ORIGINAL COMMUNICATION Regional covariance of muscarinic acetylcholine receptors in Alzheimer’s disease using (R, R) [ 123 I]-QNB SPECT Sean J. Colloby 1 • Ian G. McKeith 1 • David J. Wyper 2 • John T. O’Brien 3 • John-Paul Taylor 1 Received: 25 March 2015 / Revised: 11 June 2015 / Accepted: 13 June 2015 Ó Springer-Verlag Berlin Heidelberg 2015 Abstract 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/regis- tered 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 cog- nitive symptoms (r = 0.90, p \ 0.001), whereas the rCBF SCP expression negatively correlated with MMSE, CAM- COG and CAMCOG memory (r C |0.63|, p B 0.006). 123 I- QNB SPECT revealed an M1/M4 basocortical covariance pattern, distinct from rCBF, reflecting the duration of dis- ease rather than current clinical symptoms. This approach could be more sensitive than univariate methods in char- acterising the cholinergic/rCBF changes that underpin the clinical phenotype of AD. Keywords Alzheimer’s disease Á Muscarinic receptors Á SPECT Á Molecular imaging Á rCBF Á Spatial covariance Introduction The basal forebrain is affected in established Alzheimer’s disease (AD), with a robust loss of cholinergic neurons, including those innervating the hippocampus and cortex [2, 6, 14, 45, 52], and consequent reductions in acetylcholine have been observed in hippocampal, temporal, frontal and parietal areas [19, 37] with deficits of cortical cholinergic markers associated with amyloid plaque burden in AD [20, 38]. Cholinergic changes may manifest even at the pre- clinical stage [41], although others have demonstrated that in early stages of AD, cholinergic neurons in the basal forebrain are relatively preserved [15, 21]. Nevertheless, remediation of cholinergic function, in the form of choli- nesterase inhibitors (AChEIs), has been the mainstay of symptomatic treatment in AD for many years. However, treatment benefits are often small with these agents, and there is a wide variability in response to these medications J. T. O’Brien and J. -P. Taylor are joint senior authors. & Sean J. Colloby sean.colloby@ncl.ac.uk 1 Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK 2 SINAPSE, Institute of Neuroscience and Psychology, University of Glasgow, Glasgow G12 8QB, UK 3 Department of Psychiatry, University of Cambridge, Level E4, Box 189, Cambridge CB2 0QC, UK 123 J Neurol DOI 10.1007/s00415-015-7827-z