Dopamine transporter imaging for the diagnosis of dementia with Lewy bodies

  • Protocol
  • Diagnostic

Authors


Abstract

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows:

This review has two primary objectives.

Objective A: To estimate the accuracy of DAT imaging for the diagnosis of dementia with Lewy bodies (DLB) in patients with dementia in secondary care.
Objective B: To assess the value of DAT imaging in clinical practice by estimating the accuracy of DAT imaging for the diagnosis of DLB in secondary care patients with a pre-existing suspicion of DLB on the basis of a clinical work-up.

The secondary objective is to use subgroup analyses to investigate the following potential sources of heterogeneity.

(a) Age of participants.

(b) Severity of dementia. The performance of the index test itself may vary with dementia severity. For objective B, since the performance of the clinical criteria may also depend on the severity of dementia, the 'added value' to be obtained from the index test may vary significantly.

(c) For objective B, diagnostic status at inclusion (possible or probable DLB, or both).

(d) DAT imaging method (SPECT or PET, ligand).

Background

Target condition being diagnosed

Dementia with Lewy bodies (DLB) is a common cause of neurodegenerative dementia of old age, with an estimated prevalence of 15% to 25% of cases based on autopsy studies (Perry 1990; Heidebrink 2002). Community prevalence estimates vary more widely, with rates reported of 0% to 5% in the elderly population and 0% to 30.5% among elderly people with dementia (Zaccai 2005).

Diagnosis during life rests on a set of consensus clinical criteria which were adopted in 1996 (McKeith 1996) and revised in 2005 (McKeith 2005). The 1996 and 2005 versions are both shown in Appendix 1. Probable or possible DLB diagnoses may be made depending on the number of core features or suggestive features, or both. The core features of the illness are recurrent visual hallucinations, fluctuating cognition and Parkinsonism. The consensus criteria state that these features should occur early in the course of the illness.

As for other forms of dementia, the diagnostic gold standard is the neuropathological findings at post mortem. The neuropathological criteria for DLB have also evolved over time and remain subject to debate. The standards currently considered the most robust combine assessments of Lewy body (LB) pathology and Alzheimer's disease (AD) pathology in order to estimate the probability of an association between the LB pathology and the dementia syndrome. These are either the standards established by McKeith 2005 or a combination of LB pathology assessed according to the method described by Braak 2003, with an accepted AD pathological standard (including as a minimum Braak neurofibrillary tangle staging). Comparisons of pathological and clinical findings suggest that the typical DLB clinical syndrome is seen most clearly in patients with 'pure' DLB pathology. In contrast, patients who also have significant AD pathology are found to have an attenuated clinical syndrome which is harder to recognise in life.

Changing neuropathological standards for the diagnosis of DLB clearly impact on assessment of the accuracy of the consensus clinical criteria. Several groups have reported sensitivity and specificity using the earlier clinical and neuropathological criteria. Overall, a clinical diagnosis of probable DLB in these studies had high specificity but often poor sensitivity (McKeith 2004), although it is likely that overdiagnosis of DLB using older neuropathological standards contributed to poor sensitivity estimates. There are few published data on the accuracy of a diagnosis of possible DLB. Although it appears to be more sensitive, this is at the cost of a loss of specificity with the only reported autopsy series finding a specificity of just 28% (Verghese 1999). Nelson and colleagues (Nelson 2010) have reported on a very large clinicopathological dataset from the National Alzheimer's Disease Coordinating Center (NACC) from 2000 onwards which used current neuropathological methods. In line with earlier reports, they found a high specificity of an ante mortem diagnosis of DLB (95%), but again low sensitivity (32.1% for pure DLB and 12.1% for DLB + AD). These authors found that the accuracy of DLB diagnoses in the specialist dementia centres contributing to the NACC database is actually declining with time.

An important but poorly understood issue is how the accuracy of the clinical criteria changes with the stage of the illness. Core features, such as visual hallucinations and Parkinsonian motor symptoms, occur more commonly in other forms of dementia by the moderate to severe stages. Thus, the ability of the criteria to predict the presence of Lewy body pathology declines as dementia progresses (Nelson 2010). The consensus criteria recognise this by requiring that the core features should be present early in the course of the illness, but the application of this requirement is not operationalised.

