Iyo M

References (18)

Title : rCBF and cognitive impairment changes assessed by SPECT and ADAS-cog in late-onset Alzheimer's disease after 18 months of treatment with the cholinesterase inhibitors donepezil or galantamine - Shirayama_2019_Brain.Imaging.Behav_13_75
Author(s) : Shirayama Y , Takahashi M , Oda Y , Yoshino K , Sato K , Okubo T , Iyo M
Ref : Brain Imaging Behav , 13 :75 , 2019
Abstract : Late-onset Alzheimer's disease (AD) differs substantially from early-onset AD. In this cross sectional study we investigated brain perfusion changes after 18 months of treatment with cholinesterase inhibitors (ChEIs) donepezil or galantamine. Twenty-five drug-naive late-onset AD patients were recruited from outpatient clinics. We examined brain perfusion using single photon emission computed tomography (SPECT) and used three-dimensional stereotactic surface projection (3D-SSP) and the stereotactic extraction estimation method (SEE) level 3 to analyze classified gyrus level segments. We assessed cognitive function using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) grouped into three subgroup domains, language, memory, and praxis. In the follow-up data, some regions were further hypoperfused, reflecting worsening of the disease, while other regions showed alleviated hypoperfusion, potentially related to the ChEIs treatment. Regional cerebral blood flow (rCBF) decreased in the parietal cortex and increased in the frontal and the limbic cortices. Increased hypoperfusion significantly correlated with ADAS-cog scores changes were seen in the superior parietal lobule, inferior parietal lobule, angular gyrus, and supramarginal gyrus of the parietal cortex. Alleviated hypoperfusion significantly related to recovery of ADAS-cog scores were seen in the rectal and paracentral lobule of the frontal cortex, and the anterior cingulate of the limbic cortex. These regions showed significant relationships with total ADAS-cog and language, memory and praxis subscales scores. The current longitudinal study indicates prominent rCBF changes and their relationships with changes in ADAS-cog scores in late-onset AD patients.
ESTHER : Shirayama_2019_Brain.Imaging.Behav_13_75
PubMedSearch : Shirayama_2019_Brain.Imaging.Behav_13_75
PubMedID: 29247294

Title : Characterization of [(3)H]CHIBA-1001 binding to alpha7 nicotinic acetylcholine receptors in the brain from rat, monkey, and human - Tanibuchi_2010_Brain.Res_1348_200
Author(s) : Tanibuchi Y , Wu J , Toyohara J , Fujita Y , Iyo M , Hashimoto K
Ref : Brain Research , 1348 :200 , 2010
Abstract : Accumulating evidence suggests that the alpha7 subtype of nicotinic acetylcholine receptors (nAChRs) plays a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer's disease. Currently, there are no suitable small molecule radioligands for alpha7 nAChRs in the brain, although [(125)I]alpha-bungarotoxin has been widely used as a radioligand for alpha7 nAChRs. In the present study, we characterized a new radioligand, 4-[(3)H]methylphenyl 2,5-diazabicyclo[3.2.2]nonane-2-carboxylate ([(3)H]CHIBA-1001), a derivative of the selective alpha7 nAChR agonist SSR180711, in brain membranes from rat, monkey, and human. Scatchard analysis revealed an apparent equilibrium dissociation constant (Kd) of 193.4nM in rat brain membranes at 4 degrees C, and the maximal number of binding sites (Bmax) was 346.2fmol/mg protein. The order of drugs for the inhibition of [(3)H]CHIBA-1001 binding to rat brain membranes is SSR180711>A-844606>MG624>epibatidine>DMAB>A-582941, suggesting a similarity of alpha7 nAChR pharmacological profiles. In contrast, alpha-bungarotoxin, MLA, and nicotine were found to be very weak. The distribution of [(3)H]CHIBA-1001 binding to crude membranes from dissected regions of rat, monkey, and human brain was different from that of [(125)I]alpha-bungarotoxin binding, suggesting that [(3)H]CHIBA-1001 binding sites may not be identical to [(125)I]alpha-bungarotoxin binding in the brain. In summary, [(3)H]CHIBA-1001 would be a useful radioligand for alpha7 nAChRs in the brains of rodents, non-human primates, and humans.
ESTHER : Tanibuchi_2010_Brain.Res_1348_200
PubMedSearch : Tanibuchi_2010_Brain.Res_1348_200
PubMedID: 20537987

