Ioflupane I 123

DaTScans are normal in purely functional parkinsonism, and also in drug-induced

parkinsonism, while degenerative forms of Parkinsonism, including idiopathic
Parkinson's disease, show signs of presynaptic dopaminergic denervation (Tolosa,
Coelho, & Gallardo, 2003).

From: International Review of Neurobiology, 2018

Related terms:

Essential Tremor, Parkinsonism, Single-Photon Emission Computed Tomography,

Radioactive Tracer, Dopamine Transporter, Dopamine Agonist, Parkinson's Disease,
Iodine 123, Diffuse Lewy Body Disease

View all Topics

Approach to Central Nervous System

Imaging
In Diagnostic Imaging: Nuclear Medicine (Second Edition), 2016

Dopamine Transporter (DaT) Imaging

I-123 ioflupane (FP-CIT, DaTscan) measures the presence of dopamine transporter
in the basal ganglia, which is decreased in Parkinson disease, atypical parkinsonism
syndromes, or Lewy body disease. The radiotracer localizes to the dopamine trans-
porters in the basal ganglia. Preparation includes blocking thyroid uptake with cold
iodine (Lugol or SSKI). SPECT images are obtained 3-6 hours post tracer injection.
Normal activity in the head of the caudate and putamen leads to a comma-shaped
area of uptake on axial images. Loss of dopamine transporter in abnormal scans
occurs preferentially in the putamen, resulting in a period-shaped area of uptake
corresponding to the head of the caudate, with reduced or absent activity in the
putamen. Caution must be taken to ensure patients are not on any medications
that compete with the tracer and can artificially reduce normal activity in the basal
ganglia.
> Read full chapter

Central Nervous System

In Nuclear Medicine (Fourth Edition), 2014

Method
A protocol for I-123 ioflupane is presented in Box 15-6. One of the most difficult
things concerning I-123 ioflupane use is the ordering process as the U.S. Federal
Drug Administration (FDA) approval hinged on meeting Drug Enforcement Agency
(DEA) insistence that it be treated as a Schedule II controlled substance. Patient med-
ications should be reviewed for any drug that might interfere with the examination
(Box 15-7). Patient preparation consists of blocking thyroid uptake with potassium
iodide (400 mg) or Lugol solution (equivalent 100 mg iodide) at least 1 hour before
injection. The patient should be well hydrated and void frequently in the first 48
hours after the examination. After radiotracer injection a 3- to 6-hour delay is needed
before SPECT imaging.

> Read full chapter

Nuclear Medicine and Molecular Imag-

ing
R.S. Miyaoka, in Comprehensive Biomedical Physics, 2014

1.02.4.2 Brain
Nuclear medicine brain imaging can use both planar and SPECT techniques. Com-
mon diagnostic procedures include cerebral blood flow (brain death), evaluation
of dementia, evaluation of vasospasm, suspected trauma, epilepsy, and cerebral
vascular disease (Mettler and Guiberteau, 2006). Examples of neuro-SPECT imaging
are shown in Figure 25. In this example, an imaging agent called DaTscan is used
to differentiate between Parkinsonian syndromes (PS) and essential tremor. The
‘comma’ image is for a patient without PS (upper panel), while the abnormal ‘period’
scan is for a patient with PS (lower panel). DaTscan is a radiopharmaceutical indicated
for striatal dopamine transporter visualization. The data were collected using 128
view angles and a high-resolution, low-energy collimator. Because neuroimaging
only utilizes a portion of the imaging area of the detector, a zoom factor is used to
improve image resolution (by reducing voxel size) and more efficiently utilizing
system memory. Just as in bone imaging, a key to achieving the best image spatial
resolution is to make sure the detectors are as close to the patient's head as possible.

Figure 25. DaTscans showing patient with Parkinson's disease (bottom panel) and
patient negative for Parkinson's disease (top panel).

> Read full chapter

Central Nervous System

Fred A. MettlerJr. MD, MPH, Milton J. Guiberteau MD, FACR, FACNM, in Essentials
of Nuclear Medicine and Molecular Imaging (Seventh Edition), 2019

Parkinson Disease and Syndromes

Parkinson disease is a neurodegenerative disorder characterized by the progressive
loss of presynaptic dopaminergic neurons in the brain leading to both motor
and cognitive deficits. The symptoms can be variable in intensity and progression,
especially in the early stages, and differentiation from other conditions with Parkin-
son-like symptoms (Parkinsonian syndromes) can be difficult. Patients with Parkin-
son disease may also show decreases in regional blood flow when scanned with the
SPECT brain perfusions agents ECD or HMPAO. Decreases are seen initially in the
frontal cortex, then in the prefrontal and parietal lobes, and finally hypoperfusion in
all cortical areas.

