Gordon, Brian A.

Abstract Background Tau‐PET imaging enables in vivo detection of tau pathology in Alzheimer’s disease (AD), with early detection being critical for tracking disease progression. Here, we compare [ 18 F]FTP and [ 18 F]MK6240 in individuals with low tau burden. Method 450 individuals from the HEAD study (22 cognitively unimpaired (CU) young (CUY), 242 CU old and 186 cognitively impaired (CI)) underwent [ 18 F]FTP and [ 18 F]MK6240 tau‐PET and amyloid‐PET scans. Scans were processed using identical pipelines with inferior cerebellar gray matter as the reference region. Individuals were categorized as low tau if both [ 18 F]FTP and [ 18 F]MK6240 meta‐temporal SUVR were lower than 1.5. For comparison, [ 18 F]MK6240 and [ 18 F]FTP were transformed into one another using linear and non‐linear models; additionally, images were also z‐scored relative to the CUYs. Result Despite cognitive status and amyloid burden, several individuals showed elevated [ 18 F]FTP retention in temporal regions relative to [ 18 F]MK6240. As an example, Figure 1 shows [ 18 F]FTP and [ 18 F]MK6240 in 16 participants (4 per cognitive and amyloid status). Across most subjects with SUVRs<1.5, [ 18 F]FTP presented higher retention in meta‐temporal region as compared to [ 18 F]MK6240, though [ 18 F]MK6240 increased sharply above this threshold (Figure 2). In Figure 3, group‐average images and their transformed counterparts are shown for each group by amyloid and cognitive status, the subset of low‐tau participants in Aβ+ groups are also shown. In low tau groups, [ 18 F]FTP meta‐temporal retention is high in comparison to [ 18 F]MK6240. Additionally, z‐scored [ 18 F]FTP images show broader spread into temporal regions than [ 18 F]MK6240, reinforcing differences in retention. Conclusion [ 18 F]FTP shows meta‐temporal retention not seen with [ 18 F]MK6240 in low tau individuals. This discrepancy persists across transformed and z‐scored images, suggesting that there is a difference in early tracer retention between [ 18 F]FTP and [ 18 F]MK6240. It is unclear if the early [ 18 F]FTP retention is related to early maturity levels of tau or off‐target signal. These findings have important implications for basic understanding of early tau retention, early diagnosis, and biomarker harmonization efforts.

Abstract Background In vivo Braak staging stratifies patients across the AD spectrum and has the potential to harmonize tau PET tracer staging. This study aims to compare and test harmonization procedures for Braak staging individuals using MK6240 and Flortaucipir tau PET tracers. Methods We assessed 437 participants across the AD spectrum (245 cognitively unimpaired (CU) and 192 cognitively impaired; mean age 68.5 ± 8.6) using head‐to‐head MK6240 and Flortaucipir scans. We computed SUVRs in Braak regions of interest (ROIs) and assessed four cut‐off methods for Braak positivity: (a) mean + 2.5 SD of young controls (age <28 years), (b) mean + 2.5 SD of elderly CU Aβ−, (c) Gaussian mixture modeling (GMM), and (d) the Youden index. Braak stages were assigned using seven (0 to VI) or four (0, I–II, III–IV, V–VI) categories. We evaluated inter‐ and intra‐tracer concordance (intra‐tracer, i.e., whether it follows the sequential Braak pattern). Results The intra‐tracer seven‐class Braak staging concordance ranged from 63% to 94%. With the highest intra‐tracer Braak concordance being achieved when using GMM cutoffs: 94% (MK6240) and 89% (Flortaucipir; Figure 1). Inter‐tracer agreement concordance ranged from 56% to 76%. The highest concordance emerged from the CU Elderly Aβ– cutoff optimizing the Braak II region for spill‐off (Figure 2). Using the Braak staging simplified version improved intra‐tracer concordance in both tracers (MK6240as well as inter‐tracer agreement (86.5%). Most inter‐tracer discrepancies were observed at Braak stages II–IV. Despite showing staging discordances, the distribution of cognitive status across the Braak stages is similar for both tracers (Figure 3). Conclusion These preliminary findings reveal some discrepancies in Braak staging when comparing MK6240 and Flortaucipir. Our results also suggest that adjustments in cutoffs and regions of interest can partially mitigate both inter‐ and intra‐tracer divergences. Finally, our analysis suggests robust concordance after adjustment and using 4 classes (0, I‐II, III‐IV, V‐VI).

