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•Cellular sources of FDG-PET signals were evaluated during aging in healthy mice.•Neuronal glucose uptake peaks at 12 months, then declines.•Astroglial glucose uptake drives PET signal changes in later ages.•Astroglial glucose uptake drives metabolic connectivity changes​ during aging. 2-Fluorodeoxyglucose-PET (FDG-PET) is a powerful tool to study glucose metabolism in mammalian brains, but cellular sources of glucose uptake and metabolic connectivity during aging are not yet understood. Healthy wild-type mice of both sexes (2–21 months of age) received FDG-PET and cell sorting after in vivo tracer injection (scRadiotracing). FDG uptake per cell was quantified in isolated microglia, astrocytes and neurons. Cerebral FDG uptake and metabolic connectivity were determined by PET. A subset of mice received measurement of blood glucose levels to study associations with cellular FDG uptake during aging. Cerebral FDG-PET signals in healthy mice increased linearly with age. Cellular FDG uptake of neurons increased between 2 and 12 months of age, followed by a strong decrease towards late ages. Contrarily, FDG uptake in microglia and astrocytes exhibited a U-shaped function with respect to age, comprising the predominant cellular source of higher cerebral FDG uptake in the later stages. Metabolic connectivity was closely associated with the ratio of glucose uptake in astroglial cells relative to neurons. Cellular FDG uptake was not associated with blood glucose levels and increasing FDG brain uptake as a function of age was still observed after adjusting for blood glucose levels. Trajectories of astroglial glucose uptake drive brain FDG-PET alterations and metabolic connectivity during aging. [Display omitted]

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. Materials and methods We analyzed metabolic networks measured by interregional correlation coefficients (ICCs) of FDG–PET scans in WT mice and in mice with mutations in progranulin ( Grn ) or triggering receptor expressed on myeloid cells 2 ( Trem2 ) knockouts ( −/− ) as well as in double mutant Grn −/− / Trem2 −/− mice. We selected those rodent models as they represent opposite microglial signatures with disease associated microglia in Grn −/− mice and microglia locked in a homeostatic state in Trem2 −/− mice ; however, both resulting in lower glucose uptake of the brain . The direct influence of microglia on metabolic networks was further determined by microglia depletion using a CSF1R inhibitor in WT mice at two different ages. Within maps of global mean scaled regional FDG uptake, 24 pre-established volumes of interest were applied and assigned to either cortical or subcortical networks. ICCs of all region pairs were calculated and z-transformed prior to group comparisons. FDG uptake of neurons, microglia, and astrocytes was determined in Grn −/− and WT mice via assessment of single cell tracer uptake (scRadiotracing). Results Microglia depletion by CSF1R inhibition resulted in a strong decrease of metabolic connectivity defined by decrease of mean cortical ICCs in WT mice at both ages studied (6–7 m; p  = 0.0148, 9–10 m; p  = 0.0191), when compared to vehicle-treated age-matched WT mice.  Grn −/− , Trem2 −/− and Grn −/− /Trem2 −/− mice all displayed reduced FDG–PET signals when compared to WT mice. However, when analyzing metabolic networks, a distinct increase of ICCs was observed in Grn −/− mice when compared to WT mice in cortical ( p  < 0.0001) and hippocampal ( p  < 0.0001) networks. In contrast, Trem2 −/− mice did not show significant alterations in metabolic connectivity when compared to WT. Furthermore, the increased metabolic connectivity in Grn −/− mice was completely suppressed in Grn −/− /Trem2 −/− mice. Grn −/− mice exhibited a severe loss of neuronal FDG uptake (− 61%, p  < 0.0001) which shifted allocation of cellular brain FDG uptake to microglia (42% in Grn −/− vs. 22% in WT). Conclusions Presence, absence, and activation of microglia have a strong impact on metabolic connectivity of the mouse brain. Enhanced metabolic connectivity is associated with increased microglial FDG allocation. Highlights Microglial activation influences metabolic connectivity. Microglial depletion results in distinct decreases of metabolic connectivity. Metabolic connectivity increases in progranulin deficient mice. Cellular FDG allocation in progranulin deficient mice is shifted to microglia.

