Longitudinal TSPO expression in tau transgenic P301S mice predicts increased tau accumulation and deteriorated spatial learning

Eckenweber, Florian; Medina-Luque, José; Blume, Tanja; Sacher, Christian; Biechele, Gloria; Wind, Karin; Deußing, Maximilian; Briel, Nils; Lindner, Simon; Boening, Guido; Ungern-Sternberg, Barbara von; Albert, Nathalie L.; Zwergal, Andreas; Levin, Johannes; Bartenstein, Peter; Cumming, Paul; Rominger, Axel; Höglinger, Günter U.; Herms, Jochen; Brendel, Matthias

doi:10.1186/s12974-020-01883-5

Cited by 21 publications

(36 citation statements)

References 34 publications

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“…However, preclinical evidence with PET in tau transgenic mice suggests that inflammation increases longitudinally and predicts greater tau accumulation and lesser performance over time. 38 There are several limitations to our study. We recruited according to clinical diagnostic criteria, and although clinicopathological correlations of PSP-Richardson's syndrome are very high, including 8 of 8 cases in our study with post mortem pathology, they are not perfect.…”

Section: Discussionmentioning

confidence: 94%

Neuroinflammation predicts disease progression in progressive supranuclear palsy

Malpetti

Passamonti

Jones

et al. 2021

J Neurol Neurosurg Psychiatry

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IntroductionIn addition to tau pathology and neuronal loss, neuroinflammation occurs in progressive supranuclear palsy (PSP). However, the prognostic value of the in vivo imaging markers for these processes in PSP remains unclear. We test the primary hypothesis that baseline in vivo imaging assessment of neuroinflammation in subcortical regions predicts clinical progression in patients with PSP.MethodsSeventeen patients with PSP–Richardson’s syndrome underwent a baseline multimodal imaging assessment, including [11C]PK11195 positron emission tomography (PET) to index microglial activation, [18F]AV-1451 PET for tau pathology and structural MRI. Disease severity was measured at baseline and serially up to 4 years with the Progressive Supranuclear Palsy Rating Scale (PSPRS) (average interval of 5 months). Regional grey-matter volumes and PET ligand binding potentials were summarised by three principal component analyses (PCAs). A linear mixed-effects model was applied to the longitudinal PSPRS scores. Single-modality imaging predictors were regressed against the individuals’ estimated rate of progression to identify the prognostic value of baseline imaging markers.ResultsPCA components reflecting neuroinflammation and tau burden in the brainstem and cerebellum correlated with the subsequent annual rate of change in the PSPRS. PCA-derived PET markers of neuroinflammation and tau pathology correlated with regional brain volume in the same regions. However, MRI volumes alone did not predict the rate of clinical progression.ConclusionsMolecular imaging with PET for microglial activation and tau pathology can predict clinical progression in PSP. These data encourage the evaluation of immunomodulatory approaches to disease-modifying therapies in PSP and the potential for PET to stratify patients in early phase clinical trials.

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Section: Discussionmentioning

confidence: 94%

Neuroinflammation predicts disease progression in progressive supranuclear palsy

Malpetti

Passamonti

Jones

et al. 2021

J Neurol Neurosurg Psychiatry

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“…Two bilateral volumes of interest placed in the frontal cortex (comprising 15 mm 3 each) served for calculation of target-to-reference SUVR. We chose frontal cortex for quantification of TSPO-PET signal based on earlier findings in C57BL/6, App NL-G-F , and P301S mice [ 21 , 25 , 30 ], and due to the documented presence of neuropathology in App NL-G-F and P301S mice, along with the requirement for a sufficiently large standard volume of interest (VOI).…”

Section: Methodsmentioning

confidence: 99%

“…Iba-1, CD68, methoxy-X04, and AT8 immuno- and histochemical stainings were performed as described previously [ 21 , 25 ]. In brief, we performed a standard free-floating immunofluorescence protocol cortex and brainstem areas matching the PET brain regions.…”

Section: Methodsmentioning

confidence: 99%

“…The behavioral phenotype of P301S mice manifests as learning deficits from 2-3 months of age, and onset of motor impairment at 4 months, leading to early death before 12 months of age. Longitudinal 18 F-GE-180 data from 156 serial scans of P301S mice imaged at up to four different timepoints (2, 4, 6, and 8 months) from a previous [21] and an unpublished study were reprocessed. Six mice of each sex were imaged longitudinally at all four time-points whereas 27 female and 13 male mice were imaged from 2 to 6 months of age.…”

