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ABSTRACT: Abstract Recently, several attempts have been made to characterize the clinical symptoms and brain atrophy patterns in pathology-proven corticobasal degeneration (CBD) and corticobasal syndrome (CBS) with known histopathology. CBS is a term which was proposed to characterize the constellation of clinical features initially considered the defining characteristics of CBD. Voxel-based morphometry (VBM) analyses of MRI revealed that frontal lobe involvement is characteristic of CBD. The pathologic substrates for clinical CBS were found to be CBD, Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) inclusions. CBS was associated with perirolandic atrophy, irrespective of underlying pathology. In CBS due to FTLD, atrophy extended into the prefrontal cortex, striatum, and brainstem, whereas in CBS due to AD, atrophy extended into the temporoparietal cortex and precuneus. No functional imaging studies in pathology-proven CBD or CBS with known histopathology have yet been published. PET and SPECT studies have demonstrated decreased glucose metabolism and cerebral blood flow in the fronto-parietal cortex, particularly contralateral to the dominant symptoms in CBS patients. A PET study showed decreased acetylcholinesterase (AChE) activity in the fronto-parietal cortex, as well as a correlation between cortical AChE activity and mini-mental state examination score in CBS patients, suggesting that cholinergic stimulant therapy may be effective for dementia in CBS. Additionally, [<sup>18</sup>F] 6-fluorodopa PET and dopamine transporter SPECT studies have demonstrated nigrostriatal dopaminergic dysfunction in CBS. Antemortem prediction of CBD will remain challenging until sensitive, specific biomarkers are identified.
Brain and nerve = Shinkei kenkyū no shinpo 01/2013; 65(1):41-53.
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Hitoshi Shimada, Hitoshi Shinotoh,
Shigeki Hirano,
Michie Miyoshi,
Koichi Sato,
Noriko Tanaka,
Tsuneyoshi Ota,
Kiyoshi Fukushi,
Toshiaki Irie,
Hiroshi Ito,
Makoto Higuchi,
Satoshi Kuwabara,
Tetsuya Suhara
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ABSTRACT: The aim of this study was to investigate whether amyloid deposition is associated with Alzheimer's disease (AD)-like cortical atrophy in Lewy body (LB) disease (LBD). Participants included 15 LBD with dementia patients (8 with dementia with Lewy bodies [DLB] and 7 with Parkinson's disease [PD] with dementia [PDD]), 13 AD patients, and 17 healthy controls. Age, gender, and Mini-Mental State Examination scores were matched between patient groups. All subjects underwent PET scans with [(11) C]Pittsburgh Compound B to measure brain amyloid deposition as well as three-dimensional T1-weighted MRI. Gray-matter volumes (GMVs) were estimated by voxel-based morphometry. Volumes-of-interest analyses were also performed. Forty percent of the 15 DLB/PDD patients were amyloid positive, whereas all AD patients and none of the healthy controls were amyloid positive. Amyloid-positive DLB/PDD and AD patients showed very similar patterns of cortical atrophy in the parahippocampal area and lateral temporal and parietal cortices, with 95.2% of cortical atrophy distribution being overlapped. In contrast, amyloid-negative DLB/PDD patients had no significant cortical atrophy. Compared to healthy controls, parahippocampal GMVs were reduced by 26% in both the amyloid-positive DLB/PDD and AD groups and by 10% in the amyloid-negative DLB/PDD group. The results suggest that amyloid deposition is associated with AD-like atrophy in DLB/PDD patients. Early intervention against amyloid may prevent or delay AD-like atrophy in DLB/PDD patients with amyloid deposition. © 2012 Movement Disorder Society.
