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IntroductionTau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis.MethodsUsing head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale.ResultsA strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach.DiscussionPreliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification.HighlightsTested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

INTRODUCTION: Recently, an increasing number of tau tracers have become available. There is a need to standardize quantitative tau measures across tracers, supporting a universal scale. We developed several cortical tau masks and applied them to generate a tau imaging universal scale. METHOD: One thousand forty‐five participants underwent tau scans with either 18F‐flortaucipir, 18F‐MK6240, 18F‐PI2620, 18F‐PM‐PBB3, 18F‐GTP1, or 18F‐RO948. The universal mask was generated from cognitively unimpaired amyloid beta (Aβ)− subjects and Alzheimer's disease (AD) patients with Aβ+. Four additional regional cortical masks were defined within the constraints of the universal mask. A universal scale, the CenTauRz, was constructed. RESULTS: None of the regions known to display off‐target signal were included in the masks. The CenTauRz allows robust discrimination between low and high levels of tau deposits. DISCUSSION: We constructed several tau‐specific cortical masks for the AD continuum and a universal standard scale designed to capture the location and degree of abnormality that can be applied across tracers and across centers. The masks are freely available at https://www.gaain.org/centaur‐project. [ABSTRACT FROM AUTHOR]

Background: ZED8 is a novel monovalent antibody labeled with zirconium-89 for the molecular imaging of CD8. This work describes nonclinical studies performed in part to provide rationale for and to inform expectations in the early clinical development of ZED8, such as in the studies outlined in clinical trial registry NCT04029181 [1]. Methods: Surface plasmon resonance, X-ray crystallography, and flow cytometry were used to characterize the ZED8-CD8 binding interaction, its specificity, and its impact on T cell function. Immuno-PET with ZED8 was assessed in huCD8+ tumor-bearing mice and in non-human primates. Plasma antibody levels were measured by ELISA to determine pharmacokinetic parameters, and OLINDA 1.0 was used to estimate radiation dosimetry from image-derived biodistribution data. Results: ZED8 selectively binds to human CD8α at a binding site approximately 9 Å from that of MHCI making mutual interference unlikely. The equilibrium dissociation constant (KD) is 5 nM. ZED8 binds to cynomolgus CD8 with reduced affinity (66 nM) but it has no measurable affinity for rat or mouse CD8. In a series of lymphoma xenografts, ZED8 imaging was able to identify different CD8 levels concordant with flow cytometry. In cynomolgus monkeys with tool compound 89Zr-aCD8v17, lymph nodes were conspicuous by imaging 24 h post-injection, and the pharmacokinetics suggested a flat-fixed first-in-human dose of 4 mg per subject. The whole-body effective dose for an adult human was estimated to be 0.48 mSv/MBq, comparable to existing 89Zr immuno-PET reagents. Conclusion: 89Zr immuno-PET with ZED8 appears to be a promising biomarker of tissue CD8 levels suitable for clinical evaluation in cancer patients eligible for immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Several radiotracers targeting tau pathology in Alzheimer's disease (AD) are being used in human studies. Although abundant imaging characterization data exist for individual tracers there are only sparse in vivo data directly comparing tracers in head‐to‐head studies. As the use of tau PET increases, it is of paramount importance to enable multi‐tracer, multi‐center, multi‐national observational and therapeutic trials. We present the direct in vivo comparison of [18F]GTP1 and [18F]PI2620. Methods: To date, 21 subjects (70±6 years; 12F) have completed imaging with both [18F]GTP1 and [18F]PI2620: 10 prodromal, 9 mild, one moderate AD subjects (Aβ+), and one Aβ‐ cognitively unimpaired subject. Thirty minutes images were acquired 60 and 45 min after [18F]GTP1 and [18F]PI2620 administration, respectively. SUVR was calculated using the inferior cerebellum and used to compare tau‐specific binding and off‐target signal characteristics between the two tracers. The choroid plexus was defined manually for each subject. The whole cortical gray (WCG) and cerebellum rims were defined using the gray and white‐matter SPM tissue segmentation images (Figure 1). Results: Tracer distribution was similar for both tracers (Figures 2 and 3). Hammer atlas cortical SUVRs were linearly correlated (r2=0.88). Higher cortical [18F]PI2620 SUVR were observed in some subjects and regions (Figure 3). A lower SUVR correlation was observed in subcortical regions (r2=0.57). Regional comparisons are shown in Figure 4. Conclusions: The tau pathology distribution was similar for both tracers although each tracer presents a distinct off‐target signal pattern. These preliminary results support the development of categorical and standardized quantification scales for using both tracers in future studies and bridging existing data sets. Figure 1. Delineation of cortex and cerebellum rims. The combined gray and white matter SPM segmentations were binarized and the ventricles and internal CSF spaces filled to create a mask. Figure 2. [18F]GTP1 and [18F]PI2620 SUVR images. Figure 3. [18F]GTP1 and [18F]PI2620 SUVR in WCG and in vivo Braak regions. Figure 4: [18F]GTP1 and [18F]PI2620 SUVR correlation in target cortical regions, and off‐target signal in choroid plexus (CP), WCG and cerebellum (CBL) rims, and subcortical structures (CAU: caudate; PUT: putamen; PAL: pallidum; THA: thalamus; NAc: nucleus accumbens; SN: substantia nigra) and centrum semiovale (WM). [ABSTRACT FROM AUTHOR]

