Introduction
Dementia refers to a condition in which organic damage to the brain causes a decline in cognitive function that interferes with daily activities and social functioning. Alzheimer’s disease (AD) is the most common cause of dementia, and the number of people affected is expected to continue to rise.[1–3] This growing disease burden has led to intensive efforts to develop new therapeutic agents for AD in recent years.
The U.S. Food and Drug Administration (FDA) granted accelerated approval to lecanemab (Eisai Co., Ltd. and Biogen Inc.) in January 2023, followed by traditional approval in July of the same year.[4] In Japan, lecanemab was approved following review by the Pharmaceuticals and Medical Devices Agency (PMDA). It became eligible for coverage under Japan’s public health insurance system in December 2023, and an optimal-use guideline was also issued.[5] In addition, Donanemab (Eli Lilly Japan K.K.) also received marketing approval in Japan in 2024.[6]
Lecanemab is a humanized monoclonal antibody that targets amyloid beta (Aβ), which is thought to be involved in the pathophysiology of AD. [7] Conventional AD treatments were symptomatic therapies intended to provide temporary relief from symptoms. These newer agents, however, are disease-modifying therapies that act on the underlying disease process and are expected to slow its progression.
Amyloid positron emission tomography (PET), which visualizes Aβ accumulation in the brain, is widely used in the assessment of AD. Amyloid PET images are assessed both qualitatively, through visual interpretation by physicians, and quantitatively. One widely used quantitative measure is the Centiloid scale. In the phase III clinical trial of lecanemab (CLARITY AD), it was used for a secondary endpoint assessing changes in brain amyloid burden measured by amyloid PET. [8]
This article provides an overview of the Centiloid scale, the acquisition and analysis principles involved in its calculation, and key points to consider for its use in clinical trials.
Challenges in diagnosing Alzheimer’s disease and assessing treatment response
When determining whether a patient is eligible for treatment with an anti-Aβ antibody, it is important to confirm Aβ accumulation in the brain in addition to a clinical diagnosis. Amyloid PET and cerebrospinal fluid (CSF) testing can both be used to confirm Aβ accumulation. Amyloid PET is often used because it allows the distribution of Aβ in the brain to be assessed noninvasively. It also plays an important role in monitoring treatment response and changes in disease pathology over time.
However, when amyloid accumulation is mild, readers may disagree on whether an amyloid PET scan is positive or negative. The Centiloid scale was therefore developed as an objective measure to help address variability in visual assessment.[9]
What is the Centiloid scale?
The Centiloid scale is a standardized quantitative measure of amyloid burden on amyloid PET. It is derived by linear transformation, with 0 defined as the mean [¹¹C]PiB PET value in healthy individuals younger than 45 years with essentially no Aβ deposition, and 100 as the mean value in patients with typical AD. [9] This standardization also makes it easier to compare results obtained using amyloid PET tracers other than ¹¹C-PiB on a common scale.
Centiloid cutoffs may vary depending on the research objective, analysis method, study population, and tracer used. Several thresholds for amyloid positivity have been reported, with some reports suggesting approximately 30 CL as a guide.[10] In clinical trials and clinical diagnosis, it is important to use predefined criteria based on the study protocol or the analysis method being used.
The Centiloid scale allows quantitative results obtained using different PET tracers and analysis methods to be expressed on a common scale, making it easier to compare results across sites and studies. [11] It can also serve as an objective quantitative measure that complements visual assessment.
Calculating Centiloid values through image acquisition
Depending on the analysis method, MRI or CT images may be needed in addition to amyloid PET images to calculate Centiloid values. PET measurements may vary across sites, scanners, and acquisition conditions. In multicenter studies and clinical trials, it is therefore important to establish standardized acquisition conditions in advance and ensure consistent image acquisition at each site.
For example, variation in the interval between tracer administration and the start of imaging can affect the PET values obtained.[12] The image reconstruction settings applied after PET acquisition may also lead to differences in Centiloid values.
