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•Metabolic connectivity is a valid tool for observation of neuronal network changes.•MC shows significant functional connectivity loss in β-amyloid and tau mouse models.•MC reveals higher agreement with behavior compared to conventional µPET analysis. 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-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) imaging. We compared the results of FDG-µPET MC with conventional VOI-based analysis and behavioral assessment in the Morris water maze (MWM). The impact of awake versus anesthesia conditions on MC read-outs was studied and the robustness of MC data deriving from different scanners was tested. MC proved to be an accurate and robust indicator of functional connectivity loss when sample sizes ≥12 were considered. MC readouts were robust across scanners and in awake/ anesthesia conditions. MC loss was observed throughout all brain regions in tauopathy mice, whereas β-amyloid indicated MC loss mainly in spatial learning areas and subcortical networks. This study established a methodological basis for the utilization of MC in different β-amyloid and tau mouse models. MC has the potential to serve as a read-out of pathological changes within neuronal networks in these models.

•During disease progression in PS19 (4R tau) mice, SV2A expression levels in selected regions change in a phased, non-linear manner rather than along a linear trajectory, with an increase followed by a rapid decrease.•PS19 mice show greater deviation from the reference-derived inter-regional SV2A expression pattern, particularly at later disease stages.•Late-stage tau pathology is profound and tends to be temporally associated with decreased SV2A expression levels in PS19 mice.•Associations of longitudinal SV2A expression variation with TSPO and MAO-B PET measures differ between PS19 and wild-type mice in vulnerable brain regions and may contribute to region-specific SV2A expression level changes. In tauopathies, tau accumulation and neuroinflammation are associated with progressive synaptic and network alterations that contribute to neurodegeneration. We used 8 PS19 and 12 C57Bl/6 (WT) mice undergoing consecutive [18F]UCB-H PET scans between 5.7 and 11.0 months of age to longitudinally evaluate SV2A expression levels, with terminal validation via immunohistochemistry. A desynchronization index (DI) quantified deviation from a reference-derived inter-regional SV2A expression pattern from whole-brain SV2A-PET data, and principal component analysis (PCA) further summarized these regional deviation profiles. Baseline translocator protein (TSPO, [18F]GE-180) and monoamine oxidase B (MAO-B, [18F]F-DED) imaging for activated microglia and reactive astrogliosis were performed to detect early neuroinflammation, which was subsequently correlated with serial SV2A expression, evaluated by the area under the curve (AUC) of [18F]UCB-H z-scores (PS19 vs. WT). We observed phased SV2A expression alterations in PS19 mice in the neocortex, hippocampus CA1, brainstem, thalamus, hypothalamus, and cerebellum, showing an increasing trend from 8.4 to 10.0 months of age (+8.1% ± 3.0%), followed by a rapid decline towards 11.0 months of age (-18.4% ± 4.7%), together with greater later-stage inter-regional SV2A expression pattern deviation. Tau burden tended to show a broadly negative association with SV2A expression levels across primary and exploratory regions. Associations of SV2A-PET signal variation with early microglial activation and reactive astrogliosis differed between PS19 and WT mice. In summary, these findings suggest that longitudinal [18F]UCB-H PET may provide a feasible approach for tracking stage-dependent regional SV2A expression alterations and inter-regional deviation in this mouse model of primary tauopathy. [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.

•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]

Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and loss-of-function coding variants are major risk factors for late onset Alzheimer’s disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling in microglia, we generated a TREM2 reporter mouse. In APP transgenic animals, bulk RNA-sequencing of isolated microglia sorted based on reporter expression highlighted TREM2 level-related changes in major immunometabolic pathways, and enrichment of genes in oxidative phosphorylation and cholesterol metabolism in microglia with increased TREM2 expression. Metabolic and lipidomic profiling of sorted microglia showed that, independent of Aβ pathology, TREM2 expression correlated with signatures consistent with increased cellular redox, energetics, and cholesterol homoeostasis. In accordance, metabolic activity correlated with phagocytic capacity. Finally, we performed chronic treatment with a TREM2 agonist antibody and identified a window of TREM2 expression where microglia are most responsive, thereby informing clinical applications of TREM2 agonists. TREM2 is an important AD risk factor playing essential roles in the microglial response to amyloid pathology. Here, authors show using a TREM2 reporter mouse that TREM2 levels are critical for efficacy of TREM2 agonism informing current clinical efforts.

