Article Text

Original research
Heterogeneous distribution of tau pathology in the behavioural variant of Alzheimer’s disease
  1. Ellen Singleton1,
  2. Oskar Hansson2,
  3. Yolande A. L. Pijnenburg1,
  4. Renaud La Joie3,
  5. William G Mantyh3,
  6. Pontus Tideman2,4,
  7. Erik Stomrud2,4,
  8. Antoine Leuzy2,
  9. Maurits Johansson2,
  10. Olof Strandberg2,
  11. Ruben Smith2,
  12. Evi Berendrecht1,
  13. Bruce L Miller3,
  14. Leonardo Iaccarino3,5,
  15. Lauren Edwards3,
  16. Amelia Strom3,
  17. Emma E Wolters6,
  18. Emma Coomans6,
  19. Denise Visser6,
  20. Sandeep S V Golla6,
  21. Hayel Tuncel6,
  22. Femke Bouwman1,
  23. John Cornelis Van Swieten7,
  24. Janne M Papma7,
  25. Bart van Berckel6,
  26. Philip Scheltens1,
  27. Anke A. Dijkstra8,
  28. Gil D Rabinovici3,
  29. Rik Ossenkoppele1,2
  1. 1 Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands
  2. 2 Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
  3. 3 Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California, USA
  4. 4 Memory Clinic, Skåne University Hospital Lund, Lund, Sweden
  5. 5 In Vivo Human Molecular and Structural Neuroimaging Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
  6. 6 Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Vrije universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands
  7. 7 Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands
  8. 8 Department of Pathology, Amsterdam Neuroscience, Vrije universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands
  1. Correspondence to Ellen Singleton, Alzheimer Center, Amsterdam UMC Locatie VUmc, 1081 HV Amsterdam, Netherlands; e.singleton{at}amsterdamumc.nl

Abstract

Objective The clinical phenotype of the rare behavioural variant of Alzheimer’s disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination.

Methods For the tau PET study, seven amyloid-β positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a ‘typical’ memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7).

Results Individual regional W-scores ≥1.96 (corresponding to p<0.05) were observed in three cases, that is, case #5: medial prefrontal cortex (W=2.13) and anterior default mode network (W=3.79), case #2: lateral prefrontal cortex (W=2.79) and salience network (W=2.77), and case #7: frontal-to-entorhinal ratio (W=2.04). The remaining four cases fell within the normal distributions of the tAD group. Postmortem AT8 staining indicated no group-level regional differences in phosphorylated tau levels between bvAD and tAD (all p>0.05).

Conclusions Both in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.

Data availability statement

Data are available upon reasonable request. Anonymised data used in the present study may be available upon reasonable request to the corresponding author.

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Data availability statement

Data are available upon reasonable request. Anonymised data used in the present study may be available upon reasonable request to the corresponding author.

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Footnotes

  • Twitter @EllenSingletonn, @RikOssenkoppele

  • Contributors ES: study design, statistical analysis, analysis of imaging data, interpretation of data, writing and revising the manuscript; OH: interpretation of data and revising the manuscript; YALP: study design, interpretation of data and revising the manuscript; RLJ: study design, acquisition and interpretation of data and revising the manuscript; WGM: study design, acquisition and interpretation of data and revising the manuscript; PT: acquisition and interpretation of data and revising the manuscript; ES: acquisition and interpretation of data and revising the manuscript; AL: acquisition and interpretation of data and revising the manuscript; MJ: acquisition and interpretation of data and revising the manuscript; OS: acquisition and interpretation of data and revising the manuscript; RS: interpretation of data and revising the manuscript; EB: acquisition and analysis of postmortem data; BLM: interpretation of data and revising the manuscript; LI: interpretation of data and revising the manuscript; LE: acquisition of data and revising the manuscript; AS: acquisition of data and revising the manuscript; EEW: acquisition of data and revising the manuscript; EC: acquisition and interpretation of data, imaging analyses and revising the manuscript; DV: acquisition of data and revising the manuscript; SSVG: acquisition of data, imaging analyses and revising the manuscript; HT: imaging analyses; FB: interpretation of data and revising the manuscript; JCVS: revising the manuscript; JMP: interpretation of data and revising the manuscript; BvB: interpretation of data and revising the manuscript; PS: interpretation of data and revising the manuscript; AD: acquisition and interpretation of postmortem data and revising the manuscript; GDR: interpretation of data and revising the manuscript; RO: study design, patient selection, acquisition and interpretation of data and revising the manuscript.

  • Funding Work at the Alzheimer Center Amsterdam was supported by the Netherlands Organization for Health Research and Development, ZonMw (70-73305-98-1214 to Rik Ossenkoppele, PI). Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research programme of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. Work at the University of California San Francisco was supported by the NIH National Institute on Aging (NIA) grants R01-AG045611 (to GDR) and the Robert W. Katzman Fellowship Training Grant through the American Academy of Neurology in conjunction with the American Brain Foundation and Alzheimer’s Association (A133766) to (to WGM), as well as funding for Aging and Dementia Research Center (NIA P30-AG062422) and PPG (NIA P01-AG019724). Work at the Skåne University Hospital and Lund University was supported by the Swedish Research Council, the Knut and Alice Wallenberg foundation, the Marianne and Marcus Wallenberg foundation, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, the Skåne University Hospital Foundation and the Swedish federal government under the ALF agreement.

  • Competing interests OH has acquired research support (for the institution) from Roche, Pfizer, GE Healthcare, Biogen, Eli Lilly and AVID Radiopharmaceuticals. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Biogen and Roche. GDR reports research support from Avid Radiopharmaceuticals, GE Healthcare, Eli Lilly, Life Molecular Imaging; Scientific advisory boards for Axon Neurosciences, Eiasi, Merck, Roche; Associate Editor for JAMA Neurology. PS serves/has served on the advisory boards of: Genentech, Novartis, Pfizer, Roche, Danone, Nutricia, Jansen AI, Baxter and Lundbeck. He has been a speaker at symposia organised by Lundbeck, Lilly, Merz, Pfizer, Jansen AI, Danone, Novartis, Roche and Genentech. He serves on the editorial board of Alzheimer’s Research & Therapy and Alzheimer. Disease and Associated Disorders and is a member of the scientific advisory board of the EU Joint Programming Initiative and the French National Plan Alzheimer. The Alzheimer Center receives unrestricted funding from various sources through the VUmc Fonds. He receives no personal compensation for the activities mentioned above.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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