Biological Factors Influencing [18F]MK6240 and [18F]FTP Correlation in Target Regions.

Background: The association between [F]Flortaucipir (FTP) and [F]MK6240, two commonly used tau‐PET tracers in Alzheimer’s disease (AD), varies due to distinct binding properties and off‐target signal regions. Our study aims to elucidate the biological factors influencing this association and evaluate the applicability of a common equation across different on‐target regions.

Method: 113 individuals from the HEAD dataset (11 young, 58 cognitively unimpaired elderly, and 44 cognitively impaired) underwent [F]MK6240, [F]FTP and Aβ‐PET scans.

Comparison of tau‐PET tracers for in vivo Braak staging: the HEAD Study.

Background: Tau‐PET tracers allow for in vivo Braak staging of individuals in the Alzheimer’s disease (AD) continuum. The impact of tracers’ characteristics for Braak staging using tau‐PET remains unclear. Therefore, we performed a head‐to‐head comparison of Braak staging using first‐ and second‐generation tau‐PET tracers.

The Knight Alzheimer Research Imaging dataset: a comprehensive multimodal resource for exploring aging, preclinical, and symptomatic Alzheimer disease pathology.

Background: The Knight Alzheimer Research Imaging (KARI) dataset, a compilation of data from projects conducted at Washington University in St. Louis, represents a comprehensive effort to advance our understanding of Alzheimer disease (AD) through multimodal data collection. The overarching goal is to characterize normal aging and disease progression to contribute insights into the biological changes preceding AD symptom onset.

Connectivity as a universal predictor of tau spreading in typical and atypical Alzheimer’s disease.

Background: There is a strong link between tau and progression of Alzheimer’s disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity‐based tau spreading model in AD variants with distinct tau deposition patterns is crucial.

CSF proteomics related to the neurovascular unit are associated with white matter hyperintensity volumes and cerebral microhemorrhages in autosomal dominant Alzheimer disease.

Background: Autosomal dominant Alzheimer disease (ADAD) is characterized by genetic mutations affecting the beta‐amyloid (Aβ) pathway. However, vascular and immune factors play important roles which are not completely understood. Understanding the function of the neurovascular unit (NVU) comprised of neurons, glial cells, and vasculature, at different disease stages appears ideal to developing and evaluating therapeutics.

Relationship Between 18F‐AV‐1451 Binding in Human Brain and Tissue Alterations Defined by Quantitative Gradient Recalled Echo (qGRE) MRI Measurements.

Background: The 18F‐AV‐1451 radioligand enables in‐vivo identification of tau neurofibrillary tangles that are considered as biomarkers of neurodegeneration in Alzheimer Disease (AD). However, off‐target radioligand binding is also observed in basal ganglia, known as an iron‐rich region. Hence, it is important to distinguish between radioligand‐identified tissue neurodegeneration and iron‐related radioligand binding effects.

Comparison of [F]MK6240 and [F]Flortaucipir standardized uptake values (SUVs): the HEAD study.

Background: Differences between on‐ and off‐target retention characteristics between [F]MK6240 and [F]Flortaucipir (FTP) complicate the harmonization across tracers. Our objective here was to separate the impact of the reference region by evaluating correlations between [F]MK6240 (MK) and [F]FTP standard uptake values (SUVs).

Method: Participants (Figure 1, n=90) received an amyloid‐β (Aβ) PET scan ([C]PIB or [F]NAV4694) and two tau‐PET scans: [F]MK (90‐110 minutes post‐injection) and [F]FTP (80‐100 minutes post‐injection).

Imaging the impact of early and late life risk factors on the brain: a comparison.

Background: Alzheimer disease (AD) is a chronic progressive neurodegenerative disorder that presents with cognitive dysfunction, memory loss, language difficulties, emotion dysregulation, and the eventual loss of motor function and death. Magnetic resonance imaging (MRI) shows early atrophy in the medial temporal lobes, which then spreads to the posterior temporal lobe, parietal lobe, and finally the frontal lobe with relative sparing of the sensorimotor cortex. Social disadvantage has been shown to have potentially additive impacts on aging trajectories.

