Discussion
SUVRs, episodic memory cognitive decline, cognitive impairment
PATHOLOGY, NEUROPATHOLOGY
In the present study, we compared strategies for mitigating the influence of meningeal OTS on quantification of cross-sectional MK6240 scans in nearly 500 older adults without significant cognitive impairment. OTS was visually striking, especially in individuals with overall low tau burden, and variability in this signal was roughly normally distributed. We assessed the severity and distribution of OTS, related OTS to basic demographic and biomarker data and assessed various processing approaches to reduce OTS and optimize regional quantification. We demonstrated that meningeal OTS is associated with signal in cortical regions in MK6240 scans. This is theoretically especially problematic in older adults with lower overall tau burden because the influence of this signal on target region SUVR estimation is relatively larger. OTS also was higher in younger individuals and in females. We employed several strategies to remove OTS from target regions but found that, in general, attempts to remove OTS did not improve our ability to detect previously-reported associations with increased A While developing our MK6240 processing pipeline we examined 6 alternative approaches to our standard MRI-guided PET processing. The rationale for each of these approaches is briefly described in Our work suggests that meningeal OTS in MK6240 is unimodally distributed, which makes quantifying the prevalence of OTS challenging as it is a continuous phenomenon. Similarly, given the unimodal distribution, deriving a cut-off to exclude participants with high OTS is not a viable approach. We therefore reasoned that specific preprocessing strategies applied to all scans would be the best approach to reducing OTS in our dataset. However, our comparison of processing approaches showed that correcting for OTS is not straightforward as methods for alleviating the effects of OTS in target regions and the reference region have similar, opposing effects on SUVR. The opposing effects of eroding the reference region and applying a meningeal mask to cortical regions therefore resulted in SUVRs that were highly correlated with our standard processing. By extension, if attempts are made to remove OTS from only target regions or only the reference region this will introduce changes in target region SUVRs that are driven by OTS in the regions where it has not been reduced. For example, eroding the reference region without also masking out OTS from target regions results in higher SUVRs in target regions driven by adjacent OTS and should be avoided. We see this in We explored MK6240 tracer binding in target ROIs, regions of early tau accumulation, and regions of OTS with demographic variables of interest including age, sex, and race. We observed opposing effects of age in target ROIs (positive correlations with age) and OTS ROIs (negative correlations with age). This suggests that the tau and age association we observe, especially in ERC, is not driven by OTS which would actually weaken the expected positive association. A separate study reported negative associations between age and meningeal OTS in two other tau-PET tracers, flortaucipir and RO948, but not in MK6240 (In contrast, despite our relatively large cohort, we did not observe an effect of sex in our target ROIs. This result is somewhat surprising given previously published reports of elevated tau measured in neuropathology samples (This study had unique strengths as well as limitations. Strengths included the large dataset with nearly 500 participants, the use of native space anatomical information for quantification, and the relatively large proportion of URG individuals who have been historically underrepresented in research including in neuroimaging datasets. We did not observe any effect of race on OTS or target region SUVRs. Our simplistic approach testing race associations (URG vs white individuals) may hide patterns related to a single racial or ethnic group, which will be better addressed in the full POINTER Imaging sample. Limitations include relatively low tau pathology in our cohort of at-risk, unimpaired older adults that restricted our ability to assess effects of OTS in the context of higher tau accumulation. We focused on regions of early tau accumulation (ERC, MetaROI) for evaluating pipeline performance. Thus, it is possible that the optimal processing for other brain regions less prone to meningeal OTS may differ. In addition, the data in this study were cross-sectional so we were unable to compare longitudinal changes in OTS to changes in target regions. Future work will assess optimal methods for processing longitudinal MK6240 data. Another constraint on this work was the limited cognitive data currently available for analyses. POINTER trial participants undergo sensitive and domain-specific cognitive testing and these scores will become available as the POINTER trial releases data. Because detection of early tau associated with episodic memory cognitive decline is of critical importance, further work is needed to as-sess the sensitivity of the MK6240 tracer to memory-associated early tau.