Technical considerations for quantification of 18F-FDG uptake in carotid atherosclerosis
Technical considerations for quantification of 18 F-FDG uptake in carotid atherosclerosis
Sina Tavakoli 0
0 Reprint requests: Sina Tavakoli , MD, PhD , Departments of Radiology and Medicine (Vascular Medicine Institute), University of Pittsburgh, UPMC Presbyterian Hospital , 200 Lothrop Street, Suite E200, Pittsburgh, PA 15213 , USA
1 Departments of Radiology and Medicine (Vascular Medicine Institute), University of Pittsburgh , Pittsburgh, PA , USA
In this issue of the Journal of Nuclear Cardiology,
Johnsrud et al.1 have explored the correlation between
different quantification methods of
18F-fluorodeoxyglucose (18F-FDG) uptake and plaque inflammation in
endarterectomy specimens of patients with severe
carotid stenosis. It has been over a decade since the initial
reports of 18F-FDG accumulation in unstable carotid
plaques and its correlation with indices of plaque
vulnerability.2 This has elicited great enthusiasm to
investigate the role of 18F-FDG PET in risk stratification
of patients with carotid artery disease. However, the
clinical utilization of 18F-FDG PET in the management
of atherosclerosis has been hampered by multiple
factors, including striking technical variabilities in image
acquisition and quantification protocols between various
studies as well as metabolic and biological complexity
of 18F-FDG uptake in the vessel wall.
Despite the recent declines in the incidence and
ageadjusted mortality rate,3 stroke has remained a major
global health issue. In the United States, approximately
800,000 people suffer from a new (* 75%) or recurrent
(* 25%) stroke every year; and about 130,000 people
die from it, which puts stroke as the 5th leading cause of
Carotid atherosclerosis is a common and a
potentially preventable cause of ischemic stroke, accounting
for * 15% of cases.3,4 Currently, atherosclerosis is
suspected as a possible etiology of stroke if the patient
has significant disease ([ 50% luminal stenosis) in a
clinically relevant artery, in accordance with the Trial of
Org10172 in Acute Stroke Treatment (TOAST)
classification system.5 However, strokes caused by
thromboembolic complications of unstable non-stenotic
or mildly stenotic (\ 50%) plaques are not accounted for
in this classification;5 and such cases may instead be
classified as cryptogenic.6 This may result in an
underestimation of the true contribution of carotid
atherosclerosis as the etiology of ischemic stroke. It is
now well established that a large number of acute
coronary syndromes originate from acute complications
(e.g., rupture or ulceration) of vulnerable, but mildly
stenotic, plaques, which triggers the activation of
thrombotic cascade and luminal occlusion. 7 It is
plausible to assume similar pathophysiology may contribute
to plaque vulnerability in patients with mild carotid
stenosis, which by current management guidelines will
not be candidates for invasive interventions.8
Traditionally, the decision to proceed with carotid
intervention to prevent new or recurrent stroke has been
primarily based on the patients’ symptoms and the
extent of luminal stenosis, as detected by catheter
angiography or non-invasive imaging. Large
randomized clinical trials dating back to 1980s have shown that
carotid interventions (endarterectomy and more recently
stenting) reduce the risk of stroke compared to medical
therapy in symptomatic or asymptomatic patients with
severe stenosis ([ 70%) and in symptomatic patients
with moderate stenosis (50%-70%).8–10 However, this
approach has several shortcomings, for example:
1. Asymptomatic moderate and severe carotid artery
atherosclerosis is highly prevalent, particularly in
elderly men.11 The prevalence of moderate and
severe stenosis in men [ 80 years reaches to
*7.5% and *3.1%, respectively. Comparatively,
in women older than 80 years, the prevalence of
moderate and severe stenosis is *5% and *0.9%.11
Fortunately, about 80% of patients with high-grade
stenosis remain stroke-free during long follow-up
periods (*10-15 years). Therefore, recommending
invasive interventions, which carry a considerable
risk of complications (e.g., peri-procedural stroke,
myocardial infarction, and cranial nerve injury) based
on the extent of stenosis may not be ideal.
