Abstract
Neuroinflammation is increasingly implicated in epileptogenesis and epilepsy. Microglia are an important mediator of central nervous system inflammation, and the development of positron emission tomography (PET) radioligands which bind the Translocator Protein (TSPO), an outer mitochondrial membrane protein expressed by microglia, has enabled in vivo measurement of neuroinflammation. Here, we outline the principles and potential pitfalls of TSPO PET imaging in relation to epilepsy, and opportunities for using TSPO imaging as a biomarker for future anti-inflammatory based therapeutics in epilepsy.
Keywords
1. Introduction
Activation of the innate immune system has been implicated in the development of epilepsy (epileptogenesis) and occurrence of seizures (ictogenesis) [
[1]
]. This has led to increasing interest in the development of anti-inflammatory approaches to the treatment of epilepsy, targeting cytokine mediators of inflammation and their receptors [[2]
], as well as master genetic regulators controlling neuroinflammatory pathways [[3]
]. As new anti-inflammatory drugs emerge, it will become important to develop biomarkers which can identify those patients with epilepsy who are likely to benefit from immune-based therapies. This is particularly important given immunomodulators tend to have important adverse effects. Moreover, the ability to confirm that a novel anti-inflammatory drug is acting via the intended target in vivo will be critical to the drug development process; the demonstration that an on-target effect on neuroinflammation correlates with seizure reduction is crucial to provide confidence to proceed with expensive large-scale phase III trials. The development of biomarkers for patient stratification and establishing the on-target effects of candidate anti-inflammatory drugs is therefore of paramount importance.Here, we discuss the role of measuring neuroinflammation in vivo using positron emission tomography (PET) based on PET radioligands that bind the 18-kDa Translocator Protein (TSPO), an outer mitochondrial membrane protein. TSPO is strongly expressed in microglia, and consequently TSPO PET has been used as a means of quantifying microglial activation in vivo in a variety of CNS disorders. In this review, we provide an overview of TSPO PET imaging to support the reader’s understanding of the published epilepsy PET studies and to guide future research. We outline the principles of PET imaging (Box 1) and explain the terminology (Box 2). We introduce TSPO and highlight some of the challenges for PET imaging of this protein. For further details, the reader is directed to excellent reviews of TSPO biology [
4
, 5
], radioligand development [6
, 7
, 8
], PET methodology [9
, 10
, 11
, 12
] and applications [7
, 13
].Box 1
A primer on PET imaging.
A PET scan
PET is a nuclear medicine imaging technique for non-invasively measuring biological function. The technique relies upon administration of a radioligand, which is a ligand (a molecule that binds to a target) that is radiolabeled with a radionuclide (radioactive isotope). Frequently used PET radionuclides are 11C (half-life = 20.4 min) and 18F (half-life = 109.8 min).
A TSPO PET scan takes ∼60–120 min. The radioligand is administered to the subject, who lies in the PET scanner. As with any drug, the radioligand is distributed through the body and interacts with its target as well as other molecules (Box 2).
PET radionuclides decay by the emission of a positron, the antiparticle of the electron. The positron travels a short distance (∼1 mm) before it annihilates with a neighbouring electron to produce two gamma ray photons that travel along a straight line in opposite directions. It is the 180° angular relationship of these paired photons that forms the basis of PET. A circular array of radiation detectors around the subject identifies pairs of these coincident photons, allowing a quantitative 3D reconstruction of the in vivo radioactivity levels of the radionuclide administered. By acquiring serial data over time, a dynamic series of images are reconstructed, providing a quantitative measure of the radioactivity concentration in the tissues (in units of e.g. Becquerels/millilitre, Bq/ml) over time.
Alignment of dynamic PET images with structural images obtained from computed tomography (CT) or magnetic resonance imaging (MRI) permits extraction of PET data from anatomically-defined regions of interest (ROI) (e.g. hippocampus). The radioactivity concentration measured over time in a given ROI is called the time activity curve (TAC).
