Q J NUCL MED MOL IMAGING 2005;49:215-21

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Unique roles of SPET brain imaging

in clinical and research studies
Lessons from Parkinsons disease research
J. SEIBYL, D. JENNINGS, R. TABAMO, K. MAREK

The increasing availability of PET imaging in nuclear

medicine expands the armamentarium of clinical and
research tools for improving diagnosis and treatment
of neuropsychiatric disorders. Nonetheless, the role of
SPECT imaging remains critical to both research and
clinical practice. The development of rational strategies
for guiding the selection of imaging modalities flows
from primarily the nature of the clinical or research
question and the availability of appropriate radiopharmaceuticals. There has been extensive SPECT and PET
work in Parkinsons disease (PD) which highlights the
value of both these scintigraphic modalities. Three main
areas of interest in PD include imaging for improving
diagnostic accuracy, for monitoring the progression of
disease, and for assessing the therapeutic efficacy of
drugs with neuroprotective potential. The demands of the
clinical or research question posed to imaging dictates the
selection of radiotracer and imaging modality. Diagnosis
of PD represents the easiest challenge with many imaging biomarkers showing high sensitivity for detecting
abnormal reduction of dopaminergic function based on
qualitative review of images. On the other hand, using
imaging to evaluate treatments which purportedly slow
the rate of disease progression, indicated by the reduction in the rate of loss in a quantitative imaging signal in
patients studied over time, represents the most rigorous requirement of the imaging measure. In each of
these applications presynaptic markers of dopaminergic
function using SPECT and PET have been extremely valuable. Review of neuroimaging studies of PD provides a
useful example of optimized approaches to clinical and
research studies in neuropsychiatric disorders.
KEY WORDS: Tomography, emission computed, single photon
- Tomography, emission computed - Parkinsons disease Dopamine - Neurodegeneration - Neuroprotection.

Address reprint requests to: J. Seibyl, MD, Institute for Neurodegerative

Disorders, 60 Temple Street, Suite 8B, New Haven, Connecticut, 06510
USA. E-mail: jseibyl@indd.org

Vol. 49 - No. 2

Institute for Neurodegenerative Disorders

New Haven, CT, USA

Why SPECT in the era of PET?

ecently positron emission tomography (PET) has

become more widely available for clinical and
research studies of the brain in patients with neurological or psychiatric illness.1 This expansion of scintigraphic options requires review of clinical and
research uses of both PET and single photon emission
tomography (SPECT) to best tailor the appropriate
technique to the clinical or research question. The
increased technical sophistication of SPET devices
coupled with newer image processing approaches
underscores the important role this technology continues to have in diagnosis, management, and research
in neuropsychiatric disorders. Even as positron emission tomography becomes more available, the greater
availability of SPET technology and relative ease-ofuse of radiopharmaceuticals remains the reason that
a large burden of clinical CNS imaging is performed
with SPET. In addition, it is little recognized that the
longer half-lives of SPET nuclides relative to positron
emitters provide unique opportunities for SPET human
research studies; in particular, for efficiently performing large-volume neuroimaging clinical trials.
Hence, it is limiting to approach clinical or research
studies of the brain purely from the perspective of
scintigraphic modality. The technical parameters of
SPET or PET instruments should be secondary to the
primary question of the particular clinical or research

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TABLE I.Pharmacokinetic properties of some radioisotopes for Parkinsonss disease imaging.

Tracer

[123I]FP-CIT

[99mTc]TRODAT

[123I]Altropane

Protracted 8-18 h
Prolonged
1.4 nM Ki
1.7:1
High

Rapid 2-3 h
Prolonged
3.5 nM Ki
2.8:1
High

Rapid 2-3 h
Intermediate
9.7 nm Ki
26:1
Low

Rapid 0.5-1 h
Rapid
6.62 nM IC50
28:1
Low

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Time to peak uptake

Washout phase
DAT binding affinity
DAT:SERT selectivity
SPET target: background tissue ratio

[123I]-CIT

need: what radiopharmaceutical and imaging modality best addresses the clinical or research question?2
Specifically, following the particular goal of the investigation, the properties of the radiopharmaceutical,
the scheme for analyzing the imaging data, ease of use,
cost, and logistical feasibility may carry more weight
than technical characteristics of the tomographs. For
example, the necessity for truly quantitative outcome
measures coupled with availability of the radiotracer
and cost may be the overriding factors when deciding
which imaging examination to perform. An overly
simplistic break-down of roles for SPET and PET
underestimates the value of both scintigraphic
approaches.
Biomarkers in Parkinsons disease

