S L PIMLOTT,
BSc, PhD
and 2K P EBMEIER,
MA, MD
Radiopharmaceutical Research & Development, West of Scotland Radionuclide Dispensary, Western Infirmary,
Dumbarton Road, Glasgow G11 6NT and 2Foundation Chair of Old Age Psychiatry, Oxford University, Department of
Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK
Spect tracers
Blood flow and perfusion
Two technetium-99m (99mTc)-labelled regional brain
perfusion imaging SPECT tracers are commonly used:
99m
Tc-hexamethylpropyleneamine (99mTc-HMPAO or
CeretecTM) and 99mTc-ethylcysteinate dimer (99mTc-ECD
or NeuroliteTM). 123I-labelled isopropyl-iodoamphetamine (123I-IMP), which binds to amphetamine receptors
on neurons, can also be used as a brain perfusion SPECTimaging tracer, but its high cost and poor availability
have limited its use.
These tracers are small lipophilic compounds that
have the ability to cross the intact bloodbrain barrier by
simple diffusion. Once taken up into the brain, the
distribution of these tracers reflects regional brain
perfusion, and this fixed regional distribution is retained
for sufficient time to permit image acquisition. The use of
these tracers has been reviewed in detail in the past [1]
and has been successful in imaging brain perfusion in
dementia patients [2]. SPECT brain perfusion imaging
plays a clinical role in the diagnosis, therapeutic
management and follow-up of dementia patients.
Acetylcholine system
The cholinergic system is involved in the control of a
variety of complex functions, including learning, memory and modulation of behaviour [3]. In patients with
Alzheimers disease (AD), post-mortem studies have
consistently documented a selective loss of cholinergic
neurons in the basal forebrain [4]. Cholinergic function is
also severely affected in dementia with Lewy bodies
(DLB) [5, 6], in which dysfunction occurs earlier than in
AD [6]. Radiotracers that allow imaging of the acetylcholine system using SPECT may therefore be useful in the
diagnosis and treatment of dementia.
Address correspondence to: Klaus P Ebmeier, Oxford University,
Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX,
UK. E-mail: klaus.ebmeier@psych.ox.ac.uk
123
I-labelled iodo-dexetimide (123I-Dex) and iodo-quinuclidinyl benzilate (123I-QNB) are two SPECT tracers
that have been developed in an attempt to image the
muscarinic acetylcholine receptors in the brain. 123I-Dex
is a non-subtype-selective muscarinic radioligand [7] that
has been used to visualize muscarinic receptor abnormalities in AD [8, 9]. 123I-QNB is a specific marker for M1/
M4 muscarinic receptors [10]. Both the (R,R) and the
(R,S) stereoisomers of 123I-QNB have been developed
and used in clinical imaging studies in AD [1114] and
DLB patients [15].
Loss of cortical nicotinic acetylcholine receptors is a
neurochemical hallmark of AD. Nicotinic acetylcholine
receptors can be visualized successfully using the novel
SPECT tracer 5-123I-A-85380 [1618], which binds predominantly to the a4b2 subtype [19]. Recently, there have
been a number of preliminary studies investigating
5-123I-A-85380 binding in AD patients [2022] (Figure 1).
In order to image pre-synaptic cholinergic terminal
densities, an iodinated analogue of vesamicol that binds
to the pre-synaptic vesicular acetylcholine transporter,
123
I-iodobenzovesamicol (123I-IBVM), has been developed [23, 24]. Preliminary studies in AD patients found
123
I-IBVM imaging to be useful in monitoring the
survival of cholinergic terminals during disease progression [23].
All of the acetylcholine imaging techniques described
above require further investigation to determine their
clinical usefulness in dementia patients.
Other neurotransmitters
Various neurotransmitter systems, other than the
cholinergic system, have also been investigated in
dementia using SPECT imaging. Imaging the dopaminergic system has become particularly important with
regard to the differential diagnosis of DLB from primary
degenerative dementia. 123I-iodobenzamide (123I-IBZM)
is a promising post-synaptic dopamine D2 receptor
ligand, and studies have shown significantly reduced
uptake of this ligand in the striatum in DLB patients
compared to that in AD patients and controls [25].