Index test(s)

Brains of DLB patients show a variety of reductions in indices of dopaminergic function both in vitro and in vivo which distinguish them from healthy elderly subjects and from AD patients (Tatsch 2008). Among the distinguishing features is a reduction of pre-synaptic dopamine transporter (DAT) in the corpus striatum, reflecting degeneration of dopaminergic nigrostriatal neurons. It is possible to image striatal dopamine transporter sites in vivo with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) using a variety of radioligands. Many of these have only been used for research purposes, but the SPECT ligand [123I]-N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (123I-FP-CIT) is commercially available (under the brand name DaTscanTM). Approved indications for DaTscanTM in Europe and the United States are shown in Appendix 2.

In healthy subjects, 123I-FP-CIT SPECT images show the corpus striatum (caudate nucleus and putamen) lit up as a comma-shaped structure bilaterally, reflecting specific uptake of the DAT ligand. Most experience of abnormal DAT images derives from patients with Parkinson's disease. The typical pattern in Parkinson's disease is for the 'comma' to disappear, starting with the tail (the putamen) unilaterally. A similar pattern is seen in the majority of cases of DLB, although the change is usually more symmetrical. In a minority of DLB cases there may be more global loss of specific uptake throughout the corpus striatum from the outset. Images can be rated for the degree of abnormality either visually or using semi-quantitative or quantitative methods. Visual ratings may be reported either in a binary fashion as normal or abnormal, or degrees of abnormality (typically two or three) may be reported. Excellent agreement can be reached between experienced visual raters (McKeith 2007). Semi-quantitative or quantitative methods use a region of interest technique and derive ratios of ligand uptake in the caudate and in the putamen to non-specific background uptake, usually in the occipital cortex.

There are a number of technical and clinical factors which are important in image interpretation. Results may be influenced significantly by the method of image processing so uniformity of method within a study is essential. Particularly in multicentre studies, there is potential for systematic variation in results between centres due to use of different equipment and procedures. A pan-European initiative has recently proposed a framework to address this potential variation (Dickson 2012). This framework has been used in the production of a normative database for 123I-FP-CIT SPECT images, addressing the effects of age, gender and image processing method (Varrone 2013), which may be used as a reference resource in future studies. Vascular lesions of the corpus striatum or nigrostriatal pathway can lead to abnormal DAT images and so, in order to reduce the risk of false positive results, structural brain images may be necessary to aid interpretation. A small number of prescribed medications or drugs of abuse may affect DAT images. In any large series, a small proportion of images will be hard to classify and should be rated as 'indeterminate'. Guidelines for brain SPECT using 123I-labelled DAT ligands, which cover patient procedures, image acquisition and processing, image interpretation and reporting, were published in 2010 by the European Association of Nuclear Medicine (Darcourt 2010) and in 2012 by the Society of Nuclear Medicine (Djang 2012).

Several studies have investigated the relationship between a clinical diagnosis of DLB and the result of FP-CIT SPECT imaging. In cross-sectional case-control studies, striatal binding of FP-CIT is consistently found to be lower in groups of patients with a diagnosis of DLB than in groups of healthy controls or patients with a diagnosis of AD (Walker 2002; Ceravolo 2003; O'Brien 2004). The largest study has been a multicentre European study of 326 patients with dementia, including 151 with probable (two or more core clinical features) or possible DLB (McKeith 2007). An abnormal FP-CIT SPECT scan had a sensitivity of 77.7% (95% confidence interval (CI) 64.1% to 88.3%) and a specificity of 90.4% (95% CI 82.1% to 95.5%) for probable DLB diagnosed by a consensus panel, indicating a high degree of concordance between clinical and imaging data. Considering the performance of the clinical criteria against neuropathological findings, this result still allows for a wide range of possible performances of the imaging test against neuropathology. For example, there is no way of knowing if the nearly one-quarter of clinically probable DLB cases whose FP-CIT SPECT scan was rated as normal were all clinical false positives (although specificity of the clinical criteria in expert hands is generally high) or if SPECT scanning was missing even more true positives than the clinical criteria. Nor is there any way of knowing how many cases of DLB were missed by both the clinical criteria and the SPECT scan. Although AD is generally regarded as the main differential diagnosis for DLB, other diagnoses may also need to be considered, including frontotemporal dementia (FTD). FP-CIT SPECT imaging may be less accurate at discriminating between DLB and FTD than between DLB and AD (Morgan 2012).

On the basis of studies demonstrating a high degree of concordance between an abnormal FP-CIT SPECT result and clinical diagnosis, low dopamine transporter uptake on SPECT or PET was added to the consensus clinical criteria at their revision in 2005 as a suggestive feature. That is, a diagnosis of probable DLB can now be made on the basis of only one core clinical feature if there is also an abnormal dopamine transporter scan. The test has consequently become more widely used in Europe in the last five years. However, due largely to the absence of a local manufacturing facility, DaTscanTM was not approved for use in the US until 2011.

