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Cited by 129Tryptophan and brain disordersAdvanced MRI Techniques and ApplicationsNeuroinflammation and Neurodegeneration Mechanisms

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Quantitative Magnetization Transfer Imaging as a Biomarker for Effects of Systemic Inflammation on the Brain

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Harrison, Neil A., Cooper, Ella, Dowell, Nicholas G., Keramida, Georgia, Voon, Valerie, Critchley, Hugo D., Cercignani, Mara·2015·Biological Psychiatry
DOI 10.1016/j.biopsych.2014.09.023PMC PMC4503794
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Abstract

BACKGROUND: Systemic inflammation impairs brain function and is increasingly implicated in the etiology of common mental illnesses, particularly depression and Alzheimer's disease. Immunotherapies selectively targeting proinflammatory cytokines demonstrate efficacy in a subset of patients with depression. However, efforts to identify patients most vulnerable to the central effects of inflammation are hindered by insensitivity of conventional structural magnetic resonance imaging. METHODS: We used quantitative magnetization transfer (qMT) imaging, a magnetic resonance imaging technique that enables quantification of changes in brain macromolecular density, together with experimentally induced inflammation to investigate effects of systemic inflammatory challenge on human brain microstructure. Imaging with qMT was performed in 20 healthy participants after typhoid vaccination and saline control injection. An additional 20 participants underwent fluorodeoxyglucose positron emission tomography following the same inflammatory challenge. RESULTS: The qMT data demonstrated that inflammation induced a rapid change in brain microstructure, reflected in increased magnetization exchange from free (water) to macromolecular-bound protons, within a discrete region of insular cortex implicated in representing internal physiologic states including inflammation. The functional significance of this change in insular microstructure was demonstrated by correlation with inflammation-induced fatigue and fluorodeoxyglucose positron emission tomography imaging, which revealed increased resting glucose metabolism within this region following the same inflammatory challenge. CONCLUSIONS: Together these observations highlight a novel structural biomarker of the central physiologic and behavioral effects of mild systemic inflammation. The widespread clinical availability of magnetic resonance imaging supports the viability of qMT imaging as a clinical biomarker in trials of immunotherapeutics, both to identify patients vulnerable to the effects of systemic inflammation and to monitor neurobiological responses.

