Heterogeneous distribution of tau pathology in the behavioural variant of Alzheimer's disease

Ellen Singleton*, Oskar Hansson, Yolande A.L. Pijnenburg, Renaud La Joie, William G. Mantyh, Pontus Tideman, Erik Stomrud, Antoine Leuzy, Maurits Johansson, Olof Strandberg, Ruben Smith, Evi Berendrecht, Bruce L. Miller, Leonardo Iaccarino, Lauren Edwards, Amelia Strom, Emma E. Wolters, Emma Coomans, Denise Visser, Sandeep S.V. GollaHayel Tuncel, Femke Bouwman, John Cornelis Van Swieten, Janne M. Papma, Bart Van Berckel, Philip Scheltens, Anke A. Dijkstra, Gil D. Rabinovici, Rik Ossenkoppele

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)

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 [ 18 F]flortaucipir or [ 18 F]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.

Original languageEnglish
Pages (from-to)872-880
Number of pages9
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume92
Issue number8
DOIs
Publication statusPublished - 1 Aug 2021

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

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