The British Journal of Radiology, 80 (2007), S153S159

SPECT imaging in dementia

1

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

ABSTRACT. Single photon emission computed tomography (SPECT) is a non-invasive

functional neuroimaging technique that can be used in the diagnosis of dementia. This
review describes some of the SPECT radiotracers available for imaging dementia
patients and discusses recommendations for the clinical use of this imaging technique.

Received 19 April 2007

Revised 12 December 2007
Accepted 24 January 2008
DOI: 10.1259/bjr/89285735
2007 The British Institute of
Radiology

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

The British Journal of Radiology, Special Issue 2007

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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S L Pimlott and K P Ebmeier

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.

Imaging of dopamine transport with the now licensed

SPECT tracer 123I-2b-carbomethoxy-3b-(4-iodophenyl)N-(3-fluoropropyl) nortropane (123I-FPCIT or DatSCAN2) has highlighted a significantly reduced dopamine transporter function in DLB patients compared
with AD patients, and therefore provides a means to
differentiate clinically between DLB and AD [26, 27]. It
should be noted that a 99mTc-labelled imaging agent for
dopamine transporters (99mTc-TRODAT) is also available
[28], although to date this agent has not been used in
studies of dementia patients.
The GABA (c-aminobutyric acid)-ergic system has also
been imaged using SPECT. The peripheral benzodiazepine receptor (PBR) is present on microglia and is
upregulated during inflammation. 123I-Pk11195 is a
SPECT radiotracer for the PBR, which has previously
been used to image neuroinflammation in AD patients
[29]. However, this ligand, along with a 11C-labelled
version for positron emission tomography (PET) (11CPk11195), suffers from poor brain uptake. The development of a PET/SPECT radiotracer with more suitable
characteristics is therefore required for imaging of
neuroinflammation in dementia patients.

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
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ability of imaging to support diagnostic decisions. Such

decisions may be about a particular diagnosis, or the
prognosis or likely treatment response. This clinical
validity or usefulness is of special interest to clinicians in
charge of patients management, more often a psychiatrist or geriatrician than a neurologist. It is also of
indirect interest to health service managers and public
health physicians.
Diagnostic validity depends not only on the biochemical tissue property measured by the imaging modality
but also on the degree to which this property is
associated with the disease or clinical feature in question.
In other words, how common and characteristic are
cortical atrophy, amyloid plaques, reduced blood flow or
reduced binding of dopamine transporters in AD, DLB
or vascular dementia (VaD)? Proof of concept studies for
new diagnostic tests are usually carried out using simple
casecontrol designs, which compare specific clinically
defined patient groups with healthy or conveniently
available controls, but the investigation of clinical utility
requires different study designs. In order to gather
realistic measures of sensitivity (1 minus the proportion
of not-identified, i.e. false-negative, cases) and specificity
(1 minus the proportion of falsely identified, i.e. falsepositive, controls), paradoxically, the novel investigation
must be applied in a routine clinical context. To compute
specificity using data from a healthy volunteer group is
unhelpful [33], as is using data from patients who have
been selected according to research criteria who are
young, do not suffer from co-morbid illness and are
especially motivated and compliant with the investigation [34]. In addition, diagnostic imaging always occurs
after clinical assessment, and so it is not the isolated
diagnostic accuracy that has greatest importance but the
value added to routine clinical assessment. Finally, the
decision whether a new diagnostic test is adopted for a
particular clinical presentation depends on the balance of
costs and benefits. These include the financial costs of the
imaging technique itself and, further downstream, the
availability and cost of effective treatments that could be
prescribed as a result of the image-based diagnosis. It is
important for the radiologist and nuclear medicine
specialist to understand that the superior physical or
biochemical validity of a technique, for example that of
positron emission tomography over single photon
tomography, does not necessarily mean that technique
is clinically superior. Being able to link tracer activity
unambiguously to an underlying biological property,
such as regional cerebral blood flow, does not necessarily
imply a superior diagnostic test. Furthermore, although
the effects of cerebral atrophy on partial volume may
The British Journal of Radiology, Special Issue 2007

SPECT imaging in dementia

Figure 2. Timeline of guidelines.

PET, positron emission tomography;
SPECT, single photon emission CT.

confound attempts to measure blood flow, they may in

fact be more powerful than blood flow data in identifying disease.
A review of guidelines issued by different professional
and national bodies is instructive in tracking the
development of evidence over the past 7 years
(Figure 2). These guidelines were originally the result
of clinical consensus among opinion leaders however
(self-)defined, but now they are increasingly based on
systematic reviews, meta-analyses and even healtheconomical evaluation. The clinical utility of investigations in terms of sensitivity and specificity was not
considered in the guidelines of the European Association
of Nuclear Medicine [35, 36] nor those of the American
College of Radiologists [37]. These guidelines report
indications for imaging that are positive and inclusive of
dementias, although admittedly the emphasis of these
guidelines is on procedure rather than cost-effectiveness.
By contrast, early clinical guidelines, e.g. those by the
American Academy of Neurology [34], are conservative.
Despite the large casecontrol studies that were available
[33], they stated that SPECT should not be included in the
routine evaluation of the demented patient. The
Consensus Paper of the European Alzheimers Disease
Consortium [38] recommended, on the basis of contemThe British Journal of Radiology, Special Issue 2007