Abstract Background Tau‐PET provides critical topographic information on tau deposition in the living brain. Integrating research‐based practices into clinical settings through qualitative methods, such as visual reads, is becoming increasingly important. This study aims to compare the performance of existing visual reading methods for [ 18 F]Flortaucipir (FTP) and [ 18 F]MK‐6240 (MK) and provide preliminary data toward a unified visual reading approach for all tau‐PET tracers using a head‐to‐head dataset. Methods The study design and development plans are illustrated in Figure 1. To evaluate previously published visual reading methods, two blinded raters conducted FTP and MK visual reads on 340 participants from the HEAD study. A unified visual reading method was developed and tested on 101 participants, using a composite of adjusted Braak regions to determine 3 stages of severity while harmonizing between tracers. For external validation, the method will be tested on four additional cohorts, each using one of the following tracers: FTP, MK, PI, or RO. Results Inter‐rater agreement using previous methods (Figure 2A) showed high Cohen’s kappa values (0.71‐0.77) for the low and high tau burden categories in both FTP and MK visual reads. However, agreement was substantially lower in the non‐AD‐like category, leading to overall agreement rates of 0.55 for FTP and 0.69 for MK. In contrast, the method developed here improved inter‐rater agreement across all categories (0.87‐0.96) and introduced a moderate tau (0.79‐0.83) burden group (Figure 2B), leading to higher overall agreement rates of 0.81 for FTP and 0.87 for MK (Figure 2C). For inter‐tracer agreement (Figure 3), previous methods resulted in discordant visual reads for FTP and MK in 34.4% of cases for rater 1 and 24.7% for rater 2. The developed method reduced this disagreement to 11.9% (rater 1) and 15.8% (rater 2), demonstrating improved consistency across different tracers. Conclusion This study demonstrates that previously published visual reading methods produced varying classifications depending on the tracer used. The method proposed here improved inter‐rater and inter‐tracer visual read agreements by developing a unified, tracer‐agnostic approach easy to be used. Importantly, this clinician‐friendly method has the potential for widespread adoption, offering a single harmonized visual reading technique for all tau‐PET tracers.

Abstract Background One of the hallmarks of Alzheimer’s disease (AD) is the progressive spread of tau pathology. However, heterogeneity in the spatial patterns of tau deposition at the individual level may contribute to distinct clinical presentations. Here, we investigated the different patterns of tau deposition across disease progression and the different cognitive profiles linked to these patterns. Method We investigated 106 tau PET positive individuals (16% cognitively unimpaired, 84% amnestic cognitively impaired) from the HEAD study using head‐to‐head Flortaucipir and MK6240 tau PET. For each tracer, we extracted the SUVR values from seven major brain networks: Limbic, Visual (Vis), Default Mode (Default), Dorsal Attention (DorsAttn), Frontoparietal, Somatomotor (SomMot) and Salience Ventral Attention (SalVentAttn) as well as the Entorhinal cortex. Pathways were identified by ranking regions from highest to lowest SUVR, with the region displaying the highest SUVR value being defined as the peak region. Individuals in late stages of tau deposition displaying distinct pathways were compared. Image averages and voxel‐wise group comparisons using tau negative individuals as the reference were generated for each pathway and tau PET tracer. Cognitive differences were assessed using ANOVA for MoCA score and domain‐specific composite scores for Memory, Attention and Visuospatial skills. Result In all individuals and tracers, tau in the Entorhinal cortex progressed to the Limbic network, supporting a common starting point for tau propagation. Beyond these initial stages, tau propagation followed three main distinct pathways following either the Vis, Default or DorsAttn networks (Figure 1). Voxel‐wise comparison between individuals across these three pathways captured clear and similar differences in tau PET uptake as measured with Flortaucipir and MK6240. (Figure 2). While MoCA and Memory scores did not differ between groups, individuals following the Vis network exhibited significantly lower Attention scores compared to those in the Default and DorsAttn networks. Additionally, individuals following the Vis network exhibited lower Visuospatial scores compared to the Default network group (Figure 3). Conclusion Our results indicate a model in which, although tau progresses hierarchically, its deposition peaks mainly follow specific networks, which drive tau deposition and, consequently, the clinical manifestations of AD.