Obtaining accurate and reproducible Centiloid values therefore requires standardized acquisition conditions, site training, verification of imaging procedures, and image quality control throughout the study.
Calculating Centiloid values through image analysis
Centiloid analysis generally involves the following steps.
1. Image preprocessing
Noise reduction, summation (averaging) of image frames, image registration, and spatial normalization are performed to prepare image data for comparison across participants.
2. Calculating the standardized uptake value ratio (SUVr)
Standardized volumes of interest (VOIs) are placed on the images to calculate SUVr. The standardized uptake value (SUV) indicates the extent of radiopharmaceutical uptake in tissue, and SUVr is the SUV of the target region divided by that of the reference region. The standard Centiloid method uses the whole cerebellum as the reference region. Standardized VOIs are available through the Centiloid Project of the Global Alzheimer’s Association Interactive Network (GAAIN).[13]
3. Converting SUVr to the Centiloid scale
The calculated SUVr is converted to the Centiloid scale using a tracer-specific calibration equation. Commonly used tracers include ¹⁸F-florbetapir, ¹⁸F-flutemetamol, and ¹⁸F-florbetaben, each with a corresponding conversion equation.[13]
Conclusion
Accurate Centiloid values depend on several factors, including standardized acquisition conditions, image quality control, consistent analysis procedures, and an understanding of the characteristics of the analysis software. Proper management of these factors enables reliable use of the Centiloid scale for quantitative amyloid PET assessment.
With the recent introduction of disease-modifying therapies for Alzheimer’s disease, assessing Aβ accumulation has become increasingly important. Use of the Centiloid scale as an objective measure in clinical trials and clinical research is expected to expand further.
References
- Government Public Relations Online. “The basics of dementia you should know.” [ in Japanese].
https://www.gov-online.go.jp/useful/article/201308/1.html - Takashi Asada. “Dementia prevalence in urban areas and approaches to addressing dementia-related impairments in daily functioning.” [ in Japanese].
H24Report_Part1.pdf - Toshiharu Ninomiya. “Research on future projections of the older population with dementia in Japan.” [ in Japanese].
201405037A0001.pdf - U.S. Food and Drug Administration. July 6, 2023, FDA NEWS RELEASE. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval:
https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval - Ministry of Health, Labour and Welfare. Guidelines for Optimal Use. Lecanemab (genetical recombination). [ in Japanese].
https://www.pmda.go.jp/files/000265885.pdf - Eli Lilly Japan K.K. Press release announcing completion of the Japanese approval application for donanemab, a recombinant monoclonal antibody targeting N3pG Aβ. [ in Japanese].
https://news.lilly.co.jp/PDFFiles/2023/23-28_co.jp.pdf - Eisai Co., Ltd. “Anti-amyloid-β protofibril antibody lecanemab designated for priority review in Japan.” [News release]. [ in Japanese].
https://www.eisai.co.jp/news/2023/news202312.html - van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med. 2023;388(1):9–21.
- Klunk WE, Koeppe RA, Price JC, et al. The Centiloid project: standardizing quantitative amyloid plaque estimation by PET. Alzheimers Dement, 11, 1-15.
- Fleisher AS, Chen K, Liu X, Roontiva A, et al. Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease. Arch Neurol. 2011 Nov;68(11):1404-11.
- Hiroshi Matsuda. Current status of amyloid and tau PET in Alzheimer’s disease. Clinical Nuclear Medicine [Rinsho Kaku Igaku]. 2022; Vol. 55, No. 3. [ in Japanese].
Clinical Nuclear Medicine, Volume 55, Issue 3 (Radiology Clinical Research Group) | Medical Online literature search service - Kenji Ishii. Standardization of PET interpretation and analysis methods for the stratification of dementia disorders. [ in Japanese].
Standardization of PET interpretation and analysis methods for the stratification of dementia disorders.pdf - Global Alzheimer’s Association Interactive Network. Centiloid Project.
Centiloid Project – The Global Alzheimer’s Association Interactive Network
（Published: September 17, 2026）
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