Blood sampling
During a PET scan blood samples may be obtained, typically from the radial artery. Blood sampling provides information about the radioactivity concentration of the radioligand and its metabolites in the blood, for use in kinetic modelling (below).
It is common for a radioligand to be metabolized (e.g. by liver or kidneys) during a scan, and one or more metabolites may carry the radioactive isotope. This is normally not a problem, because metabolism yields polar molecules suitable for renal elimination, and hence the metabolites tend not to cross the blood brain barrier (BBB). The proportion of radioactivity belonging to the parent (i.e. original) radioligand versus its radioactive metabolites can be measured (e.g. using chromatography).
Centrifugation of blood samples permits calculation of the portion of radioligand bound to blood cells versus that present in plasma. The time-varying curve of the radioactivity concentration of the ligand in arterial plasma approximates the concentration of the ligand in the arterial circulation available for uptake in the brain. In kinetic modelling, this curve is called the arterial input function (or plasma input function). When significant amounts of radiolabeled metabolites are found in the blood, their contribution is subtracted from the plasma curve (yielding the parent plasma input function), because only the parent ligand crosses the BBB and binds the target.
PET kinetic modelling
PET kinetic modelling is the process of deriving mathematical models which best fit the PET data, in order to infer meaningful physiological information, e.g. about the concentration of a receptor in a volume of tissue.
The inputs to kinetic modelling are TACs for each ROI or dynamic PET images (i.e. from the PET scanner) and (optionally) an arterial input function (i.e. from blood data). The physiological parameters of interest can be calculated for each ROI (i.e. a value for hippocampus and thalamus), or dynamic images can be used to generate parametric maps (i.e. a value for each voxel in the brain).
Why do we need kinetic modelling? In TSPO PET, the TAC for a given ROI is a sum of the signal of interest (specific binding of ligand to TSPO) but also the noise (e.g. ligand present in the blood, ligand bound to other molecules, ligand free in the tissue). The goal of kinetic modelling is to account for these component signals, that superimpose to produce the TAC, in order to isolate the desired component (i.e. specific TSPO binding), and so deduce a measure of the specific binding of the ligand to TSPO in the brain (Box 2).
Compartmental models
A variety of PET kinetic models have been developed. Compartmental models are commonly used, and typically require an arterial input function. These models describe the radioligand as existing at any one time in one or more compartments (usually one, two, or three tissue compartments), which relate both to its physical location (e.g. blood, intra-cellular space), as well as its biochemical state (e.g. unbound, specifically bound). A system of differential equations describes the concentration of the radioligand within each compartment, and the possible “movement” of the radioligand between compartments (e.g. moving from the blood across the BBB into the extracellular space). By comparing the model output to the PET data, it is possible to estimate values for parameters of interest, including the volume of distribution (VT) (Box 2).
Graphical analysis methods
Other graphical analysis methods (e.g. the Logan graphical analysis) have been developed which are independent of any particular model [
[30]
].Reference tissue models
Although an arterial input function is widely considered the gold-standard for kinetic modeling, the procedure for obtaining it is challenging and also contains several sources of error. Simplified methods of analysis, such as the simplified reference tissue model (SRTM), have been developed that do not require an arterial input function [
[31]
]. The SRTM is an image-driven model that allows outcome measures to be estimated using the TAC of a reference tissue (or reference region) instead of an arterial input function.A reference tissue is a region where there is no specific binding of the radioligand, and where uptake is not affected by disease processes. Unfortunately, a true reference region does not exist in the brain for many radioligands, including TSPO. A pseudo-reference region can be used, which would contain low levels of TSPO, but not differ between comparison groups (e.g. patients versus controls) [
[32]
]. TSPO PET studies have used, for example, cortical grey matter [[33]
], whole brain [- Dimber R.
- Guo Q.
- Bishop C.
