Muscarinic acetylcholine receptor status in Alzheimer’s disease assessed using (R, R) 123I-QNB SPECT
Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, UK. Journal of Neurology
(Impact Factor: 3.38).
07/2007; 254(7):907-13. DOI: 10.1007/s00415-006-0473-8
One of the most characteristic changes in Alzheimer's disease (AD) is a deficit in cortical cholinergic neurotransmission and associated receptor changes.
To investigate differences in the distribution of M1/M4 receptors using (R, R) (123)I-iodo-quinuclidinyl-benzilate (QNB) and single photon emission computed tomography (SPECT) in patients with mild/moderate AD and age-matched controls. Also, to compare (123)I-QNB uptake to the corresponding changes in regional cerebral blood flow (rCBF) in the same subjects.
Forty two subjects (18 AD and 24 healthy elderly controls) underwent (123)IQNB and perfusion (99m)Tc-exametazime SPECT scanning. Image analysis was performed using statistical parametric mapping (SPM99) following intensity normalisation of each image to its corresponding mean whole brain uptake. Group differences and correlations were assessed using two sample t-tests and linear regression respectively.
Significant reductions in (123)I-QNB uptake were observed in regions of the frontal rectal gyrus, right parahippocampal gyrus, left hippocampus and areas of the left temporal lobe in AD compared to controls (height threshold of p < or = 0.001 uncorrected). Such regions were also associated with marked deficits in rCBF. No significant correlations were identified between imaging data and clinical variables.
Functional impairment as measured by rCBF is more widespread than changes in M1/M4 receptor density in mild/moderate AD, where there was little or no selective loss of M1/M4 receptors in these patients that was greater than the general functional deficits shown on rCBF scans.
Available from: Christian C Felder
- "For example, previous studies used a different biochemical approach to assessed global M1 binding sites (Araujo et al., 1988) and different clinical and neuropathological criteria (Araujo et al., 1988; Aubert et al., 1992). Variability in methodology and patient populations reported in the literature are similar to inconsistencies found between muscarinic neuroimaging studies evaluating both muscarinic function and density in AD (Holman, et al., 1985; Weinberger, et al., 1991; Brown, et al., 2003; Kemp, et al., 2003; Pakrasi, et al., 2007). Moreover, interpretation derived from previous postmortem tissue studies are tempered by the fact that many of the procedures used have not been validated for their ability to selectively detect M 1 receptors and may include measurement of additional muscarinic receptor subtypes. "
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ABSTRACT: Although the M(1) muscarinic receptor is a potential therapeutic target for Alzheimer's disease (AD) based on its wide spread distribution in brain and its association with learning and memory processes, whether its receptor response is altered during the onset of AD remains unclear. A novel [(35)S]GTPgammaS binding/immunocapture assay was employed to evaluated changes in M(1) receptor function in cortical tissue samples harvested from people who had no cognitive impairment (NCI), mild cognitive impairment (MCI), or AD. M(1) function was stable across clinical groups. However, [(3)H]-oxotremorine-M radioligand binding studies revealed that the concentration of M(1) cortical receptors increased significantly between the NCI and AD groups. Although M(1) receptor function did not correlate with cognitive function based upon mini-mental status examination (MMSE) or global cognitive score (GCS), functional activity was negatively correlated with the severity of neuropathology determined by Braak staging and NIA-Reagan criteria for AD. Since M(1) agonists have the potential to modify the pathologic hallmarks of AD, as well as deficits in cognitive function in animal models of this disease, the present findings provide additional support for targeting the M(1) receptor as a potential therapeutic for AD.
Journal of chemical neuroanatomy 03/2010; 40(1):63-70. DOI:10.1016/j.jchemneu.2010.03.005 · 1.50 Impact Factor
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ABSTRACT: High resolution SPECT imaging is an emerging field and there are only limited studies as yet available in this direction. Still there is continuous effort to achieve better spatial and temporal resolution in order to obtain detailed structural and functional information of different brain regions in small experimental animals. Recently, SPECT imaging system has been used to perform in vivo imaging using specific radioligands to further elucidate the role of dopaminergic, serotonergic, and cholinergic neurotransmission in relation to regional cerebral blood flow in various human CNS disorders and in gene-manipulated mouse models of neurodegeneration. Although in vivo and non-invasive translational research can be performed by high-resolution microPET imaging system, its limited spatial resolution restricts detailed anatomical and functional information of different brain regions involved in disease process. Recently developed NanoSPECT/CT imaging system has a better spatial resolution hence can be used to correlate and confirm microPET imaging data and determine the precise structural and functional anatomy of CNS disorders and their remission. Moreover SPECT imaging system reduces the cost and number of animals and provides detailed information of CNS disorders at the cellular, molecular and genetic level. Furthermore, SPECT system is economical, provides less radiation burden, and can be used to study bio-distribution of newly synthesized radioligands with increased target to non-target ratios, quality control, and clinical applications. It is envisaged that high-resolution SPECT imaging system will further improve in vivo non-invasive translational research on CNS disorders of unknown etiopathogenesis and their treatment in future.
Neurochemistry International 03/2008; 52(3):352-62. DOI:10.1016/j.neuint.2007.08.011 · 3.09 Impact Factor
Available from: Zimei Wang
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ABSTRACT: The purpose of this work is to study the effect of smilagenin on the mRNA stability of muscarinic receptor subtype 1 (M(1); m1 mRNA) in aged rat brains and its significance in improving memory. The Y-maze avoidance task showed that oral administration of smilagenin significantly improved spatial memory performance in aged rats. Mechanistic studies showed that smilagenin was neither a ligand of the M receptors nor a cholinesterase inhibitor, while radioligand binding assays revealed that smilagenin significantly increased the M(1)-receptor density. The increase of M(1)-receptor density correlated with memory improvement. Real-time polymerase chain reaction (RT-PCR) revealed that the m1 mRNA in m1 gene-transfected CHO cells increased significantly, and the average half-life of m1 mRNA was approximately doubled by smilagenin treatment. These results suggest that smilagenin improves memory of aged rats at least partially by increasing the stability of m1 mRNA. However since the ChAT activity in the cortex of aged rats was also elevated by smilagenin, it cannot be excluded that the increase of intrinsic acetylcholine excretion also plays a role in the memory-improvement effect of smilagenin.
Neurobiology of aging 09/2008; 31(6):1010-9. DOI:10.1016/j.neurobiolaging.2008.06.008 · 5.01 Impact Factor
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