Acetylcholinesterase inhibitors reduce spreading activation in dementia Paul S. Foster a,b,c,n , Kaylei K. Branch a , John C. Witt c , Tania Giovannetti d , David Libon e , Kenneth M. Heilman b , Valeria Drago b,f a Middle Tennessee State University, Murfreesboro, TN 37132, USA b University of Florida, FL, USA c Murfreesboro Medical Clinic, Murfreesboro, TN 37130, USA d Temple University, Philadelphia, PA 19122, USA e Drexel University, PA 19122, USA f Laboratorio LENITEM, IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy article info Article history: Received 8 February 2012 Received in revised form 9 April 2012 Accepted 8 May 2012 Keywords: Acetylcholinesterase inhibitor Dementia Memory Spreading activation abstract Alzheimer’s disease is associated with degeneration of the cholinergic system, which affects memory and attention functioning. Acetylcholinesterase inhibitors (AChEI) have been found to increase attention and given this effect might reduce spreading activation of memory nodes in lexical/semantic networks. We sought to determine whether this effect of AChEIs existed in a group of patients with dementia. A mixed sample of 34 patients with dementia (17 taking AChEIs and 17 not taking these medications) were administered the Controlled Oral Word Association Test and the Animal Naming Test. The average word frequency for their responses was obtained and used as a measure of spreading activation. Patients taking AChEIs had a significantly higher average word frequency for the COWAT as compared to those not taking AChEIs. No difference was found for the average word frequencies for the AN test. Administration of AChEIs appears to reduce spreading activation, possibly due to cholinergic innervations of the frontal cortex. & 2012 Elsevier Ltd. All rights reserved. 1. Introduction Post mortem studies of patients with Alzheimer’s disease (AD) have revealed that this disease is associated with a significant degeneration of the basal forebrain’s cholinergic neurons, includ- ing the nucleus of Meynert that sends cholinergic projections across widespread regions of the cerebral cortex and the medial septal nucleus that sends cholinergic projections to the hippo- campus. (Bowen et al., 1983; Davies & Maloney, 1976; Kasa, Rakonczay, & Gulya, 1997). Reduced levels of choline acetyltrans- ferase (ChAT) have been reported in patients with AD (Bowen, Benton, Spillane, Smith, & Allen, 1982; Davis et al., 1999) and a relationship exists between the extent of this reduction and the density of neuritic plaques and neurofibrillary tangles (Davis et al., 1999; Perry et al., 1978). Further, the reduction in ChAT appears to be worse in AD patients with a younger age of onset (Rossor, Iversen, Reynolds, Mountjoy, & Roth, 1984). More recent investigations using functional imagining to examine the choli- nergic system in vivo have also found a degeneration of the cholinergic system in the frontal, parietal and temporal cerebral cortex of patients with AD, as well as in the hippocampus (Araujo, Lapchak, Robitaille, Gauthier, & Quirion, 1988; Herholz et al., 2000; Shinotoh et al., 2000a,2000b). Also, the degree of choliner- gic loss is correlated with global cognitive status (Shinotoh et al., 2000b). Another study reported that patients with mild cognitive impairment who later developed dementia also had reduced levels of AChE (Herholz, Weisenbach, Kalbe, Diederich, & Heiss, 2005). The degeneration of the cholinergic system has lead to the use of acetylcholinesterase inhibitor (AChEI) medications to treat the cognitive deficits associated with AD. Reviews of the literature have generally supported the use of these AChEIs (donepezil, rivastigmine, and galantamine) to treat patients with AD (Clegg et al., 2002; Evans, Wilcock, & Birks, 2004). Studies using the anticholinergic (anti-muscarinic) agent scopolamine have revealed that this agent reduces the ability of normal subjects to allocate selective attention (Dunne & Hartley, 1986; Furey, Pietrini, Haxby, & Drevets, 2008). The degeneration of the cholinergic system in AD also has profound effects on attention (Parasuraman & Haxby, 1993), including indices of selective attention (Gorus, De Raedt, Lambert, Lemper, & Mets, 2006; Perry & Hodges, 1999). Research has also found relatively impaired focal attention as opposed to global attention in patients with AD (Delis et al., 1992; Slavin, Mattingley, Bradshaw, & Storey, 2002). Additionally, the performance of AD patients on tests of attention is correlated with changes in AChE activity and Contents lists available at SciVerse ScienceDirect journal homepage: www.elsevier.com/locate/neuropsychologia Neuropsychologia 0028-3932/$ - see front matter & 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuropsychologia.2012.05.010 n Corresponding author at: Psychology Department, Middle Tennessee State University, 1500 Greenland Drive, Murfreesboro, TN 37132, United States. Tel.: þ1 615 898 2007; fax: þ1 615 898 5027. E-mail address: paul.foster@mtsu.edu (P.S. Foster). Please cite this article as: Foster, P. S., et al. Acetylcholinesterase inhibitors reduce spreading activation in dementia. Neuropsychologia (2012), http://dx.doi.org/10.1016/j.neuropsychologia.2012.05.010 Neuropsychologia ] (]]]]) ]]]–]]]