Title : Phencyclidine-induced cognitive deficits in mice are ameliorated by subsequent subchronic administration of donepezil: role of sigma-1 receptors - Kunitachi_2009_Brain.Res_1279_189
Author(s) : Kunitachi S , Fujita Y , Ishima T , Kohno M , Horio M , Tanibuchi Y , Shirayama Y , Iyo M , Hashimoto K
Ref : Brain Research , 1279 :189 , 2009
Abstract : This study was undertaken to examine the effects of two acetylcholinesterase inhibitors (donepezil and physostigmine) on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). In the novel object recognition test, PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (14 days) administration of donepezil (1.0 mg/kg/day), but not donepezil (0.1 mg/kg/day). Furthermore, the effect of donepezil (1.0 mg/kg/day) on PCP-induced cognitive deficits was significantly antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1.0 mg/kg/day), suggesting the role of sigma-1 receptors in the active mechanisms of donepezil. In contrast, PCP-induced cognitive deficits were not improved by subsequent subchronic (14 days) administration of physostigmine (0.25 mg/kg/day). Moreover, repeated administration of PCP significantly caused the reduction of sigma-1 receptors in the hippocampus. The present study suggests that agonistic activity of donepezil at sigma-1 receptors plays a role in the active mechanisms of donepezil on PCP-induced cognitive deficits in mice. Therefore, it is likely that donepezil would be potential therapeutic drugs for the treatment of the cognitive deficits in schizophrenia.
ESTHER : Kunitachi_2009_Brain.Res_1279_189
PubMedSearch : Kunitachi_2009_Brain.Res_1279_189
PubMedID: 19433073

Title : Potentiation of nerve growth factor-induced neurite outgrowth in PC12 cells by donepezil: role of sigma-1 receptors and IP3 receptors - Ishima_2008_Prog.Neuropsychopharmacol.Biol.Psychiatry_32_1656
Author(s) : Ishima T , Nishimura T , Iyo M , Hashimoto K
Ref : Prog Neuropsychopharmacol Biological Psychiatry , 32 :1656 , 2008
Abstract : In addition to acetylcholinesterase (AChE) inhibition, donepezil binds to sigma-1 receptors. In this study, we examined the effects of donepezil on nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Donepezil significantly potentiated the NGF-induced neurite outgrowth in a concentration-dependent manner whereas the AChE inhibitor physostigmine did not alter NGF-induced neurite outgrowth. Potentiation of NGF-induced neurite outgrowth by donepezil was significantly blocked by co-administration of the selective sigma-1 receptor antagonist NE-100 or the inositol 1,4,5-triphosphate (IP3) receptor antagonist xestospongin C. These findings suggest that sigma-1 receptors and interaction with IP3 receptors may be involved in the pharmacological action of donepezil.
ESTHER : Ishima_2008_Prog.Neuropsychopharmacol.Biol.Psychiatry_32_1656
PubMedSearch : Ishima_2008_Prog.Neuropsychopharmacol.Biol.Psychiatry_32_1656
PubMedID: 18647636

Title : Alpha4 and beta2 subunits of neuronal nicotinic acetylcholine receptor genes are not associated with methamphetamine-use disorder in the Japanese population - Kishi_2008_Ann.N.Y.Acad.Sci_1139_70
Author(s) : Kishi T , Ikeda M , Kitajima T , Yamanouchi Y , Kinoshita Y , Kawashima K , Inada T , Harano M , Komiyama T , Hori T , Yamada M , Iyo M , Sora I , Sekine Y , Ozaki N , Ujike H , Iwata N
Ref : Annals of the New York Academy of Sciences , 1139 :70 , 2008
Abstract : The mesolimbic system is thought to be involved in the reinforcing action of many addictive drugs and the release of dopamine modulated by neuronal nicotine cholinergic receptors (nAChRs). Several investigations suggested that nAChRs on dopaminergic terminals play an important role in the development of some long-lasting adaptations associated with drug abuse. A majority of high-affinity nicotine binding sites in the brain have been showed in heteropentameric alpha4 (alpha4) and beta2 subunit (beta2) of nAChRs. Therefore, we conducted a genetic association analysis of the alpha4 gene (CHRNA4) and beta2 gene (CHRNB2) with methamphetamine (METH)-use disorder (191 cases and 753 controls). We first evaluated the linkage disequilibrium (LD) structure of these genes and selected 7 and 5 tagging SNPs (tag SNPs) on CHRNA4 and CHRNB2, respectively. Some tag SNPs were significantly associated with total METH-use disorder and METH-induced psychosis; however, these associations were no longer statistically significant after Bonferroni's correction for multiple testing. In conclusion, our results suggest that neither CHRNA4 nor CHRNB2 plays a major role in Japanese METH-use disorder.
ESTHER : Kishi_2008_Ann.N.Y.Acad.Sci_1139_70
PubMedSearch : Kishi_2008_Ann.N.Y.Acad.Sci_1139_70
PubMedID: 18991851