Movement Disorders 12/2012; · 4.51 Impact Factor
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ABSTRACT: Multiple factors are involved in the development of cognitive impairment in Parkinson's disease (PD) and related disorders. Notably, several underlying factors, such as monoaminergic dysfunction, Lewy body pathology, Alzheimer disease-like pathology and cerebrovascular disease are implied in the PD pathophysiology of cognitive impairment. The mesocortical dopaminergic system is associated with executive functions which are frequently affected in PD and are influenced by local levodopa concentration, dopamine metabolism and baseline performance status. The ventral striatum and frontal cortex are associated with impulse control disorders reported in PD patients treated with dopamine replacement therapy. Cholinergic impairment in PD plays a cardinal role in the development of dementia. Acetylcholinesterase positron emission tomography demonstrates that posterior brain areas are related to cognitive decline in PD patients. Amyloid radiotracer illustrates that patients with PD with severe cognitive impairment were prone to accompanied cortical amyloid deposition. Metabolism/perfusion change associated with cognitive impairment in PD, so-called PD related cognitive pattern, is characterised by reduced frontoparietal activity and is an effective way to differentiate and monitor cognitive function of individual PD patients. Cognitive impairment in PD cannot be explained by a single mechanism and is entangled by multiple factors. Imaging studies can unravel each pathological domain, further shed light on the interrelation between different pathomechanisms, not only in PD but also in other dementia related disorders, and thereby integrate its interpretation to apply to therapeutics in individual patients.
Journal of neurology, neurosurgery, and psychiatry 07/2012; 83(10):963-9. · 4.87 Impact Factor
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ABSTRACT: Diagnosis and treatment strategies for dementia are based on the sensitive and specific detection of the incipient neuropathological characteristics, combined with emerging treatments that counteract molecular processes in its pathogenesis. Positron emission tomography (PET) is used for diverse clinical and basic studies on dementia with a wide range of radiotracers. Approaches to visualize amyloid deposition in human brains non-invasively with PET depend on imaging agents reacting with amyloid fibrils. The most widely used tracer is [(11) C]-6-OH-BTA-1, also known as Pittsburgh Compound-B, which has a high affinity to amyloid β peptide (Aβ) aggregates. Some (18) F-labeled amyloid ligands with a longer radioactive half-life have also been developed for broader clinical applications. In addition, there have been demonstrated advantages of tracers with high specific radioactivity in the sensitive detection of amyloid, which have indicated the significance of Aβ-N3-pyroglutamate as a new diagnostic and therapeutic target. Furthermore, beneficial outcomes of Aβ and tau immunization in humans and mouse models have highlighted crucial roles of immunocompetent glia in the protection of neurons against amyloid toxicities. The utility of PET with a radioligand for translocator protein as a biomarker for tau-triggered toxicity, and as a complement to amyloid and tau imaging for diagnostic assessment of tauopathies with and without Aβ pathologies, has also been demonstrated. Meanwhile, brain cholinergic function can be estimated by measuring acetylcholinesterase activity in the brain with PET and radiolabeled acetylcholine analogues. It has been reported that patients with early Parkinson's disease exhibit a reduction in acetylcholinesterase activity in the cerebral cortex, and this decline is more profound in patients with Parkinson's disease with dementia and dementia with Lewy bodies than in patients with Parkinson's disease without dementia. The Alzheimer's Disease Neuroimaging Initiative was a multicentre research project conducted over 6 years that studied changes in cognition, brain structure, and biomarkers in healthy elderly controls and subjects with mild cognitive impairment and Alzheimer's disease. An international workgroup of the National Institute on Aging-Alzheimer's Association has suggested that Alzheimer's disease would be optimally treated before significant cognitive impairment, defined as a 'presymptomatic' or 'preclinical' stage. Therefore, PET will be of technical importance for both clinical and basic research aimed at prodromal pathologies of Alzheimer's disease.
Psychogeriatrics 06/2012; 12(2):106-14. · 1.21 Impact Factor
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ABSTRACT: We investigated the correlation between clinical severity and striatal [123I]β-CIT binding in 12 patients with Parkinson’s Disease (PD: 6 men and 6 women, age: 65±7 years, Hoehn & Yahr stage: 1 to
3). The clinical severity of PD patients was measured with the Unified Parkinson’s Disease Rating Scale (UPDRS) after withdrawal
of antiparkinsonian medication at least 12 hours before assessment. [123I]β-CIT binding in the caudate and putamen was measured at 3 hours [V″3 (day 1)], and at 24 hours [V″3 (day 2)] after tracer injection with small square ROIs. The specific striatal uptake index (day 2) was calculated with large
square ROIs that encompassed the whole striatum. The best correlation (r=−0.82, p<0.0012) was between putamenal V″3 (day 2) and the motor UPDRS scores. When the motor UPDRS scores were divided into four subscales, bradykinesia was the only
sign that correlated significantly with putamenal V″3 (day 2) (r=−0.81, p<0.002). [123I]β-CIT SPECT is a useful marker of disease severity in PD with potential utility in the serial monitoring of disease progression.
