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• Re:DAT-SPECT. All that glitters is not gold.
  Eduardo Tolosa
  Published on: 15 April 2010
• DAT-SPECT. All that glitters is not gold.
  Paul K Morrish
  Published on: 15 April 2010

• Published on: 15 April 2010

  Re:DAT-SPECT. All that glitters is not gold.

  • Eduardo Tolosa, Dr.
  • Other Contributors:
    • Georg Kaegi and Kailash Bhatia

  We wish to thank Dr. Morrish for his comments to our review. He argues in his letter that for diagnostic purposes a technique needs to be sensitive to the disease and reproducible and that DAT-SPECT unfortunately falls down on each. Sensitivity is poor, he says, since DAT-SPECT imaging has been found to be normal in about 5 to 15% of individuals with parkinsonism. Such individuals ( SWEDDs ("scans without evidence of dopaminergic...

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  We wish to thank Dr. Morrish for his comments to our review. He argues in his letter that for diagnostic purposes a technique needs to be sensitive to the disease and reproducible and that DAT-SPECT unfortunately falls down on each. Sensitivity is poor, he says, since DAT-SPECT imaging has been found to be normal in about 5 to 15% of individuals with parkinsonism. Such individuals ( SWEDDs ("scans without evidence of dopaminergic dysfunction") or false negatives scans), he believes, exist not because of failure of diagnosis but because of failure in the technique. These false negative cases may well have Parkinson`s disease (PD) , probably tremor dominant forms that have less abnormality in DAT-SPECT imaging. However, we maintain that available information strongly suggests that most if not all SWEDDs in fact do not have involvement of the nigrostriatal pathway and do not suffer from PD. Poor response to levodopa and lack of progression on sequential dopaminergic imaging (1), indicate that PD is an unlikely diagnosis in most cases of SWEDDs . Furthermore, withdrawal of anti-parkinsonian drug therapy in patients with parkinsonism with normal FP-CIT SPECT without any deleterious effects would not be possible in individuals with true PD, tremor dominant or not.(2) Support for this interpretation also comes from a recent study by Schwingenschuh et al. who has shown that SWEDDs share electrophysiological characteristics similar to patients with segmental dystonia and can clearly be separated from patients with PD and from patients with essential tremor.(3) We believe that the bulk of evidence suggests that the issue with the "false negative" cases (SWEDDs) is not a problem of sensitivity of the DAT-SPECT but rather an issue of an alternative diagnosis. We agree with Morrish that neuropathological studies of SWEDDs cases are needed to clarify this issue.

  Morrish also feels DAT-SPECT falls down on reproducibility since in his opinion the result of a scan can vary by 40% from day to day (4), an issue he has previously highlighted in a letter to the JNNP in 2003.(5) The study by Booij et al (6) analyzing variability of [123I] FP-CIT SPECT showed an absolute variability of 7.25 ± 3.22% (ROI method) and 7.47 ± 6.35% (VOI method) in normal volunteers and 7.90 ± 6.89% (ROI method) and 7.36 ± 6.16% (VOI method) in PD patients . The use by Morrish of absolute means may not be appropriate way to calculate the range of variability . In contrast the above mentioned study by Booij et al reported a high test-retest reliability with FP-CIT (intraclass correlation coefficient close to 1) which indicates that with some tracers reproducibility is adequate for diagnostic use and potentially for disease progression studies, where the major issue is the demonstration of sensitivity to clinical change.

  Morrish also refers to an earlier study in patients with clinically uncertain parkinsonism in which 6 scans changed over a period of 2 years.(7) As discussed in the paper, the changes in visual assessment were the result of over-interpretation of the images in a small subgroup of patients in whom a mismatch occurred between visual evaluation of the DAT-SPECT and the clinical diagnosis. When independent investigators were asked to read those images there was total consensus about that the images were normal and the same reading was obtained at 2 years follow up. The problem was not reproducibility but over-interpretation in a study done in an unusual subset of individuals with uncertain parkinsonism. We agree with Dr. Morrish that all efforts should be made to reduce variability of DAT SPECT imaging if this technique has to be used successfully in longitudinal studies of disease progression or neuroprotection and that these studies have to take into account variations due to the technique when decisions are taken about endpoints and sample size calculation (8)