Title : Estimation of plasma IC50 of donepezil hydrochloride for brain acetylcholinesterase inhibition in monkey using N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) and PET - Shiraishi_2005_Neuropsychopharmacology_30_2154
Author(s) : Shiraishi T , Kikuchi T , Fukushi K , Shinotoh H , Nagatsuka S , Tanaka N , Ota T , Sato K , Hirano S , Tanada S , Iyo M , Irie T
Ref : Neuropsychopharmacology , 30 :2154 , 2005
Abstract : Donepezil hydrochloride is a potent and selective inhibitor for brain acetylcholinesterase (AChE) and is currently used worldwide for the treatment of Alzheimer's disease. Until now, there is no in vivo study on the relation between the plasma concentration and the brain AChE inhibition. The purpose of this study was to estimate in vivo plasma IC(50) of donepezil in living monkeys by measuring plasma donepezil concentration (LC/MS/MS) and brain AChE activity with positron emission tomography (PET) and N-[(11)C]methylpiperidin-4-yl acetate, which is an acetylcholine analog recently developed by us for quantifying in vivo brain AChE activity. PET scans with donepezil at two doses, 100 microg/kg (donepezil-1; N=5) or 250 microg/kg (donepezil-2; N=5), were performed using the same monkeys at 4-week intervals. Before each PET scan, baseline PET scans (N=10 in total) were performed without donepezil. The plasma donepezil concentrations 14 min after intravenous injection were proportional to the doses, 17.2+/-2.9 ng/ml (donepezil-1) and 44.0+/-5.0 ng/ml (donepezil-2), and the mean AChE inhibitions in four neocortical regions as evaluated by PET were also dose-dependent, 27% (donepezil-1) and 53% (donepezil-2). In IC(50) estimation, measured plasma donepezil concentrations were corrected for the change during PET scan. The IC(50) values (estimate+/-SE) were 42+/-9.0 (ng/ml; donepezil-1), 34+/-3.2 (donepezil-2), and 37+/-4.1 (combined data). The present method may be useful for in vivo evaluation of other AChE inhibitors and novel drugs.
ESTHER : Shiraishi_2005_Neuropsychopharmacology_30_2154
PubMedSearch : Shiraishi_2005_Neuropsychopharmacology_30_2154
PubMedID: 15920507

Title : Evaluation of simplified kinetic analyses for measurement of brain acetylcholinesterase activity using N-[11C]Methylpiperidin-4-yl propionate and positron emission tomography - Sato_2004_J.Cereb.Blood.Flow.Metab_24_600
Author(s) : Sato K , Fukushi K , Shinotoh H , Nagatsuka S , Tanaka N , Aotsuka A , Ota T , Shiraishi T , Tanada S , Iyo M , Irie T
Ref : Journal of Cerebral Blood Flow & Metabolism , 24 :600 , 2004
Abstract : The applicability of two reference tissue-based analyses without arterial blood sampling for the measurement of brain regional acetylcholinesterase (AChE) activity using N-[11C]methylpiperidin-4-yl propionate ([11C]MP4P) was evaluated in 12 healthy subjects. One was a linear least squares analysis derived from Blomqvist's equation, and the other was the analysis of the ratio of target-tissue radioactivity relative to reference-tissue radioactivity proposed by Herholz and coworkers. The standard compartment analysis using arterial input function provided reliable quantification of k3 (an index of AChE activity) estimates in regions with low (neocortex and hippocampus), moderate (thalamus), and high (cerebellum) AChE activity with a coefficient of variation (COV) of 12% to 19%. However, the precise k3 value in the striatum, where AChE activity is the highest, was not obtained. The striatum was used as a reference because its time-radioactivity curve was proportional to the time integral of the arterial input function. Reliable k3 estimates were also obtained in regions with low-to-moderate AChE activity with a COV of less than 21% by striatal reference analyses, though not obtained in the cerebellum. Shape analysis, the previous method of direct k3 estimation from the shape of time-radioactivity data, gave k3 estimates in the cortex and thalamus with a somewhat larger COV. In comparison with the standard analysis, a moderate overestimation of k3 by 9% to 18% in the linear analysis and a moderate underestimation by 2% to 13% in the Herholz method were observed, which were appropriately explained by the results of computer simulation. In conclusion, simplified kinetic analyses are practical and useful for the routine analysis of clinical [11C]MP4P studies and are nearly as effective as the standard analysis for detecting regions with abnormal AChE activity.
ESTHER : Sato_2004_J.Cereb.Blood.Flow.Metab_24_600
PubMedSearch : Sato_2004_J.Cereb.Blood.Flow.Metab_24_600
PubMedID: 15181367