By performing SPECT brain imaging using the tropane-based radiopharmaceu-

tical 123Ioflupane (DaTscan) with high binding affinity for presynaptic dopamine
transporter (DaT), a decrease in neuronal dopaminergic function can indirectly be
determined by measuring transporter density in the striatum compared to healthy
controls. While Parkinson disease and other presynaptic syndromes (such as mul-
tiple system atrophy and progressive supranuclear palsy) demonstrate diminished
DaT concentrations, others (including vascular, drug-induced, and psychogenic
Parkinsonism, as well as benign essential tremor) generally do not, allowing a
normal DaT scan appearance to be used to differentiate among these entities. DaT
imaging has a 90% sensitivity and specificity in distinguishing patients with essential
tremor from those with Parkinson disease.

123I-ioflupane is a cocaine analog substance and in the United States is classified as a

Schedule II controlled substance and should be ordered and handled accordingly. It
is administered in a dosage of 3 to 5 mCi (111 to 185 MBq) as a slow intravenous
injection followed by a saline flush and is excreted by the kidneys. SPECT may be
performed 3 to 6 hours after administration. Although a number of drugs may
interfere with ioflupane binding and should be withheld prior to the procedure,
ambient light and normal patient activities do not affect the distribution of the
radiopharmaceutical. To reduce exposure of the thyroid to any free 123I, a single-dose
thyroid blocker such as Lugol solution or potassium iodide (equivalent to 100 mg
of iodide) is administered at least 1 hour before the radiopharmaceutical injection.
Oral potassium perchlorate (400 mg) may also be used.

Visual interpretation of DaTscan images by trained readers has proved to be reliable

and accurate when performed on a viewing station that allows image manipulation.
The visual evaluation includes determining the intensity, shape, and symmetry of
activity in the caudate nucleus and putamen. In normal patients, transaxial images
of these combined striatal components should be well defined, comma shaped, and
symmetric. Abnormal striata appear as reduced intensity either unilaterally (asym-
metry) or bilaterally, compared with a normal intensity background. The putamen is
often more affected than the caudate nucleus. The striatal shape frequently changes
from comma-shaped to a round or oval configuration with loss of the comma's tail
(Fig. 3.21). While intensity of radiopharmaceutical binding may decrease slightly
with age, it is rarely enough to interfere with image interpretation.

Although semiquantitative programs for more objective image interpretation have

been proposed and evaluated, dependence on local strategies persists and no one
method has gained broad validation or support.

> Read full chapter

Radiopharmaceuticals
In Nuclear Medicine (Fourth Edition), 2014
Single-Photon Radiopharmaceuticals other than Tc-99m

Radioiodine I-131 and I-123

I-131 as sodium iodide was the first radiopharmaceutical of importance in clinical
nuclear medicine. It was used for physiological studies of the thyroid gland for
several years in the late 1940s (Table 1-10). Subsequently, it was used to radiolabel
radiopharmaceuticals for scintigraphy, including human serum albumin, MAA, hip-
puran, and meta-iodo-benzyl-guanidine (MIBG). These radiopharmaceuticals are no
longer diagnostically used.

The disadvantages of I-131 include relatively high principal photon energy (364
keV), long half-life (8 days), and presence of beta particle emissions. However,
it is an important radiopharmaceutical for the treatment of hyperthyroidism and
differentiated thyroid cancer.

Whenever possible, I-123 is substituted for I-131 for diagnostic purposes. It has a
shorter half-life (13.2 hours) (Table 1-2), and its principal photon energy (159 keV) is
better suited to imaging with the gamma camera. It decays by electron capture, and
the dosimetry is favorable compared with that of I-131. Even in applications in which
imaging over a period of several days allows for improved target-to-background
ratio and thus making I-131 seem advantageous, I-123 is now increasingly replacing
I-131—for example, for whole-body thyroid cancer scans and MIBG imaging. I-123
ioflupane (DaTscan) has recently been approved to confirm or exclude the diagnosis
of Parkinson disease.

Quality control of radioiodinated pharmaceuticals is necessary to reduce radiation

exposure to the thyroid gland. In nonthyroid imaging applications, it is common
practice to block the thyroid gland with oral iodine (potassium iodide [SSKI], Lugol
solution, or potassium iodide tablets) to prevent thyroid accumulation of any io-
dine present as a radiochemical impurity or metabolite. Protocols vary, but thyroid
blocking medications are started 1 to 12 hours before radiotracer administration in
dosages equivalent to at least 100 mg of iodide.

Indium-111
In-111 has proved useful for clinical nuclear medicine (Table 1-10). Its principal
photon energies of 172 and 245 keV are favorable, and their abundance is high
(>90%). The 2.8-day half-life permits multiple-day sequential imaging. Examples of
radiopharmaceuticals include In-111 oxine leukocytes for detection of inflammation
and infection and the somatostatin receptor–binding peptide In-111 pentetreotide
(OctreoScan) to detect neuroendocrine tumors.
Thallium-201
Tl-201 became available in the mid-1970s for myocardial scintigraphy. It behaves
as a potassium analog, with high net clearance (~85%) in its passage through the
myocardial capillary bed, which makes it an excellent marker of regional blood flow
to viable myocardium.