Our objective was to harmonize multicenter 89Zr PET imaging for oncology trials and to evaluate lesion detection. Methods: Seven PET scanners were evaluated using a custom chest oncology phantom with 9 spheric lesions 7-20 mm in diameter. A 4:1 signal-to-background ratio simulated a patient dose of 92.5 MBq. Various image reconstructions were evaluated. Images were assessed for lesion detection, and recovery coefficients and background signal variance were measured. Results: Two scanners failed to provide acceptable images and data. Optimal reconstruction algorithms enabling adequate lesion detection and reliable quantification across the other 5 scanners were determined without compromising the data quality. On average, 95% of the 10-mm lesions were detected, and the 7-mm lesion was visualized by only 1 scanner. Background variance was 8.6%-16%. Conclusion: We established multicenter harmonization procedures for 89Zr PET imaging in oncology, optimizing small-lesion (≥10 mm) detectability and accurate quantification. [ABSTRACT FROM AUTHOR]

Background: Over the past decade, several PET tracers were developed to visualise and quantify tau pathology in vivo. However, all these tracers have distinct off‐target binding, different dynamic ranges and likely different levels of non‐specific binding resulting in large variability in semiquantification. We propose to standardise the sampling and the quantification across all available tau tracers. Method: 549 participants underwent tau scans with either 18F‐FTP (Cognitively Unimpaired (CU) = 54/AD = 14), 18F‐MK6240 (CU = 186/AD = 89), 18F‐PI2620 (CU = 17/AD = 21), 18F‐PM‐PBB3 (CU = 30/AD = 28), 18F‐GTP1 (CU = 7/AD = 38) or 18F‐RO948 (CU = 35/AD = 30). All CU individuals were Aβ‐ and all AD were Aβ+. The tau scans were spatially normalized using CapAIBL and the cerebellar cortex was used as reference region. We constructed a "universal" tau mask from the intersection of all the specific tau tracer masks, after subtracting AD from CU. All tau PET studies were sampled with a Mesial Temporal (MTL) and a Meta Temporal (MetaT) composites constrained by the universal mask. For each tracer and in composite, the mean and standard deviation of the Aβ‐ CU SUVR for each tau tracer were used to generate z‐scores (CenTauRz). Result: Using a threshold of 2 CenTauRz in the MetaT regions, all tracers highly discriminated Aβ+ AD from Aβ‐ CU (ACC = [0.94‐1], sens = [0.84‐1], spec = [0.96‐1]) with mean CenTauRz for the different AD cohorts ranging from 8 to 14. Lower accuracy was observed in the MTL (ACC = [0.78‐1]) due to lower sensitivity in some cohorts [0.65‐1] however, the specificity was similar to that in the MetaT composite (spec = [0.94,1]). Conclusion: All tracers exhibited comparably high discriminative power to separate Aβ+ AD from Aβ‐ CU, where AD Aβ+ displayed a consistent range of CenTauRz across tracers. However, there were some differences between cohorts. For example, different PET scanners, with different sensitivities were used. For some cohorts, scans were selected as extreme representative cases, while for others the scans were more representative of clinical settings, with AD patients at early stages (with low or negative tau scans) or with suspected hippocampal sparing subtype that likely explains the lower accuracy in the MTL for some cohorts. Further studies with larger cohorts to validate the universal mask and CenTauRz scale are ongoing. [ABSTRACT FROM AUTHOR]

