Is 123I-metaiodobenzylguanidine heart-to-mediastinum ratio dependent on age? From Japanese Society of Nuclear Medicine normal database
Is 123I-metaiodobenzylguanidine heart-to-mediastinum ratio dependent on age? From Japanese Society of Nuclear Medicine normal database
Kenichi Nakajima 0
Koichi Okuda 0
Shinro Matsuo 0
Hiroshi Wakabayashi 0
Seigo Kinuya 0
0 Department of Physics, Kanazawa Medical University , Uchinada, Kahoku , Japan
1 Kenichi Nakajima
Background Heart-to-mediastinum ratios (HMRs) of 123I-metaiodobenzylguanidine (MIBG) have usually been applied to prognostic evaluations of heart failure and Lewy body disease. However, whether these ratios depend on patient age has not yet been clarified using normal databases. Methods We analyzed 62 patients (average age 57 ± 19 years, male 45%) derived from a normal database of the Japanese Society of Nuclear Medicine working group. The HMR was calculated from early (15 min) and delayed (3-4 h) anterior planar 123I-MIBG images. All HMRs were standardized to medium-energy general purpose (MEGP) collimator equivalent conditions using conversion coefficients for the collimator types. Washout rates (WR) were also calculated, and we analyzed whether early and late HMR, and WR are associated with age. Results Before standardization of HMR to MEGP collimator conditions, HMR and age did not significantly correlate. However, late HMR significantly correlated with age after standardization: late HMR = − 0.0071× age + 3.69 (r2 = 0.078, p = 0.028), indicating that a 14-year increase in age corresponded to a decrease in HMR of 0.1. Whereas the lower limit (2.5% quantile) of late HMR was 2.3 for all patients, it was 2.5 and 2.0 for those aged ≤ 63 and > 63 years, respectively. Early HMR tended to be lower in subjects with the higher age (p = 0.076), whereas WR was not affected by age. Conclusion While late HMR was slightly decreased in elderly patients, the lower limit of 2.2-2.3 can still be used to determine both early and late HMR.
Scintigraphy; Sympathetic imaging; Quantitation; Aging; Standardization
The prognoses of patients with heart failure (HF) and
Lewy body diseases including dementia with Lewy body
(DLB) and Parkinson disease have been predicted based
on the uptake of 123I-metaiodobenzylguanidine (MIBG).
Decreased heart-to-mediastinum ratio (HMR), such as 1.6,
1.68, and 1.74 are predictors of serious cardiac events and
cardiac death among patients with HF [
indicate that decreased HMR (< 1.74 and 2.2) is one variable
Department of Nuclear Medicine, Kanazawa University
Hospital, 13-1 Takara-machi, Kanazawa 920-8641, Japan
for differentiating Alzheimer disease (AD) from Lewy body
]. Although some threshold values have been
proposed for diagnostic purposes, the influence of age on
123I-MIBG parameters has not been clarified. While age is
a significant predictor of cardiac events [
3, 5, 10, 11
to higher comorbidities such as diabetes, hypertension, and
other coronary risk factors, the impact of age on HMR in
patients with a very low likelihood of cardiac disease has
not been established. Furthermore, the prognosis of patients
with HF has been estimated using washout rates (WR),
which also require standardization [
The present study aimed to determine the effect of age
on HMR and WR using the Japanese Society of Nuclear
Medicine (JSNM) working group normal database [
in which potential clinical causes of decreased 123I-MIBG
uptake are minimized.
