Acetylcholine muscarinic receptors and response to anti-cholinesterase therapy in patients with Alzheimer's disease

Abstract

An acetylcholine deficit remains the most consistent neurotransmitter abnormality found in Alzheimer's disease and various therapeutic agents have been targeted at this. In this study we investigated the action of Donepezil, a cholinesterase inhibitor that has few side-effects. In particular we set out to investigate whether muscarinic acetylcholine receptor (mAChR) availability influences the response to this therapy. We used the novel single-photon emission tomography (SPET) tracer (R, R)[(123)I]I-quinuclidinyl benzilate (R, R[(123)I]I-QNB), which has high affinity for the M1 subtype of mAChR. Regional cerebral perfusion was also assessed using technetium-99m hexamethylpropylene amine oxime. We investigated 20 patients on Donepezil treatment and ten age-matched controls. The results showed a reduction in (R, R)[(123)I]I-QNB binding in the caudal anterior cingulate in patients compared with controls and relatively high binding in the putamen and rostral anterior cingulate, suggesting a relative sparing of mAChR in these regions. The main finding of the study was that mAChR availability as assessed by (R, R)[(123)I]I-QNB binding did not distinguish responders from non-responders. Interestingly, we found that the extent of cognitive improvement showed no positive correlation with (R, R)[(123)I]I-QNB binding in any brain region but was inversely related to binding in the insular cortex. This suggests that, within the advised cognitive performance band for use of Donepezil, response is greater in those patients with evidence of a more marked cholinergic deficit. A larger study should investigate this.

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

“…For the (R, R) 123 I-QNB tracer, as previously outlined, reduced binding in temporal regions [51] as well as decreased and increased uptake in caudal anterior cingulate and putamen/rostral anterior cingulate, respectively, has been shown [8], while others did not reveal any differences [26,53]. With 123 I-iodo-dexetimide (IDEX), a non-specific mAChR ligand, reductions in temporoparietal [10] and posterior cingulate [7] regions have been identified.…”

“…Using (R, R) 123 I-QNB tracer, a ligand shown to bind mainly to M1 and M4 receptors [39], has shown reduced binding in temporal [51] regions as well as both decreased and increased uptake in caudal anterior cingulate and putamen/rostral anterior cingulate, respectively [8]; in contrast, others did not reveal any differences [26,53]. However, imaging methods in evaluating both brain positron emission tomography (PET) and single photon emission computed tomography (SPECT) changes between pathological and healthy control groups have typically implemented a univariate approach that considers each region of interest or voxel as an independent measure across brain regions.…”

Muscarinic acetylcholine receptor status in Alzheimer’s disease assessed using (R, R) 123I-QNB SPECT

“…Holman et al, suggested moderate impairments to muscarinic receptor function in vivo between a single AD and single control case [32]. Weinberger et al, found significant losses bilaterally in posterior temporal cortex [33], and others have shown reduced 123 I-QNB uptake in the caudal anterior cingulate together with increased uptake in the right putamen and bilateral rostral anterior cingulate [22]. Some studies found no significant group differences in 123 I-QNB uptake between controls and AD with mild to moderate disease [34,35], suggesting marked reductions in postsynaptic receptor density occur only in severe or late stage illness [35], which seems to be consistent with our findings.…”

“…This involved production from a stannyl precursor (R, R) SnBu3-QNB by electrophilic iododestannylation. (R, R) 123 I-QNB had a radiochemical purity of >98% and a specific activity of 478.8 ± 67.9 mCi lmol )1 and was formulated as 185 MBq in 5 ml 10% ethanol in saline for intravenous injection [22]. The dose was calibrated to the time of injection and transported to the department of nuclear medicine on the day before use.…”

SPECT-Identified Neuroanatomical Predictor of the Cognitive Effects of Donepezil Treatment in Patients with Alzheimer’s Disease

“…Firstly, although the Alzheimer Disease Assessment Scale's cognitive subscale function test (ADAS-cog) is regarded as a standard assessment tool for the cognitive outcome in AD clinical trials [12] , most previous SPECT studies, with the exception of a few studies [8,13] , measured clinical outcome using the MMSE. While MMSE has the advantage of being both easy to administer and non-time-consuming, this test was not designed to assess subtle changes in cognition [12] ; on the other hand, the ADAS-cog consists of several cognitive domains, such as memory, language and praxis [14] , and it is generally believed that the ADAS-cog is more sensitive to the cognitive changes and progression in AD patients [14] .…”