Acetylcholine receptors in dementia and mild cognitive impairment

Purpose 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-[F-18] F-A-85380, which is supposed to be specific for alpha 4 beta 2 nicotinic acetylcholine receptors (nAChRs). Method We included patients with moderate to severe AD and patients with amnestic mild cognitive impairment (MCI), presumed to present preclinical AD. Results Both patients with AD and MCI showed significant reductions in alpha 4 beta 2 nAChRs in brain regions typically affected by AD pathology. These findings indicate that a reduction in alpha 4 beta 2 nAChRs occurs during early symptomatic stages of AD. The alpha 4 beta 2 nAChR availability in these regions correlated with the severity of cognitive impairment, indicating a stage sensitivity of the alpha 4 beta 2 nAChR status. Conclusion 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-[F-18] F-A-85380, we developed the new alpha 4 beta 2 nAChR-specific radioligands (+)-and (-)-[F-18] norchloro-fluoro-homoepibatidine (NCFHEB) and evaluated them preclinically. (-)-[F-18] NCFHEB shows twofold higher brain uptake and significantly shorter acquisition times. Therefore, (-)-[F-18] NCFHEB should be a suitable radioligand for larger clinical investigations.