Annals of Nuclear Medicine 04/2012; 14(3):199-203. · 1.50 Impact Factor
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NeuroImage. 01/2012; 59:3149-3158.
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ABSTRACT: Long dynamic scans (60-120 min) are often required for estimating the k(3) value, an index of receptor density, by positron emission tomography (PET). However, the precision of k(3) is usually low in kinetic analyses for reversible PET ligands compared with irreversible ligands. That is largely due to unstable estimation of the dissociation rate constant, k(4). We propose a novel '3P+' method for estimating k(3) of moderately reversible ligands, where a 3-parameter model without k(4) is applied to early-phase PET data to obtain a good model-fit of k(3) estimation. By using [(11)C] Pittsburgh compound B (PIB) (k(4) = 0.018/min) as an example of a moderately reversible ligand, the 3P+ method simulation with a 28 min PET scan yielded less than 3% k(3) relative bias with a +100% k(3) change. In [(11)C]PIB PET scans of 15 normal controls (NC) and nine patients with Alzheimer's disease (AD), the 3P+ method provided a precise k(3) estimate (mean SE of 13.6% in parietal cortex; covariance matrix method). The results revealed linear correlations (r = 0.964) of parietal k(3) values in 24 subjects between 28minute 3P+ method and conventional 90 minute 4-parameter method. A good separation of k(3) between NC and AD groups (P < 0.001; t-test) was replicated in 28 minute 3P+ method. The short-scan 3P+ method may be a practical alternative method for analyzing reversible ligands.
NeuroImage 11/2011; 59(4):3149-58. · 5.89 Impact Factor
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Shigeki Hirano, Hitoshi Shinotoh,
Hitoshi Shimada,
Akiyo Aotsuka,
Noriko Tanaka,
Tsuneyoshi Ota,
Koichi Sato,
Hiroshi Ito,
Satoshi Kuwabara,
Kiyoshi Fukushi,
Toshiaki Irie,
Tetsuya Suhara
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ABSTRACT: Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of a disease spectrum that includes common cognitive impairment and movement disorders. The aim of this study was to characterize brain cholinergic deficits in these disorders. We measured brain acetylcholinesterase activity by [11C] N-methylpiperidin-4-yl acetate and positron emission tomography in seven patients with corticobasal syndrome (67.6+/-5.9 years), 12 with progressive supranuclear palsy (68.5+/-4.1 years), eight with frontotemporal dementia (59.8+/-6.9 years) and 16 healthy controls (61.2+/-8.5 years). Two-tissue compartment three-parameter model and non-linear least squares analysis with arterial input function were performed. k3 value, an index of acetylcholinesterase activity, was calculated voxel-by-voxel in the brain of each subject. The k3 images in each disease group were compared with the control group by using Statistical Parametric Mapping 2. Volume of interest analysis was performed on spatially normalized k3 images. The corticobasal syndrome group showed decreased acetylcholinesterase activity (k3 values) in the paracentral region, frontal, parietal and occipital cortices (P<0.05, cluster corrected). The group with progressive supranuclear palsy had reduced acetylcholinesterase activity in the paracentral region and thalamus (P<0.05, cluster corrected). The frontotemporal dementia group showed no significant differences in acetylcholinesterase activity. Volume of interest analysis showed mean cortical acetylcholinesterase activity to be reduced by 17.5% in corticobasal syndrome (P<0.001), 9.4% in progressive supranuclear palsy (P<0.05) and 4.4% in frontotemporal dementia (non-significant), when compared with the control group. Thalamic acetylcholinesterase activity was reduced by 6.4% in corticobasal syndrome (non-significant), 24.0% in progressive supranuclear palsy (P<0.03) and increased by 3.3% in frontotemporal dementia (non-significant). Both corticobasal syndrome and progressive supranuclear palsy showed brain cholinergic deficits, but their distribution differed somewhat. Significant brain cholinergic deficits were not seen in frontotemporal dementia, which may explain the unresponsiveness of this condition to cholinergic modulation therapy.
