title: Cholinergic enhancement of frontal lobe activity in mild cognitive impairment.
abstract: Cholinesterase inhibitors positively affect cognition in Alzheimer's disease (AD) and other conditions, but no controlled functional MRI studies have examined where their effects occur in the brain. We examined the effects of donepezil hydrochloride (Aricept) on cognition and brain activity in patients with amnestic mild cognitive impairment (MCI), a diagnosis associated with a high risk of developing AD. Nine older adults with MCI were compared with nine healthy, demographically matched controls. At baseline, patients showed reduced activation of frontoparietal regions relative to controls during a working memory task. After stabilization on donepezil (5.7 +/- 1.7 weeks at 10 mg) patients showed increased frontal activity relative to unmedicated controls, which was positively correlated with improvement in task performance (r = 0.49, P = 0.05) as well as baseline hippocampal volume (r = 0.62, P < 0.05). The patients' overall cognitive function was stable or improved throughout the study. Short-term treatment with a cholinesterase inhibitor appears to enhance the activity of frontal circuitry in patients with MCI, and this increase appears to be related to improved cognition and to baseline integrity of the hippocampus. These relationships have implications for understanding the mechanisms by which cognition-enhancing medications exert their effects on brain function and for the use of functional MRI in early detection and treatment monitoring of AD and MCI.
authors.affiliation: Brain Imaging Laboratory, Department of Psychiatry, Dartmouth Medical School, Lebanon, NH 03756, USA. Andrew.J.Saykin@dartmouth.edu
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
authors.forename: Heather A
authors.initials: HA
authors.lastname: Wishart
authors.forename: Laura A
authors.initials: LA
authors.lastname: Rabin
authors.forename: Laura A
authors.initials: LA
authors.lastname: Flashman
authors.forename: Tara L
authors.initials: TL
authors.lastname: McHugh
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Mamourian
authors.forename: Robert B
authors.initials: RB
authors.lastname: Santulli
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000077265:Donepezil; D005260:Female; D005625:Frontal Lobe / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007189:Indans / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D010880:Piperidines / Q000627:therapeutic use*
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil