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PET Imaging of the α4β2* Nicotinic Acetylcholine Receptors in Alzheimer’s Disease

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PET and SPECT in Neurology

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. However, the development of new α4β2*-nAChR PET radioligands characterized by faster kinetics, higher receptor affinity and selectivity is needed and currently underway.

The asterisk used in the receptor nomenclature indicates that the receptor complex may contain additional subunits.

Osama Sabri and Philipp M. Meyer contributed equally to this work.

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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

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. Parts of the study were funded by Interdisziplinäres Zentrum für Klinische Forschung (IZKF) grants.

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Authors and Affiliations

  1. Department of Nuclear Medicine, University Hospital Leipzig, University of Leipzig, Liebigstrasse 18, 04103, Leipzig, Germany

    Osama Sabri MD, PhD, Philipp M. Meyer MD, Henryk Barthel MD, PhD & Swen Hesse MD

  2. Department of Psychiatry and Psychotherapy, University Hospital Leipzig, University of Leipzig, Semmelweisstr. 10, Leipzig, 04103, Germany

    Hermann-Josef Gertz MD, PhD

  3. Institute of Radiopharmacy, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Permoserstrasse 15, 04318, Leipzig, Germany

    Peter Brust PhD

Authors
  1. Osama Sabri MD, PhD
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  2. Philipp M. Meyer MD
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  3. Hermann-Josef Gertz MD, PhD
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  4. Peter Brust PhD
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  5. Henryk Barthel MD, PhD
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  6. Swen Hesse MD
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Corresponding author

Correspondence to Osama Sabri MD, PhD .

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Editors and Affiliations

  1. Dept. of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Rudi A.J.O. Dierckx

  2. Faculty of Electrical Engineering and Information Technology, University of Applied Sciences Offenburg, Offenburg, Germany

    Andreas Otte

  3. Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands

    Erik F.J. de Vries

  4. Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands

    Aren van Waarde

  5. Neurology, University Medical Center Groningen, Groningen, The Netherlands

    Klaus L. Leenders

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Sabri, O., Meyer, P.M., Gertz, HJ., Brust, P., Barthel, H., Hesse, S. (2014). PET Imaging of the α4β2* Nicotinic Acetylcholine Receptors in Alzheimer’s Disease. In: Dierckx, R., Otte, A., de Vries, E., van Waarde, A., Leenders, K. (eds) PET and SPECT in Neurology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-54307-4_11

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