Perhaps these principles are best demonstrated in

the development of scintigraphic markers for
Parkinsons disease (PD). In the past decade there
has been extensive work developing imaging markers for PD which target dopaminergic neuronal function. These presynaptic dopamine radiotracers have
been applied to a series of investigations of their utility as biomarkers for PD for the purpose of early and
more accurate diagnosis, evaluating the progression
of disease, and more recently to assess the effects of
medications which may retard the rate of disease progression.2
Each of these clinical and research applications
places a different degree of demand upon the radiopharmaceutical and imaging. Particular differences
between these agents will best illuminate the applicability and use in PD. For example, among the
dopamine transporter (DAT) imaging agents, all
demonstrate nanomolar affinity for DAT, yet there is
a wide range of properties with regard to selectivity
for the target site, time to peak uptake, washout rate
of specifically bound tracer, and signal:background
properties (Table I). These differences help direct the

216

specific clinical and research application of these tracers. For example, if the interest in using the tracer is
for diagnostic assessment based on visual read by the
nuclear medicine physician, many DAT radiopharmaceuticals appear to be useful. Considerations of
cost and logistical ease of use may be of greatest
importance. If the purpose of the imaging study lies
in serially monitoring the progression of disease based
on loss of the imaging signal over time, then a radiotracer which is amenable to accurate and reliable
quantitation is required. This is based on the fact that
the loss of striatal uptake is small and can be quite variable between patients over the course of disease.
Finally, if the purpose of the imaging study is designed
to evaluate the effect of a pharmacologic intervention, for example a neuroprotective effect over time,
then the greatest level of demand is placed on the
performance of the radioligand including requirements for extremely robust reliability and high accuracy for quantitation of the brain target (Table II). In
such a case, it is possible that a hypothetical neuroprotective agent could produce reductions in the rate
of loss of the imaging signal by 25-50% relative to
untreated patients. The rate of imaging signal loss
may be only 4-6% per annum, so the rate may slow
to 2-4% with an effective neuroprotective drug. To
successfully detect such a small imaging change in a
clinical research trial in PD patients, all means must be
taken to reduce variance in the quantitative imaging
outcome measure, starting with the selection of the
radiopharmaceutical and control over the instrumentation and image processing. This is must be coupled
with well-designed clinical trials with adequate patient
numbers and a reasonable duration of time between
baseline and postintervention scan.
The initial studies evaluating PET and SPET radiotracers in PD showed remarkable concordance of
imaging findings in cross-sectional studies over a
range of disease severity when comparing the different imaging biomarkers of PD; [18F]DOPA PET,

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TABLE II.Requirements for application of neuroimaging to clinical and research question in Parkinsons disease.

combining genomic or proteonomic markers may

enrich the potential screening value for at risk PD
patients.18-20
While such applications of neuroimaging may be
premature giving the state of the field, it seems feasible that screening applications will assume more clinical relevance with time. This is underscored by the
numerous clinical trials now underway in PD patients
evaluating the effects of putative neuroprotective treatments in disease progression, with an aim to develop
a therapeutic intervention which alters the course of
the disease, slowing progression, compared with the
symptomatic treatments currently available. Hence,
from a clinical perspective, the ability to rapidly and
accurately diagnosis the disorder becomes paramount.

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Task
Diagnosis
- Good target: background
- Qualitative assessment adequate
Monitor disease progression
- Need valid signal quantitation
- Good reproducibility of imaging measure
Evaluate potential neurotrotective or neurorestorative treatments
- Need valid signal quantitation
- Robust reproducibility of imaging measure