  Morrish indicates that DAT-SPECT has been validated as a screen for persons at risk of developing PD. While recent evidence shows that DAT-SPECT abnormalities can antedate the development of parkinsonism we do not know the predictive value of positive results in a normal population or even in a population at high risk for PD such as non manifesting carriers of genetic mutation causing autosomal dominant PD and therefore we reaffirm our opinion that DAT-SPECT has indeed not been validated yet as a useful premotor marker of PD.(9) Morrish mentions in his letter that we write that "its (DAT-SPECT) use in longitudinal monitoring has not been considered; in 2002 a large US review group did just that". We wrote that "DAT-SPECT has also been used as a potential biomarker for disease progression in PD and has shown a progressive decline of striatal DAT binding with increasing disease duration of PD and with increasing disease severity also in agreement with [18F]dopa PET studies." Our statement is in line with the comments of the review of Ravina et al (10) quoted by Morrish in which the authors indicate, referring to studies using F-dopa PET and beta CIT SPECT, that "Natural history studies for each radiotracer have had small sample sizes, but the results are consistent. This suggests that these tracers measure biologic processes that are related to the duration and severity of PD as measured by motor rating scales in the practically defined "off" state". Whether the extra information obtained from these studies may not have justified the radiation exposure of so many patients on two or more occasions, as he states in his letter, is a difficult statement to support. These studies, like the ones he and others have conducted in the past which involve radiation exposure have been performed with the hopes that the information would indeed outweigh the possible risks of this technique. We obviously agree with Morrish that a good clinician may prefer, instead of ordering a DAT-SPECT, to rely on their own judgment and the fullness of time. However, as it often happens, in the appropriate cases good clinicians may decide that ordering a DAT-SPECT may be a better course to follow than waiting that time may provide clarification of a diagnosis. Finally Dr Morrish indicates that one of us (ET) did not declare as a conflict of interest in our Review being the principal investigator of a large study on DAT SPECT in parkinsonism 7 funded by GE Healthcare. I want to thank him for bringing this to my and the readership attention and for giving me the opportunity of declaring this now (see below Disclosure).

  Reference List

  1 Marek K, Jennings DL, Seibyl JP. Long-Term Follow-Up of Patients with Scans without Evidence of Dopaminergic Deficit (SWEDD) in the ELLDOPA Study. Neurology64 (Suppl 1):(Abstract).

  2 Marshall VL, Patterson J, Hadley DM, Grosset KA, Grosset DG. Successful antiparkinsonian medication withdrawal in patients with Parkinsonism and normal FP-CIT SPECT. Mov Disord. 2006;21:2247-50.

  3 Schwingenschuh P, Ruge D, Edwards MJ, Terranova C, Katschnig P, Carrillo F, Silveira- Moriyama L, Schneider SA, Kagi G, Palomar FJ, Talelli P, Dickson J, Lees AJ, Quinn N, Mir P, Rothwell JC, Bhatia KP. Distinguishing SWEDDs patients with asymmetric resting tremor from Parkinson's disease: A clinical and electrophysiological study. Mov Disord. DOI 10.1002/mds.23019 2010.4.

  4 Morrish P. Controversies in Neuroimaging. Parkinson's disease: Diagnosis and Clinical Management 2nd edition. 2008,Eds Factor and Weiner. Demos Publishing. 28;317-326.

  5 . Morrish PK. The harsh realities facing the use of SPECT imaging in monitoring disease progression in Parkinson's disease. J Neurol Neurosurg Psychiatry 2003;74:1447

  6 Booij J, Habraken JB, Bergmans P, Tissingh G, Winogrodzka A, Wolters EC, Janssen AG,Stoof JC, van Royen EA. Imaging of dopamine transporters with iodine-123-FP-CIT SPECT in healthy controls and patients with Parkinson's disease. J Nucl.Med 1998;39:1879-84.

  7. Tolosa E, Borght TV, Moreno E. Accuracy of DaTSCAN (123I-Ioflupane) SPECT in diagnosis of patients with clinically uncertain parkinsonism: 2-year follow-up of an open-label study. Mov Disord. 2007;22:2346-51.

  8. Winogrodzka A, Bergmans P, Booij J, van Royen EA, Janssen AG, Wolters EC. [123I]FP- CIT SPECT is a useful method to monitor the rate of dopaminergic degeneration in early- stage Parkinson's disease. J Neural Transm 2001; 108(8-9):1011-1019.

  9 Tolosa E, Gaig C, Santamaria J, Compta Y. Diagnosis and the premotor phase of Parkinson disease . Neurology 2009;72 (suppl 2) :S12-S20.

  10 Ravina B, Eidelberg D, Ahlskog JE, Albin RL, Brooks DJ, Carbon M, Dhawan V, Feigin A, Fahn S, Guttman M, Gwinn-Hardy K, McFarland H, Innis R, Katz RG, Kieburtz K, Kish SJ, Lange N, Langston JW, Marek K, Morin L, Moy C, Murphy D, Oertel WH, Oliver G, Palesch Y, Powers W, Seibyl J, Sethi KD, Shults CW, Sheehy P, Stoessl AJ, Holloway R . The role of radiotracer imaging in Parkinson's disease. Neurology 2005; 64(2) 208-15.

  Conflict of Interest:

  Eduardo Tolosa was the principal investigator on an international trial on the value of DaTSCAN SPECT in parkinsonism 7 . For this he received no personal compensation. He has in the past received honoraria for lecturing in symposia on imaging in Parkinson disease sponsored by GE Healthcare

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  Conflict of Interest:
  None declared.