Title : A simple method for the detection of abnormal brain regions in Alzheimer's disease patients using [11C]MP4A: comparison with [123I]IMP SPECT - Ota_2004_Ann.Nucl.Med_18_187
Author(s) : Ota T , Shinotoh H , Fukushi K , Nagatsuka S , Namba H , Iyo M , Aotsuka A , Tanaka N , Sato K , Shiraishi T , Tanada S , Arai H , Irie T
Ref : Ann Nucl Med , 18 :187 , 2004
Abstract : We have developed a radiolabeled lipophilic acetylcholine analogue, N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) to measure brain acetylcholinesterase (AChE) activity by positron emission tomography (PET) in vivo. Aiming to develop a new SPECT tracer similar to MP4A, we first proposed a simple method for diagnosing Alzheimer's disease (AD) using [11C]MP4A PET. We performed [11C]MP4A PET and N-isopropyl [123I]iodoamphetamine ([123I]IMP) SPECT in 13 patients with AD and in 17 normal controls (NC). We calculated the ratio of radioactivity of the cortical region of interest (ROI) to that of the cerebellum measured with [11C]MP4A PET (MP4A ratio) and the ratio of regional cerebral blood flow (rCBF) to that of the cerebellum measured with [123I]IMP SPECT (IMP ratio). Eleven cortical ROIs were placed in the frontal, sensorimotor, temporal, parietal, and occipital cortices in both hemispheres and in the posterior cingulate cortex, and z-score was calculated in each ROI in patients with AD compared with NC. When the z-score was 2 or more in a ROI, it was defined as a positive ROI. When a patient had 3 or more positive ROIs, the patient was diagnosed as having AD. The reduction in the MP4A ratio was greater than that in the IMP ratio in all cortical ROIs except for in the right parietal cortex and cingulate cortex in patients with AD. MP4A ratio method showed 92% sensitivity and the IMP ratio method 69% sensitivity for the diagnosis of AD. These results encourage us to develop a new SPECT tracer similar to MP4A for the diagnosis of AD.
ESTHER : Ota_2004_Ann.Nucl.Med_18_187
PubMedSearch : Ota_2004_Ann.Nucl.Med_18_187
PubMedID: 15233279

Title : Positron emission tomography: quantitative measurement of brain acetylcholinesterase activity using radiolabeled substrates - Namba_2002_Methods_27_242
Author(s) : Namba H , Fukushi K , Nagatsuka S , Iyo M , Shinotoh H , Tanada S , Irie T
Ref : Methods , 27 :242 , 2002
Abstract : A new method for quantitative measurement of brain acetylcholinesterase (AChE) activity in living human brain using positron emission tomography (PET) is described. We tested several radiolabeled lipophilic acetylcholine analogs, e.g., N-methylpiperidyl esters, which readily entered the brain via the blood-brain barrier, were hydrolyzed selectively by AChE, and were then trapped in the brain. Among them, and tested and N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) was chosen as the tracer for PET. Quantitative measurement of cortical AChE was accomplished by fitting the time course of cerebral radioactivity concentration measured by PET and the metabolite-corrected arterial plasma input function using a nonlinear least-squares fitting method. Normal control studies of subjects with a wide range in age (24-89 years) showed no decrease in AChE activity in the cerebral cortex with age. Studies on patients with Alzheimer's disease demonstrated a widespread reduction of AChE activity in the cerebral cortex (more profound in early-onset than in late-onset Alzheimer's disease). Parkinson's disease and progressive supranuclear palsy, clinically similar disorders, could be differentiated with [11C]MP4A/PET studies. Simple methods without using an arterial input function are also proposed. The method provides a quantitative measure of the cholinergic aspect of brain function and proved to be useful in diagnosis of neurodegenerative disorders including Alzheimer's disease.
ESTHER : Namba_2002_Methods_27_242
PubMedSearch : Namba_2002_Methods_27_242
PubMedID: 12183113