porary guidelines [34, 39], that SPECT or PET be used only

in selected cases of diagnostic uncertainty where they can
provide significant incremental information. Since the
beginning of this century, larger, more clinically realistic
studies have accumulated (recently summarized in [40,
41]). These suggest that although its sensitivity is limited,
perfusion SPECT provides a higher specificity (91%) in the
differential diagnosis of AD against other types of
dementia than do clinical diagnostic criteria (70%) [41].
The last couple of years have seen a proliferation of
guidelines from various UK bodies. The Royal College of
Psychiatrists Council Report, hopefully named forgetful, but not forgotten [42], concludes in characteristically ambivalent fashion that it is clear that MRI and
SPECT can both provide additional information, but that
the value of MRI, SPECT or PET remains to be
established. In its dementia guidelines [43], The British
Association of Psychopharmacology states that SPECT
has modest diagnostic utility in separating AD from
normal ageing, mild cognitive impairment and non-AD
dementia, and that it may have utility in differentiating
frontotemporal dementia (FTD) from dementia resulting
from other causes. Furthermore, dopaminergic SPECT
may help separate DLB from AD and VaD. Finally, both
the Scottish Intercollegiate Guidelines Network (SIGN;
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S L Pimlott and K P Ebmeier

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].)
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The British Journal of Radiology, Special Issue 2007

SPECT imaging in dementia

[44]) and the English National Institute for Health and

Clinical Excellence (NICE; [45]) concur that although
clinical criteria may be more sensitive at detecting AD
than SPECT, SPECT provides greater specificity against
other types of dementia than clinical criteria. SPECT may
be used in combination with CT to aid the differential
diagnosis of dementia when the diagnosis is in doubt
[44], in fact should be used to help differentiate AD, VaD
and FTD and should be used to help establish the
diagnosis of DLB if the diagnosis is in doubt [45].
The licensing procedure for the dopamine transporter
ligand 123I-FPCIT involved a large multicentre study,
which has provided credible data fairly early in the life
of this new diagnostic marker [27, 4649]. Estimates of
sensitivity and specificity in differentiating DLB from
AD were 78% and 90%, respectively [27, 49]. Several
guidelines now acknowledge the efficacy of the 123IFPCIT marker in differentiating DLB from other types of
dementia, so that its use is likely to increase [43, 45, 50].

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

from a large European study, Kronborg Andersen and

Cairns [51] concluded that a diagnostic strategy for AD
that includes SPM [statistical parametric mapping]-based
SPECT scanning may be a cost effective strategy
compared with a strategy where the SPECT scan is
reported with visual inspection of the image [if] used
selectively in patients suspected to suffer from AD. The
case for the use of an automated voxel-based method of
scan presentation that highlights those areas of the
patients brain that have significant reductions in
perfusion appears to be particularly strong for inexperienced clinicians [54, 55].
While PET is superior to SPECT on principal grounds,
such as fully quantifiable measures, greater sensitivity to
tracer amounts of radiation and more accurate attenuation correction, there also appears to be a difference in
the diagnostic utility of the two methods. In a direct
comparison of 18FDG-PET and 99mTc-HMPAO-SPECT
scans, both acquired in a number of AD patients and
control volunteers [56, 57], loss of glucose metabolism
and reduction in perfusion were correlated in the
temporoparietal and posterior cingulate cortices
(r50.90). Reductions in tracer uptake were significantly
more pronounced when measured by PET rather than by
SPECT. The authors also measured the correlation
between dementia severity and the number of abnormal
voxels. That correlation was somewhat better for PET
than for SPECT [58]. Silverman [58] concluded that the
higher sensitivity of PET in detecting AD was especially
important if identifying disease in its earliest stages so
that patients could be targeted for therapy was the aim of
the investigation. This result is not surprising, given the
generally poor sensitivity of SPECT in identifying AD
[41]. Dementia and mild cognitive impairment are
clinical diagnoses, i.e. they come to clinical attention
through the concern of patients and their relatives.
Primary screening of patients with memory concerns
using PET is likely to be prohibited by financial and
radiodosimetric concerns. Therefore, and until early
treatment becomes an option, specificity against other
dementias above and beyond routine clinical assessment
will be more important from a clinical point of view [41].
Future developments in PET and SPECT will most
likely target the pathological mechanisms of the dementias to increase specificity, be it pre-synaptic dopamine
receptor density [27], nicotinic receptor density (Figure 1
[21, 22]) or the density of brain amyloid in vivo [59].

Acknowledgments
This study was funded in part by the EC-FP6 project:
Diagnostic Molecular Imaging (DiMI), LSHB-CT-2005512146.

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