Clinical pathway

In current clinical practice, an FP-CIT SPECT scan is used to confirm or refute a clinical suspicion of DLB so subjects undergoing the test are likely to be those who already meet other criteria for possible or probable DLB. In most cases an FP-CIT SPECT scan would be ordered for patients in secondary (or tertiary) care after a standard work-up for dementia, usually including some form of structural imaging, and after a specialist physician had determined that a patient met some or all of the core or suggestive clinical features of DLB.

Performing DAT imaging only after applying the clinical diagnostic criteria for DLB means that the estimated accuracy of DAT imaging is limited by the sensitivity of the clinical criteria. This trade-off of sensitivity against feasibility and cost may be inevitable in clinical practice, but in some research contexts a higher priority may be placed on identifying 'pure' diagnostic groups. Hence, it would also be of value to know the accuracy of DAT imaging for identifying DLB in secondary care patients with dementia who are not selected for any other DLB clinical features.

Currently, DAT imaging is the only special investigation included in the consensus diagnostic criteria (although polysomnography may be used to confirm the presence of rapid eye movement (REM) sleep behaviour disorder, another suggestive feature). Several other biomarker tests, including brain perfusion SPECT, fluorodeoxyglucose PET, I131-meta-iodobenzylguanidine (MIBG) cardiac scintigraphy and various cerebrospinal fluid (CSF) and blood biomarkers, have been shown to discriminate between DLB and AD and have been suggested as having diagnostic utility (Aarsland 2008). However, at present none of these have been approved for use in the diagnostic pathway for DLB and none is yet in regular clinical use.

Rationale

Increasing importance is attached to making precise diagnoses of the subtypes of dementia. Although patients and relatives attach value to accurate diagnosis, its real importance comes when it leads to differences of clinical management which translate into better outcomes for patients. Currently, the most important implication of a DLB diagnosis for patient management is the recognition by clinicians of the high risk of severe adverse reactions to antipsychotic medication. Although antipsychotic use is regarded as a risk factor for mortality among all patients with dementia (Schneider 2005), there is evidence that the most severe effects occur largely in patients with Lewy body disease, with Aarsland finding severe sensitivity reactions among 8/15 patients with DLB and 0/17 with AD (Aarsland 2005). Given the high rate of neuropsychiatric symptoms in DLB, including psychosis, these patients may be at increased risk for antipsychotic exposure and it is important for clinicians to recognise this risk. The other key reason for being interested in more accurate diagnosis of DLB is the prospect of treatment in the future. If, as is widely hoped, increasing understanding of the pathophysiology of the dementing illnesses is translated into disease-specific therapies capable of modifying the course of the disease, then accurate diagnosis, at the earliest stage of illness possible, will be essential to direct research efforts and subsequently treatments to the correct patients.

In the case of DLB, current diagnostic criteria are limited particularly by relatively poor sensitivity even in specialist research centres. A biologically-derived diagnostic test of sufficient accuracy could be a great help. At present, FP-CIT SPECT is the most highly developed supplementary test for DLB, but there is uncertainty about its accuracy and its place in clinical practice. As the test is invasive and expensive, it is in practice likely to be used in a two-stage diagnostic process; that is, after a clinical suspicion of DLB has been established.

This review aims to provide a rigorous assessment of the accuracy of DAT imaging for DLB diagnosis in order to identify whether and how it can usefully be employed in research and clinical practice.

Objectives

This review has two primary objectives.

Objective A: To estimate the accuracy of DAT imaging for the diagnosis of dementia with Lewy bodies (DLB) in patients with dementia in secondary care.
Objective B: To assess the value of DAT imaging in clinical practice by estimating the accuracy of DAT imaging for the diagnosis of DLB in secondary care patients with a pre-existing suspicion of DLB on the basis of a clinical work-up.

Secondary objectives

The secondary objective is to use subgroup analyses to investigate the following potential sources of heterogeneity.

(a) Age of participants.

(b) Severity of dementia. The performance of the index test itself may vary with dementia severity. For objective B, since the performance of the clinical criteria may also depend on the severity of dementia, the 'added value' to be obtained from the index test may vary significantly.

(c) For objective B, diagnostic status at inclusion (possible or probable DLB, or both).

(d) DAT imaging method (SPECT or PET, ligand).

Methods

Criteria for considering studies for this review

Types of studies

(a) Test accuracy studies with delayed verification.

