Neurobiology ofAging, Vol. 13, pp. 747-758, 1992 0197-4580/92$5.00 + .00 Printed in the USA.All rightsreserved. Copyright© 1992PergamonPressLtd. Tacrine Restores Cholinergic Nicotinic Receptors and Glucose Metabolism in Alzheimer Patients as Visualized Positron Emission Tomography AGNETA NORDBERG *l, ANDERS LILJA§, HANS LUNDQVIST§, PER HARTVIG§, KAARINA AMBERLAt, MATTI VIITANENt, ULRIKA WARPMAN*, MONIKA JOHANSSON:[:, EWA HELLSTROM- LINDAHL*, PETER BJURLING§, KARL-JOHAN FASTH§, BENGT LANGSTROM§ AND BENGT WINBLADt *Department of Pharmacology, Uppsala University, S-751 24 Uppsala, Sweden t Department of Geriatric Medicine, Karolinska lnstitutet, Huddinge Hospital, S-141 86 Huddinge, Sweden 5;Division of Pharmacotherapeutics, Medical Product Agency, S-751 03 Uppsala, Sweden § Uppsala University PET Centre, UAS, S-751 85 Uppsala, Sweden Received 19 December 1991; Accepted 11 June 1992 NORDBERG, A., A. LILJA.,.H. LUNDQVIST, P. HARTVIG, K. AMBERLA, M. VilTANEN, U. WARPMAN, M. JOHANSSON, E. HELLSTROM-LINDAHL, P. BJURLING, K. J. FASTH, B. L~,NGSTROM AND B. WINDBLAD. Tac- rine restores cholinergic nicotinic receptorsand glucose metabolism in Alzheimerpatients as visualizedby positron emission tomography. NEUROB1OL AGING 13(6)747-758, 1992.--Three patients with Alzheimer's disease, a 68-year-old woman with mild dementia and 2 men (aged 64 and 72 years) with moderate dementia were treated orally with the cholinesterase inhibitor tacrine (tetrahydroaminoacridine), 80 mg daily, for several months. The patients were investigated using positron emission tomography (PET) prior to, and after 3 weeks and 3 months of treatment. The PET studies involved a multi-tracer system consisting of [~SF]-fluoro-deoxy-glucose (JSF-FDG)(tracer for glucose metabolism); HC-butanol (cerebral blood flow) and (S)(- )- and (R)( + )-[N-~ tC-methyl]-nicotine (nicotinic receptors; cholinergic neural activity). Tacrine treatment increased the uptake of ~C-nicotine to the brain. Significant reduced difference in uptake between the two enantiomers (S)(-)- and (R)( +)] LC-nicotine was observed in the frontal and temporal cortices after tacrine treatment in all three patients. The kinetic analysis indicated increased bindingof(S)( - )~ tC-nicotine in brain compatible with a restoration of nicotinic cholinergic recep- tors. The most pronounced effect was observed after 3 weeks and 3 months treatment in the patient with mild dementia. An increase in cerebral glucose utilization was found in the 68-year-old patient with mild dementia but also slightly in the 64-year- old man with moderate dementia when treated with tacrine for 3 months. Tacrine administration did not affect cerebral blood flow. The PET data obtained after 3 weeks oftacrine treatment was paralleled by improvement in neuropsychological perfor- mance. This study shows in vivo by PET neurochemical effects induced in brain by treatment with tacrine to Alzheimer patients. Intervention with tacrine in the early course of the disease might be necessary for clinical improvement. Tacrine Alzheimer's disease llC-nicotine ILC-butanol ~SF-fluoro-deoxy-glucose Nicotinic receptors PET Brain ALZHEIMER's disease (AD) is the most common form of de- mentia characterized by progressive global deterioration of cognitive function with preservation of many other brain func- tions. Although neurochemical analysis of Alzheimer brain tis- sues at autopsy have revealed deficits in more than one neu- rotransmitter system, the cholinergic system shows the most consistent changes and these correlate best with cognitive func- tion. The cholinergic hypothesis has therefore become of great interest for treatment strategies in this disease. The outcome of various clinical trials with various cholinergic agents was, how- ever, equivocal until the report by Summers et al. (40) using the moderately long-acting cholinesterase (ChE) inhibitor tac- rine (tetrahydroaminoacridine). Interestingly, basic pharma- cological studies indicate that the mechanism of action of tac- rine in brain may involve effects induced via several neurotransmitters, receptors, and ion channels in the brain (24,26,30). Several treatment studies with tacrine in Alzheimer patients have now been performed (5,9,12,14,41) or are in tRequests for reprints should be addressed to Agneta Nordberg, Department of Pharmacology, Box 591, S-751 24 Uppsala, Sweden. 747