Brain 07/2010; 133(Pt 7):2058-68. · 9.46 Impact Factor
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Neurology 05/2010; 74(18):1406-7. · 8.31 Impact Factor
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Michie Miyoshi, Hitoshi Shinotoh,
Zbigniew K Wszolek,
Audrey J Strongosky,
Hitoshi Shimada,
Ryosuke Arakawa,
Makoto Higuchi,
Yoko Ikoma,
Fumihiko Yasuno,
Kiyoshi Fukushi,
Toshiaki Irie,
Hiroshi Ito,
Tetsuya Suhara
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ABSTRACT: Microglial activation and disrupted neurotransmissions may herald symptomatic manifestations in neurodegenerative tauopathies.
We investigated microglial activation with [(11)C]DAA1106 positron emission tomography (PET), striatal dopaminergic function with l-[beta-(11)C]dopa PET, acetylcholinesterase (AChE) activity with [(11)C]N-methylpiperidin-4-yl acetate PET, and morphologic brain changes with MRI in three persons (aged 38-41 years) with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), who were presymptomatic gene carriers (PGCs) from an American kindred with pallidopontonigral degeneration. The results from these 3 PGCs were compared with [(11)C]DAA1106 PET results from age-matched 9 healthy volunteers (HV), and with l-[beta-(11)C]dopa and [(11)C]MP4A PET results from 10 HV. Values considered significant were more than 2 SDs greater or less than the normal control mean, as the number of subjects was small for group comparisons.
Glial activities were increased in the frontal cortex of one PGC, the occipital cortex of two PGCs, and the posterior cingulate cortex of one PGC, although none of the PGCs showed overt glial activation in the brain. Only one of the PGCs showed reduced AChE activity in the temporo-parietal cortex. Three PGCs showed low dopamine synthesis rates in the putamen. Hippocampal atrophy was observed in two PGCs.
Hippocampal atrophy and striatal dopaminergic dysfunction may be early disease processes in the pathogenesis of FTDP-17. Neuroinflammation may also be an in vivo signature of tau pathology at a prodromal stage, although current PET techniques may not constantly reveal it as the earliest neuroimaging abnormality.
Parkinsonism & Related Disorders 05/2010; 16(6):404-8. · 3.80 Impact Factor
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Tsuneyoshi Ota, Hitoshi Shinotoh,
Kiyoshi Fukushi,
Tatsuya Kikuchi,
Koichi Sato,
Noriko Tanaka,
Hitoshi Shimada,
Shigeki Hirano,
Michie Miyoshi,
Heii Arai,
Tetsuya Suhara,
Toshiaki Irie
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ABSTRACT: Estimate the value of in vivo plasma IC50 of donepezil, the concentration of donepezil in plasma that inhibits brain acetylcholinesterase (AChE) activity by 50% at the steady-state conditions of donepezil between the plasma and the brain.
N-[C] methylpiperidin-4-yl acetate ([C]MP4A) positron emission tomography was performed in 16 patients with probable Alzheimer disease (AD) before and during the treatment of donepezil (5 mg/day) with a mean interval of 5.3 months. The plasma IC50 value of donepezil was estimated from plasma donepezil concentrations and cerebral cortical mean AChE inhibition rates measured by positron emission tomography, using one-parameter model.
Donepezil reduced AChE activity uniformly in the cerebral cortex compared with the baseline in each AD patient, and the mean reduction rate in the cerebral cortex was 34.6%. The donepezil concentrations in the plasma ranged from 18.5 to 43.9 ng/mL with a mean of 28.9 +/- 7.3 ng/mL. The plasma IC50 value was estimated to be 53.6 +/- 4.0 ng/mL.
Once the plasma IC50 of donepezil is determined, the brain AChE inhibition rate could be estimated from the plasma concentration of donepezil in each subject based on the plasma IC50. Now that the mean donepezil concentrations in the plasma, when the patients took 5 mg/day, remained 28.9 ng/mL, approximately half of the plasma IC50, higher dose of donepezil might provide further benefits for patients with AD. This technique can be also applied to measure the in vivo plasma IC50 of other cholinesterase inhibitors such as rivastigmine and galantamine.