(b) Diagnostic case-control studies. This applies to objective A only. These may be true case-control studies, conducted retrospectively, in which participants who underwent DAT imaging in life are included on the basis of the presence or absence of a neuropathological diagnosis of DLB at autopsy. More common may be a design in which participants are selected for inclusion on the basis of their clinically-defined DLB diagnostic status. 'Cases' will meet clinical criteria (excluding the DAT imaging criterion) for probable DLB; 'controls' will not meet these criteria but will meet clinical criteria for one or more other subtypes of dementia. There is no universally agreed term for these studies, but they have been called 'two gate designs with alternative diagnosis controls' (Rutjes 2005). These study designs will be included but will, if possible, be the subject of sensitivity analysis because of the risk of spectrum bias they entail.

Participants

Objective A: Subjects with dementia in secondary care settings. Dementia should be diagnosed using validated clinical criteria (e.g. ICD, DSM). Studies which specifically exclude subjects meeting criteria for dementias other than DLB or AD (e.g. vascular dementia) will also be included.

Objective B: Subjects meeting clinical criteria (other than the DAT imaging criterion) for possible or probable DLB, or both. This is considered the most useful test of utility in clinical practice where DAT imaging is likely to be used as an addition to clinical assessment. A population meeting clinical criteria for probable DLB will already have missed many true DLB cases (because of the relatively poor sensitivity) and the opportunity for adding diagnostic value is limited (because of the already high specificity). Hence, the potential clinical utility of the test is greatest if applied to a population meeting the more sensitive but less specific criteria for possible DLB. However, participants meeting probable DLB criteria will not be excluded; this will be examined as a potential source of heterogeneity.

Subjects with Parkinson's disease or other Parkinsonian syndromes known to be associated with abnormal DAT imaging will be excluded.

Index tests

SPECT or PET imaging of brain dopamine transporters (DAT).

Target conditions

Dementia with Lewy bodies (DLB), with or without comorbid Alzheimer's disease.

Reference standards

Neuropathological diagnosis at autopsy using contemporaneously accepted neuropathological criteria.

We will not include in this review any studies in which a clinical diagnosis of probable DLB is the reference standard. There are two reasons for this:

1. Firstly, as discussed above, the accuracy - particularly the sensitivity - of the clinical criteria measured against the neuropathological reference standard is too low for them to constitute a satisfactory proxy. There is a serious possibility that the index test might outperform clinical diagnosis, rendering the latter unsuitable as a reference standard (Reitsma 2009). For some conditions, the correct clinical diagnosis may become more evident over time so that clinical diagnosis at follow-up may be a better reference standard than the cross-sectional diagnosis. (It has been used, for example, in studies of DAT imaging in the diagnosis of Parkinson's disease.) However, this strategy is not necessarily suitable for DLB where, as the condition progresses, symptoms converge with other types of dementia. Beyond a certain (undetermined) point, therefore, clinical diagnosis may become less discriminating with time.

2. Secondly, due to their complexity and expense, SPECT scans will probably only ever be useful as an adjunct to clinical assessment. Studies which, by design, cannot demonstrate an accuracy above that of careful clinical diagnosis alone have limited usefulness.

A difficulty with a neuropathological reference standard (common to all diagnostic studies with delayed verification designs) is that the pathology may change between application of the index test and reference standard. In this context, the most likely scenario is that AD pathology may develop in the interim, reducing the likelihood that the initial clinical syndrome will be correctly classified as due to DLB. This may lead to a systematic bias, underestimating the specificity of the index test.

Search methods for identification of studies

We will use a variety of information sources to ensure all relevant studies are included. Terms for electronic database searching will be devised in conjunction with the team at the Cochrane Dementia and Cognitive Improvement Group.

Electronic searches

We will search the specialised register of the Cochrane Dementia and Cognitive Improvement Group, ALOIS, which includes both intervention and diagnostic accuracy studies; MEDLINE (OvidSP), EMBASE (OvidSP), BIOSIS (Ovid), Science Citation Index (ISI Web of Knowledge), PsycINFO (Ovid), CINAHL (EBSCO) and LILACS (Bireme) (see Appendix 3 for the proposed MEDLINE (OvidSP) strategy). Similarly structured search strategies will be designed using search terms appropriate for each database. MeSH words and other controlled vocabulary will be used where appropriate. Science Citation Index includes conference abstracts in its database and so will allow for assessment of the "grey literature".