SEIBYL

[11C]VMAT2 PET, [123I]-CIT SPET, [99mTc]TRODAT SPET,

[123I]FP-CIT SPET, [123I]altropane SPET, and [123I]IPT
SPET.3-11 This is despite the fact that the tracers measure different aspects of presynaptic dopaminergic
function. Studies comparing [18F]DOPA PET and
[123I]FP-CIT SPET within PD patients have shown similar reductions in striatal uptake as a marker of
dopaminergic cell loss.12 Other studies have compared different radiotracers for DAT within PD and
healthy subjects.6 Again, these studies suggest a general comparability for evaluation the alterations in
uptake relative to healthy, age-matched control subjects for quantitative purposes.
Of greater interest, these biomarkers show bilateral reductions of striatal tracer uptake in hemiparkinson patients with larger reductions consistently on
the side of the brain opposite (contralateral) to motor
symptoms.13-16 These studies have demonstrated
approximately 40-50% loss for contralateral striatum
compared with 20-30% loss for the ipsilateral side relative to age-matched healthy control values. PD
patients usually progress to develop bilateral symptoms,17 hence these studies suggest that measuring
these different aspects of presynaptic dopaminergic
neuronal function can provide a highly sensitive
assessment of changes occurring in brain prior to
manifestation of clinical symptoms. This speculation
has fueled interest in developing these imaging biomarkers for the very early detection of PD and potentially screening at-risk populations. Using imaging for
screening is expensive and not cost effective, but the
combination of a simple, high sensitivity screening
test or battery of tests as a 1st level screen and imaging as 2nd level screen has been suggested. Some proposals for 1st level screening include olfactory testing, simple motor tasks involving drawing evaluations, and handwriting among others. In addition,

Vol. 49 - No. 2

Parkinsons disease diagnosis

How well do imaging agents diagnose PD? What

imaging marker and modality is best suited for accurate diagnosis? There have now been several large
clinical studies comparing neuroimaging findings
against a gold standard clinical diagnosis rendered
by a movement disorder specialist.21, 22 In these studies, imaging appears to be useful in distinguishing
PD from essential tremor and other non-Parkinsonian
syndromes, although presynaptic dopamine imaging
agents do not easily distinguish amongst Parkinson
syndrome patients (progressive supranuclear palsy,
multiple system atrophy, etc). The primary imaging
outcome measure of these evaluations has been a
visual interpretation of the pattern of loss of striatal
uptake by a nuclear medicine physician. Some studies have also incorporated a quantitative or semiquantitative imaging measure based on a striatal (or
putamen) to background ratio, influx constant for
[18F]DOPA, or an equilibrium brain tissue distribution
volume for [123I]-CIT.23 In these studies, both visual
assessment of the distribution of radiotracer in striatum and quantitative or semi-quantitative measures
have shown very high overall accuracy in separating
the Parkinson syndrome from non-Parkinson syndrome controls.4, 14, 16 It may be concluded that for
SPET many DAT agents studied perform exceedingly well in this design. In addition, smaller studies suggest imaging may also be useful in special diagnostic
situations such as psychogenic, drug-induced, traumatic or vascular parkinsonism, i.e. in distinguishing
these syndromes without a presynaptic dopamine
deficit from PD.8, 24, 25

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various candidate imaging agents. Unfortunately, there

have not been large, prospective studies which fully
assess the value of imaging in patients with suspected PD. There have been only smaller studies which
provide a glimpse at the diagnostic utility and role of
neuroimaging in PD using this alternative design
involving suspected PD patients.
One preliminary study of 35 suspected Parkinson
syndrome (PS) patients evaluated the diagnostic utility of [123I]-CIT SPET imaging in blinded, prospective
fashion.32 These patients were referred to a movement disorder clinic by community neurologists who
suspected PS but were unsure of diagnosis. Patients
were followed clinically over a 6-month period for a
full clinical evaluation and gold-standard diagnosis
by a movement disorder neurologist unaware of the
imaging findings. The referring community neurologist and movement disorder expert provided an initial diagnosis. A SPET scan was performed at the time
of initial evaluation and visually read as PS or not PS
and quantitative analysis of the scan performed and
compared against a healthy control database. The 4
diagnoses assessments obtained at baseline were compared with the gold standard at 6 month follow-up.
These diagnoses showed increasing concordance (better diagnostic accuracy) in the following order from
worst to best; the initial diagnoses by the community neurologist, initial diagnosis by movement disorder
specialist, the qualitative SPET can diagnosis, and the
quantitative SPET analysis. The sensitivity of the [123I]CIT and quantitative SPET imaging diagnosis was 0.92
while the specificity of the imaging was 1 compared
to the clinical gold standard diagnosis. While promising, larger studies of this sort, with good follow-up for
ensuring the accuracy of the gold standard clinical
diagnosis are required to fully assess imaging as aid
to diagnosis in early suspected PD.
A third caveat in using any of the neuroimaging
biomarkers in PD diagnosis is the concern that symptomatic treatments may somehow alter the imaging
assessment based on regulation of the imaging target.
For example, l-dopa/carbidopa still the most common treatment of PD has been shown to cause regulatory changes in density of DAT in some animal studies. However, interpretation of these data is difficult
as some studies show increases, some show decreases, and most show no changes in DAT in animals
receiving short-duration, large doses of l-dopa.33-37 In
5 human imaging trials involving small numbers of
subjects and different SPET and PET DAT tracers, 4 of