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. Methods Transgenic P301S ( n = 33) and wild-type ( n = 18) female mice were imaged by 18 F-GE-180 TSPO μPET at the ages of 1.9, 3.9, and 6.4 months. We conducted behavioral testing in the Morris water maze, 18 F-fluordesoxyglucose ( 18 F-FDG) μPET, and AT8 tau immunohistochemistry at 6.3–6.7 months. Terminal microglial immunohistochemistry served for validation of TSPO μPET results in vivo, applying target regions in the brainstem, cortex, cerebellum, and hippocampus. We compared the results with our historical data in amyloid-β mouse models. Results TSPO expression in all target regions of P301S mice increased exponentially from 1.9 to 6.4 months, leading to significant differences in the contrasts with wild-type mice at 6.4 months (+ 11–23%, all p < 0.001), but the apparent microgliosis proceeded more slowly than in our experience in amyloid-β mouse models. Spatial learning and glucose metabolism of AT8-positive P301S mice were significantly impaired at 6.3–6.5 months compared to the wild-type group. Longitudinal increases in TSPO expression predicted greater tau accumulation and lesser spatial learning performance at 6.3–6.7 months. Conclusions Monitoring of TSPO expression as a surrogate of microglial activation in P301S tau transgenic mice by μPET indicates a delayed time course when compared to amyloid-β mouse models. Detrimental associations of microglial activation with outcome parameters are opposite to earlier data in amyloid-β mouse models. The contribution of microglial response to pathology accompanying amyloid-β and tau over-expression merits further investigation.

Alzheimer’s disease (AD) often begins with non-cognitive symptoms such as olfactory deficits, which can predict later cognitive decline, though the mechanisms remain unclear. Pathologically, the brainstem locus coeruleus (LC), the main source of the neurotransmitter noradrenalin (NA) modulating olfactory information processing is affected early. Here we show early and distinct loss of noradrenergic input to the olfactory bulb (OB) coinciding with impaired olfaction in an AD mouse model, before appearance of amyloid plaques. Mechanistically, OB microglia recognize and phagocytose LC axons. Reducing phagocytosis genetically preserves LC axons and olfaction. Prodromal AD patients display elevated TSPO-PET signals in the OB, similarly to App NL-G-F mice. We further confirm early LC axon degeneration in post-mortem OBs in patients with early AD. Our findings reveal a mechanism linking early LC damage to hyposmia in AD, suggesting olfactory testing and neurocircuit imaging for early diagnosis and enable timely therapeutic intervention for Alzheimer’s disease. Olfactory deficits occur early in Alzheimer’s disease (AD). Here, the authors identify that loss of locus coeruleus axons in the olfactory bulb underlies impaired olfaction in an AD mouse model and provide translational evidence for similar deficits in humans.