We will also search sources specific to diagnostic accuracy:

MEDION database (Meta-analyses van Diagnostisch Onderzoek www.mediondatabase.nl);

DARE (Database of Abstracts of Reviews of Effects) www.york.ac.uk/inst/crd/crddatabases.html);

HTA Database (Health Technology Assessments Database, The Cochrane Library);

ARIF database (Aggressive Research Intelligence Facility www.arif.bham.ac.uk).

We will request a search of the Cochrane Register of Diagnostic Test Accuracy Studies (maintained and managed by the Cochrane Renal Group).

No language or date restrictions will be applied to the electronic searches. Translation services will be used as necessary. We will check the reference lists of all relevant studies and reviews in the field for further possible titles and this process will be repeated until no new titles are found.

Initial searches will be performed by a single researcher with extensive experience of systematic reviewing.

Data collection and analysis

Selection of studies

Titles and abstracts of all papers retrieved by the search will be examined independently by two reviewers (JMcC, SM). Full text papers will be obtained if either reviewer considers the paper to be potentially relevant. Again working independently, each of the two reviewers will identify papers for inclusion. Any disagreements will be resolved by discussion involving a third reviewer (CH).

Data extraction and management

We will develop a data extraction form for this review and two reviewers (JMcC, SM) will use it independently to extract data from the included studies. Any disagreements will be resolved by discussion involving a third reviewer (CH). If important information is missing from published reports, then we will attempt to obtain it from the study authors. The following data will be extracted for each study.

Bibliographic details of primary paper:

  • author, title of study, year and journal;

  • reported or potential conflicts of interest.

Basic clinical and demographic details:

  • number of subjects;

  • age;

  • gender;

  • setting;

  • inclusion and exclusion criteria.

Details of index test:

  • definition of a positive and negative DAT imaging result.

Reference standard:

  • neuropathological criteria used to define presence or absence of DLB.

Data necessary for the assessment of quality (as defined below) will also be extracted.

The results of 2x2 tables relating index test results to reference standard results will be extracted directly into Review Manager (RevMan) tables.

Assessment of methodological quality

We will assess included studies for methodological quality using items derived from the QUADAS 2 tool (Whiting 2011), as recommended in the Cochrane Handbook of Diagnostic Test Accuracy reviews (Reitsma 2009), plus additional items tailored to this review. The list of quality items to be coded and the criteria used to judge each item as 'yes', 'no' or 'unclear' are given in Appendix 4. All quality items will be included in the data extraction form which will require each reviewer to record, along with a judgement, a description of the evidence supporting that judgement. Disagreements will again be discussed with a third reviewer (CH, KB or OA) until consensus is reached.

Statistical analysis and data synthesis

For both objectives A and B, we will apply the DTA framework for the analysis of a single test and extract the data from a study into a 2x2 table, showing the binary test results cross-classified with the binary reference standard and ignoring any censoring that might have occurred. We acknowledge that such a reduction in the data may represent an oversimplification.

We will use data from the 2x2 tables abstracted from the included studies (TP, FN, FP, TN) and entered into RevMan to calculate the sensitivities, specificities and their 95% confidence intervals. We will also present individual study results graphically by plotting estimates of sensitivities and specificities in both a forest plot and a receiver operating characteristic (ROC) space. If more than one threshold is published in primary studies we will report accuracy estimates for all thresholds.

If there are sufficient data we will meta-analyse the pairs of sensitivity and specificity. The preferred approach would be the hierarchical summary ROC curve (HSROC) method proposed by Rutter and Gatsonis (Rutter 2001) (Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy, chapter 10) (Macaskill 2010) because implicit thresholds are expected in primary studies. We will conduct these analyses in SAS software with support from the UK DTA Support Unit. Particularly if there are common thresholds across included studies we will also consider the bivariate random-effects approach (Reitsma 2005). When a primary study reports more than one threshold result, we will only select the threshold nearer to the upper left point of the ROC curve for the meta-analysis. We are aware that this data-driven method for threshold selection could lead to an overestimate of diagnostic accuracy (Leeflang 2008). However, there are no accepted thresholds to define positive DAT scan and, therefore, the accuracy estimates reported in primary studies are likely to be based on data-driven threshold selection.

Investigations of heterogeneity

Subgrouping the included studies in RevMan will be the initial approach to exploring heterogeneity. However, covariates such as index test threshold, variation in the reference standard, and features of methodological quality of included studies can be incorporated in the bivariate model. This will be used to investigate heterogeneity if there are sufficient included studies. The framework for the investigation includes the following factors:

  • threshold – if there is explicit variation in the index test cut-off used, the effect of this will be investigated as a priority;

  • other features of the participants, index test, and reference standard such as: mean age, gender, cognitive test score, exclusion criteria, possible or probable DLB, or both, at baseline - for objective B only); aspects of the technical quality of the examination; alternative reference standard criteria; study sponsorship.

