Validity and value of metabolic connectivity in mouse models of β-amyloid and tauopathy.

Among functional imaging methods, metabolic connectivity (MC) is increasingly used for investigation of regional network changes to examine the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD) or movement disorders. Hitherto, MC was mostly used in clinical studies, but only a few studies demonstrated the usefulness of MC in the rodent brain. The goal of the current work was to analyze and validate metabolic regional network alterations in three different mouse models of neurodegenerative diseases (β-amyloid and tau) by use of 2-deoxy-2-[F]fluoro-d-glucose positron emission tomography (FDG-PET) imaging.

Assessment of synaptic loss in mouse models of β-amyloid and tau pathology using [F]UCB-H PET imaging.

Objective: In preclinical research, the use of [F]Fluorodesoxyglucose (FDG) as a biomarker for neurodegeneration may induce bias due to enhanced glucose uptake by immune cells. In this study, we sought to investigate synaptic vesicle glycoprotein 2A (SV2A) PET with [F]UCB-H as an alternative preclinical biomarker for neurodegenerative processes in two mouse models representing the pathological hallmarks of Alzheimer's disease (AD).

Methods: A total of 29 PS2APP, 20 P301S and 12 wild-type mice aged 4.

[F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data.

Objectives: Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer`s disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions.

Depletion and activation of microglia impact metabolic connectivity of the mouse brain.

Aim: We aimed to investigate the impact of microglial activity and microglial FDG uptake on metabolic connectivity, since microglial activation states determine FDG-PET alterations. Metabolic connectivity refers to a concept of interacting metabolic brain regions and receives growing interest in approaching complex cerebral metabolic networks in neurodegenerative diseases. However, underlying sources of metabolic connectivity remain to be elucidated.

18 kDa translocator protein positron emission tomography facilitates early and robust tumor detection in the immunocompetent SB28 glioblastoma mouse model.

Introduction: The 18 kDa translocator protein (TSPO) receives growing interest as a biomarker in glioblastoma. Mouse models can serve as an important tool for the investigation of biomarkers in glioblastoma, but several glioblastoma models indicated only low TSPO-PET signals in contrast to high TSPO-PET signals of human glioblastoma. Thus, we aimed to investigate TSPO-PET imaging in the syngeneic immunocompetent SB28 mouse model, which is thought to closely represent the tumor microenvironment (TME) of human glioblastoma.

Single-Cell Radiotracer Allocation via Immunomagnetic Sorting to Disentangle PET Signals at Cellular Resolution.

With great interest, our independent groups of scientists located in Korea and Germany recognized the use of a very similar methodologic approach to quantify the uptake of radioactive glucose (F-FDG) at the cellular level. The focus of our investigations was to disentangle microglial F-FDG uptake. To do so, CD11b immunomagnetic cell sorting was applied to isolate microglia cells after in vivo F-FDG injection, to allow simple quantification via a γ-counter.

Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition.

We undertook longitudinal β-amyloid positron emission tomography (Aβ-PET) imaging as a translational tool for monitoring of chronic treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone in Aβ model mice. We thus tested the hypothesis this treatment would rescue from increases of the Aβ-PET signal while promoting spatial learning and preservation of synaptic density. Here, we investigated longitudinally for 5 months PS2APP mice ( = 23; baseline age: 8 months) and mice ( = 37; baseline age: 5 months) using Aβ-PET.

Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency.

Haploinsufficiency of the progranulin (PGRN)-encoding gene (GRN) causes frontotemporal lobar degeneration (GRN-FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology, we used genetic and pharmacological approaches to suppress TREM2-dependent transition of microglia from a homeostatic to a disease-associated state. Trem2 deficiency in Grn KO mice reduced microglia hyperactivation.

Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases.

2-Deoxy-2-[F]fluoro-d-glucose positron emission tomography (FDG-PET) is widely used to study cerebral glucose metabolism. Here, we investigated whether the FDG-PET signal is directly influenced by microglial glucose uptake in mouse models and patients with neurodegenerative diseases. Using a recently developed approach for cell sorting after FDG injection, we found that, at cellular resolution, microglia displayed higher glucose uptake than neurons and astrocytes.

Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation.

Modulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimer's disease (AD). However, determinants of a beneficial therapeutic effect are ill-understood. Thus, we investigated the potential of 18 kDa translocator protein positron-emission-tomography (TSPO-PET) for assessment of microglial activation in mouse brain before and during chronic immunomodulation.

Glitter in the Darkness? Nonfibrillar β-Amyloid Plaque Components Significantly Impact the β-Amyloid PET Signal in Mouse Models of Alzheimer Disease.

β-amyloid (Aβ) PET is an important tool for quantification of amyloidosis in the brain of suspected Alzheimer disease (AD) patients and transgenic AD mouse models. Despite the excellent correlation of Aβ PET with gold standard immunohistochemical assessments, the relative contributions of fibrillar and nonfibrillar Aβ components to the in vivo Aβ PET signal remain unclear. Thus, we obtained 2 murine cerebral amyloidosis models that present with distinct Aβ plaque compositions and performed regression analysis between immunohistochemistry and Aβ PET to determine the biochemical contributions to Aβ PET signal in vivo.

Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin-deficient mice.

Single nucleotide polymorphisms (SNPs) in TMEM106B encoding the lysosomal type II transmembrane protein 106B increase the risk for frontotemporal lobar degeneration (FTLD) of GRN (progranulin gene) mutation carriers. Currently, it is unclear if progranulin (PGRN) and TMEM106B are synergistically linked and if a gain or a loss of function of TMEM106B is responsible for the increased disease risk of patients with GRN haploinsufficiency. We therefore compare behavioral abnormalities, gene expression patterns, lysosomal activity, and TDP-43 pathology in single and double knockout animals.

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

Background: P301S tau transgenic mice show age-dependent accumulation of neurofibrillary tangles in the brainstem, hippocampus, and neocortex, leading to neuronal loss and cognitive deterioration. However, there is hitherto only sparse documentation of the role of neuroinflammation in tau mouse models. Thus, we analyzed longitudinal microglial activation by small animal 18 kDa translocator protein positron-emission-tomography (TSPO μPET) imaging in vivo, in conjunction with terminal assessment of tau pathology, spatial learning, and cerebral glucose metabolism.