Clinical neuropharmacology 11/2009; 33(2):74-8. · 2.35 Impact Factor
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Shigeki Hirano, Hitoshi Shinotoh,
Kimihito Arai,
Akiyo Aotsuka,
Fumihiko Yasuno,
Noriko Tanaka,
Tsuneyoshi Ota,
Koichi Sato,
Kiyoshi Fukushi,
Shuji Tanada,
Takamichi Hattori,
Toshiaki Irie
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ABSTRACT: To elucidate characteristic changes of brain acetylcholinesterase (AChE) in cerebellar degenerative disorders. Eight patients with the cerebellar variant of multiple system atrophy (MSA-C), 7 patients with spinocerebellar ataxia type-3 (SCA-3), 3 patients with SCA-6, and 13 healthy age-matched volunteers participated in this study. Brain AChE activity was measured by [(11)C] N-methylpiperidin-4-yl propionate PET in all subjects. Brain AChE activities were significantly decreased in the thalamus (-27%) and the posterior lobe of cerebellar cortex (-36%) in patients with MSA-C and in the thalamus (-23%) in patients with SCA-3 compared with healthy controls (P < 0.01). Thalamic AChE activities of SCA-3 patients were negatively correlated with the unified Parkinson's disease rating scale motor subscore (P < 0.001). AChE activities were not significantly altered in the cerebral cortex in any disease group. Reduction of AChE activities in the thalamus and cerebellum in MSA and in the thalamus in SCA-3 suggest that cholinergic modulating drugs may have a role in the treatment of ataxia and other symptoms in these disorders.
Movement Disorders 07/2008; 23(8):1154-60. · 4.51 Impact Factor
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Shigeki Hirano MD,
PhD Hitoshi Shinotoh MD,
Kimihito Arai MD,
PhD Akiyo Aotsuka MD,
PhD Fumihiko Yasuno MD,
PhD Noriko Tanaka MD,
PhD Tsuneyoshi Ota MD,
PhD Koichi Sato MD,
Kiyoshi Fukushi PhD,
PhD Shuji Tanada MD, [......],
Kimihito Arai,
Akiyo Aotsuka,
Fumihiko Yasuno,
Noriko Tanaka,
Tsuneyoshi Ota,
Koichi Sato,
Kiyoshi Fukushi,
Shuji Tanada,
Takamichi Hattori,
Toshiaki Irie
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ABSTRACT: To elucidate characteristic changes of brain acetylcholinesterase (AChE) in cerebellar degenerative disorders. Eight patients with the cerebellar variant of multiple system atrophy (MSA-C), 7 patients with spinocerebellar ataxia type-3 (SCA-3), 3 patients with SCA-6, and 13 healthy age-matched volunteers participated in this study. Brain AChE activity was measured by [11C] N-methylpiperidin-4-yl propionate PET in all subjects. Brain AChE activities were significantly decreased in the thalamus (−27%) and the posterior lobe of cerebellar cortex (−36%) in patients with MSA-C and in the thalamus (−23%) in patients with SCA-3 compared with healthy controls (P < 0.01). Thalamic AChE activities of SCA-3 patients were negatively correlated with the unified Parkinson's disease rating scale motor subscore (P < 0.001). AChE activities were not significantly altered in the cerebral cortex in any disease group. Reduction of AChE activities in the thalamus and cerebellum in MSA and in the thalamus in SCA-3 suggest that cholinergic modulating drugs may have a role in the treatment of ataxia and other symptoms in these disorders. © 2008 Movement Disorder Society
Movement Disorders 06/2008; 23(8):1154 - 1160. · 4.51 Impact Factor
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Hitoshi Shinotoh
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ABSTRACT: Carbon-11 labeled N-methylpiperidin-4-yl acetate ([11C]MP4A) and carbon-11 labeled N-methylpiperidin-4-yl propionate ([11C]MP4P) are acetylcholine analogues and have been successfully used for measurement of brain acetylcholinesterase (AChE) activity in vivo in humans. In Alzheimer's disease (AD), there is a significant loss of AChE activity in the cerebral cortex in association with mental decline. The reduction of AChE activity in the cerebral cortex is more remarkable in early-onset AD than late-onset AD. There is mild but significant reduction of AChE activity in the cerebral cortex, even in the early stage of Parkinson's disease (PD) without dementia. There is remarkable reduction of AChE activity in the entire cerebral cortex in both PD with dementia and dementia with Lewy bodies (DLB). In two patients with frontotemporal dementia with parkinsonism linked to chromosome 17, there was prominent reduction of AChE activity in the cerebral cortex and thalamus. In 12 patients with progressive supranuclear palsy, there was profound reduction of AChE activity in the thalamus but not in the cerebral cortex. In corticobasal degeneration, there is symmetrical loss of AChE activity in the sensori-motor cortex.