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• Published on: 15 April 2010

  DAT-SPECT. All that glitters is not gold.

  • Paul K Morrish, Consultant Neurologist

  Kagi and colleagues (1) provide a review but not a critique of a controversial technique. For a technique to have diagnostic utility it needs sensitivity to the disease and reproducibility; DAT-SPECT unfortunately falls down on each. The review describes the test as around 100% sensitive as a diagnostic tool in detecting PD. The authors conclude that the normal scans in 5-15% of patients with de-novo PD are normal becau...

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  Kagi and colleagues (1) provide a review but not a critique of a controversial technique. For a technique to have diagnostic utility it needs sensitivity to the disease and reproducibility; DAT-SPECT unfortunately falls down on each. The review describes the test as around 100% sensitive as a diagnostic tool in detecting PD. The authors conclude that the normal scans in 5-15% of patients with de-novo PD are normal because "some patients with dystonic tremor are misdiagnosed as PD" rather than that the test itself may not be perfect. The gold standard is not clinical opinion, DAT scan or PET scan, but post mortem. It can be shown, from knowledge and understanding of the technique's parameters (2), that DAT-SPECT has both false negatives and false positives, the predictive value of a result varying according to the composition of the population being tested. We know that tremor-dominant patients may have slow progression (3), and that their DAT-SPECT scan may be less abnormal than the akinetic-rigid patient (4). Many of the SWEDD's (though I prefer the term false- negative) may be tremor-dominant and slowly progressing. Only a very long time (not the one or two years quoted here) and a post-mortem will provide the evidence that they do or do not have idiopathic Parkinson's disease. The authors do not consider the issue of reproducibility, a key problem in DAT-SPECT (2). How useful is a technique in which a result can vary by 40% from day to day (2)? Some SWEDD's will undoubtedly be due to technical error. Tolosa has undermined the confidence in the technique that he expresses in this review by an earlier publication (5). In 2007 he reported 6 "uncertain parkinsonism" patients in whom the DAT-scan changed between first and second scan, over a two year period. Five went from abnormal to normal; presumably either the first scan was falsely positive or the second scan was falsely negative. In the sixth patient the scan changed from normal to abnormal; presumably, the first was a false negative. The authors write that DAT-SPECT has not been validated as a screen for persons at risk of developing PD. It has, and its limitations (particularly the low predictive value of positive results in a normal population) mean that it will not be useful (2). They also write that its use in longitudinal monitoring of disease progression has not been considered; in 2002 a large US review group did just that (6). Despite this, many SPECT progression studies have been carried out in Parkinson's disease (eg CALM, ELLDOPA,CEP- 1347). The extra information that has been gained by this addition to clinical progression studies may not have justified the radiation exposure of so many patients on two or more occasions. Despite my misgivings over the technique there may be one clinical application. Falsely positive DAT-SPECT scans are relatively uncommon in a de-novo Parkinsonian population (2) and so the scan, if reproducible, could be helpful in distinguishing the organic from the non-organic. A good clinician may instead prefer to rely on their own judgement and the fullness of time. Finally it should be noted that Dr Tolosa was chief investigator on a large recent study (5) funded by GE Healthcare, a manufacturer of a DAT- SPECT pharmaceutical agent. Its omission as a possible conflict of interest may have been an oversight but, if not, it might have been better for him to declare this so that the reader could make their own judgement. 1. Kagi G, Bhatia KP, Tolosa E . The role of DAT-SPECT in movement disorders. J Neurol Neurosurg Psychiatry. 2010 Jan;81(1):5-12. 2. Morrish P. Controversies in Neuroimaging. Parkinson's disease: Diagnosis and Clinical Management 2nd edition. 2008,Eds Factor and Weiner. Demos Publishing. 28;317-326. 3. Hoehn MM, Yahr MD. Parkinsonism:onset, progression and mortality. Neurology 1967, 17; 427-42. 4. Spiegel J, Hellwig D, Samnick S et al. Striatal FP-CIT uptake differs in the subtypes of early Parkinson's disease. J Neural Transm 2007, 114(3):331-5. 5. Tolosa E, Borght TV, Moreno E et al. Accuracy of DaTSCAN([123]I- Ioflupane) SPECT in diagnosis of patients with clinically uncertain parkinsonism: 2 year follow-up of an open label study. Mov Disord 2007;22:2346-51 6. Ravina B, Eidelberg D, Ahlskog JE et al. The role of radiotracer imaging in Parkinson's disease. Neurology 2002; 64(2) 208-15

  Conflict of Interest:

  In 2002 I received payment from Amersham International, manufacturers of a DAT-SPECT product, (via a grant from the Movement Disorders Society)for an article appearing as a supplement in Movement Disorders

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  Conflict of Interest:
  None declared.

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