Journal of Trace Elements in Medicine and Biology 62 (2020) 126579

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Journal of Trace Elements in Medicine and Biology

journal homepage: www.elsevier.com/locate/jtemb

Clinical studies

Iodine levels in different regions of the human brain T

a,b, b b c,d b
Edgar Pinto *, Patrícia Ramos , Cristiana Vital , Agostinho Santos , Agostinho Almeida
a
Department of Environmental Health, School of Health, P.Porto, Rua Dr. António Bernardino de Almeida 400, 4200-072, Porto, Portugal
b
LAQV/REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313, Porto, Portugal
c
National Institute of Legal Medicine and Forensic Sciences – North Branch, Jardim Carrilho Videira, 4050-167, Porto, Portugal
d
Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200 - 319, Porto, Portugal

A R T I C LE I N FO A B S T R A C T

Keywords: Background: Iodine is a key component of the thyroid hormones thyroxine (T4) and triiodothyronine (T3), which
Iodine are crucial for proper growth and development of the human body. In particular, a great body of literature has
Human brain been published on the link between thyroid hormones and brain development and functioning. However, there is
Brain regions a lack of knowledge on the iodine levels in the human brain. The aim of this work was to determine the brain
Age-related differences
iodine levels and to contribute to the establishment of “reference” levels for iodine in the different anatomical
ICP-MS
and functional regions of normal (i.e., subjects without neurological or psychiatric diseases) human brain.
Methods: The iodine levels were determined in 14 brain regions of 52 dead subjects without evidence of neu-
rological or psychiatric disease (n = 728 samples). Iodine was extracted from brain samples using a standard
procedure and determined by inductively coupled plasma – mass spectrometry (ICP-MS).
Results: Four subjects presented abnormally high brain iodine levels (26.0 ± 14.2 μg/g) and were excluded
from the overall data analysis. The average brain iodine levels for the remaining 48 subjects was
0.14 ± 0.13 μg/g dry weight. Iodine showed very heterogeneous distribution across the different brain regions,
with the frontal cortex, caudate nucleus and putamen showing the highest levels. Interestingly, these brain
regions are closely related to cognitive function. Iodine levels also showed a tendency to increase with age. The
high levels observed in four subjects seemed to be related to previous exposure to iodine-based contrast agents
widely used in radiology and computed tomography exams.
Conclusions: This paper provides important data on iodine levels at different brain regions in “normal” people,
which can be used to interpret eventual imbalances in subjects with mental disorders and neurodegenerative
diseases.

1. Introduction or thyroid cancer [3].

Iodine is an essential trace element for humans. It is a key compo-
nent of the thyroid hormones thyroxine (T4) and triiodothyronine (T3),
which play a major role in growth, differentiation and metabolism in
the human body [1].
Although required in small amounts, iodine deficiency is wide-
spread around the globe. It is considered one of the most common
micronutrient deficiencies, although easy to prevent [2]. If not solved,
iodine deficiency can give rise to several disorders including hy-
pothyroidism, hyperthyroidism, goiter, and mental impairment. High
iodine levels in the body can also affect the proper functioning of the
thyroid, leading to various disorders such as those described above
(goiter and hypothyroidism) and also to iodine-induced thyrotoxicosis
Iodine status is commonly monitored by determining urinary iodine
concentration (UIC), which is considered an adequate biomarker of
dietary iodine intake. Values of UIC < 100 μg/L are indicative of io-
dine deficiency, between 100 and 299 μg/L indicates adequate iodine
status and over 300 μg/L indicates excessive iodine intake [4].
In particular, thyroid hormones (and therefore iodine) are essential
for proper central nervous system (CNS) development in fetuses and
infants and there is strong evidence about the link between thyroid
hormones and brain functioning [5]. However, to date, there is a lack of
knowledge in this particular area mainly due to the many potential and
complicated interactions that thyroid hormones have on the brain. In
particular, they may affect the brain through multiple means, and at
different levels of CNS, including the macrostructure (e.g. volume of the

⁎
Corresponding author at: Department of Environmental Health, School of Health, P.Porto, Rua Dr. António Bernardino de Almeida 400, 4200-072, Porto,
Portugal.
E-mail address: ecp@ess.ipp.pt (E. Pinto).

