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.

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.

ImportanceAmyloid positron emission tomography (PET) allows the direct assessment of amyloid deposition, one of the main hallmarks of Alzheimer disease. However, this technique is currently not widely reimbursed because of the lack of appropriately designed studies demonstrating its clinical effect.ObjectiveTo assess the clinical effect of amyloid PET in memory clinic patients.Design, Setting, and ParticipantsThe AMYPAD-DPMS is a prospective randomized clinical trial in 8 European memory clinics. Participants were allocated (using a minimization method) to 3 study groups based on the performance of amyloid PET: arm 1, early in the diagnostic workup (within 1 month); arm 2, late in the diagnostic workup (after a mean [SD] 8 [2] months); or arm 3, if and when the managing physician chose. Participants were patients with subjective cognitive decline plus (SCD+; SCD plus clinical features increasing the likelihood of preclinical Alzheimer disease), mild cognitive impairment (MCI), or dementia; they were assessed at baseline and after 3 months. Recruitment took place between April 16, 2018, and October 30, 2020. Data analysis was performed from July 2022 to January 2023.InterventionAmyloid PET.Main Outcome and MeasureThe main outcome was the difference between arm 1 and arm 2 in the proportion of participants receiving an etiological diagnosis with a very high confidence (ie, ≥90% on a 50%-100% visual numeric scale) after 3 months.ResultsA total of 844 participants were screened, and 840 were enrolled (291 in arm 1, 271 in arm 2, 278 in arm 3). Baseline and 3-month visit data were available for 272 participants in arm 1 and 260 in arm 2 (median [IQR] age: 71 [65-77] and 71 [65-77] years; 150/272 male [55%] and 135/260 male [52%]; 122/272 female [45%] and 125/260 female [48%]; median [IQR] education: 12 [10-15] and 13 [10-16] years, respectively). After 3 months, 109 of 272 participants (40%) in arm 1 had a diagnosis with very high confidence vs 30 of 260 (11%) in arm 2 (P < .001). This was consistent across cognitive stages (SCD+: 25/84 [30%] vs 5/78 [6%]; P < .001; MCI: 45/108 [42%] vs 9/102 [9%]; P < .001; dementia: 39/80 [49%] vs 16/80 [20%]; P < .001).Conclusion and RelevanceIn this study, early amyloid PET allowed memory clinic patients to receive an etiological diagnosis with very high confidence after only 3 months compared with patients who had not undergone amyloid PET. These findings support the implementation of amyloid PET early in the diagnostic workup of memory clinic patients.Trial RegistrationEudraCT Number: 2017-002527-21

BackgroundPositron emission tomography (PET) provides in vivo quantification of amyloid‐β (Aβ) pathology. The most common method for assessing PET is standardized uptake value ratio (SUVr), which can be affected by physiological and technical factors. Novel, data‐driven metrics have been developed to address these sources of variability. We evaluate cross‐sectional and longitudinal performance of four data driven metrics.MethodThree cohorts were used for evaluation: Insight 46, a neuroimaging sub‐study of the 1946 British birth cohort, Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing, and a test‐retest flutemetamol dataset (Table 1). Data from participants were included if good quality volumetric MRI and amyloid PET, using florbetapir (Insight 46) or flutemetamol (AIBL and test‐retest data), was available. No partial volume correction was applied. Four data driven metrics were extracted: the Centiloid derived from non‐negative matrix factorisation (CLNMF), the Aβ PET pathology accumulation index (Aβ‐index), amyloid load (Aβ‐load), and amyloid pattern similarity score (AMPSS). These data‐driven metrics were compared to a global composite SUVr, with either a pons (flutametamol) or cerebellar grey matter (florbetapir) reference region, and a Centiloid (CL) score. They were evaluated by measures of repeatability in test‐retest data, associations with non‐displaceable binding potential (BPND, computed from Logan graphical analysis), sample size estimates to detect a 20% slowing in Aβ accumulation with 95% significance and 80% power, and accuracy in predicting the second follow‐up visit.ResultAll metrics show good to excellent reliability. The repeatability is highly influenced by the amyloid burden, the range, and the offset of each metric. (Table 1) All metrics are strongly correlated to the BPND (R 2: 0.8 to 0.94), with SUVr and CL explaining more variance in BPND than the data‐driven metrics. (Figure) Sample size estimates were lowest in CL and CLNMF compared to the SUVr. (Table 2) The Aβ‐index had the best predictive power over ∼3 years while the other metrics were comparable. (Table 3)ConclusionNovel data driven metrics provide comparable performance in terms of accuracy and performance to more established quantification methods of Aβ PET tracer uptake, but with additional benefits, such as being MRI‐free, reference region independent, or more robust to change in tracer.

Background Determining Aβ‐PET status is crucial for Alzheimer’s disease trials. Standard uptake value ratio (SUVR) using a reference region is a common semi‐quantitative technique. Sex differences in regional blood flow and white matter (WM) could impact SUVR differentially depending on the reference region. It is important to understand how methodological factors can influence SUVR derived Aβ status. Method Individuals from Insight 46 (1946 British birth cohort) underwent PET/MR scanning with [18F]florbetapir (N = 425; mean age (SD) 70.6 (0.7); 49% female). Regions derived from T1‐weighted MRI with geodesic information flows (GIF) were resampled to PET space. SUVR was calculated (50‐60 mins post‐injection) using a cortical composite target normalised to whole cerebellum (WC) or eroded WM, with/without partial volume correction (PVC). Additionally, SUV was calculated normalising to injected dose and weight. Distribution volume ratio (DVR) from Logan graphical analysis (cerebellar grey matter reference) was calculated for N = 391 (51% female). Linear regression was used to investigate differences in Aβ‐PET measures by sex adjusting for region volumes. Aβ status was defined with Gaussian‐mixture modelling. Sex differences in SUVR and DVR were investigated in individuals rated concordantly Aβ‐ with all four SUVR methods. SUVR Aβ status discordance was examined in relation to sex and APOE e4 genotype. Result Females had significantly higher SUVR with a WC reference; and there were no sex differences with a WM reference or with dynamic DVR (Figure 1). Males had higher SUV in all regions and the difference was greater in the WC compared to WM (Figure 2). PVC decreased the influence of volume on SUV in the WC but not WM. 87% of individuals were classified concordantly Aβ+/‐ on SUVR measures with equal proportion of males/females. More females were Aβ+ only with WC reference with PVC, whereas more males were Aβ‐ only on WC without PVC (Figure 3).

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