Background: Prior studies of tau PET tracers in participants with normal cognition and/or a broad range of Alzheimer's disease (AD) severity suggest baseline tau PET signal is associated with subsequent rates of cognitive decline. However, the prognostic utility of tau PET imaging is less well‐established within more homogenous cohorts limited to specific AD stages and for cognitive versus functional decline. We addressed these questions by analyzing baseline [18F]GTP1 tau PET signal and longitudinal changes in cognitive and functional measures in the Phase 2 Tauriel study of semorinemab in prodromal‐to‐mild AD. Methods: We analyzed data from a subset of Tauriel participants with prodromal AD (pAD; n=127) or mild AD (mAD; n=233) who underwent baseline [18F]GTP1 tau PET and longitudinal assessments with the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB), Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog13), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and/or Alzheimer's Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL). As no treatment effects were observed with semorinemab in Tauriel, data were pooled across semorinemab and placebo arms. Associations between baseline [18F]GTP1 SUVRs and annualized longitudinal change on each measure were explored using Pearson correlations and multiple linear mixed effects regression models adjusting for relevant baseline covariates. Results: Baseline cortical [18F]GTP1 SUVRs and longitudinal decline on clinical measures were significantly greater in mAD relative to pAD cohort. Prognostic associations with baseline cortical [18F]GTP1 were similar in pAD and mAD and more robust for predominantly cognitive measures (ADAS‐Cog13: pAD rs=0.37, mAD rs=0.35; RBANS Total Index: pAD rs=‐0.40, mAD rs=‐0.41) than measures incorporating functional status (CDR‐SB: pAD rs=0.27, mAD rs=0.29; ADCS‐ADL: pAD rs=‐0.12, mAD rs=‐0.26). Analogous results were seen using temporal or Braak stage regions of interest. [18F]GTP1 associations with cognitive decline generally remained significant after adjusting for baseline cognitive score, age, hippocampal volume, and education. Conclusions: Higher baseline [18F]GTP1 tau PET signal was associated with faster subsequent clinical decline in both prodromal and mild AD. More robust associations were seen with cognitive relative to functional measures. These results bolster prior work that suggests a role for tau PET in patient selection/stratification in AD clinical trials. [ABSTRACT FROM AUTHOR]

Background: Over the past decade, several PET tracers were developed to visualise and quantify tau pathology in vivo. However, all these tracers have distinct off‐target binding, different dynamic ranges and likely different levels of non‐specific binding resulting in large variability in semiquantification. We propose to standardise the sampling and the quantification across all available tau tracers. Method: 549 participants underwent tau scans with either 18F‐FTP (Cognitively Unimpaired (CU)=54/AD=14), 18F‐MK6240 (CU=186/AD=89), 18F‐PI2620 (CU=17/AD=21), 18F‐PM‐PBB3 (CU=30/AD=28), 18F‐GTP1 (CU=7/AD=38) or 18F‐RO948 (CU=35/AD=30). All CU individuals were Aβ‐ and all AD were Aβ+. The tau scans were spatially normalized using CapAIBL and the cerebellar cortex was used as reference region. We constructed a "universal" tau mask from the intersection of all the specific tau tracer masks, after subtracting AD from CU. All tau PET studies were sampled with a Mesial Temporal (MTL) and a Meta Temporal (MetaT) composites constrained by the universal mask. For each tracer and in composite, the mean and standard deviation of the Aβ‐ CU SUVR for each tau tracer were used to generate z‐scores (CenTauRz). Result: Using a threshold of 2 CenTauRz in the MetaT regions, all tracers highly discriminated Aβ+ AD from Aβ‐ CU (ACC=[0.94‐1], sens=[0.84‐1], spec=[0.96‐1]) with mean CenTauRz for the different AD cohorts ranging from 8 to 14. Lower accuracy was observed in the MTL (ACC=[0.78‐1]) due to lower sensitivity in some cohorts [0.65‐1] however, the specificity was similar to that in the MetaT composite (spec=[0.94,1]). Conclusion: All tracers exhibited comparably high discriminative power to separate Aβ+ AD from Aβ‐ CU, where AD Aβ+ displayed a consistent range of CenTauRz across tracers. However, there were some differences between cohorts. For example, different PET scanners, with different sensitivities were used. For some cohorts, scans were selected as extreme representative cases, while for others the scans were more representative of clinical settings, with AD patients at early stages (with low or negative tau scans) or with suspected hippocampal sparing subtype that likely explains the lower accuracy in the MTL for some cohorts. Further studies with larger cohorts to validate the universal mask and CenTauRz scale are ongoing. [ABSTRACT FROM AUTHOR]