The major disadvantage of thallium as a radioactive imaging agent is the absence

of an ideal photopeak for imaging. The gamma emissions (135 and 167 keV) occur
in low abundance (see Table 1-2). The emitted mercury characteristic x-rays in the
range of 69 to 83 keV are acquired, as sometimes are the 167-keV gamma emissions.
The ability of the gamma scintillation camera to discriminate scattered events
from primary photons is suboptimal at this energy. Because of its poor imaging
characteristics, Tc-99m–labeled cardiac perfusion radiopharmaceuticals are used.

Radioactive Inert Gases

Radioactive inert gases are used for pulmonary ventilation imaging. Xe-133 is the
most commonly used. Its advantage over Tc-99m–labeled aerosols is better distri-
bution into the lung periphery in patients with chronic obstructive lung disease. A
disadvantage is the relatively low energy of its principal photon (81 keV), dictating
the performance of ventilation scintigraphy before Tc-99m perfusion scintigraphy.
Because of its poor imaging characteristics and dosimetry issues, Tc-99m–labeled
aerosols are more commonly used. Xe-133 has a 5.2-day half-life, posing radiation
safety issues answered to some extent by a xenon trap (charcoal).

Xenon-127 is theoretically superior to Xe-133 because of its higher photon energies

(Table 1-2). Thus the ventilation study can be performed after the perfusion scan,
limited to the locations of perfusion defects. The high cost of producing Xe-127 and
long half-life (36 days) have kept it from wide use.

Krypton-81m has advantages because of its high principal gamma emission (190
keV) and short half-life (13 seconds), allowing for postperfusion imaging and multi-
ple-view acquisition without concern for retained activity or radiation dose. However,
the rubidium-81/kr-81m generator system is expensive and must be replaced daily
because of its short half-life.

> Read full chapter

Imaging of Dopamine and Serotonin

Receptors and Transporters
Andre C. Felicio, A. Jon Stoessl, in Imaging of the Human Brain in Health and
Disease, 2014

2.3.3 Dopamine Transporter

The plasmalemmal DAT is located on the presynaptic terminals of dopaminergic
neurons and is responsible for the reuptake of up to 70% of the dopamine released
into the synaptic cleft (Eisenhofer, 2001). In the healthy brain, this is the leading
mechanism responsible for terminating the actions of DA (Varrone and Halldin,
2010). DAT imaging can be assessed using both PET and SPECT tracers as presented
in Table 2. DAT scan, for instance, is a commercially available iodine-labeled SPECT
tracer previously approved in the European Union for the differentiation of PD and
Essential Tremor, and recently approved by the Food and Drug Administration (FDA)
to be used in the United States. While the majority of DAT SPECT tracers are 123I or
99mTc-labeled, PET tracers for the DAT tracers are generally 11C- or 18F-labeled. The

development of technetium-99m labeled DAT tracers, such as [99mTc]-TRODAT-1,

provided a useful and less expensive alternative in molecular neuroimaging studies
(Mozley et al., 2000) as compared to iodine-123 labeled DAT tracers such as [123-
I]-FP-CIT (DATscan) (Booij et al., 1997) or [123I]- -CIT (Marek et al., 1996). The cost
of cyclotron-produced 123I, for instance, is relatively higher than the more widely
available and generator-produced 99mTc. Moreover, [99mTc]-TRODAT-1 also shows fa-
vorable pharmacokinetics and allows for similar semiquantification. Figure 4 shows
a healthy subject submitted to brain SPECT imaging using the technetium-ligand
TRODAT-1.
Figure 4. Dopamine transporter imaging scan using a technetium-based SPECT
ligand, TRODAT-1, in a healthy subject. At the top level: Axial slice through the
striatum showing the radiotracer uptake, and the region of interest (ROI) drawn in
the area with specifically bound radioligand. At the bottom level: ROI drawn in
the occipital area or nondisplaceable radioligand tissue.Images are courtesy of the
Laboratório Interdisciplicar de Neurociências Clínicas, Universidade Federal de São
Paulo, Brazil.

Although DAT imaging is frequently used as a surrogate marker to assess dopamin-

ergic dysfunction, one should take care of the potential caveats of this methodology
(Piccini, 2003). First, age-associated physiological decline in DAT is estimated to
range from 3% to 8% per decade, and corresponds to nigrostriatal cell loss. This
is substantially lower than the approximately 8% per year pathological loss of DAT
seen in PD (Volkow et al., 1994). Another major potential confounder is that the
DAT may be subject to pharmacological regulation arising from medications such as
dopamine reuptake inhibitors (bupropion or methylphenidate) or other dopamin-
ergic medications (Kagi et al., 2010). Finally, DAT is also subject to compensatory
changes, such as may occur in the early stages of PD. The downregulation of
DAT should allow dopamine to interact for a longer time with presynaptic and
postsynaptic receptors, by preventing its rapid reuptake (Lee et al., 2000). While
several tracers are available for assessing DAT binding, it should be noted that their
specificity for the DAT (as opposed to other plasmalemmal monoamine transporters)
is variable, as are their pharmacokinetic properties. The latter point may be quite
important as tracers that are slow to reach equilibrium may require longer scan times
to provide accurate estimates of binding potential and are accordingly better labeled
with longer half-life emitters (e.g., F-18 rather than C-11 for PET).

