Brain Advance Access originally published online on June 10, 2009
Brain 2009 132(8):2068-2078; doi:10.1093/brain/awp157
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Semantic memory activation in amnestic mild cognitive impairment
1 Department of Psychology, Wayne State University, Detroit, MI, USA 2 Department of Psychology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA 3 Department of Psychology and the Integrative Neuroscience Research Center, Marquette University 4 Foley Center for Aging and Development, Medical College of Wisconsin, Milwaukee, WI, USA 5 Functional Imaging Research Center, Medical College of Wisconsin, Milwaukee, WI, USA 6 Department of Psychiatry, Medical College of Wisconsin, Milwaukee, WI, USA 7 Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, USA 8 Schey Center for Cognitive Neuroimaging, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
Correspondence to: Stephen M. Rao, PhD, Schey Center for Cognitive Neuroimaging, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave./U10, Cleveland, OH 44195, USA E-mail: raos2{at}ccf.org
Cognitively intact older individuals at risk for developing Alzheimer's disease frequently show increased functional magnetic resonance imaging (fMRI) brain activation presumably associated with compensatory recruitment, whereas mild cognitive impairment (MCI) patients tend not to show increased activation presumably due to reduced neural reserve. Previous studies, however, have typically used episodic memory activation tasks, placing MCI participants at a performance disadvantage relative to healthy elders. In this event-related fMRI study, we employed a low effort, high accuracy semantic memory task to determine if increased activation of memory circuits is preserved in amnestic MCI when task performance is controlled. Fifty-seven participants, aged 65–85 years, comprised three groups (n = 19 each): amnestic MCI patients; cognitively intact older participants at risk for developing Alzheimer's disease based on having at least one ApoE 
4 allele and a positive family history of Alzheimer's disease (At Risk); and cognitively intact participants without Alzheimer's disease risk factors (Control). fMRI was conducted on a 3T MR scanner while participants performed a famous name discrimination task. Participants also underwent neuropsychological testing outside the scanner; whole brain and hippocampal atrophy were assessed from anatomical MRI scans. The three groups did not differ on demographic variables or on fame discrimination performance (>87% correct for all groups). As expected, the amnestic MCI participants demonstrated reduced episodic memory performance. Spatial extent of activation (Fame—Unfamiliar subtraction) differentiated the three groups (Control = 0 ml, At Risk = 9.7 ml, MCI = 34.7 ml). The MCI and At Risk groups showed significantly greater per cent signal change than Control participants in 8 of 14 functionally defined regions, including the medial temporal lobe, temporoparietal junction, and posterior cingulate/precuneus. MCI participants also showed greater activation than Controls in two frontal regions. At Risk, but not MCI, participants showed increased activity in the left hippocampal complex; MCI participants, however, evidenced increased activity in this region when hippocampal atrophy was controlled. When performance is equated, MCI patients demonstrate functional compensation in brain regions subserving semantic memory systems that generally equals or exceeds that observed in cognitively intact individuals at risk for Alzheimer's disease. This hyperactivation profile in MCI is even observed in the left hippocampal complex, but only when the extent of hippocampal atrophy is taken into consideration.
Key Words:
Area under the curve (AUC); fMRI; semantic memory; mild cognitive impairment; APOE 4
Abbreviations: DRS-2, Mattis Dementia Rating Scale-2; fMRI, functional magnetic resonance imaging; GDS, Geriatric Depression Scale; HRF, haemodynamic response function; MCI, mild cognitive impairment; RAVLT, Rey Auditory Verbal Learning Test
Received January 13, 2009. Revised April 3, 2009. Accepted April 28, 2009.