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

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/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 (F1,37 = 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 (F1,37 = 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.

Recent Advances in Cholinergic Imaging and Cognitive Decline—Revisiting the Cholinergic Hypothesis of Dementia

“…This was characterized by reduced cholinergic activity. The reduced DMN activity of nAChRs is consistent with the previously reported findings of reduced M1/M4 mAChR expressions within similar regions [46]. These observations highlight the potential role of both types of receptors in AD and the potentially more fundamental role of the cholinergic system in normal functioning of the DMN network.…”

“…A spatial covariance study of M1/M4 mAChRs in AD using [ 123 I]QNB SPECT showed concurrent decreased binding in medial temporal, basal forebrain, inferior frontal, and cingulate relative to simultaneously increased binding in the frontal poles, occipital, pre-post central, precuneus and superior parietal areas [46]. This pattern may suggest a loss of M1/M4 mAChR in the medial temporal and cholinergic rich basal forebrain, accompanied by either preservation or an increase in cortical M1/M4 mAChR binding.…”

A spatial covariance 123 I-5IA-85380 SPECT study of α4β2 nicotinic receptors in Alzheimer's disease

“…One study reported convergences of amyloid deposition, metabolic disruption, and atrophy of the DMN in AD (Buckner et al., 2005), suggesting that the relative decreased pattern within this network could be in fact characterizing these pathological and/or functional deficits, although an element of concomitant DMN cholinergic dysfunction cannot be excluded. Reduced DMN activity of nAChRs was consistent with our previous findings of reduced M1/M4 mAChR expressions within similar regions (Colloby et al., 2015), highlighting the potential role of both types of receptors in AD and that the cholinergic system may have a more fundamental role in the normal functioning of the DMN. Other mappings onto established resting-state networks, included the anterior insula and anterior cingulate, which are key nodes of the “salience network,” for initiation of cognitive control and switching networks to aid access to working memory and attention resources (Menon and Uddin, 2010, Seeley et al., 2009).…”

“…We derived disease-related α4β2 nAChR and rCBF patterns of spatial covariance, which implies the presence of several dysfunctional cholinergic and perfusion networks in AD. These findings represent the first attempt to differentiate AD from controls through spatial covariance analysis of cholinergic nicotinic receptor activity and/or availability, and follow our multivariate assessment of M1/M4 mAChR binding in AD (Colloby et al., 2015). …”

“…In AD, such procedures have previously been investigated with glucose metabolism positron emission tomography and perfusion single photon emission computed tomography (SPECT) imaging (Habeck et al., 2005, Johnson et al., 1998, Scarmeas et al., 2004). Indeed, we recently successfully applied the technique to 123 I-iodo-quinuclidinyl-benzilate SPECT in AD, deriving an M1/M4 mAChR spatial covariance pattern (SCP) that characterized the receptor changes to cholinergic depletion (Colloby et al., 2015). …”