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

Lookup NU author(s): Dr Sean Colloby, Professor Ian McKeith, Professor John O'Brien, Professor John-Paul TaylorORCiD


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Alzheimer's disease (AD) is characterised by deficits in cholinergic neurotransmission and subsequent receptor changes. We investigated (123)I-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 (123)I-QNB and (99m)Tc-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). (123)I-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.

Publication metadata

Author(s): Colloby SJ, McKeith IG, Wyper DJ, O'Brien JT, Taylor JP

Publication type: Article

Publication status: Published

Journal: Journal of Neurology

Year: 2015

Volume: 262

Issue: 9

Pages: 2144-2153

Print publication date: 01/09/2015

Online publication date: 30/06/2015

Acceptance date: 13/06/2015

ISSN (print): 0340-5354

ISSN (electronic): 1432-1459

Publisher: Springer


DOI: 10.1007/s00415-015-7827-z


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Funder referenceFunder name
Biomedical Research Unit in Lewy Body Dementia based at Newcastle upon Tyne Hospitals, NHS Foundation Trust
NIHR Newcastle Biomedical Research Centre in Ageing and Chronic Disease
Research for Public Benefit, Wellcome Trust
University of Cambridge
National Institute for Health Research (NIHR)
Newcastle University
NIHR Dementia Biomedical Research Unit at Cambridge University Hospitals, NHS Foundation Trust
G9817682Medical Research Council UK