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Reduced [18F]flortaucipir retention in white matter hyperintensities compared to normal-appearing white matter

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Abstract

Purpose

Recent research has suggested the use of white matter (WM) reference regions for longitudinal tau-PET imaging. However, tau tracers display affinity for the β-sheet structure formed by myelin, and thus WM lesions might influence tracer retention. Here, we explored whether the tau-sensitive tracer [18F]flortaucipir shows reduced retention in WM hyperintensities (WMH) and how this retention changes over time.

Methods

We included 707 participants from the Alzheimer’s Disease Neuroimaging Initiative with available [18F]flortaucipir-PET and structural and FLAIR MRI scans. WM segments and WMH were automatically delineated in the structural MRI and FLAIR scans, respectively. [18F]flortaucipir standardized uptake value ratios (SUVR) of WMH and normal-appearing WM (NAWM) were calculated using the inferior cerebellar grey matter as reference region, and a 3-mm erosion was applied to the combined NAWM and WMH masks to avoid partial volume effects. Longitudinal [18F]flortaucipir SUVR changes in NAWM and WMH were estimated using linear mixed models. The percent variance of WM-referenced cortical [18F]flortaucipir SUVRs explained by longitudinal changes in the WM reference region was estimated with the R2 coefficient.

Results

Compared to NAWM, WMH areas displayed significantly reduced [18F]flortaucipir SUVR, independent of cognitive impairment or Aβ status (mean difference = 0.14 SUVR, p < 0.001). Older age was associated with lower [18F]flortaucipir SUVR in both NAWM (− 0.002 SUVR/year, p = 0.005) and WMH (− 0.004 SUVR/year, p < 0.001). Longitudinally, [18F]flortaucipir SUVR decreased in NAWM (− 0.008 SUVR/year, p = 0.03) and even more so in WMH (− 0.02 SUVR/year, p < 0.001). Between 17% and 66% of the variance of longitudinal changes in cortical WM-referenced [18F]flortaucipir SUVRs were explained by longitudinal changes in the reference region.

Conclusions

[18F]flortaucipir retention in the WM decreases over time and is influenced by the presence of WMH, supporting the hypothesis that [18F]flortaucipir retention in the WM is partially myelin-dependent. These findings have implications for the use of WM reference regions for [18F]flortaucipir-PET imaging.

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Data availability

All the data used in this study is publicly available at the Laboratory of Neuro Imaging (LONI) server of the Alzheimer’s Disease Neuroimaging Initiative.

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Acknowledgments

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.

Funding

MJG is supported by the “Miguel Servet” program (CP19/00031) of the Spanish Instituto de Salud Carlos III (ISCIII-FEDER). MS is supported by the Knut and Alice Wallenberg Foundation (Wallenberg Centre for Molecular and Translational Medicine; KAW 2014.0363), the Swedish Research Council (#2017-02869), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-813971), and the Swedish Alzheimer Foundation (#AF-740191).

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Authors and Affiliations

  1. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Alexis Moscoso, Michel J. Grothe & Michael Schöll

  2. Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden

    Alexis Moscoso, Michel J. Grothe & Michael Schöll

  3. Unidad de Trastornos del Movimiento, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Avda. Manuel Siurot, s/n, 41013, Sevilla, Spain

    Michel J. Grothe

  4. Grupo Trastornos del Movimiento, Instituto de Biomedicina de Sevilla, Campus Hospital Universitario Virgen del Rocío, Avda. Manuel Siurot, s/n, 41013, Sevilla, Spain

    Michel J. Grothe

  5. Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK

    Michael Schöll

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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 the analysis or the writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wpcontent/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

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Moscoso, A., Grothe, M.J., Schöll, M. et al. Reduced [18F]flortaucipir retention in white matter hyperintensities compared to normal-appearing white matter. Eur J Nucl Med Mol Imaging 48, 2283–2294 (2021). https://doi.org/10.1007/s00259-021-05195-5

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