- Adonis A.
- Buckley A.
- Kocsis A.
- et al.
Evidence of brain inflammation in patients with Human T Lymphotropic Virus type 1 associated myelopathy (HAM): a pilot multi modal imaging study using [11C] PBR28 PET, MR T1 w and DWI.
J Nucl Med. 2016; https://doi.org/10.2967/jnumed.116.175083
[34]
], or cerebellum [[35]
] as anatomically-defined pseudo-reference regions. However, the choice of an anatomically-defined pseudo-reference region may be problematic.Automatic reference region extraction
A variety of data-driven techniques have also been adopted to identify voxels across the brain with TACs mirroring those of controls, as a means of automatically extracting a reference tissue input function from dynamic PET images (see for review [
[11]
]).Box 2
Important PET imaging terminology.
PET radioligand binding
- •Specific binding is radioligand binding to the target molecule, but not including binding to other (non-target) molecules, nor radioligand that is unbound (called free radioligand).
- •Nonspecific binding is radioligand binding to molecules other than the target molecule.
- •Non-displaceable uptake is the sum of non-specific and free radioligand concentrations.
- •The free fraction of a radioligand in plasma is the fraction of the ligand that is not bound to plasma proteins (i.e. which is freely diffusible in plasma water). It is generally considered that in vivo only the free fraction of the radioligand is available for transport across the BBB.
PET kinetic modelling outcome measures
A standard nomenclature for outcome measures from PET kinetic modelling has been adopted [
[36]
]. Two important terms are volume of distribution and binding potential.- •Volume of distribution (VT) is the ratio, at equilibrium, of the concentration of radioligand in tissue to that in plasma. This ratio reflects the proportion of radioligand in tissue that is bound specifically to the target molecule as well as non-specifically bound and free. Because most studies are carried out using a bolus injection (and not a constant infusion) of radioligand, kinetic modelling predicts the equilibrium ratio from non-equilibrium conditions. The distribution volume ratio (DVR) for a given target region is VT/VTREF, where VT is the volume of distribution of the target region and VTREF is the volume of distribution of a reference tissue.
- •Binding potential (BP) is the ratio, at equilibrium, of the concentration of specifically bound radioligand in tissue to that in a reference fluid or region. Three versions of BP are used depending on if the reference is the free ligand in plasma (denoted BPF), the total in plasma (BPP) or a reference tissue non-displaceable component (BPND). BPND is most frequently used because only this form of BP permits estimation using a reference tissue method (i.e. not requiring blood data).
Other PET measures
- •Standardized uptake value (SUV) is a simple image-based measure, widely used in clinical practice, calculated as the ratio of tissue radioactivity concentration (e.g. in kBq/ml) at a given time, divided by the administered dose at the time of injection (e.g. in MBq) divided by body weight (e.g. in kg). SUV is vulnerable to several sources of error, and the use of SUV as a quantitative measure is generally discouraged.
- •The standardized uptake value ratio (SUVR) for a given target region is SUV/SUVREF, as for DVR.