Background: Previous research has demonstrated that the injected dose in PET examinations can be reduced without substantial effects on quantitative outcomes. These reductions can lead to lower radiation burden for subjects, reduced costs for institutions and potential for additional research scans of the same subject. Here, we investigated the effect of reduced injected doses of [18F]RO948 and [18F]Flortaucipir (FTP) on standardised uptake value ratios (SUVRs) and associated outcomes. Method: Images were manipulated from list‐mode data to simulate injected doses of 70%, 50%, 25% and 12.5% of the true injected dose. Initial analyses were scan time reduction for RO948 and dose reduction for FTP with future harmonisation of processing intended. Inferior cerebellum‐grey was used to compute SUVRs in regions‐of‐interest (ROIs) corresponding to the in vivo Braak regions of tau spread. Differences between true and reduced injected doses (given as a percentage) were calculated in individual regions as the mean of [SUVRreduced – SUVRtrue] over the means of SUVRreduced and SUVRtrue values across subjects. Result: Previously reported test‐retest variability for RO948 and FTP are 2‐6% (±6%) and 1.5‐3.3% (±3%) respectively. Regionally, RO948 remained below this TRT variability at 25% injected dose, with an average SUVR difference of 2.3% (±8%) (figure 2), whereas FTP remained below TRT variability only at 70% injected dose with an average SUVR difference of 2.9% (±3%). However, differences were above TRT variability for FTP at lower injected doses. FTP average SUVR differences were observed to be higher in CN compared to AD patients at reduced injected doses but with greater variability in AD than CN. There were no differences observed between Ab+ and Ab‐ controls. Conclusion: Preliminary findings suggest that lower injected tracer‐doses for RO948 and FTP yield robust SUVRs. However, the degree to which injected doses can be reduced must be investigated further for different demographics and for different tracers. Ongoing work aims to harmonise the simulation list‐mode processing, add MCI/AD RO948 subjects, and evaluate dose reduction in [18F]GTP1 data. Further validation will be performed against demographic and clinical variables, as well as for longitudinal data. [ABSTRACT FROM AUTHOR]

Background: In prior cross‐sectional studies using [18F]GTP1 or other tau PET tracers across a spectrum of Alzheimer's disease (AD) severity, tau PET signal has independently correlated with cognition, even after adjustments for β‐amyloid (Aβ) load and atrophy. However, it remains uncertain how robust these correlations are in more homogeneous patient populations (e.g., clinical trial participants) and after adjustment for MRI white‐matter hyperintensities (WMH). We sought to address this question by examining baseline data from the Phase 2 Tauriel study (NCT03289143), which is investigating the safety and efficacy of semorinemab (an anti‐tau antibody) in prodromal‐to‐mild AD. Method: We analyzed data from a subset of Tauriel participants who underwent baseline [18F]GTP1 tau PET imaging and met criteria for probable AD dementia (n=244) or mild cognitive impairment (MCI; n=137), with MMSE of 20‐30, global Clinical Dementia Rating (CDR) of 0.5 or 1, significant Aβ pathology (PET or CSF), and significant episodic memory impairment on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Other screening/baseline assessments included the 13‐item version of the Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog13) and MRI (WMH scored with Fazekas scale). Relationships between cognitive indices, whole cortical gray (WCG) [18F]GTP1 SUVR, WMH, and age were assessed using Pearson correlations and multiple linear regression. Result: Univariate analyses revealed significant correlations between all cognitive indices [MMSE, CDR Sum of Boxes, ADAS‐Cog13, and RBANS] and [18F]GTP1 SUVR across the whole cortical gray (WCG; p's<0.001). Significant univariate correlations were also seen between WMH and ADAS‐Cog13 scores (p=0.035) and between age and RBANS scores (p<0.001). Multivariate linear regression analyses that included all three factors consistently identified both WCG [18F]GTP1 SUVR and WMH as independent predictors of cognitive performance across all indices (p's<0.05), with a much larger proportion of variance attributable to WCG [18F]GTP1 SUVR. Conclusion: Amongst participants with prodromal‐to‐mild AD enrolled in the Tauriel study, [18F]GTP1 tau PET signal was more strongly associated with baseline cognitive performance than the extent of WMH. These data suggest that even in AD participants with co‐morbid cerebral microvascular ischemic disease, therapeutic interventions targeting tau have the potential to ameliorate subsequent cognitive decline. [ABSTRACT FROM AUTHOR]

