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British Journal of Radiology (2007) 80, S153-S159
© 2007 British Institute of Radiology
doi: 10.1259/bjr/89285735
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Full paper

SPECT imaging in dementia

S L PIMLOTT, BSc, PhD 1 and K P EBMEIER, MA, MD 2

1 Radiopharmaceutical Research & Development, West of Scotland Radionuclide Dispensary, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, 2 Foundation Chair of Old Age Psychiatry, Oxford University, Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK

Correspondence: Klaus P Ebmeier, Oxford University, Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK. E-mail: klaus.ebmeier{at}psych.ox.ac.uk


   Abstract
Top
 Abstract
Spect tracers
 Diagnostic issues
 References
 
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.


   Spect tracers
Top
 Abstract
 Spect tracers
Diagnostic issues
 References
 
Blood flow and perfusion
Two technetium-99m (99mTc)-labelled regional brain perfusion imaging SPECT tracers are commonly used: 99mTc-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 SPECT-imaging 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 blood–brain 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 Alzheimer's 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.

123I-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 [11–14] 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 [16–18], which binds predominantly to the {alpha}4β2 subtype [19]. Recently, there have been a number of preliminary studies investigating 5-123I-A-85380 binding in AD patients [20–22] (Figure 1Go).


Figure 1
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  		Figure 1. {alpha}4–β2 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.

 
In order to image pre-synaptic cholinergic terminal densities, an iodinated analogue of vesamicol that binds to the pre-synaptic vesicular acetylcholine transporter, 123I-iodobenzovesamicol (123I-IBVM), has been developed [23, 24]. Preliminary studies in AD patients found 123I-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]. Imaging of dopamine transport with the now licensed SPECT tracer 123I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FPCIT or Dat-SCANTM) 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 ({gamma}-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) (11C-Pk11195), 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]. 123I-IMPY, 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
Top
 Abstract
 Spect tracers
 Diagnostic issues
References
 
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 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 case–control 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. false-positive, 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 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 2Go). 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 health-economical 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.


Figure 2
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  		Figure 2. Timeline of guidelines. PET, positron emission tomography; SPECT, single photon emission CT.

 
By contrast, early clinical guidelines, e.g. those by the American Academy of Neurology [34], are conservative. Despite the large case–control 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 Alzheimer's Disease Consortium [38] recommended, on the basis of contemporary 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; [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, 46–49]. 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 123I-FPCIT marker in differentiating DLB from other types of dementia, so that its use is likely to increase [43, 45, 50].


Figure 3
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  		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].)

 

   Acknowledgments
 
This study was funded in part by the EC-FP6 project: Diagnostic Molecular Imaging (DiMI), LSHB-CT-2005-512146.

Received for publication April 19, 2007. Revision received December 12, 2007. Accepted for publication January 24, 2008.


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