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Amyloid-PET quantification through the tracer-independent Centiloid (CL) scale has emerged as an essential tool for the accurate measurement of amyloid-β (Aβ) pathology in Alzheimer's disease (AD) patients. The AMYPAD consortium set out to integrate existing literature and recent work from the consortium to provide clinical context-of-use recommendations for the CL scale. Compared to histopathology, visual reads, and cerebrospinal fluid, CL quantification accurately reflects the amount of AD pathology. With high certainty, a CL value below 10 excludes the presence of Aβ pathology, while a value above 30 corresponds well with pathological amounts. Values falling in between these two cutoffs ("intermediate range") are related to an increased risk of disease progression. Together, CL quantification is a valuable adjunct to visual assessments of amyloid-PET images. An abnormal amyloid biomarker assessment is a key criterion to determine eligibility for anti-amyloid disease-modifying therapies, and amyloid-PET quantification can add further value by precisely monitoring amyloid clearance, and hence guiding patient management decisions. HIGHLIGHTS: Centiloid (CL) quantification robustly reflects of the amount of Aβ pathology. CL < 10/CL > 30 reflects Aβ-negativity/positivity thresholds with high certainty. CL quantification is a valuable adjunct to visual assessments of amyloid-PET. CL quantification can support trial design and treatment management. CL quantification could support the identification of early or emerging Aβ pathology., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Assessing the potential sources of bias and variability of the Centiloid (CL) scale is fundamental for its appropriate clinical application., Methods: We included 533 participants from AMYloid imaging to Prevent Alzheimer's Disease (AMYPAD DPMS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts. Thirty-two CL pipelines were created using different combinations of reference region (RR), RR and target types, and quantification spaces. Generalized estimating equations stratified by amyloid positivity were used to assess the impact of the quantification pipeline, radiotracer, age, brain atrophy, and harmonization status on CL., Results: RR selection and RR type impact CL the most, particularly in amyloid-negative individuals. The standard CL pipeline with the whole cerebellum as RR is robust against brain atrophy and differences in image resolution, with 95% confidence intervals below ± 3.95 CL for amyloid beta positivity cutoffs (CL < 24)., Discussion: The standard CL pipeline is recommended for most scenarios. Confidence intervals should be considered when operationalizing CL cutoffs in clinical and research settings., Highlights: We developed a framework for evaluating Centiloid (CL) variability to different factors. Reference region selection and delineation had the highest impact on CL values. Whole cerebellum (WCB) and whole cerebellum plus brainstem (WCB+BSTM) as reference regions yielded consistent results across tracers. The standard CL pipeline is robust against atrophy and image resolution variation. Estimated within- and between-pipeline variability (95% confidence interval) in absolute CL units., (© None The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid-β (Aβ) accumulation based on Centiloids (CL) in pre-dementia populations., Methods: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease-Prognostic and Natural History Study (AMYPAD-PNHS) and Insight46 who underwent [ 18 F]flutemetamol, [ 18 F]florbetaben or [ 18 F]florbetapir amyloid-PET were included. A normative strategy was used to define reliable accumulation by estimating the 95 th percentile of longitudinal measurements in sub-populations (N PNHS  = 101/750, N Insight46  = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision-recall analyses. Accumulation rates were examined using linear mixed-effect models., Results: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aβ-accumulators. Rates of amyloid accumulation were tracer-independent, lower for APOE ε4 non-carriers, and for subjects with higher levels of education., Discussion: Our results support a 12-20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Deposition of amyloid and tau pathology can be quantified in vivo using positron emission tomography (PET). Accurate longitudinal measurements of accumulation from these images are critical for characterizing the start and spread of the disease. However, these measurements are challenging; precision and accuracy can be affected substantially by various sources of errors and variability. This review, supported by a systematic search of the literature, summarizes the current design and methodologies of longitudinal PET studies. Intrinsic, biological causes of variability of the Alzheimer's disease (AD) protein load over time are then detailed. Technical factors contributing to longitudinal PET measurement uncertainty are highlighted, followed by suggestions for mitigating these factors, including possible techniques