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Nonetheless, there are 3 major caveats when considering the selection of the radiotracer and modality for diagnosis of PD. First, there have been only
limited studies cited above which have directly compared the diagnostic performance of different SPET
and PET dopaminergic biomarkers in a within-subject
evaluation of Parkinson syndrome and non-Parkinson
syndrome patients.26 It is possible that there may be
some differences in performance of these agents when
viewed head-to-head. This is particularly relevant for
the use of quantitative or semi-quantitative outcomes
which may be difficult to obtain with some tracers
owing to very fast kinetics ([123I]altropane),27 or even
among tracers with slower kinetics, where there may
be between-subject differences in rates of washout
of specifically bound tracer from striatum. In this
instance, simple selection of a single post injection
time point for the acquisition of the scan could introduce variability in the determination of the striatal
uptake ratio since factors unrelated to the density of
DAT sites, such as the state of hydration of the patient
could influence the simple ratio measure.
A second, more salient caveat is that the design of
these large diagnostic accuracy studies may not reflect
the actual performance, and hence the real utility of
these tests in the type of clinical setting in which they
would be used. It seems likely that a referring neurologist or primary care physician considering the
diagnosis of PD would be seeing patients early on in
their illness course, when symptoms may be very
mild and a diagnosis difficult. Clinical studies of the
accuracy of clinical diagnosis by movement disorder
specialists in very early PD patients suggest an error
rate of approximately 10% in this early group, compared to diagnosis based on further clinical followup.28-31 In fact, the clinical diagnosis of PD is usually
based on an initial assessment, often a medication
trial with a dopaminergic drug, and clinical observation of development of symptoms and response to
treatment.
Keying off these observations, an alternative study
design for evaluating the performance of PET and
SPET biomarkers for accurate PD diagnosis would
attempt to replicate these referral conditions and the
subject population for whom these early imaging
diagnostic assessments would be employed, specifically, those patients with suspected PD rather than
an established diagnosis. It is possible that this might
pose a more stringent test of the radiopharmaceutical
and imaging modality which could tease apart the

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SEIBYL

TABLE III.Findings among different presynaptic dopamine system markers in PD patients.

Radiopharmaceutical and modality

18F-DOPA

PET

11C-VMAT2

PET

I--CIT SPET

Target
Annual reduction in normal aging
Bilateral reduction in hemiparkinsons disease
Correlates with UPDRS motor scores in Cross-sectional studies
Annual loss of signal expressed as percent loss from baseline

DA turnover
change
Yes
Yes
7-12%

5 studies demonstrated no changes of the imaging

measure with serial imaging after a controlled, therapeutic dosing of l-dopa/carbidopa in PD patients.38-41
These studies fail to conclusively rule out the possibility of short-term regulation of DAT by clinically relevant dopaminergic treatments in PD patients as the
number of subjects studied is small and some of the
imaging measures employed in these studies have
not undergone full test/retest reliability validation. A
large, multicenter international study evaluating this
question is currently underway to evaluate the shortterm effects of dopamine agonists and l-dopa/carbidopa on DAT SPET imaging in a placebo controlled
trial.

strate that subjects imaged serially over several years

show a significant reduction on the imaging signal
on the order of 5-11% per annum 43-47 (Table III).
In addition, large clinical trails involving the use of
imaging outcome measures over a number of years
have demonstrated the utility of imaging outcomes
for assessing potential effects of putative neuroprotective or neurotoxic drugs. Two recent, large clinical
trials of progression with neuroimaging outcomes are
the CALM-PD study ([123I]-CIT) and the REAL-PET
study ([18F]DOPA).41, 48 The CALM-PD and REAL-PET
studies compared imaging outcomes over 4 and 2
years, respectively, in PD patients treated initially with
either a dopamine agonist or l-dopa/carbidopa. Both
studies demonstrated relatively less loss of the SPET
or PET imaging signal in the PD patients treated with
the dopamine agonist (pramipexole for CALM-PD and
ropinirole for REAL-PET) of 35-40% less loss compared with the l-dopa/carbidopa group. Again, both
studies, targeting very different aspects of presynaptic dopamine neuronal function and using different
scintigraphic modalities, produced remarkably similar
findings. Of note, both studies were not placebo-controlled (difficult to accomplish in symptomatic patients
evaluated over several years) and could not provide
a definitive reason for the differences in the treatments on the imaging measures; whether dopamine
agonists are neuroprotective, l-dopa/carbidopa is neurotoxic, some combination of these, or an alternative
explanation.
Further, these studies do not address the question
of whether it would be feasible in a clinical setting to
use neuroimaging to follow an individual PD patients
disease progression, and perhaps eventually, assess the
efficacy of a treatment with a neuroprotective or neurorestorative agent. The studies cited above are based
on the average rates of signal loss from a large number of PD patients. For both SPET and PET radiopharmaceuticals in the CALM-PD and REAL-PET studies the variability between PD in the annualized rate