Abstract Background We showed that astrocyte reactivity, as measured by plasma GFAP levels, influences Aβ mediated tau PET pathology in cognitively unimpaired (CU) Aβ‐positive individuals. However, the link between GFAP and tau PET in individuals without detectable Aβ pathology remains elusive. The aim of the current study is to investigate the association between plasma GFAP and tau PET in CU Aβ PET‐negative individuals. Method We studied 147 CU Aβ PET‐negative participants from the HEAD cohort with plasma GFAP and p ‐tau217, as well as tau PET Flortaucipir and MK6240 data. Aβ positivity was determined by Aβ PET visual reading and Centiloid 12. Voxel‐wise linear regression models adjusted for age and sex tested the association of plasma GFAP and p ‐tau217 with tau PET. Further, the associations of plasma GFAP with peak tau PET SUVR values extracted from voxel‐wise association were fitted with a linear regression model adjusted for age and sex. Result Voxel‐wise analysis showed that plasma GFAP levels, but not plasma p ‐tau217 levels, were associated with tau PET in the medial temporal lobe (e.g., amygdala, entorhinal cortex, hippocampus) predominantly for Flortaucipir tau PET [Figure 1A, B, C, D]. The association between plasma p ‐tau217 and tau PET was weak in Aβ‐negative individuals. These results were similar when Aβ positivity was defined based on Centiloid 12. Furthermore, plasma GFAP and peak tau PET SUVR of Flortaucipir showed stronger association than that of MK6240 [Flortaucipir: β=0.4017, p <0.0001; MK6240: β=0.194, p = 0.0424; Figure 2A, B]. Conclusion We found an association between GFAP levels and tau PET uptake in individuals not expected to exhibit high levels of tau tangle‐related tracer uptake. Further analysis will be designed to elucidate the underpinning of this association, which could represent low levels of tau pathology, astrogliosis, or other factors.

Abstract Background Previous studies demonstrated an association between tau pathology and the development of neuropsychiatric symptoms (NPS) in individuals with Alzheimer’s disease (AD). However, the extent to which tau influences each specific NPS domain remains unclear. Here, we aim to investigate the association of tau and each NPS domain in the AD continuum. We hypothesized that tau plays a comparatively greater effect on the emergence of hyperactive and psychotic symptoms compared to other NPS domains. Method We assessed 385 individuals (216 cognitively unimpaired (CU), 128 MCI, and 41 AD dementia) from the HEAD study who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI‐Q) and had positron emission tomography (PET) for amyloid‐β (Aβ) ([ 18 F]AZD4694 or [ 11 C]PiB), and tau tangles ([ 18 F]MK6240) at the same visit. Tau SUVR values were tailored with a mask from Braak stages I‐VI, using the inferior cerebellar gray matter as a reference region. All individuals with dementia had a positive Aß‐PET. Voxel‐wise and Tobit censored regression tested the association between NPS domains and biomarkers accounting for age, sex, cognitive status, and study site. We used censored regression models to account for skewed data alongside a leave‐one‐out (loo) approach to identify which NPS domains most contributed to results. Result CI individuals had significantly higher NPI‐Q scores and Tau PET SUVR than CU (Figure 1A, 1B). NPI‐Q score was significantly associated with tau‐PET predominantly in fronto‐parietal regions. Removing irritability from the models strengthened this association (Figures 2A‐C). Regression loo models revealed that motor disturbances contributed most to the association between NPS and tau‐PET across all Braak stages. Notably, irritability had a negative effect on the association in all Braak stages, suggesting that tau does not play a role in the development of irritability and is highly associated with motor disturbances (Figure 3). Conclusion Our study suggests that tau contributes to the development of motor disturbances but has no effect on the development of irritability across the AD continuum. These findings provide additional rationale for the development of new therapeutics aiming to mitigate motor disturbances and irritability in AD patients.

