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Evaluation of 18F-flutemetamol amyloid PET image analysis parameters on the effect of verubecestat on brain amlyoid load in Alzheimer’s disease

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Abstract

Purpose

The BACE inhibitor verubecestat was previously found to reduce amyloid load as assessed by 18F-flutemetamol positron emission tomography (PET) composite cortical standard uptake value ratio (SUVr) in patients with mild-to-moderate Alzheimer’s disease (AD) in a substudy of the EPOCH trial. Here, we report on additional analyses relevant to the EPOCH PET data, to help inform on the use of PET for assessing amlyloid load in AD clinical trials.

Procedures

The analyses addressed (1) identification of an optimal 18F-flutemetamol reference region, (2) determination of the threshold to characterize the magnitude of the longitudinal change, and (3) the impact of partial volume correction (PVC). Pons and subcortical white matter were evaluated as reference regions. The SUVr cutoffs and final reference region choice were determined using 162 18F-flutemetamol PET scans from the AIBL dataset. 18F-flutemetamol SUVrs were computed at baseline and at Week 78 in EPOCH participants who received verubecestat 12 mg (n = 14), 40 mg (n = 20), or placebo (n = 20). Drug effects on amyloid load were computed using either Meltzer (MZ), or symmetric geometric transfer matrix (SGTM) PVC and compared to uncorrected data.

Results

The optimal subcortical white matter and pons SUVr cutoffs were determined to be 0.69 and 0.62, respectively. The effect size to detect longitudinal change was higher for subcortical white matter (1.20) than pons (0.45). Hence, subcortical white matter was used as the reference region for the EPOCH PET substudy. In EPOCH, uncorrected baseline SUVr values correlated strongly with MZ PVC (r2 = 0.94) and SGTM PVC (r2 = 0.92) baseline SUVr values, and PVC did not provide improvement for evaluating treatment effects on amyloid load at Week 78. No change from baseline was observed in the placebo group at Week 78, whereas a 0.02 and a 0.04 decrease in SUVr were observed in the 12 mg and 40 mg arms, with the latter representing a 22% reduction in the amyloid load above the detection threshold.

Conclusions

Treatment-related 18F-flutemetamol longitudinal changes in AD clinical trials can be quantified using a subcortical white matter reference region without PVC.

Clinical trial registration: clinicaltrials.gov NCT01739348.

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Abbreviations

AAL:

Automated Anatomical Labeling

AD:

Alzheimer’s disease

AIBL:

Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing

APP:

Amyloid precursor protein

AUC:

Area under the curve

BACE:

β-Site amyloid precursor protein cleaving enzyme

CSF:

Cerebrospinal fluid

CI:

Confidence interval

LS:

Least squares

MCI:

Mild cognitive impairment

MMSE:

Mini-Mental State Examination

MZ:

Meltzer

PET:

Positron emission tomography

PiB:

Pittsburgh Compound B

PVC:

Partial volume correction

ROC:

Receiver operating characteristics

SD:

Standard deviation

SGTM:

Symmetric geometric transfer matrix

SPM12:

Statistical Parametric Mapping 12

SUVr:

Standard uptake value ratio

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Acknowledgements

The authors would like to thank the study participants and staff. Medical writing assistance, under the direction of the authors, was provided by Kirsty Muirhead, PhD, of CMC AFFINITY, McCann Health Medical Communications, in accordance with Good Publication Practice (GPP3) guidelines. This assistance was funded by Merck Sharp & Dohme LLC (MSD), a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Christopher Lines (MSD) assisted with writing and editing of the paper.

Funding

Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

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Authors and Affiliations

  1. Merck & Co., Inc., Rahway, NJ, USA

    Cyrille Sur, James Kost, Idriss Bennacef & Michael F. Egan

  2. Clario, San Mateo, CA, USA

    Katarzyna Adamczuk, David Scott, Mehul Sampat & Joyce Suhy

  3. GE Health Care, Amersham, UK

    Christopher Buckley, Gill Farrar & Ben Newton

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  1. Cyrille Sur
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  2. Katarzyna Adamczuk
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  3. David Scott
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Contributions

CS, JK, BN, JS, and MFE contributed to the conception, design, and planning of the study.

DS, JS, and MFE acquired the data.

CS, KA, DS, JK, JS, MS, and MFE analyzed the data.

CS, KA, DS, JK, CB, GF, JS, IB, and MFE interpreted the results.

All authors critically reviewed the manuscript for important intellectual content, and provided final approval of the submitted manuscript.

Corresponding author

Correspondence to Cyrille Sur.

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Ethics approval

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 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Conflict of Interests

CS, JK, IB, and MFE are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, & may own stock and/or stock options in Merck and Co., Inc., Rahway, NJ, USA.

KA, DS, MS, and JS are employees of Clario, San Mateo, CA, USA.

CB, GF, and BN are employees of GE Healthcare, Amersham, UK.

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Sur, C., Adamczuk, K., Scott, D. et al. Evaluation of 18F-flutemetamol amyloid PET image analysis parameters on the effect of verubecestat on brain amlyoid load in Alzheimer’s disease. Mol Imaging Biol 24, 862–873 (2022). https://doi.org/10.1007/s11307-022-01735-z

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