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.

Quantification of tau pathology in the basal forebrain: Associations with age, amyloid, brain structure and cognition.

Background: Tau pathology accumulates early in the basal forebrain (BF) in Alzheimer’s disease (AD). The feasibility of measuring in vivo BF tau is unclear given PET resolution and possible partial volume effects of off‐target signal (OTS) which varies by tracer.

Method: We compared measurements of tau in cognitively unimpaired older adults with either an FTP or MK6240 scan: 93 FTP scans from the Berkeley Aging Cohort Study (BACS), 424 FTP scans from ADNI (N=517 FTP scans; 72.

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).

Adult lifespan neurodegeneration is associated with memory decline independent of amyloid deposition.

Background: Current models of AD posit neurodegeneration and cognitive decline occur downstream in a pathophsyiological cascade initiated by amyloid (Aβ), yet lifespan research suggests the brain regions and cognitive functions impacted most by AD exhibit the steepest, steady decline rates across life. We hypothesised adult lifespan neurodegeneration in AD‐vulnerable brain regions would predict memory decline rates detectable in healthy adults as they age, independent of Aβ.

Method: We combined MRI scans across three large longitudinal cohorts of cognitively healthy adults (age 30‐96 years) to estimate brain change relative to the change expected given a person’s age (2‐14 timepoints; 4125 scans of 1027 individuals; cohorts: LCBC, the Berkeley Aging Cohort Study [BACS]; ADNI [stable cognitively healthy]).

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).

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).

Association of F‐flortaucipir PET with tau neuropathology in AD and other neurodegenerative disorders.

Background: Tau‐PET with [18F]Flortaucipir is FDA‐approved for the identification of AD tau neuropathology in the differential diagnosis of patients with cognitive impairment. However, its performance in detecting early AD stages requires further assessment. We aimed to i) examine the relationships between Flortaucipir‐PET and AD neuropathology, and ii) characterize the relationship between Flortaucipir‐PET and emerging plasma ptau217 biomarker in autopsy cases.

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.

The prevalence of tau‐PET positivity in aging and dementia.

Background: Tau‐PET imaging allows in‐vivo detection of neurofibrillary tangles. One tau‐PET tracer (i.e.

Data‐driven analysis of 10,361 amyloid‐PET scans from the IDEAS study reveals two primary axes of variation.

Background: The variability in the regional distribution of Aβ‐PET signal and its relation to clinical features is debated. We used data‐driven approaches to uncover heterogeneity in cortical Aβ‐PET signal from a large representative sample collected through the IDEAS study.

Methods: We analysed cross‐sectional Aβ‐PET collected from 10,361 patients with MCI or mild dementia scanned in 295 PET facilities using one of the 3 FDA‐approved tracers.

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.

Resting‐state activity across cortical hierarchies provides readiness for memorizing in aging humans.

Background: The neural basis of memory aging remains elusive. The default mode network (DMN) supports memory encoding and retrieval, and its connectivity decreases in aging. Young adults with larger differences in resting‐state functional connectivity (rsFC) between higher‐order DMN and lower‐order sensory/motor network (SMN) have better cognition and memory.

Generalizability of demographic and genetic variable interactions with amyloid driving tau burden in a heterogeneous group of cognitively normal older adults: A multi‐cohort study.

Background: Efforts to increase heterogeneity in cohorts of cognitively normal older adults with Alzheimer’s disease (AD) neuroimaging biomarkers have resulted in large datasets with differing characteristics. It is unclear whether associations between AD biomarkers and key demographic and genetic factors are generalizable across heterogeneous cohorts.

Method: PET and MR scans from cognitively normal older adults aged >55 in the Berkeley Aging Cohort Study (BACS), ADNI, the Health and Aging Brain Study‐Health Disparities (HABS‐HD) and POINTER Imaging were processed using harmonized pipelines.

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.

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.