Title : Positron emission tomographic measurement of brain acetylcholinesterase activity using N-[(11)C]methylpiperidin-4-yl acetate without arterial blood sampling: methodology of shape analysis and its diagnostic power for Alzheimer's disease - Tanaka_2001_J.Cereb.Blood.Flow.Metab_21_295
Author(s) : Tanaka N , Fukushi K , Shinotoh H , Nagatsuka S , Namba H , Iyo M , Aotsuka A , Ota T , Tanada S , Irie T
Ref : Journal of Cerebral Blood Flow & Metabolism , 21 :295 , 2001
Abstract : N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) is a radiotracer that has been used successfully for the quantitative measurement of acetylcholinesterase (AChE) activity in the human brain with positron emission tomography (PET) using a standard compartment model analysis and a metabolite-corrected arterial input function. In the current study, the authors evaluated the applicability of a simple kinetic analysis without blood sampling, namely shape analysis. First, the authors used computer simulations to analyze factors that affect the precision and bias of shape analysis, then optimized the shape analysis procedure for [11C]MP4A. Before shape analysis execution, the later part of dynamic PET data except for the initial 3 minutes were smoothed by fitting to a bi-exponential function followed by linear interpolation of 8 data points between each of adjacent scan frames. Simulations showed that shape analysis yielded estimates of regional metabolic rates of [11C]MP4A by AChE (k3) with acceptable precision and bias in brain regions with low k3 values such as neocortex. Estimates in regions with higher k3 values became progressively more inaccurate. The authors then applied the method to [11C]MP4A PET data in 10 healthy subjects and 20 patients with Alzheimer's disease (AD). There was a highly significant linear correlation in regional k3 estimates between shape and compartment analyses (300 neocortical regions, [shape k3] = 0.93 x [NLS k3], r = 0.89, P < 0.001). Significant reductions in k3 estimates of frontal, temporal, parietal, occipital, and sensorimotor cerebral cortices in patients with AD as compared with controls were observed when using shape analysis (P < 0.013, two-tailed t-test), although these reductions (17% to 20%) were somewhat less than those obtained by compartment analysis (22% to 27%). The sensitivity of shape analysis for detecting neocortical regions with abnormally low k3 in the 20 patients with AD (92 out of 200 regions, 46%) also was somewhat less than compartment analysis (136 out of 200 regions, 68%). However, taking its simplicity and noninvasiveness into account, the authors conclude that quantitative measurement of neocortical AChE activity with shape analysis and [11C]MP4A PET is practical and useful for clinical diagnosis of AD.
ESTHER : Tanaka_2001_J.Cereb.Blood.Flow.Metab_21_295
PubMedSearch : Tanaka_2001_J.Cereb.Blood.Flow.Metab_21_295
PubMedID: 11295884

