Measurement of acetylcholinesterase by positron emission tomography in the brains of healthy controls and patients with Alzheimer's disease

Iyo, Masaomi; Namba, Hiroki; Fukushi, Kiyoshi; Shinotoh, Hitoshi; Nagatsuka, Shin-ichiro; Suhara, Tetsuya; Sudo, Yasuhiko; Suzuki, Kazutoshi; Irie, Toshiaki

doi:10.1016/s0140-6736(96)09124-6

Cited by 241 publications

(119 citation statements)

References 26 publications

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“…Iyo et al (1997) used PET with a radioactively labeled acetylcholine analog to obtain in vivo measures of acetylcholinesterase activity in early onset AD patients and healthy controls. Marutle, Warpman, Bogdanovic, Lannfelt, and Nordberg (1999) reported that the parietal cortex was burdened with the highest beta amyloid load compared with other cortical regions in patients with the Swedish APP Alzheimer susceptibility mutation.…”

Section: Apoe Attention and The Cholinergic Systemmentioning

confidence: 99%

The apolipoprotein E gene, attention, and brain function.

Parasuraman¹,

Greenwood²,

Sunderland³

2002

Neuropsychology

108

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The ɛ4 allele of the apolipoprotein E (ApoE) gene is associated with alterations in brain function and is a risk factor for Alzheimer's disease (AD). Changes in components of visuospatial attention with ApoE-ɛ4, aging, and AD are described. Healthy middle-aged adults without dementia who have the ApoE-ɛ4 gene show deficits in spatial attention and working memory that are qualitatively similar to those seen in clinically diagnosed AD patients. The findings support an association between ApoE polymorphism and specific components of visuospatial attention. Molecular mechanisms that may mediate the ApoE-attention link by modulating cholinergic neurotransmission to the posterior parietal cortex are discussed. Studies of attention and brain function in ApoE-ɛ4 carriers without dementia can advance knowledge of the genetics of visual attention, may enhance understanding of the preclinical phase of AD, and may lead to better methods for early AD detection.Apolipoprotein E (ApoE) is an amino acid glycoprotein that is important in lipid storage, transport, and metabolism (Mahley, 1988). Although synthesized mainly in the liver, ApoE is also found in the peripheral and central nervous systems, including the brain. ApoE has long been of interest in medicine, but its importance in neuroscience increased dramatically with the identification of the ɛ4 allele of the ApoE gene on chromosome 19 as a major risk factor for the development of late-onset Alzheimer's disease (AD) in older adults Strittmatter et al., 1993). This discovery led to a growing number of studies examining the role of the ApoE gene in normal brain function and cognition, as well as in disorders such as AD, brain injury, and stroke (Higgins, Large, Rupniak, & Barnes, 1997;Horsburgh, McCarron, White, & Nicol, 2000; J. D. Smith, 2000).Polymorphisms of the ApoE gene are associated with significant alterations in brain morphology (Plassman et al., 1997) and cognitive functioning, including attention (Greenwood, Sunderland, Friz, & Parasuraman, 2000) and memory (Bondi et al., 1995). Studies of ApoE may thus reveal information relevant to the genetics of attention and memory in normal individuals. At the same time, such studies may identify cognitive and neural changes that may be characteristic of preclinical stages of AD. In this article, we review the role of the ApoE gene in normal cognition and in the development of deficits indicative of early AD.Currently, no reliable methods exist for the early detection and treatment of AD. New techniques for preventing, slowing the progression of, and treating AD are being urgently sought. Such efforts would be aided considerably if AD could be detected prior to the clinical diagnosis of AD and before irreversible brain changes occur (Daffner & Scinto, 2000). Postmortem studies show that neuropathological changes occur decades before the onset of NIH Public Access Author ManuscriptNeuropsychology. Author manuscript; available in PMC 2006 January 25. Published in final edited form as:Neuropsychology. 2002 April ; ...

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Section: Apoe Attention and The Cholinergic Systemmentioning

confidence: 99%

The apolipoprotein E gene, attention, and brain function.

