Quantification of amyloid PET for future clinical use: a state-of-the-art review

Abstract

Amyloid-β (Aβ) pathology is one of the earliest detectable brain changes in Alzheimer’s disease (AD) pathogenesis. The overall load and spatial distribution of brain Aβ can be determined in vivo using positron emission tomography (PET), for which three fluorine-18 labelled radiotracers have been approved for clinical use. In clinical practice, trained readers will categorise scans as either Aβ positive or negative, based on visual inspection. Diagnostic decisions are often based on these reads and patient selection for clinical trials is increasingly guided by amyloid status. However, tracer deposition in the grey matter as a function of amyloid load is an inherently continuous process, which is not sufficiently appreciated through binary cut-offs alone. State-of-the-art methods for amyloid PET quantification can generate tracer-independent measures of Aβ burden. Recent research has shown the ability of these quantitative measures to highlight pathological changes at the earliest stages of the AD continuum and generate more sensitive thresholds, as well as improving diagnostic confidence around established binary cut-offs. With the recent FDA approval of aducanumab and more candidate drugs on the horizon, early identification of amyloid burden using quantitative measures is critical for enrolling appropriate subjects to help establish the optimal window for therapeutic intervention and secondary prevention. In addition, quantitative amyloid measurements are used for treatment response monitoring in clinical trials. In clinical settings, large multi-centre studies have shown that amyloid PET results change both diagnosis and patient management and that quantification can accurately predict rates of cognitive decline. Whether these changes in management reflect an improvement in clinical outcomes is yet to be determined and further validation work is required to establish the utility of quantification for supporting treatment endpoint decisions. In this state-of-the-art review, several tools and measures available for amyloid PET quantification are summarised and discussed. Use of these methods is growing both clinically and in the research domain. Concurrently, there is a duty of care to the wider dementia community to increase visibility and understanding of these methods.

Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease

“…This is also in line with the findings that showed that 26 Centiloids is an optimal cut-off in agreement with visual reads, which has been validated against CERAD pathology 23 , and with the 35.7 Centiloid cut-off for established Aβ abnormalities in PET described by Bullic et al 22 . Moreover, the range from 12 Centiloids to 30 Centiloids has been proposed to reflect the 'gray zone' of Aβ deposition 24 .…”

The amyloid imaging for the prevention of Alzheimer's disease consortium: A European collaboration with global impact

“…Our most recent focus is on the implementation of (Centiloid) quantification into the clinical routine, to not only support visual assessment of challenging cases, but also prepare the field for a potential necessity which could arise from the possible approval of disease-modifying therapies in the near future. To this end, academic and EFPIA partners collaborated on a comprehensive review regarding possible quantification approaches for the clinical setting ( 34 ) as well as engaging with regulatory bodies to share the in-depth knowledge that AMYPAD has gained using these methods during the course of the project. In this context, the AMYPAD team has investigated the robustness of the Centiloid quantification method ( 35 ), its feasibility in detecting early Aβ pathology ( 36 ), and its ability to detect changes over time.…”

Approaches for neutrophil imaging: an important step in personalized medicine

“…Several studies have reported that combining NLR metrics with positron emission tomography (PET)/computed tomography (CT) metabolic parameters can more clearly predict tumor survival time and biology [ 9 , 10 ]. PET is a pivotal molecular imaging tool for cancer diagnosis and imaging due to its relatively low spatial resolution and high sensitivity [ 11 ]. 18 F-fluorodeoxyglucose PET/CT ( 18 F-FDG PET/CT) can provide morphological and functional information for cancer management and is important for cancer diagnosis, staging, treatment planning, treatment response, and recurrence [ 12 ].…”