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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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.
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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.
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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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DOI: https://doi.org/10.1007/s11307-022-01735-z