that leverage shared information between serial scans. Controlling for intrinsic variability and reducing measurement uncertainty in longitudinal PET pipelines will provide more accurate and precise markers of disease evolution, improve clinical trial design, and aid therapy response monitoring., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: AMYPAD Diagnostic and Patient Management Study (DPMS) aims to investigate the clinical utility and cost-effectiveness of amyloid-PET in Europe. Here we present participants' baseline features and discuss the representativeness of the cohort., Methods: Participants with subjective cognitive decline plus (SCD+), mild cognitive impairment (MCI), or dementia were recruited in eight European memory clinics from April 16, 2018, to October 30, 2020, and randomized into three arms: ARM1, early amyloid-PET; ARM2, late amyloid-PET; and ARM3, free-choice., Results: A total of 840 participants (244 SCD+, 341 MCI, and 255 dementia) were enrolled. Sociodemographic/clinical features did not differ significantly among recruiting memory clinics or with previously reported cohorts. The randomization assigned 35% of participants to ARM1, 32% to ARM2, and 33% to ARM3; cognitive stages were distributed equally across the arms., Discussion: The features of AMYPAD-DPMS participants are as expected for a memory clinic population. This ensures the generalizability of future study results., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: The association between cerebral amyloid-β accumulation and downstream CSF biomarkers is not fully understood, particularly in asymptomatic stages., Methods: In 318 cognitively unimpaired participants, we assessed the association between amyloid-β PET (Centiloid), and cerebrospinal fluid (CSF) biomarkers of several pathophysiological pathways. Interactions by Alzheimer's disease risk factors (age, sex and APOE-ε4), and the mediation effect of tau and neurodegeneration were also investigated., Results: Centiloids were positively associated with CSF biomarkers of tau pathology (p-tau), neurodegeneration (t-tau, NfL), synaptic dysfunction (neurogranin) and neuroinflammation (YKL-40, GFAP, sTREM2), presenting interactions with age (p-tau, t-tau, neurogranin) and sex (sTREM2, NfL). Most of these associations were mediated by p-tau, except for NfL. The interaction between sex and amyloid-β on sTREM2 and NfL was also tau-independent., Discussion: Early amyloid-β accumulation has a tau-independent effect on neurodegeneration and a tau-dependent effect on neuroinflammation. Besides, sex has a modifier effect on these associations independent of tau., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: The Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) Prognostic and Natural History Study (PNHS) aims at understanding the role of amyloid imaging in the earliest stages of Alzheimer's disease (AD). AMYPAD PNHS adds (semi-)quantitative amyloid PET imaging to several European parent cohorts (PCs) to predict AD-related progression as well as address methodological challenges in amyloid PET., Methods: AMYPAD PNHS is an open-label, prospective, multi-center, cohort study recruiting from multiple PCs. Around 2000 participants will undergo baseline amyloid positron emission tomography (PET), half of whom will be invited for a follow-up PET 12 at least 12 months later., Results: Primary include several amyloid PET measurements (Centiloid, SUVr, BP ND , R 1 ), and secondary are their changes from baseline, relationship to other amyloid markers (cerebrospinal fluid and visual assessment), and predictive value of AD-related decline., Expected Impact: Determining the role of amyloid PET for the understanding of this complex disease and potentially improving secondary prevention trials., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Introduction: Reimbursement of amyloid-positron emission tomography (PET) is lagging due to the lack of definitive evidence on its clinical utility and cost-effectiveness. The Amyloid Imaging to Prevent Alzheimer's Disease-Diagnostic and Patient Management Study (AMYPAD-DPMS) is designed to fill this gap., Methods: AMYPAD-DPMS is a phase 4, multicenter, prospective, randomized controlled study. Nine hundred patients with subjective cognitive decline plus, mild cognitive impairment, and dementia possibly due to Alzheimer's disease will be randomized to ARM1, amyloid-PET performed early in the diagnostic workup; ARM2, amyloid-PET performed after 8 months; and ARM3, amyloid-PET performed whenever the physician chooses to do so., Endpoints: The primary endpoint is the difference between ARM1 and ARM2 in the proportion of patients receiving a very-high-confidence etiologic diagnosis after 3 months. Secondary endpoints address diagnosis and diagnostic confidence, diagnostic/therapeutic management, health economics and patient-related outcomes, and methods for image quantitation., Expected Impacts: AMYPAD-DPMS will supply physicians and health care payers with real-world data to plan management decisions., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)