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Figure 1. a4b2 Nicotinic receptor binding 4 h after injection of 5-123I-A-85380, examined with single photon emission CT
(maximum intensity projection). Left to right: rotating from facing left to facing right. Greatest tracer uptake in thalamus, brain
stem and cerebellum.
Amyloid ligands
AD is characterized by the presence of abundant
amyloid plaques in the brain at post-mortem [30]. There
has been extensive research into the development of PET
and SPECT imaging agents that target amyloid plaques
as tools for following disease progression in AD and for
monitoring novel therapeutic interventions [31]. 123IIMPY, a modified thioflavin derivative, is the only
SPECT ligand to be evaluated in humans to date [32].
Further studies are required to determine the usefulness
of 123I-IMPY for imaging amyloid plaques in AD
patients.
Diagnostic issues
Radioligand imaging, like many other diagnostic
techniques, can be validated at two levels. First, imaging
should reflect the physical and biochemical properties of
the tissue examined. The validity of an image depends
on the accuracy of the model that connects tracer activity
with the underlying biological property of interest. For
example, quantitative models can directly link blood
flow or receptor binding capacity with the measured
tracer activity. The second type of validity relates to the
S154
Figure 3. (a) 95% confidence intervals of weighted sensitivity and (b) 95% confidence intervals of weighted specificity. The
graphs summarize the results of N studies each comparing AD patients VaD, FTD and other patients (O; e.g. those with
depression) and healthy controls (C) note low sensitivity against non-demented patient controls. (c) 95% confidence intervals
of mean ages (years) in the study groups in each of the four comparisons illustrated in (a) and (b). (All data from [41].)
S156
Cost-effectiveness
A number of authors have attempted the difficult task
of gauging the cost-effectiveness of perfusion SPECT
[51], or indeed of the more expensive fluorodeoxyglucose-PET [52, 53], in the diagnosis of dementia:
making use of PET was associated with a reduced rate of
false-negative and false-positive findings compared with
the conventional approach ( at a prevalence of 51.6% in
the studied symptomatic population) and a cost savings
of $1,138 per correct diagnosis rendered The lower cost
was maintained over a wide range of tested values for
variables of sensitivity, specificity, costs of PET and longterm care, and varying approaches to the use of
structural neuroimaging [53]. However optimistic these
conclusions, the results of health economic studies
appear to be very sensitive to the analytic methods
employed. A similar study examining the cost-effectiveness of various imaging methods in dementia concludes:
the use of PET to confirm the results of the standard
clinical work-up cost more, but yielded fewer benefits,
than a strategy in which dynamic susceptibility weighted
contrast-enhanced MR imaging was substituted for the
typically performed structural computed tomography.
This remained stable in scenarios in which standard
diagnostic work-up accuracy, drug treatment effectiveness, and version of the Health Utilities Index were
altered In all scenarios, SPECT yielded fewer benefits
than other strategies at a higher cost. PET may have high
diagnostic accuracy, but adding it to the standard
diagnostic regimen at AD clinics would yield limited, if
any, benefits at very high costs [52]. It is of significance
to note that here structural non-enhanced CT was part of
the routine clinical work-up and was replaced by the
MRI procedure described above. For the analysis of
SPECT and PET data, the structural scan was retained.
Importantly for potential net savings, the results of
imaging did not limit the treatment for non-AD
dementia. The sensitivity of such complex models to
factors upstream or downstream of the actual imaging
and image interpretation is very obvious.
Methods of scan interpretation have also been evaluated using economical models. Reviewing the data
The British Journal of Radiology, Special Issue 2007
Acknowledgments
This study was funded in part by the EC-FP6 project:
Diagnostic Molecular Imaging (DiMI), LSHB-CT-2005512146.
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