Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Original Research Article Dement Geriatr Cogn Disord 2010;30:553–568 DOI: 10.1159/000322112 Functional Alterations in Brain Activation and Deactivation in Mild Cognitive Impairment in Response to a Graded Working Memory Challenge N.A. Kochan   a, d M. Breakspear   b, f, g M.J. Slavin   a M. Valenzuela   a S. McCraw   a, f H. Brodaty   a, c, e P.S. Sachdev   a, d a  Brain and Ageing Research Program, School of Psychiatry, b  School of Psychiatry, c  Dementia Collaborative Research Centre, University of New South Wales, d  Neuropsychiatric Institute, e  Academic Department for Old Age Psychiatry, Prince of Wales Hospital, and f  The Black Dog Institute, Sydney, N.S.W., and g  Queensland Institute of Medical Research, Brisbane, Qld., Australia jects was associated with greater clinical severity and a more abnormal pattern of performance variability. Conclusion: Patterns of overactivation, underactivation and deactivation during successful encoding in MCI subjects were dependent on WM load. This type of graded cognitive challenge may operate like a ‘memory stress test’ in MCI and may be a use- ful biomarker of disease at the predementia stage. Copyright © 2011 S. Karger AG, Basel Introduction There is an increasing focus on the preclinical stage of Alzheimer’s disease (AD) and other dementias in an at- tempt to identify biomarkers that can be used to predict the development of dementia. Volumetric structural brain changes are evident at the predementia stage, but these are still of uncertain diagnostic value [1]. There is a great deal of interest in the possibility of functional neu- roimaging markers which may allow diagnosis at an ear- lier stage of disease since alterations in synaptic activity precede cortical atrophy [2]. Altered patterns of brain ac- tivity under the stress of cognitive test performance have been demonstrated using functional magnetic resonance Key Words Mild cognitive impairment  Alzheimer’s disease  Functional magnetic resonance imaging  Working memory  Memory  Default mode network Abstract Aim: To investigate dynamic changes in functional brain ac- tivity in mild cognitive impairment (MCI) in response to a graded working memory (WM) challenge with increasing memory load. Methods: In an event-related functional mag- netic resonance imaging (fMRI) study, 35 MCI and 22 cogni- tively normal subjects performed a visuospatial associative WM task with 3 load levels. Potential performance differenc- es were controlled for by individually calibrating the number of items presented at each load. Results: An interaction be- tween group and WM load was observed during stimulus encoding. At lower loads, greater activity in the right ante- rior cingulate and right precuneus was observed in MCI sub- jects. As the load increased to higher levels, reduced acti- vation in these regions and greater deactivation in the pos- terior cingulate-medial precuneus were observed in MCI compared to control subjects. Stronger expression of load- related patterns of activation and deactivation in MCI sub- Published online: January 20, 2011 Nicole Kochan Neuropsychiatric Institute Prince of Wales Hospital, Randwick Sydney, NSW 2031 (Australia) Tel. +61 43 823 9200, Fax +61 2 9382 3774, E-Mail n.kochan  @  unsw.edu.au © 2011 S. Karger AG, Basel 1420–8008/10/0306–0553$26.00/0 Accessible online at: www.karger.com/dem