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Background: This study explores different approaches to estimate the clearance rate of the reference tissue (k2′) parameter used for pharmacokinetic modeling, using the simplified reference tissue model 2 (SRMT2) and further explores the effect on the binding potential (BPND) of 11C-labeled Pittsburgh Compound B (PIB) PET scans.Methods: Thirty subjects underwent a dynamic PIB PET scan and were classified as PIB positive (+) or negative (–). Thirteen regions were defined from where to estimate k2′: the whole brain, eight anatomical region based on the Hammer's atlas, one region based on a SPM comparison between groups on a voxel level, and three regions using different BPNDSRTM thresholds.Results: The different approaches resulted in distinct k2′ estimations per subject. The median value of the estimated k2′ across all subjects in the whole brain was 0.057. In general, PIB+ subjects presented smaller k2′ estimates than this median, and PIB–, larger. Furthermore, only threshold and white matter methods resulted in non-significant differences between groups. Moreover, threshold approaches yielded the best correlation between BPNDSRTM and BPNDSRTM2 for both groups (R2 = 0.85 for PIB+, and R2 = 0.88 for PIB–). Lastly, a sensitivity analysis showed that overestimating k2′ values resulted in less biased BPNDSRTM2 estimates.Conclusion: Setting a threshold on BPNDSRTM might be the best method to estimate k2′ in voxel-based modeling approaches, while the use of a white matter region might be a better option for a volume of interest based analysis.

Chronic neuroinflammation, which is primarily mediated by microglia, plays an essential role in aging and neurodegeneration. It is still unclear whether this microglia-induced neuroinflammation occurs globally or is confined to distinct brain regions. In this study, we investigated microglia activity in various brain regions upon healthy aging and Alzheimer’s disease (AD)-related pathology in both human and mouse samples. In purified microglia isolated from aging mouse brains, we found a profound gene expression pattern related to pro-inflammatory processes, phagocytosis, and lipid homeostasis. Particularly in white matter microglia of 24-month-old mice, abundant expression of phagocytic markers including Mac-2, Axl, CD16/32, Dectin1, CD11c, and CD36 was detected. Interestingly, in white matter of human brain tissue the first signs of inflammatory activity were already detected during middle age. Thus quantification of microglial proteins, such as CD68 (commonly associated with phagocytosis) and HLA-DR (associated with antigen presentation), in postmortem human white matter brain tissue showed an age-dependent increase in immunoreactivity already in middle-aged people (53.2 ± 2.0 years). This early inflammation was also detectable by non-invasive positron emission tomography imaging using [11C]-(R)-PK11195, a ligand that binds to activated microglia. Increased microglia activity was also prominently present in the white matter of human postmortem early-onset AD (EOAD) brain tissue. Interestingly, microglia activity in the white matter of late-onset AD (LOAD) CNS was similar to that of the aged clinically silent AD cases. These data indicate that microglia-induced neuroinflammation is predominant in the white matter of aging mice and humans as well as in EOAD brains. This white matter inflammation may contribute to the progression of neurodegeneration, and have prognostic value for detecting the onset and progression of aging and neurodegeneration.