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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.

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2 nd generation 18 F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples ( n  = 97 and n  = 96). We find that inter-regional connectivity is associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4-repeat tauopathies. In regional cell-type specific post-mortem tau assessments, this association is stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with neuronal tau accumulation. Using tau-PET we find further that patient-level tau patterns are associated with the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies. Tau pathology drives neuronal dysfunction in 4- repeat tauopathies. Here, the authors combine tau-PET, resting-state fMRI and histopathology data, to show that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.

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.

Purpose Off-target binding remains a significant challenge in tau-PET neuroimaging. While off-targets including monoamine oxidase enzymes and neuromelanin-containing cells have been identified, recent studies indicated a relevant binding of novel tau tracers to melanin-containing structures. To date, little is known about the effect of melanocytes in the meninges on tracer signals in brain PET data. Thus, we aimed to identify the target structure causal for the frequently observed [ 18 F]PI-2620 PET signal in the vermis and adjacent cerebellar regions. Methods 274 participants underwent dynamic [ 18 F]PI-2620 tau-PET: 3/4R-tauopathies (n = 85), 4R-tauopathies (n = 147), tau-negative disease controls (n = 24), and healthy controls (n = 18). Standardized uptake value ratio (SUVR) and kinetic parameters including the distribution volume ratio (DVR), tracer clearance (k2) and relative perfusion (R1), were compared among the cohorts and sexes using the Automated Anatomical Labelling (AAL) atlas. Age and p-Tau levels in cerebrospinal fluid (CSF) were assessed for their relationship with vermal tau-PET signal. Furthermore, we combined autoradiographic and histochemical experiments on post-mortem brain tissue of deceased patients (n = 9). Results Male participants revealed higher mean vermal [ 18 F]PI-2620 DVR (0.95 ± 0.13; vs. females 0.88 ± 0.10, p < 0.0001). Sex-related differences were most pronounced in the 3/4R-tauopathy cohort (p < 0.0001). Mean SUVR Ver/Cbl , k2 and correlation analyses of kinetic parameters did not differ among groups. Histological assessments revealed co-localization of leptomeningeal pigmented cells with strong autoradiography signal spots within the vermal fissures. Tau-related autoradiography signals, age or p-Tau levels did not correlate significantly with tau-PET signals. Iron deposits did not cause relevant autoradiography signals in the vermis. Conclusion Leptomeningeal melanocytes are the primary target structure for [ 18 F]PI-2620 PET binding in anterior vermis, whereas iron and tau deposits do not contribute significantly.

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.