> Read full chapter

Single Photon Emission Computed To-

mography☆
Andrew B. Newberg, Abass Alavi, in Reference Module in Neuroscience and Biobe-
havioral Psychology, 2017

Movement Disorders
Parkinsonian symptoms are associated with a number of neurodegenerative disor-
ders, such as Parkinson's disease, multiple system atrophy and progressive supranu-
clear palsy. These disorders are frequently associated with abnormalities in a number
of neurophysiological processes. In particular, pathological evidence has shown that
these disorders are associated with a loss of neurons, particularly in the nigrostriatal
dopaminergic pathway.

SPECT and PET have become important tools in the differential diagnosis of these
diseases, and may have sufficient sensitivity to detect neuronal changes before
the onset of clinical symptoms. Imaging is now being utilized to elucidate the
genetic contribution to Parkinson's disease, and in longitudinal studies to assess the
efficacy and mode of action of therapeutic interventions such as neuroprotective
drugs and surgery.

SPECT scans using the approved tracer, 123I ioflupane (DaTscan) are now widely used
to help diagnose patients with parkinsonian syndromes which are associated with
decreased presynaptic dopamine transporter binding. As the course of the disease
moves from posterior to anterior, the scans show a progressive loss as well. Thus,
SPECT studies have indicated a consistent pattern of dopaminergic neuronal loss
in PD, usually with a more pronounced decrease in the putamen rather than in the
caudate (Fig. 10). In addition, there is often a marked asymmetry of uptake in the
striatum, particularly in the early stages of the disease. This asymmetry usually has
a good correlation with symptom severity and illness duration. Most importantly,
SPECT imaging studies may be sensitive enough to detect very early PD, perhaps
even before clinical symptoms become apparent. Several large scale clinical trials
of treatment interventions for Parkinson's have utilized the 123I ioflupane tracer
with mixed success. However, the tracer has proved to be powerful techniques
for quantifying the loss of dopaminergic neurons in normal aging, PD, and other
neurodegenerative disorders.

Figure 10. Transverse SPECT images of [99mTc]TRODAT-1 binding to dopamine

transporters in human subjects [114]. Left: histology slice through the brain at the
level of the striatum to show the head of the caudate nucleus (CAUD) and the
putamen (PUT). Center: transverse SPECT image at the same level from a healthy
subject, showing high concentrations of [99mTc]TRODAT-1 binding to dopamine
transporters in the caudate and putamen. Right: SPECT image at the same level
in a patient with bilateral Parkinson's disease, showing significant reductions of
[99mTc]TRODAT-1 binding in the putamen, but with the caudate relatively spared.

Although most of the SPECT studies have shown highly significant differences
between groups of Parkinson's patients and age-matched normal controls, the
statistically significant differential diagnosis of an individual subject is more
problematic. Patients with severe PD are easily separated from healthy controls even
from a simple visual inspection of striatal images, which can be quantified using
some form of discriminant analysis, which has a sensitivity and specificity from 90%
to 100% in the proper clinical setting. However, patients presenting much earlier in
the course of the disease are more difficult to detect since there can be a substantial
overlap with an age-matched control group and consequently, a loss of diagnostic
accuracy. The situation may be further complicated if the early differential diagnosis
between several different movement disorders is required. Many of the symptoms
associated with parkinsonian disorders are non-specific, which is why the accurate
clinical diagnosis of these diseases is difficult. Indeed, some histopathalogical
studies have shown that as many as 25% of all patients who were diagnosed with
PD before death had been misdiagnosed. Studies measuring dopamine transporter
activity have had more difficulty in separating PD from MSA or PSP. Essential
tremor (ET) is another possible diagnostic consideration when evaluating a patient
for PD. Essential tremor may be easier to distinguish from PD since the former does
not typically involve the dopaminergic pathways to the same degree.

> Read full chapter

Volume 3
Yong Du, Habib Zaidi, in Encyclopedia of Biomedical Engineering, 2019

Neurology and Psychiatry

Brain perfusion SPECT is a method for imaging regional cerebral blood flow (Accorsi,
2008). 99mTc-HMPAO (hexamethylpropyleneamine oxime) and 99mTc-ECD (ethylene
cysteine diethylester) are two brain perfusion agents that can cross the blood–brain
barrier. Their distribution in brain is proportional to the blood flow. Cerebrovas-
cular disease can cause hypoperfusion or hyperperfusion in the brain, resulting
in abnormal uptake in brain perfusion images that can be used for diagnosis.
Because cerebral blood flow is also closely linked to neuronal activity, brain perfusion
SPECT can also be used to evaluate and monitor certain neurological disorders and
psychiatric disorders, such as dementia, Alzheimer’s diseases, mood disorders, and
attention-deficit disorder. It can also be used to assess brain trauma, substance
abuse, and chemical exposure.

