Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of dementia in the elderly. The subunits α4 and β2 of the nicotinic acetylcholine receptors (α4β2*-nAChRs) are widely abundant throughout the human brain and play an important role as neuromodulators in different neuronal systems. They are particularly important for cognitive functions and the loss of α4β2*-nAChRs, especially in cholinergic neurons may underlie memory loss in AD. Postmortem autoradiographic and immunohistochemical studies identified cortical and subcortical reductions in α4β2*-nAChR binding in patients with AD. Recently, the α4β2*-nAChR-specific PET and SPECT tracers 2-[18F]FA-85380 (2-FA) and 5-[123I]IA-85380 (5-IA) were developed enabling to study the α4β2*-nAChR availability in the living human brain. With such specific radioligands, α4β2*-nAChR binding and its association to cognitive symptoms can be quantitatively determined in patients with AD and mild cognitive impairment (MCI). Initial results show that α4β2*-nAChR availability is reduced in AD but also in amnestic MCI patients who progressed into AD. Hence, the prediction of conversion from MCI to AD seems to be feasible, and therefore, quantitative assessment of α4β2*-nAChR binding using 2-FA-PET or 5-IA-SPECT might become an early biomarker of mental dysfunction in AD. Novel, second-generation α4β2*-nAChR PET radioligands, characterized by faster kinetics, higher receptor affinity and selectivity, have been developed recently. Two first-in-human PET studies using the second-generation α4β2*-nAChR PET radioligands (-)[18F]Flubatine and (+)[18F]Flubatine, carried out successfully in patients with mild Alzheimer disease and healthy controls, showed promising results.
The asterisk used in the receptor nomenclature indicates that the receptor complex may contain additional subunits.
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Abbreviations
- 2-FA:
-
2-[18F]F-A85380
- 5-IA:
-
5-[123I]I-A85380
- AD:
-
Alzheimer’s disease
- APP:
-
β-amyloid-precursor protein
- BP:
-
Binding potential
- CC:
-
Corpus callosum
- CERAD:
-
Consortium to Establish a Registry for Alzheimer’s Disease
- CSF:
-
Cerebrospinal fluid
- DV:
-
Distribution volume
- DVR:
-
Distribution volume ratio
- DVS:
-
Specific binding of the distribution volume
- FWHM:
-
Full width at half maximum
- HC:
-
Healthy controls
- MCI:
-
Mild cognitive impairment
- MMSE:
-
Mini-Mental State Examination
- MRI:
-
Magnetic resonance imaging
- NINCDS-ADRDA:
-
National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association
- NINDS-AIREN:
-
National Institute of Neurological Disorder and Stroke-Association International pour la Recherche et l’Enseignement en Neurosciences
- PET:
-
Positron emission tomography
- ROI:
-
Region of interest
- SPECT:
-
Single-photon emission computed tomography
- SPM:
-
Statistical Parametric Mapping
- VaD:
-
Vascular dementia
- α4β2*-nAChR:
-
α4β2*-nicotinic acetylcholine receptor
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Acknowledgements
We thank the cyclotron operators, PET physicists, chemists and technologists for their assistance. The studies were funded by Interdisziplinäres Zentrum für Klinische Forschung (IZKF) and Bundesministerium für Bildung und Forschung (BMBF) grants.
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Sabri, O. et al. (2021). PET Imaging of the α4β2* Nicotinic Acetylcholine Receptors in Alzheimer’s Disease. In: Dierckx, R.A.J.O., Otte, A., de Vries, E.F.J., van Waarde, A., Leenders, K.L. (eds) PET and SPECT in Neurology. Springer, Cham. https://doi.org/10.1007/978-3-030-53168-3_11
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