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Neuroinflammation is highest in areas of disease progression in semantic dementia

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Belen Pascual, Quentin Funk, Paolo Zanotti-Fregonara, Matthew D. Cykowski, Mattia Veronese, Elijah Rockers, Kathleen Bradbury, Meixiang Yu, Mohammad O. Nakawah, Gustavo C. Román, Paul E. Schulz, Anithachristy S. Arumanayagam, David Beers, Alireza Faridar, Masahiro Fujita, Stanley H. Appel, Joseph C. Masdeu

Original languageEnglish
Pages (from-to)1565-1575
Number of pages11
Issue number5
Published1 May 2021

Bibliographical note

Funding Information: The study was funded by the Chao, Graham, Harrison, and Nantz Funds from the Houston Methodist Foundation, as well as the Moody Foundation; M.C. and A.F. received funding from the Clinical Scholar Awards Program of the Houston Methodist Academic Institute. Publisher Copyright: © 2021 The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


Despite epidemiological and genetic data linking semantic dementia to inflammation, the topography of neuroinflammation in semantic dementia, also known as the semantic variant of primary progressive aphasia, remains unclear. The pathology starts at the tip of the left temporal lobe where, in addition to cortical atrophy, a strong signal appears with the tau PET tracer 18F-flortaucipir, even though the disease is not typically associated with tau but with TDP-43 protein aggregates. Here, we characterized the topography of inflammation in semantic variant primary progressive aphasia using high-resolution PET and the tracer 11C-PBR28 as a marker of microglial activation. We also tested the hypothesis that inflammation, by providing non-specific binding targets, could explain the 18F-flortaucipir signal in semantic variant primary progressive aphasia. Eight amyloid-PET-negative patients with semantic variant primary progressive aphasia underwent 11C-PBR28 and 18F-flortaucipir PET. Healthy controls underwent 11C-PBR28 PET (n = 12) or 18F-flortaucipir PET (n = 12). Inflammation in PET with 11C-PBR28 was analysed using Logan graphical analysis with a metabolite-corrected arterial input function. 18F-flortaucipir standardized uptake value ratios were calculated using the cerebellum as the reference region. Since monoamine oxidase B receptors are expressed by astrocytes in affected tissue, selegiline was administered to one patient with semantic variant primary progressive aphasia before repeating 18F-flortaucipir scanning to test whether monoamine oxidase B inhibition blocked flortaucipir binding, which it did not. While 11C-PBR28 uptake was mostly cortical, 18F-flortaucipir uptake was greatest in the white matter. The uptake of both tracers was increased in the left temporal lobe and in the right temporal pole, as well as in regions adjoining the left temporal pole such as insula and orbitofrontal cortex. However, peak uptake of 18F-flortaucipir localized to the left temporal pole, the epicentre of pathology, while the peak of inflammation 11C-PBR28 uptake localized to a more posterior, mid-temporal region and left insula and orbitofrontal cortex, in the periphery of the damage core. Neuroinflammation, greatest in the areas of progression of the pathological process in semantic variant primary progressive aphasia, should be further studied as a possible therapeutic target to slow disease progression.

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