In neurodegenerative diseases, such as Alzheimer’s diseases and Parkinson’s disease

(PD), structural and functional integrity of neurons are diminishing. This can be
imaged with SPECT using radionuclide labeled analog or antagonist of neurotrans-
mitters. One successful application is the SPECT imaging of dopamine transporters
(DAT) in PD. In PD, changes in the nervous system can start years before the
appearance of any clinical symptoms. One important neuropathological alteration
in PD is the degeneration of dopaminergic neurons in the substantia nigra. This can
be imaged using SPECT with agents targeting the dopaminergic system. 123I-FP-CIT
(123I-Ioflupane, trade name DaTscan) is a radiopharmaceutical that binds to striatal
presynaptic DAT. Reduced 123I-FP-CIT uptake in the striatum measured from SPECT
images can provide a reliable indication of neuron degeneration and has been shown
to be a valuable tool for both routine clinical diagnosis and research studies of
Parkinsonian syndromes (Fig. 9). The DAT SPECT images are often used to confirm
or exclude Parkinsonian syndromes, or to distinguish idiopathic Parkinsonism (iPD)
from essential tremor. A multiple center study conducted in Europe showed that
123I-FP-CIT SPECT had an average sensitivity of 78% and a specificity of 97% in

diagnosing PD, compared with on-site clinical diagnosis, which had a sensitivity
of 93% but a specificity of only 46%. The DAT SPECT can also be used to assess
atypical Parkinsonian syndromes and to differentiate dementia with Lewy bodies
from Alzheimer’s disease.

Fig. 9. DAT SPECT of two patients with PD. The patient on the left had mild
symptoms, and the images showed a slightly reduced uptake in the left striatum.
The patient on the right had more severe symptoms, and the images showed
significantly reduced uptake in the right striatum. Please note in the images, right
side of a patient is located to the left.
Quantitative analysis of DAT SPECT images has been shown to be a more objective
tool for detecting subtle changes in DAT binding in striatal subregions. It allows
accurate staging of the patient based on age- and gender-specific normal reference
values. The commonly used quantitative method is the reference region-based semi-
quantitative approach that measures the striatal specific binding potential (SBP, also
called SBR, striatal binding ratio), computed using activity concentrations measured
in the striatum and in a nonspecific binding reference region as [Striatum − Refer-
ence]/Reference. The left-to-right ratio and the caudate-to-putamen ratio are other
frequently used quantities. These quantitative measures can also be used to track
the disease progression and to monitor the effects of treatment. For example,
reference region-based measures of striatal dopamine deficiency are correlated with
bradykinesia and rigidity, the most characteristic clinical feature of PD. There is also
evidence that the DAT binding loss in PD follows an exponential curve. Fitting the
DAT binding potential to the curve could help score the patient more accurately,
potentially leading to better patient management.

There are also many other brain SPECT neurotransmission agents developed for
imaging various nervous systems (Acton and Mozley, 2000). Examples include but
not limited to 123I-IBZM (Iodobenzamide) for imaging postsynaptic dopamine re-
ceptors; 123I-5-I-A for imaging the nicotinic cholinergic receptors; and 123I-IOM for
imaging the benzodiazepine receptors, etc.

> Read full chapter

Smell and Taste

Richard L. Doty, Christopher H. Hawkes, in Handbook of Clinical Neurology, 2019

Familial PD
Considerable heterogeneity in olfactory function occurs in inherited forms of PD,
although in many cases the olfactory dysfunction cannot be distinguished from
that of classic PD. Even though PD-related genes are relatively rare in the general
population, there are clear exceptions. The primary olfactory findings from studies
of various familial forms of PD are presented in Table 20.1 from Hawkes and Doty
(2018).

Table 20.1. Currently proposed genic forms of parkinsonism with some associated
pathologic features and olfactory deficits where known

