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NEUROLOGY 2009;73:612-620
© 2009 American Academy of Neurology

Semantic memory activation in individuals at risk for developing Alzheimer disease

M. Seidenberg, PhD, L. Guidotti, MS, K. A. Nielson, PhD, J. L. Woodard, PhD, S. Durgerian, BS, P. Antuono, MD, Q. Zhang, BS and S. M. Rao, PhD

From the Department of Psychology (M.S., L.G.), Rosalind Franklin University of Medicine and Science, Chicago, IL; Department of Psychology and the Integrative Neuroscience Research Center (K.A.N.), Marquette University, Milwaukee, WI; Foley Center for Aging and Development (K.A.N.), Functional Imaging Research Center (K.A.N., S.D., Q.Z., P.A., S.M.R.), and Departments of Psychiatry (K.A.N.) and Neurology (K.A.N., S.D., Q.Z., P.A., S.M.R.), Medical College of Wisconsin, Milwaukee; Department of Psychology (J.L.W.), Wayne State University, Detroit, MI; and Schey Center for Cognitive Neuroimaging (S.M.R.) and the Cleveland Clinic Lou Ruvo Center for Brain Health (S.M.R.), Neurological Institute, Cleveland Clinic, Cleveland, OH.

Address correspondence and reprint requests to Dr. Stephen M. Rao, Schey Center for Cognitive Neuroimaging, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave./U10, Cleveland, OH 44195 raos2{at}ccf.org

Objective: To determine whether whole-brain, event-related fMRI can distinguish healthy older adults with known Alzheimer disease (AD) risk factors (family history, APOE {varepsilon}4) from controls using a semantic memory task involving discrimination of famous from unfamiliar names.

Methods: Sixty-nine cognitively asymptomatic adults were divided into 3 groups (n = 23 each) based on AD risk: 1) no family history, no {varepsilon}4 allele (control [CON]); 2) family history, no {varepsilon}4 allele (FH); and 3) family history and {varepsilon}4 allele (FH+{varepsilon}4). Separate hemodynamic response functions were extracted for famous and unfamiliar names using deconvolution analysis (correct trials only).

Results: Cognitively intact older adults with AD risk factors (FH and FH+{varepsilon}4) exhibited greater activation in recognizing famous relative to unfamiliar names than a group without risk factors (CON), especially in the bilateral posterior cingulate/precuneus, bilateral temporoparietal junction, and bilateral prefrontal cortex. The increased activation was more apparent in the FH+{varepsilon}4 than in the FH group. Unlike the 2 at-risk groups, the control group demonstrated greater activation for unfamiliar than familiar names, predominately in the supplementary motor area, bilateral precentral, left inferior frontal, right insula, precuneus, and angular gyrus. These results could not be attributed to differences in demographic variables, cerebral atrophy, episodic memory performance, global cognitive functioning, activities of daily living, or depression.

Conclusions: Results demonstrate that a low-effort, high-accuracy semantic memory activation task is sensitive to Alzheimer disease risk factors in a dose-related manner. This increased activation in at-risk individuals may reflect a compensatory brain response to support task performance in otherwise asymptomatic older adults.

Abbreviations: AD = Alzheimer disease; AFNI = Analysis of Functional NeuroImages; ANOVA = analysis of variance; AUC = area under the curve; BA = Brodmann area; BOLD = blood oxygen level–dependent; CON = control; DRS-2 = Dementia Rating Scale 2; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; EM = episodic memory; FH = family history; FOV = field of view; fROI = functional region of interest; HRF = hemodynamic response function; MCI = mild cognitive impairment; MOANS = Mayo Older Americans Normative Studies; MR = magnetic resonance; MTL = medial temporal lobe; NS = not significant; RAVLT = Rey Auditory–Verbal Learning Test; SM = semantic memory; SMA = supplementary motor area; SPGR = spoiled gradient-recalled at steady state; TE = echo time; TR = repetition time; VBM = voxel-based morphometry.

Supplemental data at www.neurology.org

Supported in part by grants from the NIH (R01-AG022304, M01-RR00058) and Advancing Healthier Wisconsin Foundation.

Disclosure: Author disclosures are provided at the end of the article.

Received January 13, 2009. Accepted in final form May 18, 2009.






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