PET Imaging Estimates of Regional Acetylcholine Concentration Variation in Living Human Brain

Acetylcholine (ACh) has distinct functional roles in striatum compared with cortex, and imbalance between these systems may contribute to neuropsychiatric disease. Preclinical studies indicate markedly higher ACh concentrations in the striatum. The goal of this work was to leverage positron emission tomography (PET) imaging estimates of drug occupancy at cholinergic receptors to explore ACh variation across the human brain, because these measures can be influenced by competition with endogenous neurotransmitter. PET scans were analyzed from healthy human volunteers (n = 4) and nonhuman primates (n = 2) scanned with the M1-selective radiotracer [C-11]LSN3172176 in the presence of muscarinic antagonist scopolamine, and human volunteers (n= 10) scanned with the alpha(4)beta(2) * nicotinic ligand (-)-[F-18]flubatine during nicotine challenge. In all cases, occupancy estimates within striatal regions were consistently lower (M1/scopolamine human scans, 31 +/- 3.4% occupancy in striatum, 43 +/- 2.9% in extrastriatal regions, p = 0.0094; nonhuman primate scans, 42 +/- 26% vs. 69 +/- 28%, p < 0.0001; alpha(4)beta(2) */nicotine scans, 67 +/- 15% vs. 74 +/- 16%, p = 0.0065), indicating higher striatal ACh concentration. Subject-level measures of these concentration differences were estimated, and whole-brain images of regional ACh concentration gradients were generated. These results constitute the first in vivo estimates of regional variation in ACh concentration in the living brain and offer a novel experimental method to assess potential ACh imbalances in clinical populations.

Automated summary

The study aimed to explore the variation of acetylcholine (Ach) across the human brain using positron emission tomography (PET) imaging estimates of drug occupancy at cholinergic receptors. Results showed consistently lower occupancy estimates within striatal regions, indicating higher ACh concentration, and provided the first in vivo estimates of regional variation in ACh concentration in the living brain.