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Figure 1 Effects of inflammation on interleukin-6 and fatigue. (A) Change in circulating interleukin-6 before and after vaccine (V base and V 4 Hrs) and placebo injection (P base and P 4 Hrs). Typhoid vaccination evoked a robust inflammatory response with an approximately threefold increase in plasma interleukin-6 from mean (± SE) 1.29 ± .38 pmol/L at baseline to 3.74 ± .27 pmol/L at 4 hours [t19 = 5.93, p < .001]. The placebo condition was not associated with any change in interleukin-6 from .97 ± .23 pmol/L at baseline to .90 ± .18 pmol/L at 4 hours [t19 = −.54, p = .59]. (B) Change in fatigue before and after typhoid vaccination and placebo saline injection. Typhoid vaccination, but not placebo injection, was associated with a significant increase in fatigue as shown by mean (± SE) fatigue visual analog scale 16.18 ± 12.57 at baseline to 42.40 ± 22.52 at 4 hours [t19 = 6.05, p < .001] for typhoid vaccination and 22.08 ± 17.72 at baseline to 29.60 ± 17.94 at 4 hours [t19 = 1.93, p = .07] for placebo injection. IL-6, interleukin-6; n.s., p = non significant; VAS, visual analog scale.
Figure 1 Effects of inflammation on interleukin-6 and fatigue. (A) Change in circulating interleukin-6 before and after vaccine (V base and V 4 Hrs) and placebo injection (P base and P 4 Hrs). Typhoid vaccination evoked a robust inflammatory response with an approximately threefold increase in plasma interleukin-6 from mean (± SE) 1.29 ± .38 pmol/L at baseline to 3.74 ± .27 pmol/L at 4 hours [t19 = 5.93, p < .001]. The placebo condition was not associated with any change in interleukin-6 from .97 ± .23 pmol/L at baseline to .90 ± .18 pmol/L at 4 hours [t19 = −.54, p = .59]. (B) Change in fatigue before and after typhoid vaccination and placebo saline injection. Typhoid vaccination, but not placebo injection, was associated with a significant increase in fatigue as shown by mean (± SE) fatigue visual analog scale 16.18 ± 12.57 at baseline to 42.40 ± 22.52 at 4 hours [t19 = 6.05, p < .001] for typhoid vaccination and 22.08 ± 17.72 at baseline to 29.60 ± 17.94 at 4 hours [t19 = 1.93, p = .07] for placebo injection. IL-6, interleukin-6; n.s., p = non significant; VAS, visual analog scale.CC BY · PubMed Central
Figure 2 Effects of inflammation on brain structure and function. (A) Quantitative magnetization transfer imaging study. Brain regions showing a significant increase in magnetization transfer exchange rate constant 3–4 hours after typhoid vaccine–induced inflammation compared with control (saline) injection. Data displayed at a whole-brain corrected threshold of p < .05. Color scale denotes t score. (B) Fluorodeoxyglucose positron emission tomography imaging study. Brain regions showing a significant increase in fluorodeoxyglucose uptake 3–4 hours after typhoid vaccine–induced inflammation; exclusively masked by changes in fluorodeoxyglucose uptake 3–4 hours after placebo (mask threshold p < .005). Data displayed at a whole-brain corrected threshold of p < .05. (C) Left insula voxels showing a significant increase in magnetization transfer exchange rate constant 3–4 hours after experimentally induced inflammation (yellow) overlaid with voxels (green) additionally predicting inflammation-induced fatigue (fatigue visual analog scale, p < .05). (D) Correlation of fatigue visual analog scale scores 4 hours after typhoid vaccine minus placebo (V − P) (x-axis) with inflammation-induced changes in magnetization transfer exchange rate constant of all 1196 voxels within the posterior insula cluster (illustrated in yellow in C) on the y-axis (R2 = .2, p < .05). fVAS, fatigue visual analog scale; kf, magnetization transfer exchange rate constant.
Figure 2 Effects of inflammation on brain structure and function. (A) Quantitative magnetization transfer imaging study. Brain regions showing a significant increase in magnetization transfer exchange rate constant 3–4 hours after typhoid vaccine–induced inflammation compared with control (saline) injection. Data displayed at a whole-brain corrected threshold of p < .05. Color scale denotes t score. (B) Fluorodeoxyglucose positron emission tomography imaging study. Brain regions showing a significant increase in fluorodeoxyglucose uptake 3–4 hours after typhoid vaccine–induced inflammation; exclusively masked by changes in fluorodeoxyglucose uptake 3–4 hours after placebo (mask threshold p < .005). Data displayed at a whole-brain corrected threshold of p < .05. (C) Left insula voxels showing a significant increase in magnetization transfer exchange rate constant 3–4 hours after experimentally induced inflammation (yellow) overlaid with voxels (green) additionally predicting inflammation-induced fatigue (fatigue visual analog scale, p < .05). (D) Correlation of fatigue visual analog scale scores 4 hours after typhoid vaccine minus placebo (V − P) (x-axis) with inflammation-induced changes in magnetization transfer exchange rate constant of all 1196 voxels within the posterior insula cluster (illustrated in yellow in C) on the y-axis (R2 = .2, p < .05). fVAS, fatigue visual analog scale; kf, magnetization transfer exchange rate constant.CC BY · PubMed Central

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  1. Lin, 2010, Nonlinear coupling between cerebral blood flow oxygen consumption, and ATP production in human visual cortex, Proc Natl Acad Sci U S A, 107, 8446, 10.1073/pnas.0909711107 · DOI · Paper page

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Metadata

Authors
Harrison, N. A., Cooper, E., Dowell, N. G., Keramida, G., Voon, V., Critchley, H. D., & Cercignani, M.
Affiliations
  • Brighton and Sussex Medical School (GB)
  • Fondazione Santa Lucia (IT)
  • University of Cambridge (GB)
Corresponding author
Harrison, Neil A.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2015-07
Volume
78
Issue
1
Pages
49-57
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2014.09.023
PMC
PMC4503794
OpenAlex
W1968629304
Cited by
129
References
55
Citations by year
2026: 6 · 2025: 8 · 2024: 9 · 2023: 9 · 2022: 19 · 2021: 9 · 2020: 14 · 2019: 11 · 2018: 12 · 2017: 14 · 2016: 10 · 2015: 8
FWCI
3.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Sussex Research Online (University of Sussex) (submittedVersion, cc-by)
  • Figshare (submittedVersion, cc-by)
Funders
Wellcome Trust
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
systemic inflammation, brain microstructure, insula, typhoid vaccination, fatigue, neuroinflammation, biomarkers, immunotherapy response, depression, Alzheimer's disease
MeSH terms
Adult, Brain, Encephalitis, Fatigue, Female, Humans, Magnetic Resonance Imaging, Male, Typhoid-Paratyphoid Vaccines, Biomarkers, Fluorodeoxyglucose F18, Receptors, Interleukin-6, Positron-Emission Tomography

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