2. TSPO as a target for PET imaging
TSPO is a five transmembrane domain protein encoded by nuclear DNA and localized primarily in the outer mitochondrial membrane [
[4]
]. It is expressed in every organ but with especially high constitutive expression in steroid-synthesizing tissues [[14]
]. TSPO was discovered in 1977, when high affinity binding of diazepam was observed in the rat kidney. This specific binding was distinct from the binding to the central benzodiazepine receptor (the gamma-aminobutyric acid type A (GABAA) receptor), hence TSPO was originally named the peripheral benzodiazepine receptor (PBR). The PBR was renamed as TSPO in 2006 to reflect new understanding of its molecular structure and function [[14]
].The most well-studied putative function of TSPO relates to its proposed role in transporting cholesterol into the mitochondrial inner membrane space, which is the rate-limiting step of steroid and neurosteroid biosynthesis [
[14]
]. TSPO has also been implicated in many other important physiological processes, including cellular respiration, immunomodulation and apoptosis. However, despite almost 40 years of study, the precise functional role of TSPO is still far from clear [[5]
].In the CNS, TSPO is expressed at low levels under normal physiological conditions, and is most prominent in the olfactory bulb and non-parenchymal regions, including the ependyma and choroid plexus [
[15]
]. Increased levels of TSPO in the CNS was originally considered to be specific for activated microglia as well as infiltrating macrophages, representing a neuroinflammatory biomarker, although it has since been established that TSPO expression is also increased in reactive astrocytes [[22]
].3. [11C]PK11195—the first-generation TSPO PET radioligand
PK11195 is an isoquinoline carboxamide derivative and non-benzodiazepine TSPO selective ligand, synthesized in the 1980s. Autoradiographic studies have localized binding of PK11195 to activated microglia in the CNS and as a result PK11195 was widely adopted to target TSPO in activated microglia and infiltrating macrophages in the CNS [
[15]
]. In human studies, in vivo [11C]PK11195 brain PET has demonstrated increased TSPO expression in a range of neuroinflammatory and neurodegenerative conditions, including Rasmussen’s encephalitis [[18]
], herpes encephalitis [[19]
], multiple sclerosis [[20]
], TBI [[21]
], stroke [[22]
] and Alzheimer’s disease [[23]
] (for detailed reviews see [7
, 13
]). In the healthy human brain, [11C]PK11195 uptake is low, with relatively high binding in subcortical structures, including midbrain, thalamus and basal ganglia, with overall brain uptake increasing with age [[24]
].Aside from their use as neuroimaging agents, evidence has emerged that administration of TSPO ligands including PK11195 may have therapeutic effects in a variety of CNS disorders, including seizures, brain injury and panic disorder (for review, see [
[7]
]). For example, pre-treatment of rats with PK11195 attenuates the occurrence of seizures in a kainic acid-induced model of seizures [[25]
], and another TSPO-selective ligand, XBD173, induces neurosteroid synthesis and is anxiolytic in humans without benzodiazepine-like side effects [[26]
].4. Challenges of [11C]PK11195 PET imaging
Despite being the TSPO PET radioligand of choice for two decades, [11C]PK11195 posed significant challenges for quantification (for reviews, see [
6
, 8
, 10
, 11
]). Firstly, PK11195 is highly lipophilic and shows a high level of non-specific binding (e.g. to brain fat) [[27]
]. By increasing the background non-specific signal, this reduces the signal to noise ratio (Box 2). Because of the low level of TSPO in the normal brain, the high non-specific binding of [11C]PK11195, as well as specific binding to TSPO in brain blood vessels, becomes predominant [[28]
].Secondly, [11C]PK11195 shows highly variable kinetic behaviour in plasma [
[20]
], precluding calculation of an arterial input function for kinetic modelling (Box 1). [11C]PK11195 also binds strongly to plasma alpha1-acid glycoprotein (AGP), and changes in AGP concentration, which have been shown in neuroinflammatory diseases such as multiple sclerosis, could significantly alter the free fraction [[29]
]. The latter is particularly important because PK11195 also adheres to glass and plastic, and therefore accurate measurement of plasma levels is very difficult to achieve.- Lockhart A.
- Davis B.
- Matthews J.C.
- Rahmoune H.
- Hong G.
- Gee A.
- et al.
The peripheral benzodiazepine receptor ligand PK11195 binds with high affinity to the acute phase reactant alpha1-acid glycoprotein: implications for the use of the ligand as a CNS inflammatory marker.
