Hippocampal [(18)F]flortaucipir BP(ND) corrected for possible spill-in of the choroid plexus retains strong clinico-pathological relationships.

Off-target [18F]flortaucipir (tau) PET binding in the choroid plexus causes spill-in into the nearby hippocampus, which may influence the correlation between [18F]flortaucipir binding and measures of cognition. Previously, we showed that partial volume correction (combination of Van Cittert iterative deconvolution and HYPR denoising; PVC HDH) and manually eroding the hippocampus resulted in a significant decrease of the choroid plexus spill-in. In this study, we compared three different approaches for the quantification of hippocampal [18F]flortaucipir signal using a semi-automated technique, and assessed correlations with cognitive performance across methods. Dynamic 130 min [18F]flortaucipir PET scans were performed in 109 subjects (45 cognitively normal subjects (CN) and 64 mild cognitive impairment/Alzheimer's disease (AD) dementia patients. We extracted hippocampal binding potential (BPND) using receptor parametric mapping with cerebellar grey matter as reference region. PVC HDH was performed. Based on our previous study in which we manually eroded 40% ± 10% of voxels of the hippocampus, three hippocampal volumes-of-interest (VOIs) were generated: a non-optimized 100% hippocampal VOI [100%], and combining HDH with eroding a percentage of the highest hippocampus BPND voxels (i.e. lowering spill-in) resulting in optimized 50%[50%HDH] and 40%[40%HDH] hippocampal VOIs. Cognitive performance was assessed with the Mini-Mental State Examination (MMSE) and Rey auditory verbal learning delayed recall. We performed receiver operating characteristic analyses to investigate which method could best discriminate MCI/AD from controls. Subsequently, we performed linear regressions to investigate associations between the hippocampal [18F]flortaucipir BPND VOIs and MMSE/delayed recall adjusted for age, sex and education. We found higher hippocampal [18F]flortaucipir BPND in MCI/AD patients (BPND100%=0.27±0.15) compared to CN (BPND100%= 0.07±0.13) and all methods showed comparable discriminative effects (AUC100%=0.85[CI=0.78-0.93]; AUC50%HDH=0.84[CI=0.74-0.92]; AUC40%HDH=0.83[CI=0.74-0.92]). Across groups, higher [18F]flortaucipir BPND was related to lower scores on MMSE (standardized β100%=-0.38[CI=-0.57-0.20]; β50%HDH= -0.37[CI=-0.54-0.19]; β40%HDH=-0.35[CI=-0.53-0.17], all p<0.001) and delayed recall (standardized β100%=-0.64[CI=-0.79-0.49]; β50%HDH= -0.61[CI=-0.76-0.46]; β40%HDH=-0.59[CI=-0.75-0.44]; all p<0.001), with comparable effect sizes for all hippocampal VOIs. Hippocampal tau load measured with [18F]flortaucipir PET is strongly associated with cognitive function. Both discrimination between diagnostic groups and associations between hippocampal [18F]flortaucipir BPND and memory were comparable for all methods. The non-optimized 100% hippocampal VOI may be sufficient for clinical interpretation. However, proper correction for choroid plexus spillover and may be required in case of smaller effect sizes between subject groups or for longitudinal studies.

Wolters EE ，Ossenkoppele R ，Golla SS ，Verfaillie SC ，Timmers T ，Visser D ，Tuncel H ，Coomans EM ，Windhorst AD ，Scheltens P ，van der Flier WM ，Boellaard R ，van Berckel BN ... -  《NeuroImage-Clinical》

Compensating for choroid plexus based off-target signal in the hippocampus using (18)F-flortaucipir PET.

The hippocampus is affected by tau pathology early in Alzheimer's disease (AD) development. Accurate quantification of hippocampal tau signal using the tau-PET tracer 18F-flortaucipir is complicated, however, by off-target binding in the adjacent choroid plexus. We here present a new method for compensating for this off-target choroid plexus signal. As off-target binding in the choroid plexus is known to be higher using 18F-flortaucipir compared to 18F-RO948, we created a binary hippocampal mask in template space where 18F-flortaucipir signal was higher than 18F-RO948, using data from 30 patients that underwent both 18F-flortaucipir and 18F-RO948 PET. This mask, presumably representing hippocampal voxels affected by off-target binding from the choroid plexus, was then converted to native space and applied as an exclusion mask to 145 patients across the AD-spectrum scanned with 18F-flortaucipir. As an alternative approach exclusion masks were generated by expanding the choroid plexus ROI in native space. Results were analysed both without and with partial volume error correction (non-PVEc/PVEc). Unmasked hippocampal standardized uptake value ratios (SUVR) were significantly correlated to choroid plexus SUVRs using both non-PVEc (p < 0.001, r = 0.28) and PVEc data (p < 0.05, r = 0.18). After applying the mask, however, these correlations disappeared. The diagnostic accuracy in separating cognitively impaired (CI) from cognitively unimpaired (CU) subjects improved after masking, from an AUC of 0.792 (95% C.I.,0.715-0.869) to 0.837 (95% C.I.,0.768-0.906) for non-PVEc data (p < 0.001), and from 0.798 (95% C.I.,0.722-0.873) to 0.834 (95% C.I.,0.766-0.903) for PVEc data (p < 0.001). The correlations to memory improved significantly for MMSE for unmasked vs. masked data both without (r = -0.440 vs. r = -0.499, p < 0.001) and with (r = -0.454 vs. r = -0.503, p < 0.001) PVEc. Similar results were found using the ADAS-Cog Delayed Word Recall test. Choroid plexus off-target binding interferes with the estimation of true hippocampal retention using 18F-flortaucipir PET. Using a mask to correct for this off-target signal, we improved the diagnostic accuracy of 18F-flortaucipir in the hippocampus and the correlation between 18F-flortaucipir hippocampal SUVR and cognitive measures.