Unraveling Alzheimer's Disease Heterogeneity: A Comparative Analysis Using HYDRA and CHIMERA.

Background: Alzheimer's Disease can present with heterogenous neurodegenerative patterns. In order to optimize clinical trials and personalized medicine, the identification and characterization of diverse pathological brain patterns associated with AD have become paramount. Optimal approaches to identify such heterogeneity are unknown.

Association between Default Mode Network Connectivity Compared Between Two Tau Tracers (Flortaucipir vs. MK6240) – HEAD Study.

Background: Default mode network (DMN) resting state connectivity has been correlated with heightened amyloid and tau – hallmarks of Alzheimer's Disease (AD). Tau is postulated to impact a meta‐temporal area including DMN‐associated regions like amygdala, entorhinal cortex, fusiform gyrus, parahippocampus, inferior temporal, and middle temporal gyrus. We recruited individuals with varying cognitive status to undergo resting state connectivity and imaging with two tau tracers (Flortaucipir and MK6240).

Harmonization of amyloid PET radiotracers using ComBat and its influence on detecting treatment effects in a simulated clinical trial.

Background: Differences in amyloid PET radiotracer pharmacokinetics and binding properties lead to discrepancies in amyloid uptake measurements, which may adversely affect the statistical power of clinical trials that utilize multiple tracers to track brain amyloid deposition. To address this, Centiloid was developed for standardizing global amyloid SUVRs across tracers to a common scale. Alternatively, ComBat is a technique for harmonizing batch effects while preserving variations from biologically‐relevant covariates.

Exploring the effects of using multiple different cerebellar reference regions to improve tau‐PET harmonization ‐ The HEAD Study.

Background: Tau‐PET tracers have been used to diagnose and stage Alzheimer’s disease. However, different tau tracers present distinct patterns of binding throughout the brain, challenging the harmonization of their results. We hypothesize that the choice of a reference region can impact the harmonization of the tau‐PET standardized uptake value ratio (SUVR).

Longitudinal multicenter head‐to‐head harmonization of tau‐PET tracers: an overview of the HEAD study cohort.

Background: Standardizing 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.

Evaluating brain age using functional connectivity in autosomal dominant Alzheimer disease.

Background: Brain‐predicted age estimates are used to quantify an individual's brain age compared to a normative trajectory. We have recently shown that brain age from structural MRI is elevated in autosomal dominant Alzheimer disease (ADAD), a unique sample that allows the study of AD progression independently of age‐related confounds. Resting‐state functional connectivity (FC) may capture a biphasic response to sporadic AD, and thus may complement structural measures of brain aging in ADAD.

Exploring a weighted composite score for harmonization of 18F‐MK6240 and 18F‐ Flortaucipir: linearity and correlations with cognitive measures in a head‐to‐head tau PET dataset – The HEAD Study.

Background: Harmonization of the two most commonly used Tau PET tracers, 18F‐Flortaucipir and 18F‐MK6240 has proven to be complex. Unlike the centiloid scale for amyloid tracers, Tau PET SUVRs of the two tracers are not linearly comparable and vary markedly in dynamic range and sensitivity.

Method: Tau PET SUVRs for Braak stage (1‐6) in 18F‐MK6240 and 18F‐Flortaucipir were obtained from the Longitudinal multicenter head‐to‐head harmonization of tau‐PET tracers (HEAD) project.

Brain Volumetric Trajectories in Down Syndrome and Autosomal Dominant Alzheimer Disease.

Background: Alzheimer disease (AD) related cognitive decline occurs at relatively young ages in individuals with Down syndrome (DS, early‐mid 50s) and in those with autosomal dominant mutations (ADAD, 40‐50s). Both groups show similar patterns of amyloid accumulation. We examined if brain volumes are similarly affected by AD pathology in individuals with DS and ADAD.

Universal tau PET scale (Uniτ) – The HEAD Study.

Background: The HEAD study aims to collect a large dataset of multiple tau‐PET tracers to provide robust anchor values for tau‐PET harmonization. Here, we tested the hypothesis that anchoring two tau tracer uptake values using head‐to‐head measurements has the potential to generate an accurate universal tau‐PET scale, named Uniτ(tau).

