Comparison of Monoamine Oxidase-A, Aβ Plaques, Tau, and Translocator Protein Levels in Postmortem Human Alzheimer’s Disease Brain

Abstract

Increased monoamine oxidase-A (MAO-A) activity in Alzheimer’s disease (AD) may be detrimental to the point of neurodegeneration. To assess MAO-A activity in AD, we compared four biomarkers, Aβ plaques, tau, translocator protein (TSPO), and MAO-A in postmortem AD. Radiotracers were [18F]FAZIN3 for MAO-A, [18F]flotaza and [125I]IBETA for Aβ plaques, [124/125I]IPPI for tau, and [18F]FEPPA for TSPO imaging. Brain sections of the anterior cingulate (AC; gray matter GM) and corpus callosum (CC; white matter WM) from cognitively normal control (CN, n = 6) and AD (n = 6) subjects were imaged using autoradiography and immunostaining. Using competition with clorgyline and (R)-deprenyl, the binding of [18F]FAZIN3 was confirmed to be selective to MAO-A levels in the AD brain sections. Increases in MAO-A, Aβ plaque, tau, and TSPO activity were found in the AD brains compared to the control brains. The [18F]FAZIN3 ratio in AD GM versus CN GM was 2.80, suggesting a 180% increase in MAO-A activity. Using GM-to-WM ratios of AD versus CN, a >50% increase in MAO-A activity was observed (AD/CN = 1.58). Linear positive correlations of [18F]FAZIN3 with [18F]flotaza, [125I]IBETA, and [125I]IPPI were measured and suggested an increase in MAO-A activity with increases in Aβ plaques and tau activity. Our results support the finding that MAO-A activity is elevated in the anterior cingulate cortex in AD and thus may provide a new biomarker for AD in this brain region.

[125I]IPC-Lecanemab: Synthesis and Evaluation of Aβ-Plaque-Binding Antibody and Comparison with Small-Molecule [18F]Flotaza and [125I]IBETA in Postmortem Human Alzheimer’s Disease

“…Iodine-124 is a long-half-life PET radioisotope that has been used for imaging various CNS targets [26]. We have successfully radiolabeled small molecules with iodine-124 for imaging Aβ plaques [15,28].…”

“…Based on these values, the Braak scores of the CN subjects were I-II, and those of the AD subjects were V-VI. Further details of these subjects have been previously reported [26].…”

Glutamate’s Effects on the N-Methyl-D-Aspartate (NMDA) Receptor Ion Channel in Alzheimer’s Disease Brain: Challenges for PET Radiotracer Development for Imaging the NMDA Ion Channel

“…Although an NMDA ion channel blocker, memantine, is used therapeutically in advanced AD [ 20 , 36 , 57 ], our findings suggest that the diagnostic and therapeutic targeting of the ion channel, glutamate site and glycine site may be appropriate in further refining and complementing the diagnosis and treatment of mild to severe AD [ 58 , 59 ]. Radiolabeling approaches with carbon-11, fluorine-18 and iodine-123/124 could be pursued to demonstrate their feasibility.…”

[125I]INFT: Synthesis and Evaluation of a New Imaging Agent for Tau Protein in Post-Mortem Human Alzheimer’s Disease Brain

“…Both [ 125 I]INFT and [ 125 I]IPPI provide reasonable GM/WM ratios in AD postmortem brains, although ratios with [ 125 I]IPPI are higher [14,15]. The availability of radioiodinated Tau imaging agents will enable in vitro evaluation of drugs [23,24].…”