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.

Altered Brain Activation During a Verbal Working Memory Task in Subjects with Amnestic Mild Cognitive Impairment

“…The activation of the core regions found in the present study was consistent with previous studies, showing activation in inferior parietal areas, DLPFC, and language areas in the temporal lobe [16][17][18] to be key regions for verbal WM. The DLPFC is recruited for executive components of a task [57] and this region is also thought responsible for initiating the controlled processing of verbal working memory material [58][59].…”

“…The areas that we found activated in all three phases may be due to (a) maintenance processes that are activate during encoding and recall phases or (b) these regions mediated computational processes that are common in all three phases such as phonological processing and access to long term memory. Previous studies that examined WM obtained the average activation pattern across all phases of the WM task or the nback design was utilized, which did not allow for a separation of the different components of the task [16][17][18]62]. We demonstrated in this study that the MCI use alternative regions to subserve performance of a WM task.…”

“…For example using the n-back WM task in MCI subjects Goekoop and colleagues [16] found a network of activation that included the bilateral parietal lobes and prefrontal cortex with the extent of activation increasing in the 2-back compared to 1-back WM task. Another study that examined a verbal 0-, 1-, and 2-back WM tasks found that the MCI had reduced activation compared to HC bilaterally in the parietal and frontal regions [17]. A recent study found that aMCI and HC in a 2-back WM task using visually presented emotional stimuli activated a wide network including bilaterally the parietal and frontal lobes with a group by emotion interaction effect in the left cuneus, where the HC group had lower activation for the positive valence stimuli compared to the neutral valence stimuli [18].…”

Task-dependent posterior cingulate activation in mild cognitive impairment

“…Eight of the MCI participants were taking stable doses of cholinesterase inhibitors, and this may have affected their BOLD responses. Empirical investigation into the effect of cholinesterase inhibitors is limited, although there is some evidence that these medications may increase the BOLD response in some populations (Saykin et al, 2004;Thiel, Bentley, & Dolan, 2002). Taking cholinesterase medication would have the effect of improving cognitive function in the MCIs, and it is possible that this would be associated in a more robust task-related BOLD signal in MCI participants (i.e., mitigation of the difference in BOLD signal between controls and MCI participants).…”

Model‐free group analysis shows altered BOLD FMRI networks in dementia

“…The most common method of analyzing data from a standard FMRI activation experiment is to create a model of the expected BOLD response [using an a-priori model of the haemodynamic response function (HRF)] and estimate the magnitude of the response using methods of parameter fitting within the framework of the generalized linear model (GLM). Such methods have successfully been used to detect regionally altered brain activation in AD and MCI [see for example Dickerson et al, 2004;Golby et al, 2005;Lustig et al, 2003;Rombouts et al, 2005b], and brain activation changes after pharmacologic treatment in dementia [Goekoop et al, 2004;Rombouts et al, 2002;Saykin et al, 2004]. Modelbased analysis approaches, however, rely heavily on assumptions about the temporal characteristics of haemodynamic signals and are limited to cases where these underlying assumptions well characterize the effects of interest.…”