Positron emission tomography: quantitative measurement of brain acetylcholinesterase activity using radiolabeled substrates.
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.
Namba
Hiroki
H
Department of Neurosurgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan. hnamba@hama-med.ac.jp
Fukushi
Kiyoshi
K
Nagatsuka
Shin-ichiro
S
Iyo
Masaomi
M
Shinotoh
Hitoshi
H
Tanada
Shuji
S
Irie
Toshiaki
T
D000110:Acetylcholinesterase / Q000032:analysis* / Q000097:blood / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology; D001921:Brain / Q000201:enzymology*; D002250:Carbon Radioisotopes; D005260:Female; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000201:enzymology; D010880:Piperidines / Q000097:blood; D011849:Radioactive Tracers; D012016:Reference Values; D014055:Tomography, Emission-Computed / Q000379:methods*
D002250:Carbon Radioisotopes; C471399:N-methylpiperidin-4-yl acetate; D010880:Piperidines; D011849:Radioactive Tracers; D000110:Acetylcholinesterase