Sensitivity analyses

Where appropriate we will explore the sensitivity of any summary accuracy estimates to aspects of study quality, focusing particularly on unrepresentative patient spectrum and lack of blinding, as well as on any other QUADAS items which are found to present significant threats to validity in the light of the detailed quality assessment.

Assessment of reporting bias

Reporting bias will not be investigated because of current uncertainty about how it operates in test accuracy and about the interpretation of existing analytical tools such as funnel plots.

Acknowledgements

The authors would like to thank Anna Noel-Storr, Trials Search Co-ordinator of the Cochrane Dementia and Cognitive Improvement Group, for her assistance with writing the search strategy, searching and initial screening of search results.

Appendices

Appendix 1. Consensus criteria for the clinical diagnosis of possible and probable dementia with Lewy bodies

CriteriaConsensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. McKeith 1996.

Revised criteria:

Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. McKeith 2005.

Central featureProgressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression. Deficits on tests of attention and of frontal-subcortical skills and visuospatial ability may be especially prominent.Progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression. Deficits on tests of attention, executive function, and visuospatial ability may be especially prominent (essential for a diagnosis of possible or probable DLB).
Core features
(probable DLB - two; possible DLB - one)
  • Fluctuating cognition with pronounced variations in attention and alertness.

  • Recurrent visual hallucinations that are typically well formed and detailed.

  • Spontaneous motor features of parkinsonism.

  • Fluctuating cognition with pronounced variations in attention and alertness.

  • Recurrent visual hallucinations that are typically well formed and detailed.

  • Spontaneous motor features of parkinsonism.

Suggestive features (2005 criteria only)-

If one or more of these is present in the presence of one or more core features, a diagnosis of probable DLB can be made. In the absence of any core features, one or more suggestive features is sufficient for possible DLB. Probable DLB should not be diagnosed on the basis of suggestive features alone.

  • Rapid eye movement (REM) sleep behaviour disorder.

  • Severe neuroleptic sensitivity.

  • Low dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET imaging.

Supportive features
  • Repeated falls.

  • Syncope.

  • Transient loss of consciousness.

  • Neuroleptic sensitivity.

  • Systematized delusions.

  • Hallucinations in other modalities.

  • Repeated falls and syncope.

  • Transient, unexplained loss of consciousness.

  • Severe autonomic dysfunction, e.g. orthostatic hypotension, urinary incontinence.

  • Hallucinations in other modalities.

  • Systematised delusions.

  • Depression.

  • Relative preservation of medial temporal lobe structures on CT or MRI scan.

  • Generalised low uptake on SPECT or PET perfusion scan with reduced occipital activity.

  • Abnormal (low uptake) MIBG myocardial scintigraphy.

  • Prominent slow wave activity on EEG with temporal lobe transient sharp waves.

A diagnosis of DLB is less likely
  • In the presence of stroke disease, evident as focal neurologic signs or on brain imaging.

  • Evidence on physical examination and investigation of any physical illness or other brain disorder sufficient to account for the clinical picture.

  • In the presence of cerebrovascular disease evident as focal neurologic signs or on brain imaging.

  • In the presence of any other physical illness or brain disorder sufficient to account in part or in total for the clinical picture.

  • If parkinsonism only appears for the first time at a stage of severe dementia.

Temporal sequence of symptoms-DLB should be diagnosed when dementia occurs before or concurrently with parkinsonism (if it is present). The term Parkinson's disease dementia (PDD) should be used to describe dementia that occurs in the context of well-established Parkinson's disease. In a practice setting the term that is most appropriate to the clinical situation should be used and generic terms such as LB disease are often helpful. In research studies in which distinction needs to be made between DLB and PDD, the existing 1-year rule between the onset of dementia and parkinsonism DLB continues to be recommended. Adoption of other time periods will simply confound data pooling or comparison between studies. In other research settings that may include clinicopathologic studies and clinical trials, both clinical phenotypes may be considered collectively under categories such as LB disease or alpha-synucleinopathy.

Appendix 2. Marketing approvals for DaTscanTM

European Union

First marketing authorisation in 2000.

Currently approved for the following therapeutic indications:

This medicinal product is for diagnostic use only.