Title : Kinetic analysis of [(11)C]MP4A using a high-radioactivity brain region that represents an integrated input function for measurement of cerebral acetylcholinesterase activity without arterial blood sampling - Nagatsuka_2001_J.Cereb.Blood.Flow.Metab_21_1354
Author(s) : Nagatsuka Si S , Fukushi K , Shinotoh H , Namba H , Iyo M , Tanaka N , Aotsuka A , Ota T , Tanada S , Irie T
Ref : Journal of Cerebral Blood Flow & Metabolism , 21 :1354 , 2001
Abstract : N -[(11)C]methylpiperidin-4-yl acetate ([(11)C]MP4A) is an acetylcholine analog. It has been used successfully for the quantitative measurement of acetylcholinesterase (AChE) activity in the human brain with positron emission tomography (PET). [(11)C]MP4A is specifically hydrolyzed by AChE in the brain to a hydrophilic metabolite, which is irreversibly trapped locally in the brain. The authors propose a new method of kinetic analysis of brain AChE activity by PET without arterial blood sampling, that is, reference tissue-based linear least squares (RLS) analysis. In this method, cerebellum or striatum is used as a reference tissue. These regions, because of their high AChE activity, act as a biologic integrator of plasma input function during PET scanning, when regional metabolic rates of [(11)C]MP4A through AChE (k(3); an AChE index) are calculated by using Blomqvist's linear least squares analysis. Computer simulation studies showed that RLS analysis yielded k(3) with almost the same accuracy as the standard nonlinear least squares (NLS) analysis in brain regions with low (such as neocortex and hippocampus) and moderately high (thalamus) k(3) values. The authors then applied these methods to [(11) C]MP4A PET data in 12 healthy subjects and 26 patients with Alzheimer disease (AD) using the cerebellum as the reference region. There was a highly significant linear correlation in regional k(3) estimates between RLS and NLS analyses (456 cerebral regions, [RLS k(3) ] = 0.98 x [NLS k(3) ], r = 0.92, P < 0.001). Significant reductions were observed in k(3) estimates of frontal, temporal, parietal, occipital, and sensorimotor cerebral neocortices (P < 0.001, single-tailed t-test), and hippocampus (P = 0.012) in patients with AD as compared with controls when using RLS analysis. Mean reductions (19.6%) in these 6 regions by RLS were almost the same as those by NLS analysis (20.5%). The sensitivity of RLS analysis for detecting cortical regions with abnormally low k 3 in the 26 patients with AD (138 of 312 regions, 44%) was somewhat less than NLS analysis (52%), but was greater than shape analysis (33%), another method of [(11)C]MP4A kinetic analysis without blood sampling. The authors conclude that RLS analysis is practical and useful for routine analysis of clinical [(11)C]MP4A studies.
ESTHER : Nagatsuka_2001_J.Cereb.Blood.Flow.Metab_21_1354
PubMedSearch : Nagatsuka_2001_J.Cereb.Blood.Flow.Metab_21_1354
PubMedID: 11702050

Title : Human cerebral acetylcholinesterase activity measured with positron emission tomography: procedure, normal values and effect of age - Namba_1999_Eur.J.Nucl.Med_26_135
Author(s) : Namba H , Iyo M , Fukushi K , Shinotoh H , Nagatsuka S , Suhara T , Sudo Y , Suzuki K , Irie T
Ref : Eur J Nucl Med , 26 :135 , 1999
Abstract : The regional cerebral metabolic rate of [11C]N-methyl-4-piperidyl acetate, which is nearly proportional to regional cerebral acetylcholinesterase (AChE) activity, was measured by dynamic positron emission tomography in 20 healthy subjects with a wide age range (24-89 years). Quantitative measurement was achieved using a kinetic model which consisted of arterial plasma and cerebral tissue compartments. The plasma input function was obtained using thin-layer chromatography and an imaging phosphor plate system at frequent sampling intervals to catch the rapid metabolism of the tracer in the blood. The distribution of the rate constant k3, an index of AChE activity, agreed well with reported post-mortem AChE distribution in the cerebral cortex (0.067-0.097 min-1) and thalamus (0.268 min-1), where AChE activity was low to moderate. The k3 values in the striatum and cerebellum, where AChE activity was very high, did not respond linearly to AChE activity because of increased flow dependency. No significant effect of age was found on AChE activity of the cerebral cortex, suggesting that the ascending central cholinergic system is preserved in normal aging. This study has shown that quantitative measurement of enzyme activity in the living brain is possible through appropriate modelling of tracer kinetics and accurate measurement of the input function. The method should be applicable to patients with Alzheimer's disease and those with other kinds of dementia whose central cholinergic system has been reported to be disturbed.
ESTHER : Namba_1999_Eur.J.Nucl.Med_26_135
PubMedSearch : Namba_1999_Eur.J.Nucl.Med_26_135
PubMedID: 9933347

