Elsevier

The Lancet Neurology

Volume 6, Issue 4, April 2007, Pages 305-313
The Lancet Neurology

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Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: a phase III, multicentre study

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Summary

Background

Dementia with Lewy bodies (DLB) needs to be distinguished from other types of dementia because of important differences in patient management and outcome. Current clinically based diagnostic criteria for DLB have limited accuracy. Severe nigrostriatal dopaminergic degeneration occurs in DLB, but not in Alzheimer's disease or most other dementia subtypes, offering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the sensitivity and specificity, in the ante-mortem differentiation of probable DLB from other causes of dementia, of single photon emission computed tomography (SPECT) brain imaging with the ligand 123I-2β-carbometoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT), which binds to the dopamine transporter (DAT) reuptake site. Diagnostic accuracy, positive and negative predictive values, and inter-reader agreement were the secondary endpoints and a subgroup of possible DLB patients was also included.

Methods

We did a phase III study in which we used a 123I-FP-CIT SPECT scan to assess 326 patients with clinical diagnoses of probable (n=94) or possible (n=57) DLB or non-DLB dementia (n=147) established by a consensus panel (in 28 patients no diagnosis could be made). Three readers, unaware of the clinical diagnosis, classified the images as normal or abnormal by visual inspection. The study had 90% power to detect the differences between our anticipated sensitivity (0·80) and specificity (0·85) targets and prespecified lower thresholds (sensitivity 0·65, specificity 0·73) using one-sided binomial tests with a significance level of α=0·025.

Findings

Abnormal scans had a mean sensitivity of 77·7% for detecting clinical probable DLB, with specificity of 90·4% for excluding non-DLB dementia, which was predominantly due to Alzheimer's disease. A mean value of 85·7% was achieved for overall diagnostic accuracy, 82·4% for positive predictive value, and 87·5% for negative predictive value. Inter-reader agreement for rating scans as normal or abnormal was high (Cohen's κ=0·87). The procedure was well tolerated with few adverse events.

Interpretation

A revision of the International Consensus Criteria for DLB has recommended that low DAT uptake in the basal ganglia, as shown by SPECT or PET imaging, be a suggestive feature for diagnosis. Our findings confirm the high correlation between abnormal (low binding) DAT activity measured with 123I-FP-CIT SPECT and a clinical diagnosis of probable DLB. The diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from Alzheimer's disease.

Introduction

The importance of early and accurate diagnosis of dementia subtype to inform prognosis and best management has been emphasised by international good practice guidelines1, 2 and is appreciated by patients and their carers. The findings of neuropathological autopsy studies suggest that 50–60% of cases of dementia in people aged 65 years or older are due to Alzheimer's disease, with a further 10–20% each attributable to dementia with Lewy bodies (DLB) or vascular cognitive impairment.3 Operationalised clinical diagnostic criteria have been agreed for all of these syndromes, but even in specialist research settings they have limited accuracy when compared with neuropathological autopsy findings. The situation in non-specialist clinical settings is likely to be even more imperfect.

The most frequent diagnostic confusion in clinical practice in older patients with dementia is between DLB and Alzheimer's disease.4 Accurate clinical detection of DLB is particularly important because half of patients with DLB have severe neuroleptic sensitivity to typical and atypical antipsychotics, with a two to three-fold increase in short-term mortality.5 This increase is over and above the recently recognised risk of neuroleptic-induced cerebrovascular events in all patients with dementia.6 There is also emerging evidence that some patients with DLB respond especially well to cholinesterase inhibitors.7

Diagnostic difficulties have arisen for two main reasons. The first has been a lack of valid and reliable methods to assess the core clinical features by which DLB is usually identified—namely, fluctuating cognition with pronounced variations in attention and alertness, recurrent visual hallucinations that are typically well formed and detailed, and spontaneous features of parkinsonism.8 Second, results of autopsy studies show that patients with DLB who, in addition to subcortical and cortical Lewy bodies, carry a great burden of neocortical Alzheimer pathology may not have these clinical features as prominently and will often present with an amnestic syndrome in clear consciousness, more typical of Alzheimer's disease than of DLB.9 There are, therefore, limitations on the level of accuracy that can be achieved by making diagnoses solely on the grounds of clinical history and examination. As such, there is a clear need for biological markers to assist with accurate ante-mortem diagnosis.

A striking biological difference between DLB and Alzheimer's disease is the severe nigrostriatal degeneration and consequent dopamine transporter (DAT) loss that occurs in DLB, but not to any significant extent in Alzheimer's disease.10 This difference is most profound in patients with a long history of severe extrapyramidal motor features, but also arises when these features are minimal or absent.11 Several radioligands have been developed for use in single-photon emission computed tomography (SPECT) to bind in vivo to the striatal DAT or reuptake site. These include an 123I-labelled-cocaine analogue 123I-2β-carbometoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (I-FP-CIT; DaTSCAN, GE Healthcare).12 The efficacy of this ligand in detecting the loss of nigrostriatal neuron terminals in patients with Parkinson's disease has been shown13 and it has been approved for use in Europe since 2000 to distinguish between patients with clinically uncertain parkinsonian syndromes and individuals with essential tremor.

Findings of two pilot studies14, 15 have independently shown that 123I-FP-CIT SPECT imaging provides essential information about nigrostriatal dopaminergic neuronal integrity in patients with DLB. In both studies, patients with DLB and Alzheimer's disease were included and both visual and region-of-interest based semi-quantitative assessments of the images were undertaken. There were highly significant differences (p<0·0001) in striatal binding between patients with DLB and Alzheimer's disease and between controls and patients with DLB. Significant differences were also seen for the visual assessment. When compared with autopsy diagnosis, the sensitivity and specificity of imaging was 88% and 100%, respectively.14

The primary aim of this multicentre study was to determine the sensitivity and specificity of 123I-FP-CIT SPECT imaging in the ante-mortem differentiation of DLB from other causes of dementia. Diagnostic accuracy and positive and negative predictive values of the technique were estimated as secondary outcomes, as was inter-reader agreement for the visual rating of scans. A final aim was to undertake similar analyses on a group of patients clinically diagnosed with possible DLB.

Section snippets

Participants

Between November, 2003, and August, 2005, we did a phase III, multicentre study in 40 European sites. We included patients aged 55–90 years who met the criteria for dementia detailed in the diagnostic and statistical manual of mental disorders—fourth edition (DSM-IV)16 and fulfilled at least one of the following: consensus criteria for probable or possible DLB,8 National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer Disease and Related Disorders Association

Results

Figure 2 shows the flow of the 351 patients through the study. 25 individuals withdrew from the trial before 123I-FP-CIT administration; these individuals are not included in the safety assessment. Of the 326 individuals who received the radiopharmaceutical and who comprised the safety population, 38 were not assessed for efficacy because 11 had unreadable images and 28 were not given a clinical diagnosis by the expert consensus panel (one subject was excluded on both grounds). The on-site

Discussion

Our results indicate a high rate of agreement between abnormal striatal DAT binding measured in vivo with 123I-FP-CIT SPECT and a clinical diagnosis of probable DLB (two or more core clinical features present).8 This finding confirms and further extends findings of earlier single-site studies.14, 15 Given the high specificity of probable DLB clinical diagnosis against the neuropathological diagnosis reported in a review of autopsy controlled studies31 (mean 92%), it is reassuring to find that

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