JSNM working group database
The JSNM working group database for 123I-MIBG included
patients with a low likelihood of cardiac disease in whom
cardiac MIBG study was indicated as well as routine
cardiac examinations [
]. The exclusion criteria comprised
patients with electrocardiographic evidence of myocardial
ischemia, baseline cardiac diseases including coronary
artery disease, valvular heart disease and severe
arrhythmia, a history of HF, severe liver dysfunction, renal
dysfunction, hypertension, diabetes and dyslipidemia managed with
medications. Patients who had coronary stenosis of < 50%
and those who had no indications for coronary angiography
could be included if they had none of the exclusion criteria
listed above. Patients with neurological disorders were also
The databases (average age, 57 ± 19 years; median age, 63
years; range 20–84 years) contained 37 patients who were
assessed using low-energy (LE) collimators (50 ± 19 years,
16 males) and 25 who were assessed using
low-mediumenergy (LME) or medium-energy (ME) collimator (68 ± 13
years, 12 males) [
]. The HMR determined using LE
collimator and a calibration phantom was corrected based on
multicenter phantom experiments [
Early and late anterior planar images were acquired in
256 × 256 matrices at 15 and at 180–240 min after an
intravenous injection of 111 MBq of 123I-MIBG. The
acquisition time was 180–300 s. The energy for 123I was centered
at 159 keV with a window of 20%. Early and late planar
anterior images were assessed in this study. Early and late
HMR (HMRE and HMRL) were calculated from circular and
rectangular regions of interest (ROI) set on images of the
heart and mediastinum, respectively, using a semi-automated
ROI setting software .
Conversion of institutional HMR to standardized HMR
According to published phantom-based findings, average
conversion coefficients (CC) of various collimators were
used to calculate standardized HMR. That is
HMRstd = 0.88∕Ki × HMRi − 1 + 1,
where 0.88 is a CC of ME general purpose collimator, Ki is
the CC of the institutional camera-collimator, and HMRi is
the institutional HMR.
Washout rates were calculated from early and late heart
counts (HE and HL) and mediastinal counts (ME and ML)
using the following formulae for WRBDC, WRDC and WRHMR:
WRBDC, with background (mediastinal counts) and
HE − ME − HL − ML ∕DCF ∕ HE − ME × 100(%),
where DCF is a decay correction factor calculated as
0.5^(time [h] between early and late images/13).
WRDC, decay correction for late image:
HE − HL∕DCF ∕HE × 100(%).
WRHMR, WR was calculated from early and late HMR
values after standardization of collimators:
(HMRE − HMRL)∕HMRE × 100(%).
Data are expressed as means and standard deviation (SD).
Goodness-of-fit to the Normal distribution was examined
for distribution of HMR using the hypothesis that the data
are from Normal distribution (small p values reject the
hypothesis by Shapiro–Wilk test). Relationships between
123I-MIBG parameters and age were calculated using
linear regression analysis. Regression lines and confidence
intervals [CI] are shown when values were significant at
p < 0.10. Differences in variables between groups were
determined using T tests and analyses of variance. Since
the median age was 63 years, the patients were divided into
groups according to age ≥ 63 (n = 31) and < 63 (n = 31)
years, respectively. P < 0.05 was considered significant.
Before standardization, distributions of HMRE and HMRL
were not Normal distribution (p = 0.014 and 0.0003,
respectively), whereas after the standardization both
distributions of HMRE and HMRL became Normal distributions
(p = 0.99 and 0.84, respectively) by goodness-of-fit test.
Table 1 summarizes the normal values determined from
the JSNM working group databases. The normal values
were 3.10 ± 0.43 and 3.29 ± 0.48 for HMRE and HMRL,
respectively. The lower limits (2.5% quantile) of HMRE
and HMRL were 2.18 and 2.26, respectively. The mean
clearance from the heart or washout calculated using early
and late HMR was − 6.5%, indicating that mean HMRL
was higher than mean HMRE. In fact, HMRL was higher
than HMRE in 50 (81%) of 62 of the patients.
The HMRE and HMRL did not significantly correlate
with age before standardization of collimators. However,
WR, % (background and
WR, % (decay
a weakly positive correlation emerged after
phantombased correction to the standardized MEGP condition was
applied (Fig. 1) for HMRL (p = 0.028), whereas the p value
was marginal for HMRE (p = 0.076).