Title : Positron emission tomographic measurement of acetylcholinesterase activity reveals differential loss of ascending cholinergic systems in Parkinson's disease and progressive supranuclear palsy - Shinotoh_1999_Ann.Neurol_46_62
Author(s) : Shinotoh H , Namba H , Yamaguchi M , Fukushi K , Nagatsuka S , Iyo M , Asahina M , Hattori T , Tanada S , Irie T
Ref : Annals of Neurology , 46 :62 , 1999
Abstract : We measured brain acetylcholinesterase activity in 16 patients with Parkinson's disease (PD), 12 patients with progressive supranuclear palsy (PSP), and 13 age-matched controls, using N-methyl-4-[11C]piperidyl acetate and positron emission tomography. Kinetic analysis was performed to calculate k3, an index of acetylcholinesterase activity. In PD patients, there was a significant reduction (-17%) of cerebral cortical k3 compared with normal controls, whereas there was only a nonsignificant reduction (-10%) of cortical k3 in PSP patients. However, there was a prominent reduction (-38%) of thalamic k3 in PSP patients compared with normal controls, whereas there was only a nonsignificant reduction (-13%) of thalamic k3 in PD patients. The results suggest that there is a loss of cholinergic innervation to the cerebral cortex in association with cholinergic innervation to the thalamus in PD, whereas there is a preferential loss of cholinergic innervation to the thalamus in PSP. When the thalamic to cerebral cortical k3 ratio was taken for each subject, PD and PSP were separated, suggesting that positron emission tomography measurement of acetylcholinesterase activity may be useful for differentiating the two similar disorders.
ESTHER : Shinotoh_1999_Ann.Neurol_46_62
PubMedSearch : Shinotoh_1999_Ann.Neurol_46_62
PubMedID: 10401781

Title : Preserved acetylcholinesterase activity in aged cerebral cortex [letter] -
Author(s) : Namba H , Iyo M , Shinotoh H , Nagatsuka S , Fukushi K , Irie T
Ref : Lancet , 351 :881 , 1998
PubMedID: 9525373

Title : Measurement of acetylcholinesterase by positron emission tomography in the brains of healthy controls and patients with Alzheimer's disease - Iyo_1997_Lancet_349_1805
Author(s) : Iyo M , Namba H , Fukushi K , Shinotoh H , Nagatsuka S , Suhara T , Sudo Y , Suzuki K , Irie T
Ref : Lancet , 349 :1805 , 1997
Abstract : BACKGROUND: Acetylcholinesterase activity, a marker for degeneration of the central cholinergic system, has consistently been reported, in necropsy brain studies, to be reduced in the cerebral cortex of patients with Alzheimer's disease. We have shown regional acetylcholinesterase activity in vivo in rodent and primate brains with radioactive acetylcholine analogues. In the present study, we used one of the analogues to map acetylcholinesterase activity in the brains of living people. METHODS: Positron emission tomography (PET) and a radiolabelled acetylcholine analogue with high hydrolytic specificity to acetylcholinesterase [11C]N-methyl-4-piperidyl acetate (MP4A), was used in eight elderly healthy controls and five patients with Alzheimer's disease who had mild dementia. All participants were given an intravenous injection of [11C]MP4A and then sequential patterns of radioactivity in various brain regions were obtained by PET. Time courses of [11C]MP4A concentration in arterial blood were also measured to obtain an input function. A three-compartment model was used to estimate regional acetylcholinesterase activity in the brain. FINDINGS: The estimated acetylcholinesterase distribution in the brain of the control participants agreed with the acetylcholinesterase distribution at necropsy. All patients with Alzheimer's disease had multiple cortical regions with a reduced estimated acetylcholinesterase activity in comparison with control participants. The reduction was more pronounced in the parietotemporal cortex, with an average reduction rate of 31% in temporal and 38% in parietal cortex, and less pronounced in other cortical lesions (19% in frontal, 24% in occipital, and 20% in sensorimotor cortex). Each patient was found to have at least two cortical regions with significantly reduced acetylcholinesterase activity. INTERPRETATION: The method we describe for non-invasive in-vivo detection of regional acetylcholinesterase changes in the living human brain that is feasible for biochemical assessment of Alzheimer's disease.
ESTHER : Iyo_1997_Lancet_349_1805
PubMedSearch : Iyo_1997_Lancet_349_1805
PubMedID: 9269216