https://doi.org/10.1016/j.jtemb.2020.126579
Received 26 January 2020; Received in revised form 18 May 2020; Accepted 5 June 2020
0946-672X/ © 2020 Elsevier GmbH. All rights reserved.
E. Pinto, et al.
right hippocampus) [6], microstructure (e.g. myelin production), and
neurotransmitters production [7].
It is important to consider that human brain is a highly hetero-
geneous organ, with anatomically and physiologically very different
areas [8], which may be affected in different manners and different
extension by, for example, iodine deficiency. So, as a first step, to un-
derstand the role of iodine in normal brain function and the eventual
association of changes in brain iodine levels with brain diseases, par-
ticularly mental and neurodegenerative disorders, a detailed study of
the anatomical distribution of iodine in “normal” (i.e., without evi-
dence of neurological disease) human brain seems indispensable. To
date, few data exist on iodine levels in human brain and data on its
topographical distribution in the human brain are even scarcer.
Based on this background, the main goal of the present study was to
contribute to the establishment of “reference” (“normal”) levels for
iodine in the different anatomical and functional regions of normal
human brain.
2. Materials and methods
2.1. Subjects
Brain samples were collected at the North Branch (Porto) of the
Portuguese National Institute of Legal Medicine and Forensic Science
(INMLCF) during autopsy exams. The subjects were not registered in
the Portuguese National Registry of Refusal to Organ Donation database
and all current regulations regarding human tissue collection for sci-
entific research purposes were observed in the sampling process.
Samples from men (n = 29; 65 ± 16 years old) and women (n = 23;
71 ± 17 years old) were obtained. Inclusion criteria were: (1) absence
of known neurodegenerative, neurological or psychiatric disorder his-
tory; (2) absence of injuries involving CNS; (3) macroscopically normal
brain tissue.
2.2. Samples collection
Samples were collected by INMLCF pathologists following a stan-
dard protocol. In order to prevent sample contamination, all materials
that came in contact with the samples were thoroughly rinsed with
ultrapure water. After removing the brain from the skull, the excess
blood was carefully washed with ultrapure water. The meninges were
removed with tweezers and the brain tissue was washed again with
ultrapure water to minimize samples contamination with blood or
cerebrospinal fluid. Fourteen brain areas were collected individually
according to Paine and Lowe [8] study on an approach to the post-
mortem investigation of neurodegenerative diseases. Using deconta-
minated plastic knives, tissue fragments (approximately 1 cm3) were
collected from the following brain areas: 1) frontal cortex, 2A) superior
and 2B) middle temporal gyri, 3A) caudate nucleus, 3B) putamen, 3C)
globus pallidus, 4) cingulated gyrus, 5) hippocampus, 6) inferior par-
ietal lobule, 7) visual cortex of the occipital lobe, 8) mid-brain (in-
cluding the substantia nigra at the level of the third nerve), 9) pons-
locus coeruleus, 10) medulla and 11) cerebellum-dentate nucleus.
Samples were stored in decontaminated polypropylene tubes at −20 °C
until further analysis.
2.3. Reagents
Tetramethylammonium hydroxide (TMAH, 25 wt. % in H2O) and
tellurium (TraceCERT®, 1000 mg/L) were purchased from Sigma-
Aldrich (St. Louis, MA). Iodide (TraceCERT®, 1000 mg/L iodide in
water) was obtained from Supelco (Bellefonte, PA)). All solutions were
prepared using ultrapure water (> 18.2 MΩ.cm at 25 °C) obtained with
a Sartorius (Gottingen, Germany) Arium® pro water purification
system.
2
Journal of Trace Elements in Medicine and Biology 62 (2020) 126579
2.4. Sample pre-treatment
After thawing, brain samples were thoroughly washed with ultra-
pure water and dried at 110 °C until constant weight (∼24 h). Dried
samples (ca. 100–500 mg) were weighed directly in borosilicate glass
tubes (16 × 125 mm) previously washed with 0.5 % (v/v) TMAH and
rinsed with ultrapure water. Iodine extraction was performed according
to the European Standard EN 15111:2007 [9]. Briefly, it consists of
using a strong alkaline reagent (TMAH) at high temperature
(90 ± 3 °C) for iodine extraction. After extraction for 3 h, sample so-
lutions were diluted to 25 mL with ultrapure water (> 18.2 MΩ.cm at
25 °C) and filtered through a 0.22 μm PTFE syringe filter prior to ICP-
MS analysis. Blank solutions were prepared in the same way. All solu-