Abstract Background Standardizing tau pathology quantification in vivo is challenged by inherent characteristics of 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 tracers' outcomes and develop tools to generalize findings across studies and trials. Here, we provide an update on the progression of the HEAD study. Method HEAD is a multicentric study comprising nine performance sites. Recruitment aimed for 620 individuals between 18‐28 or 50‐90 years, classified as Young/CU/MCI/Dementia. The HEAD protocol involves clinical assessment utilizing the NACC Uniform Data Set, blood collection for banking of plasma/serum/buffy coat/whole blood, and MRI acquisition based on ADNI4. All participants undergo amyloid‐PET with either PiB/NAV4694/Florbetaben/Flutemetamol. All undergo head‐to‐head tau‐PET with at least two tracers, including MK‐6240 (90‐110), Flortaucipir (80‐100), PI‐2620 (45‐75), and RO948 (70‐90). PET data is reconstructed and processed uniformly similarly to ADNI4. The Laboratory of Neuroimaging (LONI) provides centralized databasing, and the National Centralized Repository for ADRD (NCRAD) provides the blood biorepository for all samples. All study procedures are repeated at 18 months. Result Over 26 months, N = 679 participants were enrolled into HEAD, exceeding our proposed enrollment by 9.5%. Mean age of older adults is 72.1 years, female distribution is 54%, and 24% of individuals are from underrepresented groups (race/ethnicity/rurality). Progression in data collection has led to N = 551 (81%) of enrolled participants having a completed initial timepoint, and 1,489 total acquired head‐to‐head tau‐PET scans (mean acquisition window=34.9 days). Clinical characteristics including group distribution, APOEε4 carriership, plasma biomarker distribution (Aβ42/40 ratio/NfL/GFAP/PTau217), consensus visual rating of amyloid‐PET, and Braak stage classification are summarized in Figure 1. Two representative cases (CU/AD) of head‐to‐head tau‐PET with four tau tracers are shown in Figure 2. Longitudinal data collection has been initiated in N = 95 participants. Figure 3. demonstrates two cases (CU/MCI) of 18‐month longitudinal head‐to‐head tau‐PET with MK‐6240 and Flortaucipir. Conclusion The HEAD study cohort represents a continued effort in the optimization of AD imaging biomarkers. Cross‐sectional and longitudinal data collection in HEAD are ongoing, in addition to comprehensive plasma biomarker measurements. Generation of findings from HEAD cohort data will provide novel and crucial guidance on the use of tau‐PET tracers.

Abstract Background Quantifying tau aggregates in the human brain can be achieved using Positron Emission Tomography (PET) techniques, which can potentially be affected by binding competition due to medication use. Patients with dementia often have high rates of comorbidities and polypharmacy. Therefore, this study aims to investigate the potential influence of multiple medications on the uptake of the tau tracers MK6240 (MK) and Flortaucipir (FTP). Method Five classes of medications were evaluated: Anti‐Hypertensives, Statins, Anti‐Diabetics, Psychoactive drugs, and NSAIDs (Table 1). We included 292 individuals [170 cognitively unimpaired (CU) Aβ‐negative and 122 cognitively impaired (CI) Aβ‐positive] from the HEAD study (Table 2). We compared MK and FTP SUVR in the Medial Temporal Lobe (MTL) and Neotemporal Cortex (NTC) in individuals on and off medications. The linear regressions that tested associations were corrected for confounding factors, including age, sex, education, and MoCA score. Correction for multiple comparisons was applied using the Bonferroni method (adjusted p ‐value at 0.00125). Result Among CI Aβ‐positive individuals, Anti‐Diabetics were associated with lower SUVR in the NTC for both FTP and MK. However, these associations did not remain significant after correction for multiple comparisons. (Table 3). Conclusion Our findings indicate that there are no significant associations between the use of the medications studied and MK or FTP uptake when accounting for covariates and applying multiple comparison corrections.