2. There is a 1.6% annual risk of stroke in patients with
asymptomatic mild-to-moderate stenosis. While,
some of these cases are likely caused by vulnerable
plaques, these patients are not usually considered as
candidates for carotid interventions.12
3. Advances in risk factor modifications and medical
therapy, e.g., intensive statin therapy, since the
original trials have significantly reduced the risk of
stroke in patients who are treated non-invasively.
Thus, more information is required to establish
whether the severity of stenosis can still be used as
a reliable criterion to identify patients who benefit
from endarterectomy versus medical therapy.10
Development and validation of non-invasive
imaging techniques that can identify high-risk carotid
atherosclerotic lesions have been a subject of extensive
research over the past decade. Characteristics of
vulnerable plaques that may be imaged non-invasively
include intra-plaque hemorrhage,13,14 thin fibrous
cap,15,16 large necrotic core,14,16 and high inflammatory
burden.17 Such detailed characterization of carotid
plaques through non-invasive approaches may ultimately
improve the risk stratification of patients and allow for
more accurate selection of patients who benefit from
HIGH-RESOLUTION CAROTID MRI
MRI and MRA of carotid arteries have been
commonly utilized clinically to determine the severity
of luminal compromise. Recent improvements in the
spatial resolution and development of new sequences
have allowed for detailed structural characterization of
carotid plaques, and identification of features that are
associated with plaque vulnerability.18 While MRI has a
low sensitivity for detection of molecular processes that
contribute to plaque vulnerability, it has a great potential
for structural characterization of carotid plaques with a
number of avenues yet to be explored. For example,
dense fibrous tissue, loose fibrous matrix, and lipid/
necrotic core can be accurately and reproducibly
differentiated using T1, T2, proton density, and time-of-flight
images.19 High-resolution MRI is also capable to
differentiate between the intact and ruptured fibrous cap
with * 90% agreement with histological analysis of
endarterectomy specimens.15 The T1-shorterning effect
caused by intra-plaque hemorrhage may be detected by
various sequences, e.g., magnetization-prepared rapid
gradient echo (MP-RAGE), time-of-flight, and fast spin
echo.20,21 Additionally, dynamic contrast-enhanced MRI
provides information on carotid plaque
Complementing the structural information obtained
by MRI, PET can track ongoing metabolic, molecular
and cellular processes that contribute to the pathogenesis
of plaque vulnerability. So far, a large number of PET
tracers have been tested in pre-clinical investigations,
which target various aspects of atherosclerosis, such as
vessel wall inflammation, plaque hypoxia, protease
activity, and extra-cellular matrix remodeling.7
However, the most commonly used PET tracer in the clinical
setting is 18F-FDG, reflecting its widespread availability
as a Food and Drug Administration (FDA)-approved
radiopharmaceutical with excellent safety profile.