tions were analyzed in triplicate and the results were expressed in μg/g
dry weight (dw).
2.5. Iodine determination
An iCAP™ Q inductively coupled plasma mass spectrometry (ICP-
MS) instrument (Thermo Fisher Scientific, Bremen, Germany) was used
for iodine determination. The ICP-MS instrument was equipped with a
Meinhard™ TQ + quartz nebulizer (Golden, CO), a Peltier-cooled baf-
fled cyclonic spray chamber, a standard quartz torch and standard two-
cone interface design (nickel sample and skimmer cones). High-purity
argon (99.9997 %; Gasin, Portugal) was used as the nebulizer and
plasma gas. The ICP-MS instrument operational parameters were as
follow: RF power 1550 W; plasma gas flow (14 L/min); auxiliary gas
flow (0.8 L/min); nebulizer flow rate (1.02 L/min). The elemental iso-
tope 127I was monitored for the analytical determination of iodine and
the elemental isotope 125Te was used as internal standard (IS).
An eight-point calibration curve (0.5, 1, 2, 5, 10, 20, 50 and 100 μg/
L) was generated with iodine standards prepared in 0.5 % (v/v) TMAH.
A diluent consisting of 0.5 % (v/v) TMAH + 10 μg/L IS was used in the
dilution of the sample solutions.
The method limit of detection (LoD) was calculated as the con-
centration corresponding to 3.3 times the standard deviation of the
measurement of ten blank solutions (prepared in the same way as the
samples solutions; see at 2.4). The method LOD was 0.01 μg/g.
2.6. Analytical quality control
For analytical quality control purposes, the certified reference ma-
terial (CRM) ERM® –BD151 (skimmed milk powder) and ERM® – BB422
(fish muscle), both supplied by EC Institute for Reference Materials and
Measurements (Geel, Belgium), were analyzed under the same condi-
tions as for the samples. The average recoveries obtained in the CRM
analysis are presented in supplementary material (Table S1).
2.7. Statistical data analysis
Statistical analysis of the data was performed using GraphPad Prism
(version 8.0, GraphPad Software Inc., San Diego, CA). For statistical
calculations, results below the LOD were imputed as the LOD divided
by the square root of 2 [10]. Descriptive statistics was used to sum-
marize the results. Data normality was tested using the Shapiro-Wilk's
test. Differences in brain iodine content between genders or age-groups
were tested with the non-parametric Kruskal-Wallis test followed by the
Dunn’s multiple comparison test. The correlation between the mean
brain iodine content and age was assessed using Spearman's rank cor-
relation coefficient. Statistical significance was considered for p < 0.05.
3. Results and discussion
A total of 728 samples (14 brains regions from 52 subjects) were
analyzed for their iodine content. Overall, the mean iodine level for 48
out of 52 subjects was 0.14 ± 0.13 μg/g, ranging from < LOD to
E. Pinto, et al.
Fig. 1. Iodine levels (mean ± SD, μg/g dw) in 14 different brain regions of 48
(out of 52) subjects studied. Brain areas: 1) frontal cortex, 2A) superior and 2B)
middle temporal gyri, 3A) caudate nucleus, 3B) putamen, 3C) globus pallidus,
4) cingulated gyrus, 5) hippocampus, 6) inferior parietal lobule, 7) visual cortex
of the occipital lobe, 8) mid-brain (including the substantia nigra at the level of
the third nerve), 9) pons-locus coeruleus, 10) medulla and 11) cerebellum-
dentate nucleus. Statistical differences between the iodine content in the dif-
ferent brain regions were assessed by the Kruskal-Wallis non-parametric test
(p < 0.05).
1.04 μg/g. Four subjects presented iodine levels well above this value,
with a mean level of 26.0 ± 14.2 μg/g, which is more than 150x fold
higher. The results from these four subjects were excluded from the
overall data analysis and will be discussed in a separated sub-section
below.
3.1. Iodine levels in different anatomical regions of the brain
The iodine levels for 48 out of 52 subjects studied at each of the 14
different brain regions are summarized in Fig. 1. In general, the highest
mean iodine content was observed in the brain region 3A (caudate
nucleus, 0.21 ± 0.16 μg/g) and the lowest in the brain region 8 (mid-
brain/substantia nigra, 0.097 ± 0.054 μg/g). The differences observed
among the different brain regions were not statistically significant. A
great interindividual variability was observed within each brain re-
gions, with RSD values above 56 %. We also analyzed the correlations
between iodine levels in different brain regions and, in general, strong
positive correlations were observed (r > 0.6). A heat map was created