Microglial energy metabolism has gained attention for the treatment of neurodegenerative diseases. methods provide important insights; however, it remains unclear whether the metabolism of highly motile microglia is preserved outside their regular environment. Therefore, we directly compared the microglial glucose uptake and in vitro in mice. Microglia and astrocytes were isolated from the brain using immunomagnetic cell sorting following [ F]FDG injection in living mice, followed by gamma and single-cell radiotracing (scRadiotracing). Enriched cell fractions were incubated with excess [ F]FDG (50,000-fold) , washed, and measured equivalently. For all fractions, radioactivity per cell was normalized to the injected or incubated radioactivity, and ratios of microglialuptake were calculated relative to astrocytes and the microglia/astrocyte-negative fraction. The experiment was repeated using a glucose-free buffer and validated by in vitro incubation without prior in vivo [ F]FDG injection to exclude the influence of fasting and glucose injection. scRadiotracing results were compared against cell culture [ F]-FDG incubation. The in vivo glucose uptake of microglia was higher when compared to astrocytes (50.4-fold, < 0.0001) and non-microglia/ non-astrocyte cells (10.6-fold, < 0.0001). Microglia still exhibited the highest glucose uptake in vitro, but with a distinct reduction in microglia-to-astrocyte (5.7-fold, < 0.0015) and microglia-to-microglia/astrocyte-negative ratios (1.7 fold, < 0.0001). Fasting and in vitro incubation were used to validate the results. Cell culture indicated low microglial uptake compared to that in neurons (1:100) or astrocytes (1:10). Compared to astrocytes and other cells, microglia show a distinct reduction in uptake in vitro compared to in vivo uptake. Our results emphasize that in vitro experiments should be interpreted with caution when studying microglial energy metabolism.

Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD. van Lengerich et al. developed a human TREM2 antibody with a transport vehicle (ATV) that improves brain exposure and biodistribution in mouse models. ATV:TREM2 promotes microglial energetic capacity and metabolism via mitochondrial pathways.

Tau PET has attracted increasing interest as an imaging biomarker for 4-repeat (4R)-tauopathy progressive supranuclear palsy (PSP). However, the translation of in vitro 4R-tau binding to in vivo tau PET signals is still unclear. Therefore, we performed a translational study using a broad spectrum of advanced methodologies to investigate the sources of [ 18 F]PI-2620 tau PET signals in individuals with 4R-tauopathies, including a pilot PET autopsy study in patients. First, we conducted a longitudinal [ 18 F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and detected elevated [ 18 F]PI-2620 PET signals in the presence of high levels of neuronal tau. An innovative approach involving cell sorting after radiotracer injection in vivo revealed higher tracer uptake in single neurons than in the astrocytes of PS19 mice. Regional [ 18 F]PI-2620 tau PET signals during the lifetime correlated with the abundance of fibrillary tau and with autoradiography signal intensity in PSP patients and disease controls who underwent autopsy 2–63 months after tau PET. In autoradiography, tau-positive neurons and oligodendrocytes with a high AT8 density, but not tau-positive astrocytes, were the drivers of [ 18 F]PI-2620 autoradiography signals in individuals with PSP. The high tau abundance in oligodendrocytes at the boundary of gray and white matter facilitated the identification of an optimized frontal lobe target region to detect the tau burden in patients with PSP. In summary, neuronal and oligodendroglial tau constitutes the dominant source of tau PET radiotracer binding in 4-repeat-tauopathies, translating to an in vivo signal.

Background Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. Methods To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. Results Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. Conclusion Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.

