Bloomquist, Madeleine

Abstract Background The Alzheimer's Association workgroup criteria (AA‐2024) suggest four biological stages based on PET imaging. However, the application of this framework may vary depending on the tau PET tracer used, and the distribution of clinical stages by biological stage may differ. Here, we aim to compare the diagnostic performance of the biological staging of Alzheimer Disease using two different tau PET tracers. Method We analyzed 446 individuals and further stratified 167 Aβ‐positive participants from the HEAD study (Longitudinal multicenter head‐to‐head harmonization of tau PET tracers) that underwent both MK‐6240 and Flortaucipir (FTP) tau PET. Four clinical stages (normal, transitional, MCI, and dementia) were defined based on the AA‐2024 criteria. Within stage‐2 we assessed subgroups: subjective cognitive decline (SCD), subtle objective cognitive decline (SOCD), and mild behavioral impairment (MBI). Logistic and linear models corrected by age and sex tested association of groups with amyloid and tau pathology. The biological staging was performed using tracer‐specific thresholds for regional SUVR and testing two regions of interest schemes: (i) proposed by AA‐2024 and (ii) Braak stages (Figure 1). Cohen's weighted‐kappa (K) statistic measured clinical‐biological agreement. Positive predictive value (PPV) of an individual being clinically impaired (MCI or dementia) was calculated for each biological stage. Result Clinical stages showed a progressively increased prevalence of Aβ‐positivity and higher entorhinal tau PET pathology from cognitively normal (CN) to SOCD, MCI, and dementia in both tracers. MBI and SCD transitional groups showed no increased Aβ or tau pathology compared to CN (Figure 2). For this reason, only SOCD was considered part of stage 2 for following analyses. All tested biological staging strategies showed moderate agreement (0.34‐0.59) with clinical stages using either tracers. The distribution of biological across clinical stages were similar for FTP and MK, with MK‐6240 showing lower PPV values in earlier stages than FTP (Table 1). Conclusion Our results support that AA‐2024 biological and clinical stages show similar clinical‐biological concordance using either Flortaucipir or MK‐6240, although this can vary based on methods tested in the study. The MBI and SCD clinical subgroups showed no difference of pathological burden to clinical stage 1, while SOCD transitional stage showed higher burden compared to stage 1.

AbstractBackgroundStandardizing tau pathology quantification in vivo is challenged by differences in binding characteristics between tau‐PET tracers. The HEAD study aims to generate a leading, longitudinal head‐to‐head dataset of MK‐6240, Flortaucipir, RO948, and PI‐2620 tau‐PET to harmonize these tracers' outcomes and develop tools allowing for the generalization of findings across large studies and trials. Here, we present current advancements in building the HEAD study cohort and dataset.MethodsThe HEAD study is managed at the University of Pittsburgh. HEAD comprises several sites across the US and Canada in which 620 subjects (young, cognitively unimpaired, mild cognitive impairment, and Alzheimer’s disease (AD)) will undergo tau‐PET with at least two tracers, amyloid‐PET with PiB or NAV4694, MRI, blood collection, and standardized neuropsychological testing at baseline and at 18‐month follow‐up. PET and MRI acquisition parameters are based on ADNI4 protocols and neuropsychological testing employs the NACC Uniform Data Set. The National Centralized Repository for AD serves as the biorepository for blood samples and the Laboratory of Neuroimaging provides a centralized database for imaging and neuropsychological archiving. PET data is reconstructed to maximize cross‐scanner harmonization and is processed uniformly similarly to ADNI4 PET.ResultsIn one year of active enrollment (Jan 2023‐Jan 2024), 362 participants were enrolled at six active sites; over 80% of participants completed neuropsychological testing and MRI, and over 70% completed Flortaucipir, MK‐6240, and amyloid‐PET, with a mean tau‐PET acquisition window of 29.1 days. RO948 and PI‐2620 tau‐PET are additionally acquired in a subset currently including 41 participants (Figure 1). Current HEAD cohort demographics including age, sex, underrepresented populations, and group distributions, APOEε4 carrier status, and amyloid positivity are shown in Figure 2. A case of a subject with AD with all 4 tau‐PET tracers acquired head‐to‐head within 49 days is shown in Figure 3.ConclusionThe HEAD study represents a continued effort in the optimization of AD imaging biomarkers. Baseline data collection is projected to be completed in 2024; results being generated by multiple groups from this dataset will provide novel and crucial guidance on the use of tau‐PET tracers in research, clinical trials, and prospectively in clinical practice.

