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Age and APOE‐ϵ4 genotype influence the effect of physostigmine infusion on the in‐vivo distribution volume of the muscarinic‐2‐receptor dependent tracer [ 18 F]FP‐TZTP
Author(s) -
Cohen Robert M.,
Carson Richard E.,
Filbey Francesca,
Szczepanik Joanna,
Sunderland Trey
Publication year - 2006
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20276
Subject(s) - apolipoprotein e , physostigmine , muscarinic acetylcholine receptor , medicine , cholinergic , endocrinology , allele , acetylcholinesterase , genotype , in vivo , chemistry , agonist , biology , receptor , biochemistry , genetics , disease , gene , enzyme
The apolipoprotein E‐ϵ4 allele (APOE‐ϵ4) confers greater susceptibility to age‐related memory disorders. Abnormalities in the cholinergic system are likely contributors to these disorders with both age and APOE‐ϵ4 genotype modifying behavioral and physiological responses to drugs that alter cholinergic pathway function. Recently, we reported a greater in vivo distribution volume of the F‐18 labeled muscarinic‐2 (M2) selective agonist, 3‐(3‐(3‐[ 18 F]Flouropropyl)thio)‐1,2,5‐thiadiazol‐4‐yl)‐1,2,5,6‐tetrahydro‐1‐methylpyridine ([ 18 F]FP‐TZTP), in aging healthy subjects with an APOE‐ϵ4 allele. To examine the effects of aging and the APOE‐ϵ4 allele on the response of the muscarinic component of cholinergic pathway to pharmacologic augmentation, two [ 18 F]FP‐TZTP PET scans were conducted in 19 subjects varying in age from 22 to 74 years, the first served as baseline for the second scan that was performed while the subjects were either infused with saline ( n = 6) or with the acetylcholinesterase inhibitor physostigmine (6 with an APOE‐ϵ4 allele and 7 without an APOE‐ϵ4 allele). Using a multiple regression analysis, both AGE (β = 0.621 ± 0.135, B = 0.353 ± 0.077, t (10) = 4.61, P < 0.001) and APOE‐ϵ4 genotype (β = 0.742, B = 14.8 ± 2.69, t (10) = 5.51, P < 0.0003) were found to be significant contributors to subject response to physostigmine. The adjusted R 2 for the model as a whole was 0.786 ( F (2,10) = 23.00, P < 0.0002) with both increasing age and the presence of the APOE‐ϵ4 allele modifying the response to physostigmine in the direction of larger decreases in [ 18 F]FP‐TZTP distribution volumes in all brain regions examined. The findings, particularly the absence of an interaction between AGE and APOE‐ϵ4 genotype, contribute to the growing body of evidence that suggests that the APOE‐ϵ4 genotype is likely to contribute to brain structure and function prior to aging. Synapse 60:86–92, 2006. Published 2006 Wiley‐Liss, Inc.