Pawlik D ，Leuzy A ，Strandberg O ，Smith R ... -  《-》

Associations between quantitative [(18)F]flortaucipir tau PET and atrophy across the Alzheimer's disease spectrum.

Timmers T ，Ossenkoppele R ，Wolters EE ，Verfaillie SCJ ，Visser D ，Golla SSV ，Barkhof F ，Scheltens P ，Boellaard R ，van der Flier WM ，van Berckel BNM ... -  《Alzheimers Research & Therapy》

Regional [(18)F]flortaucipir PET is more closely associated with disease severity than CSF p-tau in Alzheimer's disease.

Wolters EE ，Ossenkoppele R ，Verfaillie SCJ ，Coomans EM ，Timmers T ，Visser D ，Tuncel H ，Golla SSV ，Windhorst AD ，Boellaard R ，van der Flier WM ，Teunissen CE ，Scheltens P ，van Berckel BNM ... -  《-》

Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F 18.

Alzheimer disease (AD) is characterized by β-amyloid (Aβ) plaques and tau neurofibrillary tangles. There are several PET imaging biomarkers for Aβ including 11C-PiB and 18F-florbetapir. Recently, PET tracers for tau neurofibrillary tangles have become available and have shown utility in detection and monitoring of neurofibrillary pathology over time. Flortaucipir F 18 is one such tracer. Initial clinical studies indicated greater tau binding in AD and mild cognitive impairment patients than in controls in a pattern consistent with tau pathology observed at autopsy. However, little is known about the reproducibility of such findings. To our knowledge, this study reports the first data regarding test-retest reproducibility of flortaucipir F 18 PET. Methods: Twenty-one subjects who completed the study (5 healthy controls, 6 mild cognitive impairment, and 10 AD) received 370 MBq of flortaucipir F 18 and were imaged for 20 min beginning 80 min after injection and again at 110 min after injection. Follow-up (retest) imaging occurred between 48 h and 4 wk after initial imaging. Images were spatially normalized to Montreal Neurological Institute template space. SUVRs were calculated using AAL (Automated Anatomical Labeling atlas) volumes of interest (VOIs) for parietal, temporal, occipital, anterior, and posterior hippocampal, parahippocampal, and fusiform regions, as well as a posterior neocortical VOI composed of average values from parietal, temporal, and occipital areas. Further, a VOI derived by discriminant analysis that maximally separated diagnostic groups (multiblock barycentric discriminant analysis [MUBADA]) was used. All VOIs were referenced to a subsection of cerebellar gray matter (cere-crus) as well as a parametrically derived white matter-based reference region (parametric estimate of reference signal intensity [PERSI]). t test, correlation analyses, and intraclass correlation coefficient were used to explore test-retest performance. Results: Test-retest analyses demonstrated low variability in flortaucipir F 18 SUVR. The SD of mean percentage change between test and retest using the PERSI reference region was 2.22% for a large posterior neocortical VOI, 1.84% for MUBADA, 1.46% for frontal, 1.98% for temporal, 2.28% for parietal, and 3.27% for occipital VOIs. Further, significant correlations (R2 > 0.85; P < 0.001) were observed for all regions, and intraclass correlation coefficient values (test-retest consistency) were greater than 0.92 for all regions. Conclusion: Significant test-retest reproducibility for flortaucipir F 18 was found across neocortical and mesial temporal lobe structures. These preliminary data suggest that flortaucipir F 18 tau imaging could be used to examine changes in tau burden over time.

Devous MD Sr ，Joshi AD ，Navitsky M ，Southekal S ，Pontecorvo MJ ，Shen H ，Lu M ，Shankle WR ，Seibyl JP ，Marek K ，Mintun MA ... -  《-》