Methods: We assessed 200 individuals across the aging and AD spectrum (Training: HEAD data freeze 2.

A highly accurate blood test for Alzheimer’s disease pathology has performance equivalent or superior to clinically used CSF tests.

Background: With the emergence of Alzheimer's disease (AD) disease‐modifying therapies, identifying patients who could benefit from these treatments becomes critical. We evaluated whether a precise blood test could perform as well as established cerebrospinal fluid (CSF) tests in detecting amyloid‐β (Aβ) plaques and tau tangles.

Method: Plasma %p‐tau217 (ratio of phosporylated‐tau217 to non‐phosphorylated mid‐region tau) was analyzed by mass spectrometry in the Swedish BioFINDER‐2 cohort (n=1,422) and the US Knight ADRC cohort (n=337, Table 1).

Clinical use of tau PET in Aβ PET positive individuals: a case series.

Background: Identifying individuals’ levels of tau PET pathology could prove to be beneficial in clinical settings, given that emerging therapies aimed reducing Aβ seem to be most effective in these individuals. Here, we present the cases of four patients who visited the memory clinic at the University of Pittsburgh Medical Center between June and December 2023 and underwent both Aβ and tau‐PET scans.

Method: These individuals had standard clinical and cognitive outcomes, typical blood tests order in patients with memory impairment, MRI, and, as part of the HEAD study, PET PIB Aβ and two tau PET tracers (MK6240 and Flortaucipir).

Direct comparisons of the associations between the tau PET tracers [F]Flortaucipir and [F]MK6240 with tests of general cognitive performance ‐ The HEAD study.

Background: Tau PET tracers are employed to measure the accumulation of tau in vivo in the brain. Each tau tracer possesses unique characteristics, including binding affinity, sensitivity, and specificity to tau aggregates. This study leverages the HEAD study dataset, which is currently performing baseline tau PET tracers and conducting multiple clinical and cognitive assessments.

Early Alterations of White Matter Neuroinflammation in Autosomal Dominant Alzheimer's Disease.

Background: Autosomal Dominant Alzheimer's Disease (ADAD) is a rare and early‐onset form of Alzheimer's disease with a familial pattern of inheritance. While the pathological features of ADAD, such as amyloid plaques and neurofibrillary tangles, have been extensively studied, the involvement of white matter (WM) neuroinflammation is not well‐explored. In sporadic AD, the hindered ratio (HR) derived from diffusion basis spectrum imaging (DBSI) has been used to study neuroinflammation in WM.

Alzheimer's disease staging with [F]MK6240 and [F]Flortaucipir ‐ the HEAD study.

Background: Utilizing 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 [F]MK6240 or [F]Flortaucipir in individuals participating in a head‐to‐head study of tau PET tracers.

Impact of anchoring cutoff point of tau positivity on CU young or older adults using Flortaucipir and MK‐6240 – Head Study.

Background: Tau PET provides continuous measurements of tau tangle pathology in the human brain. However, establishing cutoffs is crucial for selecting individuals for treatment in clinical trials or practice. In the absence of postmortem data, PET cutoffs must be established using statistical methods based on what is considered normal tracer uptake.

Creating Universal Tau PET Scale (Uniτ) Parametric Images – The HEAD Study.

Background: The HEAD study focuses on collecting an extensive dataset from various tau‐PET tracers, aiming to establish robust anchor values, which are essential for harmonizing tau‐PET measurements. Here, we aim to showcase the capability of converting 3D tau‐PET images into a common scale using the Universal Tau‐PET Scale, Uniτ (tau), and to use these 3D images to subsequently obtain ROIs as needed.

Methods: We assessed 185 individuals across the aging and AD spectrum from the HEAD study, with [F]Flortaucipir and [F]MK‐6240 tau‐PET tracers.

A multiple cohort study exploring the influence of partial volume correction on age and sex effects on tau PET imaging.

Background: Tau PET imaging has become pivotal in understanding the pathophysiological processes underlying Alzheimer disease (AD). In individuals without amyloid pathology, there is evidence tau levels are elevated with increase age and that females show greater levels of binding. An unknown question is how consistent these effects are, and whether they are susceptible to methodological choices impacting PET quantification.