PARK Gene and Inheri- Age onset Function LB OLF Comment

number common tance or effect
 muta- pattern of
tions and locus mutation
1/4 A AD- 30–40 Dopamine transmission
++ +++ Early
synuclein 4q21.3-q22 onset.
(SNCA). Good
G209A. response
Missense to
muta- levodopa.
tions: Impaired
A53T, olfaction
A30P and in 1 case
E46K. (-
Also Markopoulou et al., 1997). Abnormal
duplica-
tions and
triplica-
tions.
2 Parkin- AR6q26 < 40 Mitochon- +? + Early
Over 200 drial onset,
mutations disorder. slow
UPS, progres-
E3-ubiqui- sion. Good
tin ligase response
to
levodopa.
No
dementia.
Nor-
mal/mild
impair-
ment of
olfaction
in
manifest-
ing and
nonmani-
festing
carriers,
heterozy-
gotes but
not
com-
pound
heterozy-
gotes
(Khan et
al., 2004;
Alcalay
et al.,
2011).
Susceptibil-
ity to
glioma,
lung
cancer,
possibly
leprosy,
and TB
3 and 5 Not confirmed
6 PINK1- AR- 20–50 Mitochon- + ++ Early
Over 60 1p36.12 drial onset and
mutations kinase. slow
Defective progres-
mi- sion. Good
tophagy response
to
levodopa.
Dementia.
 Moderate
impair-
ment of
olfaction
in all cases
and some
asympto-
matic
heterozy-
gotes
(Ferraris
et al.,
2009;
Eggers
et al.,
2010).
One
autopsy
showed LB
but
sparing of
locus
coeruleus
and
amygdala.
OB not
examined
(Sama-
ranch et
al., 2010)
7 DJ-110 AR1p36 20–40 Oxidative ? 0? Good
mutations stress. response
Defective to
mi- levodopa.
tophagy Normal
olfaction
based on 1
patient
(Verbaan
et al.,
2008)
8 LRRK2/DardarinG2019S;
AD12q12 40–60
N1437H Mem- ++ +++ Moderate
brane to severe
traffick- olfactory
ing,kinase impair-
ment in
manifest-
ing
patients
from
London,
New York,
Lisbon,
Brazil, and
Germany
(Berg et
al., 2005;
Khan et
al., 2005;
Lin et al.,
 2008;
Kertelge
et al.,
2010;
Sil-
veira-Moriyama et al., 2010b; Saun
9 ATP13A2- AR1p36 11–16 Lysosome ? ++ Ku-
10 ATPase for-Rakeb
mutations disease.
Based on
four
subjects
(Kertelge
et al.,
2010).
Similar to
Hallervor-
den-Spatz
disease.
Lev-
odopa-re-
sponsive
PD with
pyramidal
signs,
supranu-
clear gaze
palsy, and
dementia
(Klein et
al., 2009)
10–13 Not confirmed
14 PLA2G6- AR- 20–25 Phospholi- +++ ? Karak
Karak 22q13.1 pase syndrome.
syndrome enzyme Adult
onset
dysto-
nia-parkin-
sonism.
Temporary
response
to
levodopa.
Dementia.
Cortical
LB in four
autopsies.
No OB
data but
hippocam-
pus
involved in
some
(-
Paisan-Ruiz et al., 2012)
15 FBOX7AR AR- 10–19 Ubiquitin ? ? Early
22q11.2-qter protein onset
ligase lev-
odopa-re-
sponsive
parkinson-
ism with
dystonia
 and
spasticity
16 Not confirmed
17 Heterozy- AD16q12 40–60 Mem- 0 (- ? Indistin-
gous brane One lim- guishable
mutation trafficking ited au- from
(D620 N) topsy) tremor-dominant PD. Dementia uncomm
in VPS35
gene

AD = autosomal dominant; AR = autosomal recessive; LB = Lewy bodies; OLF = ol-

factory defect.

Modified from Hawkes, C.H., Doty, R.L. 2018. Smell and taste disorders. Cambridge
University Press, Cambridge.

To identify possible familial PD, some investigators have administered olfactory tests
and other PD-related measures to first degree relatives of PD patients. Lower UPSIT
scores have been found in sons and daughters, in particular, where the affected
parent was the father (Montgomery Jr. et al., 1999, 2000). One study evaluated
olfaction and dopamine striatal transporter activity (DATScan) in 78 asymptomatic
first-degree relatives of nonfamilial PD patients (Ponsen et al., 2004). Forty were
hyposmia patients at baseline. 2 years later, four had abnormal DATScans and
displayed clinical evidence of PD. In the remaining 36 individuals with hyposmia
who displayed no sign of PD, the rate of decline of dopamine transporter binding
was higher than in normosmic relatives.

The impact of familial PD on olfactory function is perhaps best exemplified by

studies of patients with PARK 8. The leucine-rich repeat kinase 2 gene (LRRK2) at the
PARK 8 locus on chromosome 12p11.2-q13.1 is one of the most prevalent causes
of familial PD. While only around 1% of North American PD patients carry this
mutation (Correia et al., 2010), over 40% of Arab-Berbers of North Africa with PD
do so (Lesage et al., 2005). This condition gives rise to late onset benign tremor and
may be indistinguishable from sporadic PD. Penetrance of the most common LRRK2
mutation (G2019S) is incomplete and age dependent (Lesage et al., 2007). Limited
pathologic studies show Lewy and tau pathology in olfactory pathways at all levels
(Silveira-Moriyama et al., 2009a).

UPSIT scores typical of classic PD were found in five PARK 8 patients with the G2019S
mutation from London (Silveira-Moriyama et al., 2008) and 16 PARK 8 patients with
this mutation from Lisbon (Ferreira et al., 2007). Unaffected relatives at 50% risk of
PARK 8 were not similarly impacted. In another preliminary study from Brazil that
used SS, impaired olfaction was found in 22 LRRK2 patients carrying the G2019S
mutation, but it was less severe than those with classic PD (Silveira-Moriyama et al.,
2010b). In a German study, seven PARK 8 patients, three of whom were symptomatic
and four of whom were nonsymptomatic, exhibited low UPSIT scores relative to
controls (Kertelge et al., 2010). Less clear-cut results were documented in a large
French pedigree that carried the G2019S mutation (Lohmann et al., 2009).