When patients were divided into groups based on a
median age (63 years), mean ages of the two groups were
41 ± 14 years and 73 ± 6 years. Goodness-of-fit test showed
that HLRE and HMRL were Normal distribution for the two
groups (for age < 63 year, p = 0.63 and 0.18, respectively; for
age ≥ 63 year, p = 0.60 and 1.00, respectively). Both HMRE
and HMRL were lower in patients aged ≥ 63 years than in
those who were < 63 years (p = 0.0097 and 0.016 for HMRE
and HMRL, respectively; Fig. 2). If the lower limit is defined
as the 2.5% quantile of 2.3 HMRL for all patients, then 2.5
and 2.0 would be the lower limits in patients with median
Fig. 1 Relationships between
age and early and late HMR.
a, b Early and late HMR
before correction of
collimator types. c, d Early and late
HMR after standardization to
medium-energy general purpose
collimator conditions. Red
and blue symbols, female and
male individuals, respectively.
Unfilled and filled symbols,
younger (age < 63 years) and
older (age ≥ 63 years)
ages of < 63 and ≥ 63 years, respectively. The lower limit of
HMRE was 2.2 for all patients, and 2.4 and 2.1 in patients
with age < 63 and ≥ 63 years, respectively. Washout rates
calculated using the three formulae did not significantly
correlate with age (Fig. 3).
A weak age-dependent decline in HMR was revealed in the
JSNM working group 123I-MIBG normal databases. Since
HMR has been used as a basis for the prognostic
evaluation of patients with HF [
1, 3, 5, 11
] and differential
diagnoses of Lewy body diseases [
], this tendency should
be considered to appropriately understand clinical results
Fig. 2 Early and late HMR in younger and older individuals.
Early (a) and late (b) HMR in younger (age < 63 years) and older
(≥ 63 years) individuals. Red and blue symbols, female and male
individuals, respectively. Unfilled and filled symbols, younger
(age < 63 years) and older (age ≥ 63 years) individuals, respectively.
Box plot indicates median, 25 and 75% quartiles with whiskers at
both ends. Green lines, mean values. Dotted line, HMR = 2.2 (lower
limit of normal) as used in Japan using the JSNM working group
Fig. 3 Relationship between
age and washout rate (WR). a
WRBDC, WR with background
(BG) and decay correction.
b WRDC, WR with decay
correction. c WRHMR, WR
calculated using early (HMRE)
and late HMR (HMRL),
of 123I-MIBG uptake. The effect of age notably appeared
only after standardization for collimator differences, which
showed the importance of correction for collimator types
when different studies include various camera-collimator
18, 19, 21
Although age was considered as an important factor for
the prognosis of HF, the incidence of comorbidities such
as diabetes, hypertension ischemic heart disease, and renal
dysfunction might also increase with age. Therefore, the
tendency of only age versus HMR should be examined in
near-normal individuals. The JSNM working group
database includes multicenter data, and patients with
underlying cardiac disease and those with medications for
diabetes, hypertension and neurological diseases were carefully
]. Therefore, although the patients were not
truly as normal as volunteers, the possibility of primary and
secondary cardiac diseases was excluded as far as possible
in clinical practice.
Few studies have examined HMR in near-normal
individuals. As part of the ADMIRE-HF trial, a cohort
comprising 94 control individuals with a 10% likelihood of having
coronary artery disease according to normal stress
myocardial perfusion imaging, stress echocardiography or coronary
angiography findings has been investigated [
analyses did not identify a significant relationship between
age and planar HMR values, and suggested only a slightly
lower HMR for persons aged > 70 years. Another study of
180 patients with HF also found significantly lower early
and late HMR compared with younger patients (p < 0.05),
although values were adjusted for all remaining significant
]. The uptake of 123I-MIBG with respect to
HMR in a baseline study of 39 patients with cancer before
undergoing chemotherapy, found a decrease in 123I-MIBG
uptake with aging [
]. However, the mean HMR was
1.85 ± 0.29 (range 1.31–2.62) in that study, and much lower
than that in the JSNM working group database (HMRL range
2.12–4.52). Although HMRL was significantly lower among
older individuals in the JSNM working group database, the
average degree of HMRL decline was ~ 0.2 over 30 years
(0.07 for 10 years). Therefore, caution might be required to
interpret the findings of studies that include patients with a
large age range.
