Early ReportMeasurement of acetylcholinesterase by positron emission tomography in the brains of healthy controls and patients with Alzheimer's disease
Introduction
Alzheimer's disease is a brain disorder characterised by a progressive dementia that starts in middle-to-late life. The presence of pathological changes such as neuritic plaques and neurofibrillary tangles is required for the definitive diagnosis of the disease. These changes can, however, be detected only by microscopic examination of brain tissue, usually at necropsy. Extensive studies into neurochemical changes in the brain in Alzheimer's disease have been reported1, 2, 3 and correlation of these changes with dementia severity has been sought.4, 5, 6, 7 However, most of these studies have been based on clinical assessment and observation of biological changes of brains at necropsy.
One of the principal difficulties is in the direct comparison between cognitive and functional performance of living patients who have Alzheimer's disease and healthy individuals and biological changes found at necropsy. Studies of cerebral biopsy samples may also be limited by lack of sampling from multiple brain regions.8 Therefore, detection of neurochemical and neuropathological changes by in-vivo techniques such as positron emission tomography (PET)9, 10 and single photon emission computed tomography (SPECT)11 must be developed. Such methods will allow clinical diagnosis and prognosis for dementia severity, understanding of the disease mechanisms, and development of therapeutic drugs.
The degeneration of the cortical cholinergic system is one of the most consistent neurochemical changes in Alzheimer's disease.1, 2, 3, 4, 7, 12 It has been shown that choline acetyltransferase and acetylcholinesterase activities in the cerebral cortex, the reduction of which accompany degeneration of cholinergic neurons in the basal forebrain, were significantly negatively correlated with the number of senile plaques4 and severity of dementia before death.7 Therefore, if choline acetyltransferase and/or acetylcholinesterase in the living human brain could be measured, it would give new insights into Alzheimer's disease.
In the present study, we measured regional acetyl-cholinesterase activity in the living brains of normal elderly people and patients with Alzheimer's disease by PET.
Section snippets
Methods
The principle of the method we used is that a radiolabelled lipophilic substrate analogue, [11C]N-methyl-4-piperidyl acetate (MP4A), for the target enzyme acetylcholinesterase is given as an intravenous injection. The [11C]MP4A then reaches the brain via the blood-brain barrier in a regional cerebral blood-flow dependent manner. A proportion of the [11C]MP4A that reaches the brain tissue diffuses back across the blood-brain barrier, while the rest of the [11C]MP4A is hydrolysed by
Healthy participants
The representative curves of radioactivity in the brain regions—ie, cerebellum for regions with high acetylcholinesterase activity, thalamus for moderate, and temporal cortex for low—and of the metabolite-corrected [11C]MP4A in the arterial plasma from a participant without Alzheimer's disease are shown in figure 3.24, 25 The radioactivity in the cerebellum, following an initial increase, further increases to reach a plateau, whereas that in the cerebral cortex gradually decreases to a certain
Discussion
The ratios for the k3 values for the cerebral cortex/thalamus/cerebellum/striatum found in healthy participants were 1/3/8/10, respectively, corresponding well with the acetylcholinesterase activity ratios in the brain at necropsy (1/3/8/38),24, 25 except for the striatum. The reason that the k3 value in the striatum did not correspond with the necropsy data is explained by the nature of the tracer.13 Most of the tracer entering the region with a very high acetylcholinesterase activity is
References (28)
- et al.
Alzheimer's disease: correlation of cortical choline acetyltransferase activity with severity of dementia and histological abnormalities
J Neurol Sci
(1982) - et al.
Selective loss of central cholinergic neurons in Alzheimer's disease
Lancet
(1976) - et al.
Design and evaluation of radioactive acetylcholine analogs for mapping brain acetylcholinesterase (AChE)
in vivo. Nucl Med Biol
(1994) - et al.
In vivo measurement of acetylcholinesterase activity in the brain with a radioactive acetylcholine analog
Brain Res
(1994) - et al.
Mini-mental state: a practical method for grading the cognitive state of patients for the clinician
J Psychiatr Res
(1975) Brain neurotransmitters in aging and dementia: similar changes across diagnostic dementia groups
Gerontology
(1987)Alzheimer's disease and senile dementia: biochemical characteristics and aspects of treatment
Psychopharmacology
(1985)- et al.
Neocortical morphometry, lesion counts and choline acetyltransferase level in the age spectrum of Alzheimer's disease
Neurology
(1988) - et al.
Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia
BMJ
(1978) - et al.
Presynaptic cholinergic dysfunction in patients with dementia
J Neurochem
(1983)
Neurochemical correlates of dementia severity in Alzheimer's disease: relative importance of the cholinergic deficits
J Neurochem
Cortical biopsy results in Alzheimer's disease correlation with cognitive deficits
Neurology
Mapping muscarinic receptors in human and baboon brain using [N-11C-methyl]- benztropine
Synapse
In vivo imaging of human cerebral acetylcholinesterase
J Neurochem
Cited by (246)
The effect of wavelength on the variability of the flash visual evoked potential P2: A potential biomarker for mild cognitive impairment and Alzheimer's dementia
2021, International Journal of PsychophysiologyCitation Excerpt :In fact, research has shown that a decline in the cholinergic functioning could be the underlying cause of the symptoms associated with AD, given that acetylcholine supports many cognitive functions associated with the disease, including learning, attention, and memory (Bajalan et al., 1986; Kihara and Shimohama, 2004). Consequently, the accurate measurement of the cholinergic system's functioning might lead to the early detection and treatment of AD (Iyo et al., 1997). One such measure is the flash visual-evoked potential-P2 (FVEP-P2; Case et al., 2016; Coburn et al., 2005; Moore et al., 1996).
PET Agents in Dementia: An Overview
2021, Seminars in Nuclear MedicineCitation Excerpt :Most PET studies of cerebral AChE have used radiolabeled AChE substrates, particulary [11C]MP4A and to a lesser extent [11C]PMP (= MP4P). In an initial study with [11C]MP4A, 31%-38% reductions of AChE activity were noted in the temporal and parietal cortex of AD patients, whereas smaller reductions were observed in other cortical areas.300 This result was confirmed in later studies that reported a global decrease of cerebral AChE activity in dementia301 with particular decreases in the lateral temporal lobes.302
Molecular Imaging of Extrapyramidal Movement Disorders With Dementia: The 4R Tauopathies
2021, Seminars in Nuclear MedicinePositron emission tomography imaging agents for evaluating the pathologic features of Alzheimer's disease and drug development
2020, Neurotherapeutics in the Era of Translational MedicineMolecular Imaging of the Cholinergic System in Parkinson's Disease
2018, International Review of Neurobiology