A US-based investigation that used UPSIT in a study of 126 G2019S mutation carriers
found no significant olfactory dysfunction in nonmanifesting carriers, suggesting
to the authors that microsmia is not predictive of LRRK2-related parkinsonism
(Saunders-Pullman et al., 2014). Another group from Spain assessed UPSIT scores in
(a) 29 subjects with parkinsonism due to the G2019S mutation, (b) 49 asymptomatic
mutation carriers, (c) 47 noncarrier relatives, (d) 50 subjects with idiopathic PD and
(e) 50 community-based controls (Sierra et al., 2013). In the G2019S manifesting
carrier group, 50% were hyposmia patients compared to 82% in the IPD group,
and there was no significant difference between these two. Hyposmia was less
frequent in the asymptomatic carrier group (26%) and asymptomatic noncarriers
(28%), suggesting that olfactory dysfunction is not found in asymptomatic carriers
of the G2019S mutation. Normal B-SIT scores were found in a Norwegian study
of 47 nonsymptomatic family members of LRRK2 PD patients, of whom 32 were
positive and 15 negative for either the G2019S or the N1437H mutation (Johansen
et al., 2011).

In summary, PD patients with LRRK2 mutations appear, on average, to have a

decreased sense of smell, but the severity is less than that of idiopathic PD. Non-
manifesting carriers appear to have no olfactory impairment. Before it is concluded
that hyposmia is not a premotor feature in this monogenetic disorder, much larger
populations need to be tested.

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SPECT Imaging in Movement Disor-

ders
A. Antonini, in Encyclopedia of Movement Disorders, 2010

SPECT with Receptor-Binding Tracers

Dopaminergic System: Presynaptic Issues

Target and tracers

Available presynaptic ligands for SPECT bind selectively the dopamine transporter
(DAT). The DAT is a 620-amino acid protein with 12 -helical hydrophobic trans-
membrane domains, two to four extracellular glycosylation sites, and up to five
intracellular phosporylation sites. Ex vivo studies have shown the expression of DAT
in the dopaminergic neurons of the substantia nigra and in the ventral tegemental
dopaminergic neurons. DAT controls dopaminergic neurotransmission by spatial
and temporal buffering, making the molecule an imaging target for diseases af-
fecting the dopaminergic nigrostriatal pathway. DAT levels correlate with striatal
dopamine concentration.

Introduction of radioactive iodine (123I) into the tracer molecules provides a suitable
method for DAT-SPECT imaging. A large number of 123I-labeled compounds have
been prepared, and DAT receptor-specific imaging agents are routinely used for
SPECT imaging studies. All of the successful agents for imaging DAT belong to a
group of tropane derivatives that share a similar backbone structure of cocaine. The
first successful DAT imaging agent for SPECT, [123I] -CIT, was reported in the early
1990s, and studies suggested a strong correlation between the decrease in local-
ization in the putamen area and PD symptoms. Currently, [123I] -CIT, [123I]FP-CIT,
[123I]IPT, and [123I]altropane are being developed for this purpose.

The two most widely used ligands to study PD patients are [123I] -CIT and [123-
I]FP-CIT. A direct comparison of the two compounds has been attempted in only
a few studies; briefly: (1) the nonspecific uptake of [123I]FP-CIT is greater than [123I]-
-CIT, causing [123I] -CIT to have a lower ratio of specific to non-displaceable striatal
uptake (V 3); (2) [123I] -CIT shows a lower selectivity for DAT, having an equivalent
affinity for the serotonin transporter (SERT), which results in a higher thalamic/mid-
brain [123I] -CIT uptake; (3) washout period of [123I] -CIT is about 1% per hour and
of [123I]FP-CIT is 5–8% per hour, making striatal V 3 values of [123I]FP-CIT stable as
early as 3–6 h, whereas [123I] -CIT stabilizes only after 18–27 h. In Europe [123I]FP-CIT
(DatScan, Amersham PLC, Buckinghampshire, UK) is commercially available for
routine clinical use.

One of the major drawbacks of using 123I-labeled compounds for routine imaging
is the availability of the isotope. Produced by cyclotrons or by accelerators, it is
not readily available in standard nuclear medicine clinics and requires overnight
shipment from production sites. As a consequence, it is relatively expensive and
inaccessible. As an alternative, 99mTc-labeled tropane derivatives have been inves-
tigated. Only [99mTc] TRODAT-1 has been tested successfully in normal subjects
and parkinsonian patients. This compound has some logistical advantages over the
most commonly used SPECT 123I-ligands, including absence of thyroid uptake, ready
availability, ease of use, and lower cost.

Clinical application

Diagnosis of PD
The effectiveness to demonstrate changes in presynaptic DAT sites in vivo in PD
patients has been demonstrated by using [123I] -CIT, [123I]FP-CIT, [123I]IPT, [123I]al-
tropane, and [99mTc]TRODAT-1.