Tau-PET receives growing interest as an imaging biomarker for the 4-repeat tauopathy progressive supranuclear palsy (PSP). However, the translation of in vitro 4R-tau binding to in vivo tau-PET signals is still unclear. Therefore, we conducted a longitudinal [18F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and found elevated [18F]PI-2620 PET signal in the presence of high neuronal tau. Cell sorting after radiotracer injection in vivo revealed higher tracer uptake in single neurons compared to astrocytes of PS19 mice. Regional [18F]PI-2620 tau-PET signals during lifetime correlated with abundance of fibrillary tau in subsequent autopsy samples of PSP patients and disease controls. In autoradiography, tau-positive neurons and oligodendrocytes with high AT8 density but not tau-positive astrocytes were the driver of [18F]PI-2620 autoradiography signals in PSP. In summary, neuronal and oligodendroglial tau constitutes the dominant source of tau-PET radiotracer binding in 4-repeat-tauopathies, yielding the capacity to translate to an in vivo signal.

Various cellular sources hamper interpretation of positron-emission-tomography (PET) biomarkers in the tumor microenvironment (TME). We developed immunomagnetic cell sorting after in vivo radiotracer injection (scRadiotracing) in combination with 3D-histology via tissue clearing to dissect the cellular allocation of PET signals in the TME. In SB28 glioblastoma mice, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs). Cellular radiotracer uptake was validated by proteomics and confirmed for in vitro samples of patients with glioblastoma. Regional agreement between PET signals and single cell tracer uptake predicted the individual cell distribution in 3D-histology. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma, however proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D-histology facilitates precise allocation of complex PET signal sources and will serve to validate novel TAM-specific radioligands.Competing Interest StatementNLA and MB are members of the Neuroimaging Committee of the EANM. JCT received research grants from Novocure and Munich Surgical Imaging and a speaker honorarium from Seagen. NLA received funding from Novocure. MB received speaker honoraria from Roche, GE healthcare and Life Molecular Imaging and is an advisor of Life Molecular Imaging. VCR received speaker honoraria from Novocure. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Footnotes* error in batch author import

The emergence of spatial and temporal coherence of light emitted from solid-state systems is a fundamental phenomenon intrinsically aligned with the control of light-matter coupling. It is canonical for laser oscillation, emerges in the superradiance of collective emitters, and has been investigated in bosonic condensates of thermalized light, as well as exciton-polaritons. Our room temperature experiments show the strong light-matter coupling between microcavity photons and excitons in atomically thin WSe 2 . We evidence the density-dependent expansion of spatial and temporal coherence of the emitted light from the spatially confined system ground-state, which is accompanied by a threshold-like response of the emitted light intensity. Additionally, valley-physics is manifested in the presence of an external magnetic field, which allows us to manipulate K and K’ polaritons via the valley-Zeeman-effect. Our findings validate the potential of atomically thin crystals as versatile components of coherent light-sources, and in valleytronic applications at room temperature. Here, the authors show that the interaction between microcavity photons and excitons in an atomically thin WSe 2 results in a hybridized regime of strong light-matter coupling. Coherence build-up is accompanied by a threshold-like behaviour of the emitted light intensity, which is a fingerprint of a polariton laser effect.

The emergence of spatial and temporal coherence of light emitted from solid-state systems is a fundamental phenomenon, rooting in a plethora of microscopic processes. It is intrinsically aligned with the control of light-matter coupling, and canonical for laser oscillation. However, it also emerges in the superradiance of multiple, phase-locked emitters, and more recently, coherence and long-range order have been investigated in bosonic condensates of thermalized light, as well as in exciton-polaritons driven to a ground state via stimulated scattering. Here, we experimentally show that the interaction between photons in a Fabry-Perot microcavity and excitons in an atomically thin WSe\\(_2\\) layer is sufficient such that the system enters the hybridized regime of strong light-matter coupling at ambient conditions. Via Michelson interferometry, we capture clear evidence of increased spatial and temporal coherence of the emitted light from the spatially confined system ground-state. The coherence build-up is accompanied by a threshold-like behaviour of the emitted light intensity, which is a fingerprint of a polariton laser effect. Valley-physics is manifested in the presence of an external magnetic field, which allows us to manipulate K and K' polaritons via the Valley-Zeeman-effect. Our findings are of high application relevance, as they confirm the possibility to use atomically thin crystals as simple and versatile components of coherent light-sources, and in valleytronic applications at room temperature.