DaTscan is indicated for detecting loss of functional dopaminergic neuron terminals in the striatum:

  • In patients with clinically uncertain Parkinsonian Syndromes, in order to help differentiate Essential Tremor from Parkinsonian Syndromes related to idiopathic Parkinson's Disease, Multiple System Atrophy and Progressive Supranuclear Palsy. DaTscan is unable to discriminate between Parkinson's Disease, Multiple System Atrophy and Progressive Supranuclear Palsy.

  • To help differentiate probable dementia with Lewy bodies from Alzheimer's disease. DaTscan is unable to discriminate between dementia with Lewy bodies and Parkinson's disease dementia.

United States

FDA approval in 2011 for the following indications and usage:

DaTscan (Ioflupane I 123 Injection) is a radiopharmaceutical indicated for
striatal dopamine transporter visualization using single photon emission
computed tomography (SPECT) brain imaging to assist in the evaluation of
adult patients with suspected Parkinsonian syndromes (PS). In these patients,
DaTscan may be used to help differentiate essential tremor from tremor due to
PS (idiopathic Parkinson's disease, multiple system atrophy and progressive
supranuclear palsy). DaTscan is an adjunct to other diagnostic evaluations.

Appendix 3. MEDLINE search strategy (Ovid SP)

1. Lewy Bodies/

2. dement*.ti,ab.

3. (LDB or DLB or LBD).ti,ab.

4. (lewy* adj2 bod*).ti,ab.

5. Lewy Body Disease/

6. or/1-5

7. ((DAT scan*) or ( DAT adj2 imag*)) .ti,ab.

8. Dopamine Plasma Membrane Transport Proteins/

9. "dopamine transporter".ti,ab.

10. Dopaminergic Neurons/

11. FP-CIT.ti,ab.

12. DaTSCAN.ti,ab.

13. "[123I]β-CIT" or "[123I]beta-CIT").ti,ab.

14. "[123I]FP-CIT".ti,ab.

15. SPECT.ti,ab.

16. "[99mTc]TRODAT-1".ti,ab.

17. " [123I]PE2I".ti,ab.

18. "[123I]altropane".ti,ab.

19. "[11C]cocaine".ti,ab.

20. " [3H]WIN".ti,ab.

21. "[11C]altropane".ti,ab.

22. ("[11C]/[18F]beta-CFT" or " [11C]/[18F]β-CFT").ti,ab.

23. "[11C]FE-CIT".ti,ab.

24. "[11C]dMP".ti,ab.

25. Tomography, Emission-Computed, Single-Photon/

26. SPET.ti,ab.

27. "single photon emission tomography".ti,ab.

28. "single photon emission computed tomography".ti,ab.

29. or/7-28

30. 6 and 29

Appendix 4. Items used to assess methodological quality (adapted QUADAS 2)

DOMAIN 1 – PATIENT SELECTION

Signalling question 1: Was a consecutive or random sample of patients enrolled?

Signalling question 2: Was a case-control design avoided?

Signalling question 3: Did the study avoid inappropriate exclusions?

QuestionJudgementCriteria

1.1 Was a consecutive or random sample of patients enrolled?

 

Yes

Objective A  Study participants are a consecutive or random sample of all eligible patients with dementia.

Objective B  Study participants are a consecutive or random sample of all eligible patients meeting criteria for possible or probable DLB.

 NoA sampling method other than consecutive or random sampling of eligible patients is used.
 UnclearInsufficient information is given to make a judgement.

1.2 Was a case-control design avoided?

 

Yes

Objective A  Study participants are included without regard to presence or absence of a clinical or neuropathological diagnosis of DLB.

Objective B Not applicable. (All participants have possible or probable DLB.)

 No

Objective A Study participants are included on the basis of presence or absence of a clinical or neuropathological diagnosis of DLB.

Objective B Not applicable.

 UnclearInsufficient information is given to make a judgement.
1.3 Did the study avoid inappropriate exclusions?Yes

Objective A Patients are excluded on the following grounds only: (a) diagnosis made using validated criteria of a specific dementia subtype other than DLB or AD; (b) dementia outside specified severity range; (c) presence of any other condition known to be associated with an abnormal DATscan; (d) presence of a recognised contraindication to DATscanning.

Objective B Patients are excluded on the following grounds only: (a) dementia outside specified severity range; (b) presence of any other condition known to be associated with an abnormal DATscan; (c) presence of a recognised contraindication to DATscanning.

 NoExclusion criteria other than those specified above are present.
 UnclearInsufficient information is given to make a judgement.

 

DOMAIN 2 – INDEX TEST

Signalling question 1: Were the index test results interpreted without knowledge of the results of the reference standard?

Signalling question 2: If a threshold was used, was it pre-specified?