At the point when cardinal motor signs required for a clinical diagnosis of PD appear,
as many as 58–64% of dopaminergic neurons in the substantia nigra (SN) have been
lost, and striatal dopamine content has been reduced by 60–80%. Imaging studies
of the dopaminergic system and postmortem cell counts of pigmented neurons in
the SN suggest that the onset of dopaminergic neuronal loss precedes the clinical
diagnosis of PD by approximately 4–6 years. Abnormalities have been shown in
individuals at risk for the disease years before disease onset.

In some large clinical drug trials of PD where patients were enrolled based on their
clinical diagnosis of early ‘untreated’ PD, a significant proportion of patients has
normal scans. These individuals have been defined ‘subjects with scans without
evidence of dopaminergic deficit’ (SWEDD) and represented from 5.7% to 14.7% of
cases clinically diagnosed as early PD. Uptake values measured by fluorodopa PET
(REAL-PET study) and by [123I] -CIT (ELLEDOPA study) remained normal after 2-
and 4-year follow up respectively, thus questioning the diagnosis of a progressive
and neurodegenerative disorder as PD in these subjects. Alternative explanations on
false-negative PD at DAT SPECT are the theoretical possibility of scans in the normal
range at a very early stages of the disease and greater specificity of quantitative versus
qualitative analysis of the SPECT scans.

Differential diagnosis

Essential tremor

Although distribution, frequency, severity, age of onset, and evolution of symptoms

should ensure a correct separation of PD from essential tremor (ET) overlapping
features may make differential diagnosis a challenge. Both [123I] -CIT and [123-
I]FP-CIT showed no evidence of PD-like dopaminergic disruption in ET, and [123-
I]FP-CIT/SPECT proved a specificity of 95% and sensitivity of 80% in discriminating
ET from PD patients (Figure 1). Comparable results have been recently shown with
SPECT and [99mTc]TRODAT-1.Recent evidence suggests that DAT imaging is cost
effective for separating PD and ET.
Figure 1. DAT binding in patients with essential tremor (left: normal tracer distrib-
ution in the head of the caudate nucleus and the putamen) and Parkinson’s disease
(right: reduced uptake mainly in the right putamen).

Atypical parkinsonism

Presynaptic tracers have low accuracy in differentiating PD from atypical neurode-

generative parkinsonism (APS) (e.g., multiple system atrophy (MSA) and progressive
supranuclear palsy (PSP)). However, marked asymmetry in reductions of putaminal
DAT finding is more typical for PD when compared to APS. A recent study found
reduced midbrain [123I] -CIT uptake in patients with the Parkinson variant of mul-
tiple system atrophy (MSA-P), and the authors were able to correctly classify 95% of
MSA-P and PD patients.

Vascular parkinsonism

Presynaptic dopaminergic circuitry is generally preserved in vascular parkinsonism

(VP) although a slight reduction in lateral substantia nigra may occur probably due
to transneuronal degeneration. Because VP is a somewhat controversial clinical
concept and there are no clear cutoff values to separate VP from PD according
to striatal DAT availability, conventional techniques such as CT and MRI are still
considered necessary diagnostic tools.

Drug-induced parkinsonism

Drug-induced parkinsonism (DIP) is a frequent cause of secondary parkinsonism,

developing in patients during treatment with antipysychotic or dopamine receptor
blocking agents. The same syndrome can develop after treatment with agents that
deplete dopamine. About 60–70% of patients recover after medication withdrawal in
2 months. In the remaining cases, motor symptoms persist or sometimes worsen in
 the following months suggesting that DIP unmasked an already low dopaminergic
state that was preclinical before drug exposure and that the patients had very early
PD. DIP is clinically not easily distinguishable from PD because similar clinical
signs may occur in both diseases making the differential diagnosis a challenge Few
SPECT studies are available on DIP and all with [123I]FP-CIT/SPECT. Significant
putaminal [123I]FP-CIT/SPECT binding abnormalities may be found in some DIP
patients, consistent with loss of dopamine nerve terminals.

Assessment of disease progression

Disease progression in PD was originally evaluated with [123I] -CIT/SPECT. The mean
reduction of [123I] -CIT binding in PD patients versus healthy controls was reported
of 5.8% for a period of 15 months and, when calculated for 1 year, 5.6%. Further
studies with [123I] -CIT showed similar results with an annual rate of progression
ranging between 5% and 8%, although one report documented a higher rate
of 11.2% per year. One study with a 2 years follow up reported striatal [123I]IPT
binding decreases of 6.6% in the first year and 5.3% in the second year. Similarly,
[123I]FP-CIT/SPECT showed a mean annual decrease in striatal binding ratios of about
8% (of the baseline mean) (Figure 2).

Figure 2. Progressive loss of dopamine nerve terminals in the putamen in a patient

with Parkinson’s disease. The loss (see arrow becomes evident at the 12-month
follow-up scan in the left putamen).

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