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Published online before print December 12, 2007, doi:10.1212/01.wnl.0000281689.28759.ab)
© 2008 American Academy of Neurology Patients with MCI and N400 or P600 abnormalities are at very high risk for conversion to dementiaFrom the Department of Neurology (J.M.O., J.R.T.), University of California, Davis; VA San Diego Healthcare System (J.M.O., A.J.B., V.J.I.-M.), CA; School of Medicine (J.G.), Case Western Reserve University, Cleveland, OH; and Departments of Neurosciences (D.P.S., M.K., V.J.I.-M.) and Cognitive Science (M.K.), University of California, San Diego. Address correspondence and reprint requests to Dr. John M. Olichney, Center for Mind and Brain, 267 Cousteau Place, Davis, CA 95618 jmolichney{at}ucdavis.edu Objective: We sought cognitive event-related potential (ERP) biomarkers of disease progression and subsequent conversion to dementia in mild cognitive impairment (MCI). Background: Two ERP components, the P600 and N400, are sensitive to abnormal episodic/declarative memory and semantic processing. When congruous category-exemplars are repeated, smaller P600s (relative to initial presentation) are normally elicited. Repetitions of semantically incongruous words yield smaller N400 amplitude. In mild Alzheimer disease (AD), abnormalities of both the N400 and P600 repetition effects are present, suggesting a widespread failure of synaptic plasticity. Methods: Patients with amnestic MCI (n = 32) were longitudinally studied annually with an ERP paradigm in which semantically congruous (50%) and incongruous target words are repeated 10 to 140 seconds after initial presentation. ERP data were analyzed to contrast MCI-to-AD converters (within 3 years) vs nonconverters, using split-plot analyses of variance. Results: A statistically significant P600 congruous word repetition effect was found only in the nonconverter group (F = 9.9, p = 0.005 vs MCI converters). This effect correlated with verbal memory measures. Repetition of incongruous words produced a significant N400 amplitude attenuation (across right-hemisphere sites) in nonconverters, but not in converters. Patients with MCI with abnormal/reduced N400 or P600 word repetition effects had an 87 to 88% likelihood of dementia within 3 years while those with normal/spared N400 and P600 repetition effects had only an 11 to 27% likelihood. Conclusions: Abnormalities of the P600 or N400 in mild cognitive impairment are associated with an increased risk of subsequent conversion to Alzheimer disease (AD). These event-related potential components may offer useful biomarkers for the detection and staging of very early AD.
Abbreviations: AD = Alzheimer disease; ADRC = Alzheimer’s Disease Research Center; ANOVA = analyses of variance; CDR = Clinical Dementia Rating scale; CVLT = California Verbal Learning Test; ERP = event-related potential; LPC = late positive component; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; PPV = positive predictive value; UCSD = University of California, San Diego.
Supplemental data at www.neurology.org e-Pub ahead of print on December 12, 2007, at www.neurology.org. Supported by NIH grants R01 AG18442, R01 AG08313, and P50 AG05131. Marta Kutas was a Lady Davis Fellow at Hebrew University during the writing of this article. Disclosure: The authors report no conflicts of interest. Received December 8, 2006. Accepted in final form July 9, 2007. This article has been cited by other articles:
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