AbstractBackgroundUtilizing PET amyloid‐beta (Aβ) and tau for staging Alzheimer’s Disease (AD) has demonstrated potential in identifying individuals with varying degrees of disease severity, applicable to both clinical trials and practice. However, the diverse binding characteristics of tau tracers pose challenges to the application of this staging across different ligands. In this study, we evaluate a novel staging framework proposed by the AA working group, employing Aβ PET and either [18F]MK6240 or [18F]Flortaucipir in individuals participating in a head‐to‐head study of tau PET tracers. This will provide insights into the robustness of this framework when applied across different tau ligands.MethodWe evaluated 154 people (89 CU and 65 CI), with MK6240, Flortaucipir, Aβ‐PET, MRI. SUVRs used inferior cerebellar gray as reference. Participants were categorized in Aβ positivity(A), using visual read, and tau positivity (T) in medial temporal lobe(MTL) and neocortex(NEO). Tau MTL(TMTL) and NEO positivity were defined as average +3 SD of youngs. NEO moderate(TMOD) and high(THIGH) was defined as below and above median SUVR of NEO‐positive individuals. Individuals were grouped as: A‐T‐, A+T‐, A+TMTL+(early), A+TMOD+(intermediary), and A+THIGH+(advanced).ResultsWe found that the distribution of the number of individuals across the five AD stages was comparable when using both MK6240 and Flortaucipir tracers (Figure 1). However, upon examining the concordance within each group, we found a low concordance of 30% (3/10) between tracers in the early tau stage (A+TMTL+). Concordance increased in the intermediary stage A+TMOD+, with a rate of 65% (9/14), and further increased to 79% (11/14) in the advanced stage (A+THIGH+). The A+T‐ group exhibited the highest concordance between tracer results, at 95% (21/22).ConclusionOur findings indicate that the application of this framework across different populations using different tau tracers can lead to a compatible distribution among groups. However, in a direct comparison, we noted that this did not necessarily result in high concordance between groups, as group shifts were observed that depended on the cutoffs used (data not shown). These results emphasize the necessity for harmonization of tau PET tracers prior to their utilization for stage determination.

AbstractBackgroundStandardizing tau pathology quantification in vivo is challenged by differences in binding characteristics between tau‐PET tracers. The HEAD study aims to generate a leading, longitudinal head‐to‐head dataset of MK‐6240, Flortaucipir, RO948, and PI‐2620 tau‐PET to harmonize these tracers' outcomes and develop tools allowing for the generalization of findings across large studies and trials. Here, we present current advancements in building the HEAD study cohort and dataset.MethodsThe HEAD study is managed at the University of Pittsburgh. HEAD comprises several sites across the US and Canada in which 620 subjects (young, cognitively unimpaired, mild cognitive impairment, and Alzheimer’s disease (AD)) will undergo tau‐PET with at least two tracers, amyloid‐PET with PiB or NAV4694, MRI, blood collection, and standardized neuropsychological testing at baseline and at 18‐month follow‐up. PET and MRI acquisition parameters are based on ADNI4 protocols and neuropsychological testing employs the NACC Uniform Data Set. The National Centralized Repository for AD serves as the biorepository for blood samples and the Laboratory of Neuroimaging provides a centralized database for imaging and neuropsychological archiving. PET data is reconstructed to maximize cross‐scanner harmonization and is processed uniformly similarly to ADNI4 PET.ResultsIn one year of active enrollment (Jan 2023‐Jan 2024), 362 participants were enrolled at six active sites; over 80% of participants completed neuropsychological testing and MRI, and over 70% completed Flortaucipir, MK‐6240, and amyloid‐PET, with a mean tau‐PET acquisition window of 29.1 days. RO948 and PI‐2620 tau‐PET are additionally acquired in a subset currently including 41 participants (Fig.1). Current HEAD cohort demographics including age, sex, underrepresented populations, and group distributions, APOEe4 carrier status, and amyloid positivity are shown in Fig.2. A case of a subject with AD with all 4 tau‐PET tracers acquired head‐to‐head within 49 days is shown in Fig.3.ConclusionThe HEAD study represents a continued effort in the optimization of AD imaging biomarkers. Baseline data collection is projected to be completed in 2024; results being generated by multiple groups from this dataset will provide novel and crucial guidance on the use of tau‐PET tracers in research, clinical trials, and prospectively in clinical practice.

AbstractBackgroundUtilizing PET amyloid‐beta (Aß) and tau for staging Alzheimer’s Disease (AD) has demonstrated potential in identifying individuals with varying degrees of disease severity, applicable to both clinical trials and practice. However, the diverse binding characteristics of tau tracers pose challenges to the application of this staging across different ligands. In this study, we evaluate a novel staging framework proposed by the AA working group, employing Aß PET and either [18F]MK6240 or [18F]Flortaucipir in individuals participating in a head‐to‐head study of tau PET tracers. This will provide insights into the robustness of this framework when applied across different tau ligands.MethodWe evaluated 154 people (89 CU and 65 CI), with MK6240, Flortaucipir, Aß‐PET, MRI. SUVRs used inferior cerebellar gray as reference. Participants were categorized in Aß positivity(A), using visual read, and tau positivity (T) in medial temporal lobe(MTL) and neocortex(NEO). Tau MTL(TMTL) and NEO positivity were defined as average +3 SD of youngs. NEO moderate(TMOD) and high(THIGH) was defined as below and above median SUVR of NEO‐positive individuals. Individuals were grouped as: A‐T‐, A+T‐, A+TMTL+(early), A+TMOD+(intermediary), and A+THIGH+(advanced).ResultsWe found that the distribution of the number of individuals across the five AD stages was comparable when using both MK6240 and Flortaucipir tracers (Figure 1). However, upon examining the concordance within each group, we found a low concordance of 30% (3/10) between tracers in the early tau stage (A+TMTL+). Concordance increased in the intermediary stage A+TMOD+, with a rate of 65% (9/14), and further increased to 79% (11/14) in the advanced stage (A+THIGH+). The A+T‐ group exhibited the highest concordance between tracer results, at 95% (21/22).ConclusionOur findings indicate that the application of this framework across different populations using different tau tracers can lead to a compatible distribution among groups. However, in a direct comparison, we noted that this did not necessarily result in high concordance between groups, as group shifts were observed that depended on the cutoffs used (data not shown). These results emphasize the necessity for harmonization of tau PET tracers prior to their utilization for stage determination.