PET/CT/MRI in Clinical Trials of Alzheimer’s Disease

Issue title: Therapeutic Trials in Alzheimer’s Disease: Where Are We Now?

Guest editors: Paula I. Moreira, Jesus Avila, Daniela Galimberti, Miguel A. Pappolla, Germán Plascencia-Villa, Aaron A. Sorensen, Xiongwei Zhu and George Perry

Article type: Review Article

Authors: Høilund-Carlsen, Poul F.^{a; b; *} | Alavi, Abass^c | Barrio, Jorge R.^d

Affiliations: [a] Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark | [b] Department of Clinical Research, University of Southern Denmark, Odense, Denmark | [c] Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA | [d] Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, CA, USA

Correspondence: [*] Correspondence to: Poul F. Høilund-Carlsen, MD, DMSc, Prof (Hon), Professor of Clinical Physiology, Department of Nuclear Medicine, Odense University Hospital, 5000 Odense C, Denmark. E-mail: pfhc@rsyd.dk; ORCID: 0000-0001-7420-2367.

Abstract: With the advent of PET imaging in 1976, 2-deoxy-2-[18F]fluoro-D-glucose (FDG)-PET became the preferred method for in vivo investigation of cerebral processes, including regional hypometabolism in Alzheimer’s disease. With the emergence of amyloid-PET tracers, [11C]Pittsburgh Compound-B in 2004 and later [18F]florbetapir, [18F]florbetaben, and [18F]flumetamol, amyloid-PET has replaced FDG-PET in Alzheimer’s disease anti-amyloid clinical trial treatments to ensure “amyloid positivity” as an entry criterion, and to measure treatment-related decline in cerebral amyloid deposits. MRI has been used to rule out other brain diseases and screen for ‘amyloid-related imaging abnormalities’ (ARIAs) of two kinds, ARIA-E and ARIA-H, characterized by edema and micro-hemorrhage, respectively, and, to a lesser extent, to measure changes in cerebral volumes. While early immunotherapy trials of Alzheimer’s disease showed no clinical effects, newer monoclonal antibody trials reported decreases of 27% to 85% in the cerebral amyloid-PET signal, interpreted by the Food and Drug Administration as amyloid removal expected to result in a reduction in clinical decline. However, due to the lack of diagnostic specificity of amyloid-PET tracers, amyloid positivity cannot prevent the inclusion of non-Alzheimer’s patients and even healthy subjects in these clinical trials. Moreover, the “decreasing amyloid accumulation” assessed by amyloid-PET imaging has questionable quantitative value in the presence of treatment-related brain damage (ARIAs). Therefore, future Alzheimer’s clinical trials should disregard amyloid-PET imaging and focus instead on assessment of regional brain function by FDG-PET and MRI monitoring of ARIAs and brain volume loss in all trial patients.

Keywords: Alzheimer’s disease, amyloid-PET, amyloid-related imaging abnormalities, FDG-PET, cerebral volume, immunotherapy, MRI

DOI: 10.3233/JAD-240206

Journal: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S579-S601, 2024