Acetylcholine receptors in dementia and mild cognitive impairment

To clarify whether changes in the cholinergic transmission occur early in the course of Alzheimer's disease (AD), we carried out positron emission tomography (PET) with the radioligand 2-[(18)F]F-A-85380, which is supposed to be specific for alpha4beta2 nicotinic acetylcholine receptors (nAChRs).

We included patients with moderate to severe AD and patients with amnestic mild cognitive impairment (MCI), presumed to present preclinical AD.

Both patients with AD and MCI showed significant reductions in alpha4beta2 nAChRs in brain regions typically affected by AD pathology. These findings indicate that a reduction in alpha4beta2 nAChRs occurs during early symptomatic stages of AD. The alpha4beta2 nAChR availability in these regions correlated with the severity of cognitive impairment, indicating a stage sensitivity of the alpha4beta2 nAChR status.

Together, our results provide evidence for the potential of 2-[(18)]F-A-85380 nAChR PET in the diagnosis of patients at risk for AD. Because of the extraordinary long acquisition time with 2-[(18)F]F-A-85380, we developed the new alpha4beta2 nAChR-specific radioligands (+)- and (-)-[(18)F]norchloro-fluoro-homoepibatidine (NCFHEB) and evaluated them preclinically. (-)-[(18)F]NCFHEB shows twofold higher brain uptake and significantly shorter acquisition times. Therefore, (-)-[(18)F]NCFHEB should be a suitable radioligand for larger clinical investigations.