Medications taken by elderly patients might have affected
HMR. Although a threshold HMR of 1.6 was set in the
ADMIRE-HF study, the effects of several medications
determined using heart failure medication scores were not
significant, whereas the event group had low HMR [
Whether the effect of age and medications affect threshold
values for the prognostic application of 123I-MIBG should
be further examined.
The lower limit of HMR 2.1–2.2 has been used to
differentiate DLB from AD in a Japanese multicenter study [
lower limit of 2.2 remained valid for general use according
to an assessment of HMR distribution in the JSNM
working group database. However, in patients aged ≥ 63 years,
the HMRL was lower by 0.2–0.3 compared with patients
aged < 63 years. Only one 64-year-old female patient had
HMR of < 2.2 in this database, and HMRE and HMRL were
2.1 and 2.0, respectively (decay and background-corrected
WR = 17%). Whether this difference is critical to
differentially diagnose DLB from AD has not been investigated.
Washout rates did not correlate with age. However, a
standard method of calculation is desirable to correctly
understand the significance of WR. The third calculation
formula using early and late HMR has not been applied in
Japan, but it is included in European studies [
] and some
studies have used this formula when original heart and
mediastinal counts were not available. In this calculation, most
of the patients (81%) had higher HMRL than HMRE, which
does not necessarily indicate that the actual WR calculated
by the heart count shows negative values. This means that
when HMRL is lower than HMRE, increased WR or
abnormal sympathetic innervation should be suspected.
Immunohistochemical and histochemical analyses have
also uncovered age-dependent changes in the human
conduction system [
]. Initial sympathetic dominance found in
the infant neural supply to the cardiac conduction system in
humans is gradually replaced by sympathetic and
parasympathetic co-dominance in adulthood, and a reduced density
of conduction tissue innervation with aging might also be
reflected in 123I-MIBG images [
One limitation of the present study is that the number of
participants was essentially too small to evaluate
physiological changes. Early HMR was not significantly affected by
age (p = 0.076) while late HMR was significant (p= 0.028),
which might be due to statistical power from the limited
number of patients. Although truly normal volunteers were
not available, the JSNM working group databases seem to
have practical values to visualize age-dependent changes in
aged patients using normal ranges. Another limitation was
reproducibility of calculating HMR. However, we
minimized inter-operator variations using semi-automatic ROI
setting software [
]. In this ROI setting algorithm, an
operator pointed into the center of the heart, and the
following processing was automatically performed. Tomographic
studies might be used to integrate whole heart activity, but
the present investigation was limited to planar studies.
An age-dependent decline in HMR, particularly late HMR,
was found using JSNM working group normal 123I-MIBG
databases after collimator standardization. Although the
decline in HMR is relatively small, at about 0.2 over 30
years, MIBG results should be interpreted carefully when the
study group includes only aged subjects such as in patients
with dementia. However, in clinical practice the lower limit
of 2.2 and 2.3 for early and late HMR, respectively, can
still be used to determine both early and late HMR, and
in patients with borderline HMR it would be important to
repeat 123I-MIBG studies both in cardiology and neurology
during their follow-up periods.
Acknowledgements Normal databases were created as part of the
activity of a Japanese Society of Nuclear Medicine (JSNM) working
group (October 2005–November 2007, October 2013–November 2015,
PI: K. Nakajima). The authors appreciate Arnold Jacobson for his
comments on this manuscript. The authors also thank Reo Usami for help
with data analysis and Norma Foster for editorial assistance during
Funding This study was partly funded as a JSNM working group by
JSPS Grants-in-Aid for Scientific Research (C) in Japan (PI: K.
Nakajima, no. 15 K09947) and FUJIFILM RI Pharma Co. Ltd. (Tokyo,
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