to easily show these correlations (Fig. S1, supplementary material).
A detailed inspection of the obtained results shows that the regions
with higher iodine levels are those known to play important roles in
cognitive function – frontal cortex (0.19 ± 0.22 μg/g), caudate nucleus
(0.21 ± 0.16 μg/g) and putamen (0.17 ± 0.17 μg/g) (Fig. 2). These
findings are in accordance with the widely accepted knowledge of the
role of thyroid hormones in cognition in human adults [1,5,7]. The
frontal cortex participates in many brain functions, including the cog-
nitive ones. In particular, the dorsal prefrontal cortex is the area in-
volved in higher cognitive processes or “executive” functions [11,12].
In addition, a clear link has been shown between the caudate and the
specific regions of the frontal lobe known to be responsible for “ex-
ecutive” functions, showing the important role of caudate in the cog-
nitive function [13]. Despite its well-known role in motor functions, it
has been shown that the putamen is involved to some extent in cog-
nitive functions as well [14].
The obtained results are in good agreement with the available lit-
erature data. Using neutron activation analysis, Andrási, Bélavári,
Stibilj, Dermelj and Gawlik [15] studied the iodine levels in three
Hungarian and five German subjects and reported values ranging from
0.05 to 0.91 μg/g dw. The same authors also observed higher iodine
levels in the brain regions responsible for cognitive functions, namely
the cortex frontalis parasagittalis and the cortex frontalis basalis.
3
Journal of Trace Elements in Medicine and Biology 62 (2020) 126579
3.2. Iodine levels in different age-groups
The iodine levels in the studied subjects was compared considering
different age-groups. In particular, four age-groups were created for this
purpose: 50–59 years (n = 11), 60–69 years (n = 11), 70–79 years
(n = 9), 80–89 years (n = 11). Iodine levels were higher in the older
age-groups (70–79 and 80–89 years: 0.16 ± 0.14 μg/g and
0.15 ± 0.14 μg/g, respectively) compared to the other two age-groups
(0.11 ± 0.11 μg/g and 0.12 ± 0.11 μg/g for the age groups 50–59
years and 60–69 years, respectively) (Fig. 3). However, these differ-
ences were not statistically different. A scatter plot was also constructed
with the mean brain iodine content and the individual’s age (supple-
mentary material, Fig. S2), and the nonparametric Spearman’s rank
correlation coefficient was calculated. Although a positive correlation
was observed (r = 0.21), a p-value above 0.05 was obtained, which
indicates that the correlation is not significant.
No literature data is available on iodine levels in human brain
stratified by age-groups for data comparison. Despite that, data on the
UIC is available by age-groups, which can be used to understand some
of the trends observed in this study. In the US, the National Health and
Nutrition Examination Surveys (NHANES) gathers detailed information
on UIC of the US population. A detailed observation of their results
shows that the UIC increase between the age-group 50–59 years to
the > 70 years, which are in accordance with the results obtained in the
present study for the human brain [16].
3.3. Iodine levels by gender
The iodine levels were also compared considering subjects’ gender.
The mean iodine level of males was slightly higher than for females
(0.14 ± 0.14 μg/g vs. 0.13 ± 0.12 μg/g), but not statistically different
(Fig. 4). We also checked whether differences could exist between the
mean iodine level in males and females in the four age groups (50–59
years, 60–69 years, 70–79 years and 80–89 years). No statistically
significant differences were observed.
No data is available on iodine levels in human brain stratified by
gender. However, if we look at the UIC values from the NHANES, a
significantly higher median value was observed for males [16]. The
same trend – higher UIC in males – was observed in a study conducted
in the Switzerland with ca. 400 subjects [17]. So, it can be hypothesized
that a similar trend (i.e., higher iodine levels in males) can be observed
in other human fluids or tissues, including the brain.
3.4. Abnormally high iodine levels
The brain iodine levels of 4 out of the 52 subjects studied were
significantly higher compared to the other subjects. Results are pre-
sented in Fig. 5. The mean iodine level for these subjects was
26.0 ± 14.2 μg/g. Despite the significantly higher values observed, a
similar trend was observed with regard to the regions with higher and
lower iodine levels. In particular, iodine levels were higher (> 40 μg/g)
