yvonne Claire; Höglund, Caroline Olgart; Catana, Ciprian; Cervenka, Simon; Akeju, Oluwaseun; Lekander, Mats; Cohen, George; Halldin, Christer; Taylor, Norman; Kim, Minhae; Hooker, Jacob M.; Edwards, Robert R.; Napadow, Vitaly; Kosek, Eva; Loggia, Marco L.

In: Brain, Behavior, and Immunity, Vol. 75, 01.01.2019, p. 72-83.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation

AU - Albrecht, Daniel S.

AU - Forsberg, Anton

AU - Sandström, Angelica

AU - Bergan, Courtney

AU - Kadetoff, Diana

AU - Protsenko, Ekaterina

AU - Lampa, Jon

AU - Lee, Yvonne Claire

AU - Höglund, Caroline Olgart

AU - Catana, Ciprian

AU - Cervenka, Simon

AU - Akeju, Oluwaseun

AU - Lekander, Mats

AU - Cohen, George

AU - Halldin, Christer

AU - Taylor, Norman

AU - Kim, Minhae

AU - Hooker, Jacob M.

AU - Edwards, Robert R.

AU - Napadow, Vitaly

AU - Kosek, Eva

AU - Loggia, Marco L.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 [11C]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 [11C]-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 [11C]PBR28 PET. 11 FM patients and 11 HC were scanned using [11C]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (VT) were computed from the [11C]PBR28 data. [11C]-L-deprenyl-D2 was quantified using λ k3. 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 [11C]PBR28 VT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [11C]-L-deprenyl-D2 signal, including those demonstrating elevated [11C]PBR28 signal in patients (p's ≥ 0.53, uncorrected). The elevations in [11C]PBR28 VT 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 [11C]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 [11C]PBR28 signal were not also accompanied by increased [11C]-L-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [11C]-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.

AB - 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 [11C]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 [11C]-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 [11C]PBR28 PET. 11 FM patients and 11 HC were scanned using [11C]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (VT) were computed from the [11C]PBR28 data. [11C]-L-deprenyl-D2 was quantified using λ k3. 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 [11C]PBR28 VT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [11C]-L-deprenyl-D2 signal, including those demonstrating elevated [11C]PBR28 signal in patients (p's ≥ 0.53, uncorrected). The elevations in [11C]PBR28 VT 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 [11C]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 [11C]PBR28 signal were not also accompanied by increased [11C]-L-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [11C]-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.

KW - Astrocytes

KW - Chronic overlapping pain conditions

KW - Deprenyl-D2

KW - Fibromyalgia

KW - Functional pain

KW - MRI/PET

KW - Microglia

KW - Neuroimmunology

KW - Neuroinflammation

KW - Positron emission tomography

KW - TSPO

UR - http://www.scopus.com/inward/record.url?scp=85053820060&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053820060&partnerID=8YFLogxK

U2 - 10.1016/j.bbi.2018.09.018

DO - 10.1016/j.bbi.2018.09.018

M3 - Article

VL - 75

SP - 72

EP - 83

JO - Brain, Behavior, and Immunity

T2 - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

SN - 0889-1591

ER -