Regulation of attention and response to therapy in dementia by butyrylcholinesterase.
OBJECTIVE
To determine the response of patients with different butyrylcholinesterase genotypes to therapy, and the influence of butyrylcholinesterase on cognition. Acetylcholine plays a key role in attention and memory and reduced cortical acetylcholine is associated with the severity of dementia. Inhibitors of the enzyme acetylcholinesterase are an effective dementia treatment, though the role of the related enzyme butyrylcholinesterase is less well understood.


METHODS
We examined the response of a cohort of dementia patients enrolled in a trial of a cholinesterase inhibitor who had been genotyped at the butyrylcholinesterase locus. Additionally a prospectively assessed cohort of dementia patients was genotyped and rate of cognitive decline examined, along with baseline cognitive performance in a group of elderly non-demented individuals. We identified that the presence of reduced-activity butyrylcholinesterase variants correlates with preserved attentional performance and reduced rate of cognitive decline. During cholinesterase inhibitor therapy, patients with normal butyrylcholinesterase show improved attention, though patients carrying reduced-activity enzyme do not, possibly due to being at ceiling performance. Butyrylcholinesterase did not however affect attentional performance in non-demented individuals with mild cognitive impairment.


CONCLUSIONS
These findings indicate that the butyrylcholinesterase enzyme is a major regulator of attention especially in cholinergic deficiency states through its ability to hydrolyse acetylcholine. Pharmacologic manipulation of this enzyme may be a viable strategy in dementia treatment and, with butyrylcholinesterase genotyping, may provide pharmacogenomic treatment of dementia.
O'Brien
Kirsty K
KK
MRC Building, MRC/University of Newcastle Centre Development for Clinical Brain Ageing, Newcastle upon Tyne, NE1 3BZ, UK.
Saxby
Brian K
BK
Ballard
Clive G
CG
Grace
Jan
J
Harrington
Frances
F
Ford
Gary A
GA
O'Brien
John T
JT
Swan
Alan G
AG
Fairbairn
Andrew F
AF
Wesnes
Keith
K
del Ser
Teodoro
T
Edwardson
James A
JA
Morris
Christopher M
CM
McKeith
Ian G
IG
D000109:Acetylcholine / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000523:psychology; D019943:Amino Acid Substitution; D001288:Attention / Q000187:drug effects*; D002091:Butyrylcholinesterase / Q000172:deficiency / Q000235:genetics* / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D003071:Cognition; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D003704:Dementia / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000523:psychology; D005838:Genotype; D006801:Humans; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction
D002800:Cholinesterase Inhibitors; D017931:DNA Primers; D004247:DNA; D002091:Butyrylcholinesterase; D000109:Acetylcholine