Determining Amyloid-β Positivity Using ¹⁸F-AZD4694 PET Imaging

Area of Science:

• Neurology
• Nuclear Medicine
• Biomarkers

Background:

• Amyloid-β plaque deposition is a key pathological marker of Alzheimer's disease (AD), detectable years before symptom onset.
• Accurate quantification of amyloid-β burden is crucial for AD diagnosis, clinical management, and clinical trial participant selection.
• ¹⁸F-AZD4694 is a high-affinity positron emission tomography (PET) ligand for imaging amyloid-β plaques, but quantitative cutoffs are lacking.

Purpose of the Study:

• To establish a reliable quantitative threshold for determining amyloid-β positivity using ¹⁸F-AZD4694 PET imaging.
• To compare multiple methods for deriving this quantitative cutoff in a diverse cohort.

Main Methods:

• 176 individuals (young adults, cognitively unimpaired elderly, cognitively impaired) underwent ¹⁸F-AZD4694 PET, lumbar puncture, MRI, and APOE genotyping.
• Five methods were used to derive quantitative thresholds: comparison with young-control SUV ratios (SUVRs), ROC curves (clinical and visual classification), Gaussian Mixture Modeling, and comparison with CSF Aβ₄₂/Aβ₄₀ ratio.
• ¹⁸F-AZD4694 SUVRs were normalized to cerebellar gray matter.

Main Results:

• Four methods (ROC curves based on visual/clinical classification, Gaussian Mixture Modeling, CSF Aβ comparison) showed good convergence, yielding optimal cutoffs between 1.51-1.56 SUVR.
• A threshold of 1.55 SUVR demonstrated reliable discriminative accuracy across multiple methods.
• A method based on young controls' means and 2 SDs produced a lower threshold (1.33 SUVR), disagreeing with other methods.

Conclusions:

• Several methods converge to support a quantitative ¹⁸F-AZD4694 PET threshold of 1.55 SUVR for amyloid-β positivity.
• This quantitative cutoff offers reliable discriminative accuracy for amyloid-β plaque detection.
• While visual assessment is current standard, quantitative thresholds can aid in resolving rater disagreements and evaluating borderline cases in clinical practice.