Multiple studies have shown the association of 18F-FDG
uptake and the inflammatory burden of carotid plaques
and its capacity to retrospectively identify culprit lesions
after strokes or transient ischemic attacks.23 18F-FDG
PET has also been promising in prospective risk
stratification of patients with carotid artery disease and
in prediction of the future risk of cardiovascular
events.23. However, the routine application of 18F-FDG
PET in the clinical practice and risk stratification of
patients with carotid atherosclerosis has been challenged
by several limitations, which will be briefly discussed
LIMITED BIOLOGICAL SPECIFICITY
18F-FDG accumulation in sites of inflammation,
including atherosclerosis, has been commonly attributed
to the high glycolytic activity of inflammatory cells,
particularly activated macrophages.7,23 However,
glucose uptake represents a nearly ubiquitous metabolic
process; hence, the uptake by other vascular and
perivascular cells limits the specificity of 18F-FDG PET for
imaging of plaque inflammation.7,23–26 This is
particularly problematic in imaging of coronary arteries, in
which the high background uptake of 18F-FDG by the
myocardium obscures the visualization of coronary
plaques and complicates the quantification of uptake.27
Among different constituents of plaques,
macrophages, particularly upon activation into
proinflammatory states, have been considered as the main
contributors to 18F-FDG uptake.28 However, recent data
suggest that 18F-FDG uptake may not adequately
characterize the metabolic divergence of macrophages upon
activation into different pro-inflammatory (M1) or
antiinflammatory (M2) polarization states.24–26,29
Striking technical variability is another limitation of
18F-FDG PET of atherosclerosis.30,31 This is of
particular concern as the small size of plaques and their close
proximity to blood pool make them prone to
partialvolume effects, which influence the accuracy of
18FFDG uptake quantification.31 Therefore, any
meta-analysis or comparison between the results of different
studies need to be performed with extreme caution to
account for these technical variabilities.32
PATIENT PREPARATION, IMAGE ACQUISITION,
The fasting period (usually from 4 to 12 hours) and
the pre-scan blood glucose level affect 18F-FDG
uptake.32 High levels of glucose reduce 18F-FDG uptake
in cultured cells and vessel wall, presumably through
competition for glucose transporters, while it increases
the blood pool activity.30,32,33 It is recommended that a
blood glucose level \ 130 mg/dl is optimal for 18F-FDG
PET of vessel wall.30 But, glucose levels of up to 200
mg/dl have been used in multiple investigations.32
The injected dose of 18F-FDG is another potential
confounding factor, which varies between studies from
185 to 925 MBq.30 Low doses of 18F-FDG have been
shown not to influence the standardized uptake value
(SUV) and target-to-background ratio (TBR).33
Therefore, doses of 3-4 MBq/kg have been advocated for
imaging of atherosclerosis to reduce the patients’
radiation exposure, particularly if repetitive scans are being
The wait time post-injection varies from 30 to 210
minutes in different studies. Delayed scans (* 2 hours)
seem to improve the target-to-background contrast and
reduce the influence of partial-volume effect from blood
pool, allowing for better visualization and quantification
of 18F-FDG uptake in atherosclerotic plaques.30–32
Vascular PET is highly susceptible to
partial-volume effect due to the small size of the vessel wall, which
is usually below or at the resolution of PET. Thus,
quantitative 18F-FDG imaging is strongly influenced by
the plaque volume and morphology as well as multiple
scan-related factors, e.g., voxel size, slice thickness,
reconstruction algorithms and attenuation protocols,
reviewed elsewhere.30,31 Plaque uptake seems to be
generally underestimated by multiple folds due to the
Standardized uptake values (SUVs) and
target-tobackground ratios (TBR) are the two most commonly
reported parameters for quantification of 18F-FDG
uptake in atherosclerosis. SUV is a semi-quantitative
measure of uptake and attempts to account for variations
in the injected dose of radiotracers and the patient’s size
through correction for body weight, lean body weight, or
body surface area. Mean SUV (SUVmean), maximum
SUV (SUVmax), or the average SUVmax over multiple
slices (either throughout or over the most diseased
segments of plaques) (mean of SUVmax) have often been
reported in different studies.31,32.
Normalization of vessel wall SUV to that of a
reference tissue (most commonly SUVmean of blood
pool) has been widely used to remove the influence of
compounding factors, such as the clearance rate and
blood glucose level, on the estimated 18F-FDG uptake.
The normalization may be performed through either
subtraction of the blood pool SUV from vessel wall
SUV (i.e., corrected SUV), or more commonly by
calculating the ratio of plaque-to-blood pool SUV (i.e.,
TBR). Both corrected SUV and TBR remove the effect
of blood pool spill-in the vessel wall; thus, may more
accurately represent the 18F-FDG uptake and plaque
inflammation,32,34 though they will be influenced by
factors which alter the blood pool activity, e.g., renal
failure and increased 18F-FDG uptake by circulating
cells.30 Importantly, TBR is more reproducible under
different scan settings32 and has been shown to have a
higher association with plaque inflammation and
macrophage burden compared to SUV.32 However, the
potential of the various quantification techniques in
prediction of long-term risk of carotid atherosclerosis
progression and stroke is not yet available.