Background: White matter hyperintensities (WMH) on MRI are commonly seen in Alzheimer's disease (AD) and thought to represent co‐morbid microvascular ischemic disease. However, the relationship between WMH and tau pathology in AD remains incompletely understood. We explored this question using screening/baseline data from a Phase 2 study of the anti‐tau antibody semorinemab (Tauriel; NCT03289143), which included both MRI and [18F]GTP1 tau PET imaging. Method: Participants in the Tauriel study are aged 50‐80, meet criteria for AD dementia or mild cognitive impairment (MCI), have MMSE of 20‐30, global Clinical Dementia Rating (CDR) of 0.5 or 1, evidence of significant amyloid pathology, and significant episodic memory impairment (RBANS delayed memory index < 85), and undergo screening MRIs, with WMH quantified using the Fazekas scale. Analyses were performed on a subset of participants (n=381) who received baseline [18F]GTP1 tau PET scans. Relationships between WMH, [18F]GTP1 SUVR in an AD‐specific temporal lobe ROI, age, and cognitive scales were assessed graphically and quantified using Pearson correlations, Cohen's D, t‐tests, and multiple linear regression. Result: Tauriel participants had Fazekas scores of zero (n=161), one (n=208), or two (n=12). Per the Figure, participants with Fazekas scores > 0 tended to be older (Cohen's D=0.69, p < 0.001) and have lower temporal [18F]GTP1 SUVR (Cohen's D=0.35, p<0.001). The relationship between temporal [18F]GTP1 SUVR and baseline ADAS‐Cog13 (r=0.39, p<0.001) remained significant after adjusting for Fazekas score and age via multiple regression (p<0.001). Conclusion: Given the circumscribed range of disease severity seen in prodromal‐to‐mild AD participants at screening/baseline in the Tauriel study, the relationships between MRI WMH and [18F]GTP1 tau PET suggest that these pathologies have additive and independent contributions to cognition that may be age‐related. Clinical trials of anti‐tau therapeutics in similar patient populations may need to account for cerebrovascular co‐morbidities in patient selection and/or efficacy analyses. [ABSTRACT FROM AUTHOR]

Introduction: Recently, an increasing number of tau tracers have become available. There is a need to standardize quantitative tau measures across tracers, supporting a universal scale. We developed several cortical tau masks and applied them to generate a tau imaging universal scale., Method: One thousand forty-five participants underwent tau scans with either 18 F-flortaucipir, 18 F-MK6240, 18 F-PI2620, 18 F-PM-PBB3, 18 F-GTP1, or 18 F-RO948. The universal mask was generated from cognitively unimpaired amyloid beta (Aβ)- subjects and Alzheimer's disease (AD) patients with Aβ+. Four additional regional cortical masks were defined within the constraints of the universal mask. A universal scale, the CenTauR z , was constructed., Results: None of the regions known to display off-target signal were included in the masks. The CenTauR z allows robust discrimination between low and high levels of tau deposits., Discussion: We constructed several tau-specific cortical masks for the AD continuum and a universal standard scale designed to capture the location and degree of abnormality that can be applied across tracers and across centers. The masks are freely available at https://www.gaain.org/centaur-project., Competing Interests: Victor Villemagne has received research grants from NHMRC (GNT2001320), the Aging Mind Foundation (DAF2255207) and NIH (2P01AG025204‐16) and is and has been a consultant or paid speaker at sponsored conference sessions for Eli Lilly, Life Molecular Imaging, ACE Barcelona, and IXICO. Sandra Sanabria Bohorquez and Robby Weimer are a full‐time employees and stock owners of Roche. Santiago Bullich and Andrew Stephen are full‐time employees of Life Molecular Imaging GmbH. Hitoshi Shimada and Makoto Higuchi hold patents on compounds related to the present report (JP 5422782/EP 12 884 742.3/CA2894994/HK1208672). Christopher C. Rowe has received research grants from NHMRC, Enigma Australia, Biogen, Eisai, and Abbvie. He is on the scientific advisory board for Cerveau Technologies and consulted for Prothena, Eisai, Roche, and Biogen Australia. Oskar Hansson has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Genentech, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens. The other authors did not report any conflict of interest., (© 2023 CSIRO and The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Our objective was to harmonize multicenter 89 Zr PET imaging for oncology trials and to evaluate lesion detection. Methods: Seven PET scanners were evaluated using a custom chest oncology phantom with 9 spheric lesions 7-20 mm in diameter. A 4:1 signal-to-background ratio simulated a patient dose of 92.5 MBq. Various image reconstructions were evaluated. Images were assessed for lesion detection, and recovery coefficients and background signal variance were measured. Results: Two scanners failed to provide acceptable images and data. Optimal reconstruction algorithms enabling adequate lesion detection and reliable quantification across the other 5 scanners were determined without compromising the data quality. On average, 95% of the 10-mm lesions were detected, and the 7-mm lesion was visualized by only 1 scanner. Background variance was 8.6%-16%. Conclusion: We established multicenter harmonization procedures for 89 Zr PET imaging in oncology, optimizing small-lesion (≥10 mm) detectability and accurate quantification., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)