Section: Animals and Study Designmentioning

confidence: 99%

“…A recent human study in cognitively healthy individuals revealed significant sex differences of 11 C-PBR28 binding in brain, with women showing a higher TSPO-PET signal [17]. However, although TSPO-PET is increasingly used for investigation in vivo of microglial activation in mouse models of AD [19][20][21][22], preclinical studies have not previously considered possible sex effects on TSPO-PET findings.…”

Section: Introductionmentioning

confidence: 99%

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Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases

Biechele

Franzmeier²,

Blume

et al. 2020

J Neuroinflammation

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Background In vivo assessment of neuroinflammation by 18-kDa translocator protein positron-emission-tomography (TSPO-PET) ligands receives growing interest in preclinical and clinical research of neurodegenerative disorders. Higher TSPO-PET binding as a surrogate for microglial activation in females has been reported for cognitively normal humans, but such effects have not yet been evaluated in rodent models of neurodegeneration and their controls. Thus, we aimed to investigate the impact of sex on microglial activation in amyloid and tau mouse models and wild-type controls. Methods TSPO-PET (18F-GE-180) data of C57Bl/6 (wild-type), AppNL-G-F (β-amyloid model), and P301S (tau model) mice was assessed longitudinally between 2 and 12 months of age. The AppNL-G-F group also underwent longitudinal β-amyloid-PET imaging (Aβ-PET; 18F-florbetaben). PET results were confirmed and validated by immunohistochemical investigation of microglial (Iba-1, CD68), astrocytic (GFAP), and tau (AT8) markers. Findings in cerebral cortex were compared by sex using linear mixed models for PET data and analysis of variance for immunohistochemistry. Results Wild-type mice showed an increased TSPO-PET signal over time (female +23%, male +4%), with a significant sex × age interaction (T = − 4.171, p < 0.001). The Aβ model AppNL-G-F mice also showed a significant sex × age interaction (T = − 2.953, p = 0.0048), where cortical TSPO-PET values increased by 31% in female AppNL-G-F mice, versus only 6% in the male mice group from 2.5 to 10 months of age. Immunohistochemistry for the microglial markers Iba-1 and CD68 confirmed the TSPO-PET findings in male and female mice aged 10 months. Aβ-PET in the same AppNL-G-F mice indicated no significant sex × age interaction (T = 0.425, p = 0.673). The P301S tau model showed strong cortical increases of TSPO-PET from 2 to 8.5 months of age (female + 32%, male + 36%), without any significant sex × age interaction (T = − 0.671, p = 0.504), and no sex differences in Iba-1, CD68, or AT8 immunohistochemistry. Conclusion Female mice indicate sex-dependent microglia activation in aging and in response to amyloidosis but not in response to tau pathology. This calls for consideration of sex difference in TSPO-PET studies of microglial activation in mouse models of neurodegeneration and by extension in human studies.

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In Vivo Assessment of Neuroinflammation in 4‐Repeat Tauopathies

et al. 2020

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A BS TRACT: Background: Neuroinflammation has received growing interest as a therapeutic target in neurodegenerative disorders, including 4-repeat tauopathies. Objectives: The aim of this cross-sectional study was to investigate 18 kDa translocator protein positron emission tomography (PET) as a biomarker for microglial activation in the 4-repeat tauopathies corticobasal degeneration and progressive supranuclear palsy. Methods: Specific binding of the 18 kDa translocator protein tracer 18 F-GE-180 was determined by serial PET during pharmacological depletion of microglia in a 4-repeat tau mouse model. The 18 kDa translocator protein PET was performed in 30 patients with corticobasal syndrome (68 ± 9 years, 16 women) and 14 patients with progressive supranuclear palsy (69 ± 9 years, 8 women), and 13 control subjects (70 ± 7 years, 7 women). Group

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Longitudinal TSPO expression in tau transgenic P301S mice predicts increased tau accumulation and deteriorated spatial learning

Cited by 21 publications

References 34 publications

Neuroinflammation predicts disease progression in progressive supranuclear palsy

Neuroinflammation predicts disease progression in progressive supranuclear palsy

Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases

In Vivo Assessment of Neuroinflammation in 4‐Repeat Tauopathies

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