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Cross sectional PET study of cerebral adenosine A1 receptors in premanifest and manifest Huntington’s disease

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Abstract

Purpose

To study cerebral adenosine receptors (AR) in premanifest and manifest stages of Huntington’s disease (HD).

Methods

We quantified the cerebral binding potential (BP ND) of the A1AR in carriers of the HD CAG trinucleotide repeat expansion using the radioligand [18 F]CPFPX and PET. Four groups were investigated: (i) premanifest individuals far (preHD-A; n = 7) or (ii) near (preHD-B; n = 6) to the predicted symptom onset, (iii) manifest HD patients (n = 8), and (iv) controls (n = 36).

Results

Cerebral A1AR values of preHD-A subjects were generally higher than those of controls (by up to 31 %, p < .01, in the thalamus on average). Across stages a successive reduction of A1AR BPND was observed to the levels of controls in preHD-B and undercutting controls in manifest HD by down to 25 %, p < .01, in the caudatus and amygdala. There was a strong correlation between A1AR BP ND and years to onset. Before onset of HD, the assumed annual rates of change of A1AR density were −1.2 % in the caudatus, −1.7 % in the thalamus and −3.4 % in the amygdala, while the corresponding volume losses amounted to 0.6 %, 0.1 % and 0.2 %, respectively.

Conclusions

Adenosine receptors switch from supra to subnormal levels during phenoconversion of HD. This differential regulation may play a role in the pathophysiology of altered energy metabolism.

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Acknowledgements

We thank all patients and their families for their kind support. The authors gratefully acknowledge the fruitful discussions with J. Ermert, M. Holschbach, D. Bier and K. Hamacher as well as the excellent technical assistance of S. Grafmuller, M. Lang, B. Palm, S. Rehbein, E. Wabbals (Institute of Nuclear Chemistry), M. Vögeling (Molecular Neuroimaging Group), S. Schaden, L. Tellmann, E. Theelen, C. Frey (PET Instrumentation Group), B. Elghahwagi, P. Engels, G. Oefler, J. N. Shah (MRI Instrumentation Group, Research Center Juelich).

Sponsorship and funding

Expenses for the entire study and personal budget for A.M., D.E. and A.B.. were financed by Forschungszentrum Jülich. C.S. was supported by the Ruhr-University Bochum (FoRUM grant K040/09).

Author’s financial disclosures

For all authors, there was no sponsorship or funding related to the present study.

A. M., D.E. and A.B.. received no industrial funding.

R. G. has received payments for consultancy from Biogen and Teva. He has also received speaker honoraria and research grants from Biogen Idec Germany, Teva, Sanofi-Aventis, Novartis, Bayer Healthcare, and MerckSerono.

H. P. Hartung has received personal compensation for activities with Biogen Idec, Teva, Sanofi Aventis, Novartis Pharma, Merck Serono, and Bayer Schering.

P. H. K. received funding from Boehringer Ingelheim Pharma and TEVA.

C. S. received honorarium from Temmler Pharma GmbH & Co.KG for scientific talks, compensation in the context of the Registry-Study of the Euro-HD-Network, in the context of the ACR16-Study (Neurosearch), the AFQ-Study (Novartis), the Selisistat-Studies (Siena Biotech) and received research support for a research project with Teva Pharma GmbH and the Cure Huntington’s Disease Initiative (CHDI).

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Authors and Affiliations

  1. Institute of Neuroscience and Medicine (INM-2), Forschungszentrum Jülich, 52425, Jülich, Germany

    Andreas Matusch, David Elmenhorst & Andreas Bauer

  2. Department of Neurology, Huntington Centre NRW, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany

    Carsten Saft, Peter H. Kraus & Ralf Gold

  3. Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany

    Hans-Peter Hartung & Andreas Bauer

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  1. Andreas Matusch
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  2. Carsten Saft
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  3. David Elmenhorst
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  4. Peter H. Kraus
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  5. Ralf Gold
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  6. Hans-Peter Hartung
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  7. Andreas Bauer
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Corresponding author

Correspondence to Andreas Matusch.

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Individual contributions of the authors

Andreas Matusch: data analysis, statistics, interpretation, drafting and revising of the MS

Carsten Saft: conceptualization of the study, interpretation, drafting and revising of the MS

David Elmenhorst: data analysis, revising of the MS

Peter H. Kraus: revising the MS

Ralf Gold: revising the MS

Hans-Peter Hartung: revising the MS

Andreas Bauer: conceptualization of the study, interpretation of the data, revising the MS

Matusch and Saft are authors that contributed equally to this study.

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Matusch, A., Saft, C., Elmenhorst, D. et al. Cross sectional PET study of cerebral adenosine A1 receptors in premanifest and manifest Huntington’s disease. Eur J Nucl Med Mol Imaging 41, 1210–1220 (2014). https://doi.org/10.1007/s00259-014-2724-8

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