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Prospective F-18 FDOPA PET Imaging Study in Human PD

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Abstract

Purpose

We present the findings of our final prospective study submitted to the U.S. Food and Drug Administration (FDA) for New Drug Application (NDA) approval for the use of 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine (F-18 FDOPA) positron emission tomography (PET) imaging for Parkinson’s disease (PD). The primary aim was to determine the sensitivity, specificity, and predictive values of F-18 FDOPA PET in parkinsonian patients with respect to clinical standard-of-truth (SOT). Secondary outcomes included the inter-rater reliability, and correlation of quantitative measures for PET with dopaminergic status.

Methods

In 68 parkinsonian subjects, F-18 FDOPA PET scan from 80 to 100 min was acquired following a CT scan. Scan images were presented to one expert in F-18 FDOPA image interpretation and two physicians with prior experience in I-123 FPCIT single-photon emission computed tomography image interpretation. Fifty-six subjects completed the study with a follow-up for SOT determination. Image readers were blind to the clinical/quantitative data; SOT clinician was blind to the image data.

Results

For 47 of the 56 patients, SOT was in agreement with the PET scan results. For nine patients, SOT suggested dopaminergic deficit, whereas the imaging showed normal uptake. The specificity and positive predictive values are 91% and 92%, respectively, suggesting high probability that those who test positive by the PET scan truly have dopaminergic degeneration. The sensitivity was 73%. Inter-rater agreement was 0.6–0.8 between the different readers.

Conclusion

Our prospective study demonstrates high specificity and moderate sensitivity of F-18 FDOPA PET for PD. We received NDA approval in October 2019.

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Data Availability

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Acknowledgments

Special thanks to Mr. Claude Margouleff and Ms. Limei Zhuo for technical assistance with the PET studies.

Funding

This research was supported by funds from the Department of Radiochemistry/Cyclotron directed by Thomas Chaly. He is the senior author and had a role in the study design, data analysis, interpretation and preparation of the manuscript.

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Authors and Affiliations

  1. Center for Neurosciences, Feinstein Institutes for Medical Research, 350 Community Drive, Manhasset, NY, USA

    Vijay Dhawan, Martin H Niethammer, Toni M Fitzpatrick, Loreta M Quatarolo, Yoon Young Choi, Alice Oh & David Eidelberg

  2. Biostatistics Unit, Feinstein Institutes for Medical Research, Manhasset, NY, USA

    Martin L Lesser, Karalyn N Pappas & David Bjelke

  3. Department of Radiochemistry/Cyclotron, Feinstein Institutes for Medical Research, Manhasset, NY, USA

    Matthew Hellman, Jaskirat Singh & Thomas Chaly

Authors
  1. Vijay Dhawan
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  2. Martin H Niethammer
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  3. Martin L Lesser
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  4. Karalyn N Pappas
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  5. Matthew Hellman
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  6. Toni M Fitzpatrick
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  7. David Bjelke
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  8. Jaskirat Singh
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  9. Loreta M Quatarolo
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  10. Yoon Young Choi
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  11. Alice Oh
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  12. David Eidelberg
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  13. Thomas Chaly
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Contributions

The study was designed by Vijay Dhawan, Martin H Niethammer, Matthew Hellman, David Eidelberg, and Thomas Chaly. Material preparation and data collection were performed by Vijay Dhawan, Martin H Niethammer, Matthew Hellman, Toni M Fitzpatrick, David Bjelke, Jaskirat Singh, Loreta M Quatarolo, and Yoon Young Choi. The data analysis was performed by Vijay Dhawan, Martin L Lesser, Karalyn N Pappas, David Bjelke, Alice Oh, and Thomas Chaly. Project administrative support was provided by Toni M Fitzpatrick, Loreta M Quatarolo, Yoon Young Choi, and Alice Oh. Supervision was provided by David Eidelberg. The first draft of the manuscript was written by Vijay Dhawan, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Vijay Dhawan.

Ethics declarations

Ethics Approval and Consent to participate

This study was performed with Institutional Review Board approval of the Feinstein Institutes for Medical Research, and in compliance with the HIPAA Privacy Rule. Informed consent was obtained from all individual participants included in the study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 2013 Helsinki declaration and its later amendments or comparable ethical standards.

Consent for Publication

Informed consent was obtained from all individual participants included in the study.

Competing Interests

Vijay Dhawan, Martin H Niethammer, Martin L Lesser, Karalyn N Pappas, Matthew Hellman, Toni M Fitzpatrick, David Bjelke, Jaskirat Singh, Loreta M Quatarolo, Yoon Young Choi, Alice Oh, David Eidelberg, and Thomas Chaly declare that they have no competing financial interests.

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Supplementary Information

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Appendix

Appendix

Table 3 A summary of the baseline variables for clinical study #18
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Table 4 SOR quantification (n = 56)
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A Fluorodopa F-18 FDOPA PET scan has the unique capability to quantify striatal neuronal loss. This SOR quantification may be helpful as an additional tool to evaluate the scans. Even though we have used SOR quantification procedure in the past for routine clinical interpretation of the PET scan results, for this clinical study the SOR values were not used for the visual determination of the PET scan results. The SOR values were blinded to the image readers and the physician collecting SOT. This SOR quantification is straightforward and does not require any special software program (see below).

We calculated the SOR values for all patients to see how the PET scan results correlate with the SOR values to assess loss of dopaminergic neurons. If the SOR values can be used to further confirm the visual interpretation of the PET scan results, it may be used as a supportive tool for the differential diagnosis of Parkinsonian syndromes. The average values of the left posterior putamen for the positive scans are 1.790 compared to the average values of the left posterior putamen for the negative scans is 2.627. The negative scans are normal, and the values agree with the SOR values for normal subjects (2.545) from our previously unpublished retroactive study (study #17). L = left; R = right.

We did not use ipsilateral/contralateral classification because the images were only read visually without any additional quantification or clinically relevant data. Moreover, instead of focusing on the contralateral posterior putamen (the site of early-stage dopaminergic deficit) this also represents the worst-case scenario for image interpretation.

SOR estimation:

Even though we have an automated MRI-supported ROI selection methodology for F-18 FDOPA PET data analysis available, for this study we used our manual method that is in use for more than 20 years that we find very straightforward and easy to use and does not require any special software except what is supplied by the PET scanner manufacturers for image processing, thereby making it easy to implement anywhere.

Region-of-interest (ROI) analysis is carried out on the F-18 FDOPA PET images by first adding the central five slices on which the striatum is visible (usually 8–9 slices on most scanners; composite slice thickness is 16–18 mm). Large circular ROIs (20 cm2) are placed on both left and right occipital lobes. The average count value is calculated and then the whole image is divided by this value to generate the striatal/occipital ratio (SOR) image. Four small circular ROIs (1.2 cm2) are placed on the transaxial slice along the axis of the striatum covering the caudate and anterior, middle, and posterior sections of the putamen. The ratio values are then compared with the values obtained from a database of normal control subjects. Anything less than two standard deviations below the normal value is considered abnormal

Fig. 3
figure 3

SOR values for positive and negative scans

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Distribution of striatal/occipital ratio (SOR) values for the 56 subjects with F-18 FDOPA PET imaging and SOT data in the right (left panel) and left (right panel) posterior putamen.

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Dhawan, V., Niethammer, M.H., Lesser, M.L. et al. Prospective F-18 FDOPA PET Imaging Study in Human PD. Nucl Med Mol Imaging 56, 147–157 (2022). https://doi.org/10.1007/s13139-022-00748-4

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