Abstract Background Amyloid related imaging abnormality edema (ARIA‐E) occurs in about 19% of individuals with autosomal dominant Alzheimer disease (ADAD) treated with an anti‐amyloid‐b monoclonal antibody (Salloway et al., 2021). In a previously reported case, ARIA‐E appeared to colocalize with decreases in PiB‐PET uptake (Joseph‐Mathurin, Llibre‐Guerra, et al, 2022), suggesting an association between amyloid‐b (Aβ) removal and ARIA‐E. Here, we compare longitudinal neuroimaging and corresponding neuropathology in an ADAD individual treated with gantenerumab, who experienced multiple ARIA‐E episodes as sulcal effusions that resolved by the end of the four‐year trial. Methods PiB‐PET and MRI were collected pre‐ and post‐randomization (2 and 4 years). The participant consented to brain donation, which was received a year after trial completion. Four tissue samples were taken from the location of the ARIA‐E in the parieto‐occipital left hemibrain as identified by MRI (one block contained the sulcus affected by ARIA‐E; the rest of the coronal section was captured in the remaining three blocks). Area fractions (AFs) of Aβ (10D5 immunohistochemistry (IHC)), tauopathy (PHF1), microglia (Iba1), and astrocytes (GFAP) in one sulcal region of interest (ROI) from each block and PiB‐PET SUVRs of corresponding ROIs were extracted ( n = 4, Figure 1). Additionally, we included PiB‐PET SUVRs corresponding to ARIA‐E findings observed in the right hemisphere at baseline, two‐year, and four‐year visits ( n = 6). Results Overall PiB‐PET uptake increased during the first two years (before ARIA‐E) and decreased during the last two years (including ARIA‐E episodes) (0.03±0.05 vs. ‐0.04±0.04 SUVR/year, p ‐value=0.01, Figure 2). The decrease seemed more pronounced in ARIA‐E ROIs versus normal‐appearing sulcus ROIs (‐0.05±0.04 vs. ‐0.02±0.03 SUVR/year). Lower PiB uptake at last visit appeared associated with lower Aβ AF (estimates=0.03±0.01, p ‐value=0.07). The ARIA‐E ROI had an Aβ AF of 0.009 while normal‐appearing sulcus ROIs had a mean of 0.02+0.003 (Figure 3). AFs for tauopathy, microglia, and astrocytes were within the range of those of normal‐appearing sulcus ROIs, suggesting an Aβ‐specific effect, although unexamined markers may play a role. Conclusions Our preliminary findings indicated that ARIA‐E is associated with longitudinal PiB‐PET decrease and Aβ AF, supporting the link between ARIA‐E, changes in PiB‐PET, and local Aβ removal observed at autopsy. Funding : K01AG080123; U01AG042791; R01AG046179; R01AG053267

Abstract Background Tau PET tracers present distinct binding characteristics that might influence their trajectories and relationship with other biomarkers along the AD continuum. In a head‐to‐head study, we investigated the relationship between the emergence of PET tracers MK6240 and Flortaucipir, and plasma p ‐tau217 abnormalities as a function of Aβ PET deposition. We further assessed the concordance between tau PET and plasma p ‐tau217 positivity and its relationship with cognitive scores. Method We evaluated 352 individuals from the HEAD study (205 cognitively unimpaired and 147 cognitively impaired) with Aβ PET, MK6240 and Flortaucipir tau PET, and plasma p ‐tau217 (ALZpath) and GFAP (Quanterix) measures. Tau PET Braak regions, plasma p ‐tau217 trajectories were modeled as functions of Aβ burden (Centiloid scale) using the Lowess method. Biomarkers were z‐scored anchored on young individuals ( n = 19, < 28 years old) as anchors. Tau PET (Braak 1 region) and plasma p ‐tau217 were considered positive/abnormal when surpassing 2.5 z‐score. Result Among the tested markers, MK6240 was the earliest to show abnormality as a function of Centiloid, occurring at 22 Centiloids, followed by plasma p ‐tau217 at 38 Centiloid and Flortaucipir at Centiloid 56 (Figure 1). Tau PET and plasma p ‐tau217 positivity showed an overall high concordance (∼80% for both tracers; Figure 2). In MK6240 discordant cases, most individuals were MK6240+/ p ‐tau217‐ (13.8%), while 6.6% were MK6240‐/ p ‐tau217+ (Figure 2A). For Flortaucipir, 15% of discordant cases were Flortaucipir‐/ p ‐tau217+, while 4.8% were Flortaucipir+/ p ‐tau217‐ (Figure 2B). The discordant groups present higher Centiloid than the ptau217‐/Tau‐ group and overall decreased scores in cognitive tests, except for p ‐tau217+/MK6240‐ group (Figure 3). Conclusion MK6240 becomes abnormal at lower levels of Aβ burden compared to plasma p ‐tau217 and Flortaucipir. The relatively high prevalence of discordant tau PET positive or plasma p ‐tau217 positive and suggests that some individuals may show tau PET positivity first, while others may exhibit plasma p ‐tau217 positivity first. The distinct cognitive profiles of this groups suggest potential clinical relevance, warranting further investigation.