Abstract
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Introduction: Neurofibrillary tangles of hyperphosphorylated tau protein are an important biomarker for Alzheimer’s disease and can be accurately quantified in vivo using the second-generation tau PET tracer 18F-MK-6240. Although 18F-MK-6240 shows low intracerebral off-target binding, individually varying levels of tracer binding to meningeal melanocytes are observed. Short-term 18F-MK-6240 test-retest (TRT) shows excellent characteristics, but long-term stability of brain uptake and potential confounding meningeal uptake (MU) is needed for longitudinal studies. We examined 6-month 18F-MK-6240 TRT in healthy controls (HC) and investigated stability of MU by means of a validated quantification algorithm in both HC and patients with amnestic mild cognitive impairment (aMCI).
Methods: A total cohort of 40 HC (57 ± 19 years, 21F/19M) and 24 aMCI (72 ± 8 years, 14F/10M) underwent baseline 18F-MK-6240 PET-MR (GE Signa), 90 to 120 minutes post injection (mean injected activity 143 ± 25 MBq with specific activity of 577 ± 462 GBq/μmol). Baseline differences in MU between HC and aMCI were assessed and we investigated if MU could be partially explained by demographics such as age, sex, education and smoking in the HC group. Of the total cohort, 10 HC (56 ± 12 years, 8F/2M) underwent 6-month follow-up 18F-MK-6240 PET-MR to determine TRT and longitudinal differences in MU. Moreover, 10 aMCI (72 ± 5.8 years, 5F/5M) underwent a 2-year follow-up 18F-MK-6240 PET-MR, analyzed here to assess longitudinal changes in MU. 18F-MK-6240 was quantified by standardized uptake value ratios (SUVR) relative to the cerebellar cortex and average TRT was calculated over all grey matter Volumes-Of-Interest (VOIs) as well as 9 bilateral composite VOIs: frontal cortex, parietal cortex, occipital cortex, temporal cortex, cingulate cortex, mesotemporal cortex, hippocampus, insula and striatum. MU was quantified as the mean SUVR of the skull parcel (FreeSurfer) which includes the meninges.
Results: In the total cohort, MU was significantly higher in HC compared to aMCI (median SUVR 1.28 versus 1.07; p = 0.004) (Fig. 1). In the HC group, MU was significantly higher in women compared to men (mean SUVR 1.41 versus 1.18; p = 0.01; R2 = 0.16) but MU was not influenced by educational level (p = 0.2), smoking (p = 0.2) or age (rs = -0.28, p = 0.07) in a univariate analysis. Adding both sex and smoking in a multivariate analysis predicting MU resulted in the preferred model based on the Akaike information criterion (adjusted R2 = 0.21) while adding age and/or education did not result in a better estimation of MU. Six-month TRT for HC was 1.6 ± 3.4% on average over all grey matter VOIs (Table 1). As for stability of MU, no significant differences over 6 months in HC (1.5 ± 14%) or over 2 years in aMCI (5.2 ± 13%) were observed (Fig. 2).
Conclusions: 18F-MK-6240 SUVR shows excellent long-term test-retest. Meningeal tracer uptake is significantly higher in HC compared to aMCI as well as in women compared to men. These results indicate that meningeal tracer uptake is variable between subjects but remains stable over time.
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