Reproducibility of Centiloid Values in Real‐World Amyloid PET Data: Comparison of the Imaging Dementia‐Evidence for Amyloid Scanning (IDEAS) to Four Large Research Datasets.

Background: The Centiloid framework was developed to harmonize amyloid‐PET quantification across radiotracers and processing pipelines to facilitate data sharing and merging; it is now widely used across research and clinical trials. As we just completed the quantification of 10,361 amyloid‐PET scans from the largest “real‐world” study of amyloid‐PET (IDEAS) and are about to release the data, we aimed to compare the distribution of IDEAS Centiloid values with other available datasets.

Method: In IDEAS, amyloid scans were acquired across 343 facilities and centrally processed at UCSF using a PET‐only pipeline.

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.

The Berkeley PET Imaging Pipeline: Harmonization of Alzheimer’s disease PET biomarkers across studies.

Background: Collection of neuroimaging data is resource‐intensive. Multi‐site studies have emerged as an effective way to amass large collections of PET scans, but data collected across many sites and scanners require specialized processing approaches. The Berkeley PET Imaging Pipeline (BPIP) and tools for numerical data post‐processing allow us to 1) process multi‐site and multi‐study PET scans using harmonized, largely automated tools and 2) disseminate numerical quantitative data.

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.

The unique contribution of tau pathology in the amygdala to depressive symptoms in cognitively normal older adults.

Background: Although most PET imaging studies have focused on entorhinal cortex as an early site of medial temporal lobe tau accumulation, the amygdala displays substantial tau deposition in cognitively normal individuals. We examined amygdala tau in relation to changes in affective health that often precede Alzheimer’s disease (AD).

Methods: We ran parallel analyses in non‐depressed, cognitively normal older adults from ADNI (60‐91 years) and the Berkeley Aging Cohort Study (BACS, 60‐96 years).

CU PET Aβ and Tau Positive Individuals Show Impairment in MoCA Delayed Recall.

Background: Identification of cognitively unimpaired (CU) individuals who may progress to mild cognitive impairment (MCI), is a pressing issue in the Alzheimer’s disease (AD) field, since therapeutic interventions may be more effective in the absence of cognitive impairment and neurodegeneration. CU individuals positive for amyloid and tau PET are very likely in the AD pathway. In out‐patient cognitive screening, we use rapid and simple tests such as The Montreal Cognitive Assessment (MoCA) ‐ a composite of executive, visuospatial, naming, attention, language, abstraction, delayed recall, and orientation performances.

Voxel‐wise comparison of [F]MK6240 and [F]Flortaucipir for the diagnosis of individuals across the Alzheimer’s disease spectrum – the HEAD study.

Background: In vivo studies using the tau PET tracers have shown high performance for the diagnosis of Alzheimer’s disease dementia and patterns of tracer uptake that resemble those observed in post‐mortem studies. However, tau tracers present distinct patterns of binding that might influence their performance in detecting AD pathology. In a head‐to‐head study, we investigated the performance of [F]MK6240 and [F]Flortaucipir for the diagnosis of AD.

Task fMRI networks predict memory in cognitively unimpaired older adults.

Background: Episodic memory decline is a hallmark feature of aging and Alzheimer’s disease, but the mechanisms underlying its earliest stages are unknown.

Method: Cognitively unimpaired older adults from the Berkeley Aging Cohort Study (n=49) completed an fMRI memory encoding task preceded by 15 minutes rsfMRI and standard neuropsychological testing. Participants viewed object, scene, and object‐in‐scene (pair) stimuli in the scanner for 40 minutes.

Genetic and Sex Associations with Earlier Estimated Onset of Amyloid Positivity from over 4000 Harmonized Positron Emission Tomography Images.

Background: New techniques have been developed to estimate the age when someone converted to amyloid positivity (EAOA) from PET, oftentimes offering information Aβout a participant decades before they joined a research study. EAOA is variable across populations but we do not know the causes for these differences. This study aims to validate associations with EAOA and explore genetic and sex‐based factors with EAOA.