Rinsho shinkeigaku = Clinical neurology 12/2007; 47(11):822-5.
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Tetsuya Shiraishi,
Tatsuya Kikuchi,
Kiyoshi Fukushi, Hitoshi Shinotoh,
Shin-ichiro Nagatsuka,
Noriko Tanaka,
Tsuneyoshi Ota,
Koichi Sato,
Shigeki Hirano,
Shuji Tanada,
Masaomi Iyo,
Toshiaki Irie
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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.
Neuropsychopharmacology 01/2006; 30(12):2154-61. · 7.99 Impact Factor
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Koichi Sato,
Kiyoshi Fukushi, Hitoshi Shinotoh,
Shinichiro Nagatsuka,
Noriko Tanaka,
Akiyo Aotsuka,
Tsuneyoshi Ota,
Tetsuya Shiraishi,
Shuji Tanada,
Masaomi Iyo,
Toshiaki Irie
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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.
Journal of Cerebral Blood Flow & Metabolism 07/2004; 24(6):600-11. · 5.01 Impact Factor
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Tsuneyoshi Ota, Hitoshi Shinotoh,
Kiyoshi Fukushi,
Shin-ichiro Nagatsuka,
Hiroki Namba,
Masaomi Iyo,
Akiyo Aotsuka,
Noriko Tanaka,
Koichi Sato,
Tetsuya Shiraishi,
Shuji Tanada,
Heii Arai,
Toshiaki Irie
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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.
Annals of Nuclear Medicine 06/2004; 18(3):187-93. · 1.50 Impact Factor
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ABSTRACT: Several cholinesterase (ChE) inhibitors have been labeled with carbon-11 for visualizing binding sites on acetylcholinesterase (AChE) by positron emission tomography (PET). Following intravenous injection of 1,2,3,4-tetrahydro-9-[(11)C]methylaminoacridine or [(11)C]donepezil, however, the radioactivity distribution does not reflect the regional distribution of AChE in the brain of animals, probably because these compounds have high non-specific binding and/or other specific binding sites in vivo in the brain. PET studies with [(11)C]physostigmine and [(11)C]CP-126,998 in the brain of healthy subjects have shown a radioactivity distribution corresponding to the regional distribution of AChE activity measured in postmortem human brains. These radiotracers may be useful for measuring the occupancy of binding sites on AChE by AChE inhibitors, and for investigating the cerebral pharmacokinetics of such therapeutic drugs. An alternative approach to map AChE is the use of acetylcholine analogue substrates. We have developed N-methylpiperidinyl esters labeled with carbon-11 for quantitative measurement of AChE activity. Currently, two N-[(11)C]methylpiperidine esters, N-[(11)C]methylipiperidin-4-ylacetate (MP4A) and N-[(11)C]methylpiperidin-4-yl propionate (MP4P or PMP), have been used for clinical studies of Alzheimer's disease and other neurodegenerative diseases. Both [(11)C]MP4A- and [(11)C]MP4P-PET have demonstrated not only the reduction of AChE activity in the cerebral cortex of patients with Alzheimer's disease (AD) but also the inhibitory effects of donepezil and rivastigmine on AChE activity in the brain of AD patients. AChE imaging should prove useful for therapeutic monitoring of the effects of ChE inhibitors, including determination of the appropriate clinical doses of newly developed compounds, and can thus prompt the development of novel drugs targeting AChE.
Current Pharmaceutical Design 02/2004; 10(13):1505-17. · 3.87 Impact Factor
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ABSTRACT: We examined the autopsied brains of two parkinsonian patients who had malignant syndrome (MS). Neopterin and biopterin contents, and GTP cyclohydrolase I activity were measured in various region of the brain. We found relatively higher GTP cyclohydrolase I activities in the hypothalamus compared with other regions of the brain from patients with MS. This finding suggested a possible involvement of biopterin metabolism in pathophysiology of MS. This is the first report on biopterin metabolism in the brains of patients with MS.
Parkinsonism & Related Disorders 05/2003; 9 Suppl 1:S11-4. · 3.80 Impact Factor
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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.
Methods 08/2002; 27(3):242-50. · 4.01 Impact Factor