Nucl Med Biol. 2003; 30: 199-206
Thirdly, [11C]PK11195 is typically analyzed using reference tissue models but, because of the ubiquitous low-level expression of TSPO in the brain, a true reference region, devoid of specific binding, is lacking (Box 1) [
[10]
]. Furthermore, the choice of an anatomically-defined pseudo-reference region (i.e. which contains low levels of TSPO, similar between patient and control groups) may be challenging without prior pathological validation. In the case of disorders with widespread or heterogeneous patterns of microglial activation, an anatomically-defined reference may not be feasible. A variety of data-driven methods have been adopted to circumvent this problem (Box 1).5. Challenges of second-generation TSPO PET radioligands
The limitations of [11C]PK11195 motivated the development of second-generation TSPO radioligands with improved signal-to-noise ratio. More than 50 candidate TSPO ligands have been introduced preclinically, including [18F]FEPPA, [18F]PBR-111, [11C]PBR28, and [11C]DPA-713 (see for review [
15
, 8
, 13
]). Human studies using these second-generation ligands have demonstrated increased TSPO expression in a variety of CNS disorders, including Alzheimer’s disease [[37]
], amyotrophic lateral sclerosis [[34]
], and multiple sclerosis [[38]
].However, the application of second-generation TSPO radioligands has been complicated by the fact that their binding affinities to TSPO are influenced by a common polymorphism (rs6971) in the TSPO gene which causes a single amino acid substitution (A147T) in the protein [
[39]
]. Because 147T TSPO binds ligands with lower affinity than 147A, this produces three classes of binding affinity across a population: high-affinity (HABs) and low-affinity binders (LABs) express only the 147A or 147T variants respectively, whereas mixed-affinity binders (MABs) are heterozygotes and express both in equal proportion [[40]
]. Therefore, for a given level of TSPO expression, the specific PET signal will have the rank order HABs > MABs > LABs. The magnitude of the difference in PET signal between the 3 binding affinity classes is radioligand specific. For example, [11C]PBR28 has a ∼50 fold difference in binding affinity between the 147A and 147T variants. Therefore, LABs have negligible specific signal, and the specific signal in HABs is virtually twice that of MABs. However, for [18F]PBR111, the differences in binding affinity between 147A and 147T is only ∼4 fold, and hence the differences in [18F]PBR111 PET signal between HABs and LABs will also be smaller. In Caucasians, 49% of subjects are HABs, 42% MABs, and 9% are LABs, but this distribution varies across ethnic groups [[41]
]. Studies must control for this confound, so subjects are genotyped a priori. For ligands with a large 147A/T binding affinity ratio like [11C]PBR28, LAB subjects are typically excluded. If both HAB and MAB subjects are included, then subjects are matched for TSPO genotype, or genotype is modelled as a covariate. Recently, because [11C]PBR28 volume of distribution (VT) (Box 2) in HABs is about 40% higher than in MABs, to account for the effect of genotype, Gershen et al. multiplied the VT of the MAB group by 1.4 [[42]
].Nevertheless, even after accounting for TSPO genotype, many second-generation radioligands show high between-subject variability in uptake when using analysis methods which rely on measuring the radioligand in the blood [
[41]
]. As for [11C]PK11195, high and variable plasma protein binding may be a factor [[43]
]. To account for this, VT can be corrected by dividing by the measured free fraction of the ligand in plasma (fp) (Box 2) (i.e. VT/fp) (e.g. [[42]
]). However, accurate measurement of the free fraction (fp) is difficult, and errors in fp may increase the variability in corrected VT (VT/fp) [[44]
]. Another more complex issue is whether the free concentration of the radioligand in the arterial plasma, routinely used for the input function in PET studies, is appropriate for TSPO radioligands. Unlike most CNS PET targets, TSPO is very highly expressed in the blood. It may therefore be that the free concentration of TSPO ligand in the arterial plasma is not an accurate reflection of the true input function.6. Microglial PET imaging in epilepsy
Among the recent TSPO PET imaging studies in human subjects, Gershen and colleagues recently studied patients with temporal lobe epilepsy (TLE) using [11C]PBR28 [
[42]
