Measurement of Cerebral Perfusion Indices from the Early Phase of [¹⁸F]MK6240 Dynamic Tau PET Imaging

Abstract

6-(fluoro-¹⁸F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([¹⁸F]MK6240) has high affinity and selectivity for hyperphosphorylated tau and readily crosses the blood–brain barrier. This study investigated whether the early phase of [¹⁸F]MK6240 can be used to provide a surrogate index of cerebral perfusion. Methods: Forty-nine subjects who were cognitively normal (CN), had mild cognitive impairment (MCI), or had Alzheimer’s disease (AD) underwent paired dynamic [¹⁸F]MK6240 and [¹¹C]Pittsburgh compound B (PiB) PET, as well as structural MRI to obtain anatomic information. Arterial blood samples were collected in a subset of 24 subjects for [¹⁸F]MK6240 scans to derive metabolite-corrected arterial input functions. Regional time–activity curves were extracted using atlases available in the Montreal Neurologic Institute template space and using FreeSurfer. The early phase of brain time–activity curves was analyzed using a 1-tissue-compartment model to obtain a robust estimate of the rate of transfer from plasma to brain tissue, K₁ (mL⋅cm⁻³⋅min⁻¹), and the simplified reference tissue model 2 was investigated for noninvasive estimation of the relative delivery rate, R₁ (unitless). A head-to-head comparison with R₁ derived from [¹¹C]PiB scans was performed. Grouped differences in R₁ were evaluated among CN, MCI, and AD subjects. Results: Regional K₁ values suggested a relatively high extraction fraction. R₁ estimated noninvasively from simplified reference tissue model 2 agreed well with R₁ calculated indirectly from the blood-based compartment modeling (r = 0.99; mean difference, 0.024 ± 0.027), suggesting that robust estimates were obtained. R₁ measurements obtained with [¹⁸F]MK6240 correlated strongly and overall agreed well with those obtained from [¹¹C]PiB (r = 0.93; mean difference, −0.001 ± 0.068). Statistically significant differences were observed in regional R₁ measurements among CN, MCI, and AD subjects, notably in the temporal and parietal cortices. Conclusion: Our results provide evidence that the early phase of [¹⁸F]MK6240 images may be used to derive a useful index of cerebral perfusion. The early and late phases of a [¹⁸F]MK6240 dynamic acquisition may thus offer complementary information about the pathophysiologic mechanisms of the disease.