•Three distinct small animal PET scanners show high agreement in Aβ-PET quantification, crucial for multicentric AD research.•Variability in scanner sensitivity affects individual-level interpretation despite stable group differences.•Spatial analysis confirms consistency, while PET imaging correlates well with histological staining, validating its reliability. β-amyloid (Aβ) small animal PET facilitates quantification of fibrillar amyloidosis in Alzheimer's disease (AD) mouse models. Thus, the methodology is receiving growing interest as a monitoring tool in preclinical drug trials. In this regard, harmonization of data from different scanners at multiple sites would allow the establishment large collaborative cohorts and may facilitate efficacy comparison of different treatments. Therefore, we objected to determine the level of agreement of Aβ-PET quantification by a head-to-head comparison of three different state-of-the-art small animal PET scanners, which could help pave the way for future multicenter studies. Within a timeframe of 5 ± 2 weeks, transgenic APPPS1 (n = 9) and wild-type (WT) (n = 8) mice (age range: 13–16 months) were examined three times by Aβ-PET ([18F]florbetaben) using a Siemens Inveon DPET, a MedisonanoScan PET/MR, and a MedisonanoScan PET/CT with harmonized reconstruction protocols. Cortex-to-white-matter 30–60 min p.i. standardized uptake value ratios (SUVRCTX/WM) were calculated to compare binding differences, effect sizes (Cohen's d) and z-score values of APPPS1 relative to WT mice. Correlation coefficients (Pearson's r) were calculated for the agreement of individual SUVR between different scanners. Voxel-wise analysis was used to determine the agreement of spatial pathology patterns. For validation of PET imaging against the histological gold standard, individual SUVR values were subject to a correlation analysis with area occupancy of methoxy‑X04 staining. All three small animal PET scanners yielded comparable group differences between APPPS1 and WT mice (∆PET=20.4 % ± 2.9 %, ∆PET/MR=18.4 % ± 4.5 %, ∆PET/CT=18.1 % ± 3.3 %). Voxel-wise analysis confirmed a high degree of congruency of the spatial pattern (Dice coefficient (DC)PETvs.PET/MR=83.0 %, DCPETvs.PET/CT=69.3 %, DCPET/MRvs.PET/CT=81.9 %). Differences in the group level variance of the three scanners resulted in divergent z-scores (zPET=11.5 ± 1.6; zPET/MR=5.3 ± 1.3; zPET/CT=3.4 ± 0.6) and effect sizes (dPET=8.5, dPET/MR=4.5, dPET/CT=4.1). However, correlations at the individual mouse level were still strong between scanners (rPETvs.PET/MR=0.96, rPETvs.PET/CT=0.91, rPET/MRvs.PET/CT=0.87; all p ≤ 0.0001). Methoxy-X04 staining exhibited a significant correlation across all three PET machines combined (r = 0.76, p < 0.0001) but also at individual level (PET: r = 0.81, p = 0.026; PET/MR: r = 0.89, p = 0.0074; PET/CT: r = 0.93, p = 0.0028). Our comparison of standardized small animal Aβ-PET acquired by three different scanners substantiates the possibility of moving towards a multicentric approach in preclinical AD research. The alignment of image acquisition and analysis methods achieved good overall comparability between data sets. Nevertheless, differences in variance of sensitivity and specificity of different scanners may limit data interpretation at the individual mouse level and deserves methodological optimization.

[Display omitted] In Alzheimer`s disease (AD), regional heterogeneity of β-amyloid burden and microglial activation of individual patients is a well-known phenomenon. Recently, we described a high incidence of inter-individual regional heterogeneity in terms of asymmetry of plaque burden and microglial activation in β-amyloid mouse models of AD as assessed by positron-emission-tomography (PET). We now investigate the regional associations between amyloid plaque burden, microglial activation, and impaired spatial learning performance in transgenic mice in vivo. In 30 AppNL-G-F mice (15 female, 15 male) we acquired cross-sectional 18 kDa translocator protein (TSPO-PET, 18F-GE-180) and β-amyloid-PET (18F-florbetaben) scans at ten months of age. Control data were obtained from age- and sex-matched C57BI/6 wild-type mice. We assessed spatial learning (i.e. Morris water maze) within two weeks of PET scanning and correlated the principal component of spatial learning performance scores with voxel-wise β-amyloid and TSPO tracer uptake maps in AppNL-G-F mice, controlled for age and sex. In order to assess the effects of hemispheric asymmetry, we also analyzed correlations of spatial learning performance with tracer uptake in bilateral regions of interest for frontal cortex, entorhinal/piriform cortex, amygdala, and hippocampus, using a regression model. We tested the correlation between regional asymmetry of PET biomarkers with individual spatial learning performance. Voxel-wise analyses in AppNL-G-F mice revealed that higher TSPO-PET signal in the amygdala, entorhinal and piriform cortices, the hippocampus and the hypothalamus correlated with spatial learning performance. Region-based analysis showed significant correlations between TSPO expression in the right entorhinal/piriform cortex and the right amygdala and spatial learning performance, whereas there were no such correlations in the left hemisphere. Right lateralized TSPO expression in the amygdala predicted better performance in the Morris water maze (β = -0.470, p = 0.013), irrespective of the global microglial activation and amyloid level. Region-based results for amyloid-PET showed no significant associations with spatial learning. Elevated microglial activation in the right amygdala-entorhinal-hippocampal complex of AppNL-G-F mice is associated with better spatial learning. Our findings support a protective role of microglia on cognitive function when they highly express TSPO in specific brain regions involved in spatial memory.

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.