Title : Brain acetylcholinesterase activity: validation of a PET tracer in a rat model of Alzheimer's disease - Irie_1996_J.Nucl.Med_37_649
Author(s) : Irie T , Fukushi K , Namba H , Iyo M , Tamagami H , Nagatsuka S , Ikota N
Ref : J Nucl Med , 37 :649 , 1996
Abstract : We developed three radioactive acetylcholine analogs--N[14C]methyl-4-piperidyl acetate ([14C]MP4A), propionate ([14C]MP4P) and isobutyrate ([14C]MP4IB)--as radiotracers for measuring brain acetylcholinesterase (AchE) activity in vivo. The principle of our method is that the lipophilic analog diffuses into the brain where it is metabolized by AchE to produce a hydrophilic metabolite, which is trapped at the site of its production. The purpose of this study was to examine whether the tracers would have the sensitivity needed for early diagnosis of Alzheimer' disease using rats with a unilateral lesion in the nucleus basalis magnocellularis (NBM), an animal model of the cholinergic deficit in Alzheimer's disease. METHODS: Rats with a unilateral NBM lesion were prepared, and the N[14C]methyl-4-piperidyl esters and N-Isopropyl-p-[123I]iodoamphetamine([123I]IMP were injected intravenously 30 and 2 min, respectively, before the rats were killed. Uptake of 14C and 123I and AchE activity in the lesioned and unlesioned (control) sides of the cortex were measured simultaneously. RESULTS: The NBM lesion showed reduced cortical AchE activity by 30%-50%, with no side-to-side differences in [123I]MP uptake. Autoradiographic studies showed that uptake of 14C from [14C]MP4A and [14C]MP4P was significantly lower in the lesioned than unlesioned side of the cortex, which agreed well with the AchE histochemical staining patterns. Tissue dissection studies showed different uptake changes for the three compounds when AchE activity in the lesioned side of the cortex was reduced by 50%: 14C uptake from [14C]MP4P, [14C]MP4A and [14C]MP4IB was reduced by 27%, 21% and 7.3%, respectively. Theoretical analysis of the observed sensitivities of the tracers in relation to their in vitro enzymatic properties indicated that tracer sensitivity was highly dependent on the enzymatic hydrolysis rate of the tracer. CONCLUSION: The [14C]MP4A and [14C]MP4P esters had sufficient sensitivity to enable AchE activity changes in the rat cortex of less than 50% to be detected, indicating that the present method is applicable to PET diagnosis of Alzheimer's disease.
ESTHER : Irie_1996_J.Nucl.Med_37_649
PubMedSearch : Irie_1996_J.Nucl.Med_37_649
PubMedID: 8691261

Title : In vivo measurement of acetylcholinesterase activity in the brain with a radioactive acetylcholine analog - Namba_1994_Brain.Res_667_278
Author(s) : Namba H , Irie T , Fukushi K , Iyo M
Ref : Brain Research , 667 :278 , 1994
Abstract : A novel method for visualization of brain acetylcholinesterase (AChE) in vivo has been developed. Following intravenous administration of a radiolabelled acetylcholine analog, N-methyl-3-piperidyl acetate, there was very good agreement between the distribution of radioactivity and AChE activity in the brain of rat and monkey. The method would be applicable for in vivo studies of human brain AChE activity in disorders of central cholinergic systems such as Alzheimer's disease
ESTHER : Namba_1994_Brain.Res_667_278
PubMedSearch : Namba_1994_Brain.Res_667_278
PubMedID: 7697367

Title : Evaluation of phenylmethanesulfonyl fluoride (PMSF) as a tracer candidate mapping acetylcholinesterase in vivo - Irie_1993_Nuc.Med.Biol_20_991
Author(s) : Irie T , Fukushi K , Iyo M
Ref : Nuclear Medicine & Biology , 20 :991 , 1993
Abstract : The availability of phenylmethanesulfonyl fluoride (PMSF), an irreversible cholinesterase inhibitor, for a tracer mapping acetylcholinesterase (AchE) in vivo in brain and other organs was evaluated using [35S]PMSF in mice and rats. [35S]PMSF was well taken up into the brain, heart and muscle, and the radioactivities were trapped in these organs. Pretreatment with non-labeled PMSF decreased 33-40% of the trapped radioactivities in the brain and other organs in mice. However, regional distribution of [35S]PMSF in rat brain did not correlate well with that of AchE activity, suggesting that the selectivity of PMSF toward AchE may be insufficient for use as an in vivo tracer mapping AchE.
ESTHER : Irie_1993_Nuc.Med.Biol_20_991
PubMedSearch : Irie_1993_Nuc.Med.Biol_20_991
PubMedID: 8298579