Signalling question 3: Were uninterpretable or intermediate test results reported?

Signalling question 4: Were structural brain images available for comparison?

Signalling question 5: Was the method of image reconstruction consistent throughout the study?

Signalling question 6: Had test operators had appropriate training?

Signalling question 7: Were data on observer variation in DAT image interpretation reported and within an acceptable range?

QuestionJudgementCriteria

2.1 Were the index test results interpreted without knowledge of the results of the reference standard?

 

 

YesDAT images are interpreted without knowledge of neuropathological diagnosis.
 NoDAT images are interpreted retrospectively by someone with knowledge of neuropathological diagnosis.
 UnclearInsufficient information to make a judgement.

2.2 If a threshold was used, was it pre-specified?

 

YesA 'positive' DAT imaging result is clearly defined prior to the start of the study. If a quantitative or semi-quantitative RoI analysis is used, then cut-off values are defined before the start of the study.
 NoDefinition of a positive result or cut-off values, or both, are not established prior to the start of the study.
 UnclearInsufficient information to make a judgement.

2.3 Were uninterpretable or intermediate test results reported?

 

YesThe number or proportion of uninterpretable or intermediate test results is reported.
 NoUninterpretable or intermediate test results arose but the number or proportion is not reported.
 UnclearIt is not possible to tell whether or not there were any uninterpretable or intermediate test results.
2.4 Were structural brain images available for comparison?YesStructural brain images taken within 6 months of the DAT images were available to aid interpretation.
 NoNo structural brain images (± 6 months) were available to aid image interpretation.
 UnclearInsufficient information to make a judgement.
2.5 Was the method of image reconstruction consistent throughout the study?YesThe method of image reconstruction is stated and was the same for all participants in the study.
 NoThe method of image reconstruction varied within the study.
 UnclearInsufficient information to make a judgement.
2.6 Had test operators had appropriate training?YesDAT image interpreters were fully qualified or certified nuclear medicine specialists with prior experience of the technique.
 NoDAT image interpreters lacked this training or experience.
 UnclearInsufficient information to make a judgement.
2.7 If visual readings were used, were data on observer variation in DAT image interpretation reported and within an acceptable range?YesData on intra- and inter-observer variation in DAT image interpretation are reported and agreement is good (kappa > 0.6).
 NoObserver variation is not reported or agreement was poor (kappa < 0.6).
 UnclearIt is not clear whether observer variation was measured.

DOMAIN 3 - REFERENCE STANDARD

Signalling question 1: Is the reference standard likely to correctly classify the target condition?

Signalling question 2: Were the reference standard results interpreted without knowledge of the results of the index test?

QuestionJudgementCriteria

3.1 Is the reference standard likely to correctly classify the target condition?

 

Yes

Neuropathological criteria used included:

McKeith (2005) or Braak (2003) staging of alpha-synuclein/Lewy bodies, and Braak staging of neurofibrillary tangles (NFTs), and tau and alpha-synuclein immunohistochemistry, and an assessment of vascular pathology.

 

 NoOther neuropathological criteria were used and/or one or more of the above criteria was not applied.
 UnclearInsufficient information to make a judgement.

3.2 Were the reference standard results interpreted without knowledge of the results of the index test?

 

YesNeuropathology data are interpreted blind to knowledge of the DAT imaging result.
 NoNeuropathological data are interpreted by someone with knowledge of the DAT imaging result.
 UnclearInsufficient information to make a judgement.

 

DOMAIN 4 - FLOW AND TIMING

Signalling question 1: Did all patients receive the same reference standard?

Signalling question 2: Were all patients included in the analysis?

QuestionJudgementCriteria

4.1 Did all patients receive the same reference standard?

 

YesThe same neuropathological technique is used for all participants regardless of DAT imaging result.
 NoA different neuropathological technique is used depending on DAT imaging result.
 UnclearInsufficient information to make a judgement.

4.2 Were all patients included in the analysis?

 

 

YesAll participants entering the study are accounted for at the time of the report, either as living or dead. The proportion of patients who receive DAT imaging and who have an autopsy diagnosis at specified follow-up durations is reported. Participants who die but do not receive an autopsy diagnosis are described.
 NoSome participants who have DAT imaging are unaccounted for in the study report.
 UnclearIt is not clear how many participants enter the study.

 

Contributions of authors

All authors contributed to the drafting of the protocol.

Declarations of interest

JMcC acted as an investigator in a trial sponsored by GE Healthcare, manufacturer of DaTscan, for which her institution received payment.

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