Parasuraman¹,

Greenwood²,

Sunderland³

2002

Neuropsychology

108

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“…In recent years, N-[ 11 C]methylpiperidin-4-yl acetate ([ 11 C]MP4A) (Irie et al, 1994) and N-[ 11 C]methylpiperidin-4-yl propionate ([ 11 C]MP4P) (Irie et al, 1994;Kilbourn et al, 1996) have been developed as radiotracers for brain AChE mapping and applied to quantification of neocortical AChE activity in healthy subjects (Namba et al, 1999;Koeppe et al, 1999) and in patients with AD (Iyo et al, 1997;Kuhl et al, 1999). Both tracers were also applied to evaluating the inhibitory effect of donepezil on brain AChE activity in AD patients (Kuhl et al, 2000;Shinotoh et al, 2001;Kaasinen et al, 2002) and in monkeys (Tsukada et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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

Kikuchi

Fukushi

et al. 2005

Neuropsychopharmacol

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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 mg/kg (donepezil-1; N ¼ 5) or 250 mg/kg (donepezil-2; N ¼ 5), were performed using the same monkeys at 4-week intervals. Before each PET scan, baseline PET scans (N ¼ 10 in total) were performed without donepezil. The plasma donepezil concentrations 14 min after intravenous injection were proportional to the doses, 17.272.9 ng/ml (donepezil-1) and 44.075.0 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 (estimate7SE) were 4279.0 (ng/ml; donepezil-1), 3473.2 (donepezil-2), and 3774.1 (combined data). The present method may be useful for in vivo evaluation of other AChE inhibitors and novel drugs.

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“…Evidence from early histological postmortem studies [9] is consistent with the reduction in cortical acetylcholinesterase (AChE) activity demonstrated in PET studies [10] and the atrophy of the nucleus basalis of Meynert as revealed using structural MRI [11]. This nucleus in the basal forebrain is the major source of AChE, as well as the origin of cholinergic neurotransmission and projections to cortical brain areas associated with learning and memory, e.g.…”

Section: Pharmacological Treatment Of MCImentioning

confidence: 64%

Pharmacological Treatment of Mild Cognitive Impairment as a Prodromal Syndrome of Alzheimer's Disease

Karakaya

Fußer²,

Schröder³

et al. 2013

Current Neuropharmacology

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Mild cognitive impairment (MCI) is a syndrome which, depending on various neurobiological, psychological and social factors, carries a high risk of developing into dementia. As far as diagnostic uncertainty and the heterogeneous underlying pathophysiological mechanisms are concerned, only limited therapeutic options are currently available. Clinical trials involving a wide range of substances have failed to show efficacy on primary and secondary outcome parameters. Most results reflect not only a lack of effectiveness of drug therapy but also methodological constraints in true prodromal Alzheimer´s disease (AD) based on clinical criteria. Biomarkers may help to identify MCI as a prodromal phase of dementia, so it is important to use them to improve specificity of case selection in future studies. For MCI as a prodromal syndrome of AD, clinical trials with disease modifying drugs that target underlying pathological mechanisms such as amyloid-beta accumulation and neurofibrillary tangle formation may help develop effective treatment options in the future. Alternative pharmacological approaches are currently being evaluated in ongoing phase 1 and phase 2 studies. Nevertheless, a lack of approved pharmacotherapeutic options has led to specific interventions that focus on patient education and life-style related factors receiving increasing attention.

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Measurement of acetylcholinesterase by positron emission tomography in the brains of healthy controls and patients with Alzheimer's disease

Cited by 241 publications

References 26 publications

The apolipoprotein E gene, attention, and brain function.

The apolipoprotein E gene, attention, and brain function.

Estimation of Plasma IC50 of Donepezil Hydrochloride for Brain Acetylcholinesterase Inhibition in Monkey Using N-[11C]methylpiperidin-4-yl Acetate ([11C]MP4A) and PET

Pharmacological Treatment of Mild Cognitive Impairment as a Prodromal Syndrome of Alzheimer's Disease

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