in the brain regions 2A (superior temporal gyri), 3A (caudate nucleus)
and 3B (putamen) and lower (< 20 μg/g) in the brain regions 8 (mid-
brain) and 11 (cerebellum-dentate). These data show that for high-dose
exposure, iodine accumulates preferably in the brain regions 1–7 (va-
lues ranging from 29.6–42.9 μg/g), and less in the brain regions 8–11
(values ranging from 19.3–24.0 μg/g) (Fig. 6).
Such abnormally high iodine levels (reaching values of 12.4 μg/g
dw) were also found by Andrási, Bélavári, Stibilj, Dermelj and Gawlik
[15] in two out of five German subjects. The origin of these abnormally
high iodine levels is unknown but probably they resulted from the
previous administration of iodine-based contrast agents to the subjects
for conducting radiological exams. Once administered, iodine is rapidly
distributed from the intravascular compartment to highly perfused or-
gans, such as brain, liver, and kidney. Usually, the elimination half-life
of most iodine-based contrast agents is within the range of 90−120 min
E. Pinto, et al.
Fig. 2. Graphical presentation of the mean iodine level in the 14 different brain regions studied. Brain regions are colored in a blue gradient where darker blue
regions present a higher mean iodine content.(For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this
article).
Fig. 3. Iodine levels (mean ± SD, μg/g dw) in the human brain stratified by
age-groups.
Fig. 4. Iodine levels (mean ± SD, μg/g dw) in the human brain stratified by
gender.
in patients with normal renal function. However, this period of time can
be delayed, on the order of weeks, in patients with renal insufficiency
[18]. Under normal conditions, the blood-brain barrier is impermeable
4
Journal of Trace Elements in Medicine and Biology 62 (2020) 126579
Fig. 5. Iodine content (mean ± SD, μg/g dw) in the 14 different brain regions
studied for 4 subjects showing abnormally high iodine levels. Brain areas: 1)
frontal cortex, 2A) superior and 2B) middle temporal gyri, 3A) caudate nucleus,
3B) putamen, 3C) globus pallidus, 4) cingulated gyrus, 5) hippocampus, 6)
inferior parietal lobule, 7) visual cortex of the occipital lobe, 8) mid-brain
(including the substantia nigra at the level of the third nerve), 9) pons-locus
coeruleus, 10) medulla and 11) cerebellum-dentate nucleus. Statistical differ-
ences between the iodine content in the different brain regions were assessed by
the Kruskal-Wallis non-parametric test (p < 0.05).
to radiographic contrast medium, either containing iodine or another
element [19]. However, some studies have shown the disruption of the
blood-brain barrier after the administration of iodine-based contrast
agents [20,21].
4. Conclusion
The present study provides data on iodine levels at 14 different
brain regions of 52 subjects. Overall, iodine was found at low levels
(0.14 ± 0.13 μg/g dw) and presented a very heterogeneous distribu-
tion. Interestingly, the highest iodine levels were found in the regions
involved in cognitive functions – frontal cortex, caudate nucleus and
putamen. Iodine levels increased with age but further studies are ne-
cessary to support this trend. Abnormally high iodine levels in the
human brain were found in four subjects, which seems to be the result
E. Pinto, et al.
Fig. 6. Graphical presentation of the mean iodine level in the 14 different brain regions studied for the 4 subjects showing abnormally high iodine levels. Brain
regions are colored in a blue gradient where darker blue regions present a higher mean iodine content. (For interpretation of the references to colour in this figure
legend, the reader is referred to the web version of this article).
of an exposure to iodine-based contrast agents that may have been
administrated for medical exams.
CRediT authorship contribution statement
Edgar Pinto: Conceptualization, Methodology, Software,
Validation, Writing - original draft. Patrícia Ramos: Investigation,
Formal analysis. Cristiana Vital: Investigation, Formal analysis.
Agostinho Santos: Project administration, Resources. Agostinho
Almeida: Funding acquisition, Supervision, Writing - review & editing,
Resources.
Declaration of Competing Interest
The authors declare that there are no conflicts of interest.
Acknowledgements
This work was financed by National Funds through FCT/MCTES –
Portuguese Foundation for Science and Technology within the scope of
the project UIDB/50006/2020.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.jtemb.2020.126579.
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