Johnsrud et al.1 recruited 44 patients with carotid
artery atherosclerosis associated with[70% stenosis for
18F-FDG PET/CT. Of these patients, 30 underwent
endarterectomy and histological assessment of
inflammation to evaluate the correlation between different
18FFDG uptake quantification methods and histological
indices of inflammation. 18F-FDG uptake has been
quantified using various parameters, including mean SUVmax,
maximal SUVmax throughout the plaques or through the
most diseased segment, blood background-corrected
SUV (cSUV), and TBR. The authors have found strong
correlations between the various 18F-FDG uptake
quantification parameters (correlation coefficients of
0.570.99, P \ 0.001). Inter-observer variability analysis,
performed through assessment of the correlation between
two independent nuclear medicine physicians, showed a
higher agreement for uncorrected SUVmax (correlation
coefficients of 0.96-0.98) compared to both cSUV and
TBR (correlation coefficients of 0.63-0.68 for TBR and
0.90-0.93 for cSUV).
The study reports moderate correlations between
the different 18F-FDG uptake parameters and the extent
of inflammation in endarterectomy specimens
(correlation coefficients of 0.44-0.59, P \ 0.02). Correlations
between 18F-FDG uptake and histology were overall
very similar using the different parameters, although
they were slightly stronger when mean SUVmax was
used compared to the other parameters.
A strength of this study is the concurrent
comparison between the different quantification methods and
histology in patients who have undergone
endarterectomy in a relatively short interval from 18F-FDG PET. A
more detailed histological approach, including
immunological profiling of inflammatory cells, and determining
the correlation between different quantitative measures
of 18F-FDG uptake and other indices of plaque
vulnerability (e.g., thin fibrous cap, large necrotic core,
intraplaque hemorrhage) would have brought a more
indepth insight into this topic.
Together, this study demonstrates a higher
interobserver agreement for SUVmax and a slightly higher
association between SUVmax and plaque inflammation.
However, it should be noted that SUV is highly prone to
variations in tracer dose as well as patients’ (e.g., body
weight) and scans parameters, which adversely influence
the reproducibility of quantification compared to TBR.30
Therefore, the use of TBR has been recommended for
quantification of 18F-FDG uptake in atherosclerosis by
the Cardiovascular Committee of the European
Association of Nuclear Medicine.30
18F-FDG uptake has been shown to be associated with
carotid plaque inflammatory burden and risk of
cardiovascular events in a number of investigations.23 However, the
application of 18F-FDG in clinical practice has been
hampered by several limitations, including the limited
biological specificity of 18F-FDG towards inflammatory
cell,24–26 myocardial and skeletal muscle uptake
interfering with visualization and quantification of vascular
uptake, and lack of standardized protocols leading to large
variabilities in patients’ preparation, image acquisition/
reconstruction and quantification. Over the recent years,
there has been a growing interest in optimization of image
acquisition and quantification methods and standardization
of vascular 18F-FDG PET.30–32 This approach may
ultimately lead to development of more reliable and
reproducible protocols, which allow for widespread
clinical utility and validation in large cohorts of patients to
determine the value of 18F-FDG PET in predicting the risk
of stroke and disease outcome. Additionally, other novel
PET tracers have been developed, which may overcome
the limited biological specificity of 18F-FDG. While most
such approaches are still in the pre-clinical stage, a few
have already provided promising results in early clinical
studies, e.g., 18F-NaF, 68Ga- and 64Cu-DOTATATE,
11Ccholine, and 11C-acetate;30 and their clinical utility is
beginning to be explored.
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