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Review
. 2016 Apr 20;7(4):470-83.
doi: 10.1021/acschemneuro.6b00056. Epub 2016 Mar 25.

In Vivo Imaging of Human Neuroinflammation

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Free PMC article
Review

In Vivo Imaging of Human Neuroinflammation

Daniel S Albrecht et al. ACS Chem Neurosci. .
Free PMC article

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Abstract

Neuroinflammation is implicated in the pathophysiology of a growing number of human disorders, including multiple sclerosis, chronic pain, traumatic brain injury, and amyotrophic lateral sclerosis. As a result, interest in the development of novel methods to investigate neuroinflammatory processes, for the purpose of diagnosis, development of new therapies, and treatment monitoring, has surged over the past 15 years. Neuroimaging offers a wide array of non- or minimally invasive techniques to characterize neuroinflammatory processes. The intent of this Review is to provide brief descriptions of currently available neuroimaging methods to image neuroinflammation in the human central nervous system (CNS) in vivo. Specifically, because of the relatively widespread accessibility of equipment for nuclear imaging (positron emission tomography [PET]; single photon emission computed tomography [SPECT]) and magnetic resonance imaging (MRI), we will focus on strategies utilizing these technologies. We first provide a working definition of "neuroinflammation" and then discuss available neuroimaging methods to study human neuroinflammatory processes. Specifically, we will focus on neuroimaging methods that target (1) the activation of CNS immunocompetent cells (e.g. imaging of glial activation with TSPO tracer [(11)C]PBR28), (2) compromised BBB (e.g. identification of MS lesions with gadolinium-enhanced MRI), (3) CNS-infiltration of circulating immune cells (e.g. tracking monocyte infiltration into brain parenchyma with iron oxide nanoparticles and MRI), and (4) pathological consequences of neuroinflammation (e.g. imaging apoptosis with [(99m)Tc]Annexin V or iron accumulation with T2* relaxometry). This Review provides an overview of state-of-the-art techniques for imaging human neuroinflammation which have potential to impact patient care in the foreseeable future.

Keywords: MRS; Neuroimmunology; astrocyte; blood-brain barrier; brain imaging; microglia.

Figures

Figure 1
Figure 1
Neuroimaging targets for the major players in neuroinflammation. This figure depicts an overview of the major nuclear imaging and MRI tools to study human neuroinflammation. Nuclear imaging methods are displayed in red font, MRI methods in blue font. Categories are broken into: 1) activation of CNS immunocompetent cells (microglia and astrocytes), 2) disruption of BBB, 3) infiltration of peripheral immune cells, and 4) consequences of neuroinflammation (e.g. demyelination and cell death). TSPO – translocator protein 18kDa; MAO-B – monoamine oxidase B; SPIO – superparamagnetic iron oxide particle; USPIO – ultrasmall SPIO; COX-1 – cyclooxygenase-1; MRS – magnetic resonance spectroscopy; DCE – dynamic contrast enhanced; DSC – dynamic susceptibility contrast; ASL – arterial spin labeling; BBB – blood brain barrier; PS – phosphatidylserine; mcMRI – multiple contrast MRI; DWI – diffusion weighted imaging; MTR – magnetization transfer ratio; NAA – N-acetyl aspartate; VBM – voxel based morphometry.
Figure 2
Figure 2
Elevated [11C]PBR28 binding in patients with chronic low back pain (cLBP; A) and amyotrophic lateral sclerosis (ALS; B) compared to healthy controls. All SUVRs represent standardized uptake value (SUV) normalized by whole-brain uptake. For both cLBP and ALS patients, regional increases in glial activation correspond to brain regions implicated in disease pathology. A) Median SUVR images for cLBP patients (top row) and controls (middle row). Bottom row – clusters are regions where SUVR in cLBP patients was significantly higher than controls. B) Mean SUVR images for ALS patients (top row) and controls (middle row), overlaid on average structural MRI. Bottom row – clusters represent voxels where ALS SUVR was significantly higher than controls. Modified from Loggia et al. “Evidence for brain glial activation in chronic pain patients”, Brain published online Jan 12. DOI: 10.1093/brain/awu377, with permission from Oxford University Press, and Zurcher et al. “Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: Assessed with [11C]-PBR28”, NeuroImage:Clinical 7: 409–414, DOI:10.1016/j.nicl.2015.01.009, with permission from ScienceDirect under the terms of Creative Commons Attribution-NonCommercial-No Derivatives License (CC BY NC ND; http://creativecommons.org/licenses/by-nc-nd/4.0/).
Figure 3
Figure 3
Examples of BBB imaging with contrast in MS patients. (A) Examples of leptomeningeal contrast enhancement in two representative relapsing-remitting MS cases. Foci of high signal (arrows) on 3T post-contrast T2-FLAIR images indicate leptomeningeal enhancement. Extracerebral tissues have been masked for clarity. (B) Signal intensity on different MRI sequences. Three foci of leptomeningeal enhancement are visible on post-contrast T2-FLAIR scans (left column), but not on the corresponding pre-contrast T2-FLAIR (middle column). In the right column, post-contrast T1-weighted images show minimal abnormal signal that would not routinely be classified as enhancement. T2-FLAIR = T2-weighted, fluid-attenuated inversion recovery. Reproduced from Absinta et al., “Gadolinium-based MRI characterization of leptomeningeal inflammation in multiple sclerosis”, Neurology vol. 85 no. 1, 18–28 with permission from Wolters Kluwer Health.

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