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Vesicular transporter
0.5%
Yes
Yes
10%

123

Imaging the progression of disease

As noted above, it may be more difficult to evaluate the progression of PD with imaging than to detect
differences in dopaminergic function in PD patients
compared with non-PD subjects.42 This is due to the
very slow and often variable progression of PD.
Nonetheless, there has been considerable enthusiasm for using imaging as an objective marker of disease status because PD patients are invariably treated
with symptom-modifying medications and clinical
assessments of progression are muddied by inability
to completely wash-out medications from brain.
Imaging requires more of the radiopharmaceutical
and imaging modality than for diagnostic assessment
of dopaminergic deficit. First, visual assessment is not
adequate for determining the rate of PD progression.
The estimation of signal loss (usually expressed as a
percent change) is difficult and inaccurate based on
visual interrogation of the images. Using quantitative
or semi-quantitative approaches, a number of studies
employing different PET and SPET ligands have
demonstrated signal loss over time. In studies of disease progression these tracers consistently demon-

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DA transporter
0.8-1.4%
Yes
Yes
4-13%

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12. Ishikawa T, Dhawan V, Kazumata K, Chaly T, Mandel F, Neumeyer
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13. Asenbaum S, Brucke T, Pirker W, Podreka I, Angelberger P, Wenger
S et al. Imaging of dopamine transporters with iodine-123-betaCIT and SPET in Parkinson's disease. J Nucl Med 1997;38:1-6.
14. Brucke T, Djamshidian S, Bencsits G, Pirker W, Asenbaum S,
Podreka I. SPET and PET imaging of the dopaminergic system in
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18. Pal PK, Wszolek ZK, Uitti R, Markopoulou K, Calne SM, Stoessl AJ
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19. Kang UJ, WY Lee, Chang JW. Gene therapy for Parkinson's disease:
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20. Heinz A, Goldman D, Jones DW, Palmour R, Hommer D, Gorey JG
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21. Parkinson Study Group. A multicenter assessment of dopamine
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22. Benamer TS, Patterson J, Grosset DG, Booij J, de Bruin K, van
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of signal loss was high, similar to clinical reports of

variable progression in PD. This variability raises question whether it would be feasible to successfully follow some PD patients with neuroimaging biomarkers
and what the optimal interval between imaging assessments would be for a clinical assessment of this sort.
Therefore, the question of whether any imaging agent
can be used successfully in individuals as a routine
clinical marker for disease progression remains unresolved pending further study.
The roles of SPET or PET imaging in PD and
other neuropsychiatric disorders

The lessons from both PET and SPET studies of PD

to date have been critically important in effecting clinical approaches to treatment as well as posing important challenges and issues about the role of neuroimaging biomarkers in clinical practice with PD
patients. The considerable progress in the application of imaging outcomes to PD diagnosis, to evaluating disease progression, and assessing potential protective effects of treatments against ongoing progression have utilized both PET and SPET biomarkers.
The roles of these modalities will continue to develop as the clinical and research questions direct and
tools are refined. In the instance of PD, the question
of SPET versus PET is probably improper as scintigraphic modality is subservient to the clinical or
research question. These issues directly speak to clinical and research issues in other neurodegenerative
disorders like Alzheimers dementia where debates
about the diagnostic and monitoring role of [18F]FDG
PET, perfusion SPET, and more specific putative biomarkers like -amyloid ligands are fueled similarly
by the promise and urgency for developing diseasemodifying treatments.
Conclusions

In summary, current experience with presynaptic

markers of dopamine function in Parkinsons disease
suggest that both PET and SPET biomarkers can provide useful information about diagnosis, monitoring
disease progression, and evaluating disease-modifying therapies. The future role of the imaging modalities for assessment of PD will depend on the clinical
or research need and the radiopharmaceutical best
suited to the question.

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Booij J, Bergmans P, Winogrodzka A, Speelman JD, Wolters EC.
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