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Reference region selection and the association between the rate of amyloid accumulation over time and the baseline amyloid burden

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Abstract

Relative quantitative analysis of amyloid plaque burden in Alzheimer’s disease (AD) patients can be reported as standardized uptake value ratio (SUVR) from positron emission tomography (PET). Here, the SUVR is the ratio of the mean amyloid radioligand retention in a composite (COMP) neocortical volume of interest (VOI) to that in a reference VOI, such as the cerebellum, brainstem (BST)/pons, or white matter (WM). Some longitudinal PET investigations show that the rate of amyloid accumulation to follow-up has an inverted U relationship with baseline amyloid SUVR relative to cerebellar or brainstem/pons reference VOIs. The corresponding association with SUVR relative to WM is unknown. To test the possible benefits of WM normalization, we analyzed [18F]-AV45 PET data from 404 subjects in the AD Neuroimaging Initiative (ADNI) database at baseline and 2-year follow-up (144 cognitively normal controls, 225 patients with mild cognitive impairment, and 35 AD patients). Reference regions included subcortical WM as well as conventional cerebellar gray matter (CBL), and BST. We tested associations between each subject’s inter-session change (∆) of SUVR and their baseline SUVR by applying linear, logarithmic, and quadratic regression analyses. Unscaled standardized uptake values (SUVs) were correlated between VOIs at baseline and follow-up, and within VOIs in the longitudinal run. The association between ∆SUVR and baseline SUVR relative to WM reference was best described by an inverted U-shaped function. Correlation analyses demonstrated a high regional and temporal correlation between COMP and WM VOI SUVs. For WM normalization, we confirm that the rate of amyloid accumulation over time follows an inverted U-shaped function of baseline amyloid burden. Reference region selection, however, has substantial effects on SUVR results. This reflects the extent of covariance between SUVs in the COMP VOI and those in the various reference VOIs. We speculate that PET labeling of amyloid deposition within target regions is partially confounded by effects of longitudinal changes of cerebral blood flow (CBF) on tracer delivery. Indeed, CBF may be the leading factor influencing longitudinal SUV changes. We suggest that SUVR relative to WM may be more robust to changes in CBF, and thus fitter for sensitive detection of amyloid accumulation in intervention studies.

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Acknowledgements

Language editing was provided by Inglewood Biomedical Editing. Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI; National Institutes of Health grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

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Authors and Affiliations

  1. Department of Nuclear Medicine, University of Munich, Munich, Germany

    Janusch Blautzik, Matthias Brendel, Julia Sauerbeck, Sebastian Kotz, Franziska Scheiwein, Peter Bartenstein & Axel Rominger

  2. MNI, New Haven, USA

    John Seibyl

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  1. Janusch Blautzik
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  2. Matthias Brendel
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  3. Julia Sauerbeck
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  4. Sebastian Kotz
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Correspondence to Axel Rominger.

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures described in the study were approved by the institutional review boards of each participating institution and were in accordance with the 1964 Helsinki Declaration and its later amendments.

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

Additional information

Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

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Blautzik, J., Brendel, M., Sauerbeck, J. et al. Reference region selection and the association between the rate of amyloid accumulation over time and the baseline amyloid burden. Eur J Nucl Med Mol Imaging 44, 1364–1374 (2017). https://doi.org/10.1007/s00259-017-3666-8

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  • DOI: https://doi.org/10.1007/s00259-017-3666-8

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