]. Several TLE patients, including patients with mesial temporal sclerosis (MTS), had significantly increased hippocampal [11C]PBR28 uptake which was generally higher ipsilateral to the seizure focus than contralateral. However, binding of [11C]PBR28 was also increased significantly in extra-temporal regions, including the thalamus, highlighting that TSPO increases are more widespread and remote than the seizure focus or focal lesion itself. The relevance of extra-temporal increases in TSPO in terms of stratifying patients likely to respond to anti-inflammatory drugs is currently unexplored.In another recent study, Butler et al. used 11C]PK11195 to study microglial activation in relation to seizure occurrence [
[45]
]. In this study, a patient with frontal epilepsy and normal structural MRI was imaged approximately 36 h after a seizure as well as during a seizure-free period and compared to a group of 12 matched controls. Whilst both of the patient’s scans identified a frontal (supplementary motor area) region of increased inflammation corresponding to the clinically defined seizure focus, the post-seizure PET showed significantly greater inflammation. These data are important because they suggest that microglial activation may increase following a seizure, lending some support to the notion that seizures themselves generate inflammation that contributes to the occurrence of further seizures. However, they also highlight that in within-subject studies, for example performed to determine if there has been a decrease in inflammation in response to a therapeutic intervention, it will be very important to consider the timing of the last seizure when interpreting TSPO PET results.To date, no studies have addressed the question of the normal intra-subject variability in TSPO signal, which will be critical to determine to accurately calculate sample size for an interventional study aimed at showing on-target drug effects on neuroinflammation related to the seizure focus.
Finally, for TSPO PET imaging studies in epilepsy patients, there may be valid concerns about use of benzodiazepine drugs, which bind the TSPO, and so may affect TSPO PET radioligand binding. Although chronic benzodiazepine use is relatively uncommon in patients with epilepsy, in the psychiatry literature, concerns about this interaction have led to the withdrawal of benzodiazepine treatment from subjects prior to TSPO PET scanning in at least one study [
[46]
]. More often, patients taking benzodiazepines are excluded from enrolment in most TSPO imaging studies. A recent study addressed this issue empirically by measuring the in vitro affinity of different benzodiazepines for the [3H]PK11195 binding site on TSPO in human brain tissue. An appreciable effect was only found in the case of diazepam (at concentrations only reached with high doses of 30 mg and above), resulting in an estimated 9% decrease in TSPO availability [[46]
]. This may have implications for cross-sectional TSPO PET studies more than for serial imaging in the same patient; for a within-subject design, for example comparing pre- and post-treatment scans, concurrent doses of benzodiazepines are unlikely to affect the results providing the benzodiazepine dose is maintained between scans.7. Conclusions
In summary, TSPO imaging has been used across a wide range of CNS disorders to detect microglial activation. The concept that microglial activation has causal relevance to epileptogenesis and ictogenesis has been gaining traction recently, and recent small TSPO PET studies in patients with focal epilepsy has provided corroborating evidence by demonstrating increased signal in vivo. However, substantial conceptual and technical barriers remain to translating the observation of microglial activation in epilepsy patients to the development of anti-inflammatory therapeutics to treat epilepsy. Among these, it has yet to be determined whether microglial activation in epilepsy contributes to maladaptive neuroplasticity underlying the disease, or rather may in fact play a role in recovery from seizure related neural damage. Ultimately, this question will be addressed by clinical trials of anti-inflammatory therapeutics coupled with sensitive in vivo measures of neuroinflammation. Here we have highlighted some of the pitfalls as well as opportunities of the current in vivo measures of neuroinflammation.
Conflict of interest
None.
Acknowledgements
We acknowledge funding from Imperial College/Imperial College Healthcare, who received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres (BRC) funding scheme, and the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602102 (EPITARGET).
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Article info
Publication history
Published online: November 13, 2016
Accepted:
October 27,
2016
Received:
October 21,
2016
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© 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
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