Neuroinflammation is highest in areas of disease progression in semantic dementia

Abstract

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 pathologic process in semantic variant primary progressive aphasia, should be further studied as a possible therapeutic target to slow disease progression.

Relationships among tau burden, atrophy, age, and naming in the aphasic variant of Alzheimer's disease

“…All participants were suspected to have a primary AD neuropathologic diagnosis. All flortaucipir images were manually reviewed for the patterns of off-target binding in white matter that have previously been shown in autopsy-confirmed corticobasal degeneration 36 or TDP-43 cases 37 .…”

A crosstalk between gut and brain in sepsis-induced cognitive decline

“…We hypothesized that sepsis triggers gut bacterial translocation into the blood compartment, triggering a systemic inflammatory response that affects the brain.. To test our hypothesis, Wistar rats were subjected to in vivo [ 11 C]PBR28 positron emission tomography (PET)/computed tomography (CT) imaging at 24 h and 10 days after cecal ligation and perforation (CLP), a gold standard model to study sepsis which closely is similar to the development and characteristics of human sepsis [ 9 ], or non-CLP surgeries. The radiotracer [ 11 C]PBR28 utilized in this experiment binds to the translocator protein 18 kDa (TSPO), which is upregulated in activated microglia and astrocyte cells [ 10 , 11 ], and neurons in the human olfactory bulb [ 12 ]. TSPO is a radioligand extensively used for inflammatory brain imaging, and it is considered a marker of neuroinflammation [ 10 , 11 , 13 ].…”

Diffusion tractography of superior cerebellar peduncle and dentatorubrothalamic tracts in two autopsy confirmed progressive supranuclear palsy variants: Richardson syndrome and the speech-language variant

“…The underlying representation of diffusivity parameters remains uncertain, it is possible to interpret FA as a general indicator of axonal degeneration, and assume MD as a measure of interstitial diffusivity, ( Gatto et al, 2021 ). In the context of PSP, the decrease in FA could be part of the tau-driven pathology mechanism, whereas MD findings may be related to underlying gliotic infiltrative and neuroinflammatory processes, ( Ling et al, 2016 , Pascual et al, 2021 ) ( Whitwell et al, 2011b ), or the presence of brain atrophy on the macro-pathological (ie millimeter) level. As the differences between groups in FA were greater than differences in MD it is possible that the two PSP variants are not equally affected by tau aggregation, with a different distribution across the neuroaxis determining the different connectivity changes and clinical presentations.…”