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Regional covariance of muscarinic acetylcholine receptors in Alzheimer’s disease using (R, R) [123I]-QNB SPECT

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Abstract

Alzheimer’s disease (AD) is characterised by deficits in cholinergic neurotransmission and subsequent receptor changes. We investigated 123I-iodo-quinuclidinyl-benzilate (QNB) SPECT images using spatial covariance analysis (SCA), to detect an M1/M4 receptor spatial covariance pattern (SCP) that distinguished AD from controls. Furthermore, a corresponding regional cerebral blood flow (rCBF) SCP was also derived. Thirty-nine subjects (15 AD and 24 healthy elderly controls) underwent 123I-QNB and 99mTc-exametazime SPECT. Voxel SCA was simultaneously applied to the set of smoothed/registered scans, generating a series of eigenimages representing common intercorrelated voxels across subjects. Linear regression identified individual M1/M4 and rCBF SCPs that discriminated AD from controls. The M1/M4 SCP showed concomitant decreased uptake in medial temporal, inferior frontal, basal forebrain and cingulate relative to concomitant increased uptake in frontal poles, occipital, pre-post central and precuneus/superior parietal regions (F 1,37 = 85.7, p < 0.001). A largely different perfusion SCP was obtained showing concomitant decreased rCBF in medial and superior temporal, precuneus, inferior parietal and cingulate relative to concomitant increased rCBF in cerebellum, pre-post central, putamen, fusiform and brain stem/midbrain regions (F 1,37 = 77.5, p < 0.001). The M1/M4 SCP expression correlated with the duration of cognitive symptoms (r = 0.90, p < 0.001), whereas the rCBF SCP expression negatively correlated with MMSE, CAMCOG and CAMCOGmemory (r ≥ |0.63|, p ≤ 0.006). 123I-QNB SPECT revealed an M1/M4 basocortical covariance pattern, distinct from rCBF, reflecting the duration of disease rather than current clinical symptoms. This approach could be more sensitive than univariate methods in characterising the cholinergic/rCBF changes that underpin the clinical phenotype of AD.

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Acknowledgments

The authors acknowledge the Medical Research Council UK [Grant number G9817682], the National Institute for Health Research (NIHR), Research for Public Benefit, Wellcome Trust (Fellowship funding for J-P.T), NIHR Newcastle Biomedical Research Centre in Ageing and Chronic Disease and Biomedical Research Unit in Lewy Body Dementia based at Newcastle upon Tyne Hospitals, NHS Foundation Trust and Newcastle University and the NIHR Dementia Biomedical Research Unit at Cambridge University Hospitals, NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

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Authors and Affiliations

  1. Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK

    Sean J. Colloby, Ian G. McKeith & John-Paul Taylor

  2. SINAPSE, Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, G12 8QB, UK

    David J. Wyper

  3. Department of Psychiatry, University of Cambridge, Level E4, Box 189, Cambridge, CB2 0QC, UK

    John T. O’Brien

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  1. Sean J. Colloby
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  2. Ian G. McKeith
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  3. David J. Wyper
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  4. John T. O’Brien
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Correspondence to Sean J. Colloby.

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Conflicts of interest

Dr. Colloby reports no disclosures. Professor Wyper has no disclosures. Dr. Taylor has been a consultant of Lundbeck and received honoraria for talks from GE Healthcare and Flynn pharmaceuticals. Professor O’Brien has been a consultant for GE Healthcare, Lilly, Bayer Healthcare, TauRx and Nutricia and has received honoraria for talks from GE Healthcare, Lilly and Novartis. Professor McKeith has been a consultant for GE Healthcare, Bayer Healthcare and Nutricia.

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This study has been approved by the appropriate committee and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

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J. T. O’Brien and J. -P. Taylor are joint senior authors.

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Colloby, S.J., McKeith, I.G., Wyper, D.J. et al. Regional covariance of muscarinic acetylcholine receptors in Alzheimer’s disease using (R, R) [123I]-QNB SPECT. J Neurol 262, 2144–2153 (2015). https://doi.org/10.1007/s00415-015-7827-z

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  • DOI: https://doi.org/10.1007/s00415-015-7827-z

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