Structural and Functional Patterns in Healthy Aging, Mild Cognitive Impairment, and Alzheimer Disease Ariadna Besga, MD, PhD,* Laura Ortiz, MD, PhD,w Alberto Ferna ´ndez, PhD,w Fernando Maestu, PhD,w Juan Arrazola, MD, PhD,z Pedro Gil-Gregorio, MD, PhD,* Manuel Fuentes, MD,y and Toma ´s Ortiz, MD, PhDw Abstract: The aim of this study was to analyze the combined contribution of magnetic resonance imaging and magnetoencepha- lography (MEG) to the diagnosis of mild cognitive impairment (MCI) and AD. To whole—head MEG recordings were obtained from three diagnosis groups: Alzheimer disease (AD), MCI, and control. Magnetic resonance imaging volumetric data of global brain, temporal lobe, and hippocampal volumes, were also obtained. Results indicated that a reduction of volume in the hippocampal structure allowed the discrimination between AD and MCI patients as compared with controls. The percentage of correct classification was 91.3% when AD versus controls was compared, and 83.3% when we compared MCI versus control. MEG data showed that AD patients exhibit higher y and d activity than MCI and controls. Such higher activity was significant in parietal, temporal, and occipital areas. Left parietal theta classified controls versus MCIs with 78.3% rate of correct classification. Right occipital theta and the left parietal delta allowed the discrimination of controls versus ADs, with 81.8% rate of correct classification. Left parietal theta discriminated between ADs and MCIs with 56.6% rate of correct classification. In addition, the combination of both techniques significantly improved the rate of correct classification, thus indicating that a multidisciplinary perspective of techniques may improve the diagnostic capabilities. Key Words: magnetoencephalography, MRI volumetry, Alzheimer disease, mild cognitive impairment (Alzheimer Dis Assoc Disord 2010;24:1–10) A lzheimer disease (AD) is the most prevalent cause of dementia, accounting for 60% to 70% of all dementia cases. AD prevalence doubles each 5 years after age 60, so that AD affects 10% of individuals over 65 years of age, and more than 50% of persons over 80 years. 1 Although the understanding of the etiology and pathophysiologic mechanisms of AD is improving, the nosological bound- aries of the disease are not accurately delimited, because a definitive diagnostic marker is still unknown. Relatively, recent therapeutic strategies that improve symptoms have been developed. Such therapeutic strategies need an early diagnosis, before symptoms and clinical signs have reached the stage at which a diagnosis of probable AD could be made according to currently recommended criteria. 2 The definitive diagnosis is actually confirmed by postmortem histopathology with observation of specific pathologic lesions: intracellular neurofibrillary tangles (NFT), b amyloid deposition in the form of extra cellular plaques and blood vessel deposit. 3 Several studies showed that AD patients exhibit a selective neuronal damage, and the progression of AD pathology in the brain can be staged. 4 The histologic changes could be illustrated from a macro- scopic perspective as volume reductions revealed by magnetic resonance imaging (MRI), and functional ab- normalities such as focal d activity revealed by magneto- encephalography (MEG). 5,6 Clinicopathologic studies demonstrated the relationship between the hippocampal atrophy progress and the severity of the disease: the greater the atrophy the lower the punctuation of the mini mental state examination (MMSE). 7 In a postmortem study, it was found that the hippocampal volume on MRI was a better predictor of AD neuropatho- logy, as compared with the clinical diagnosis or measures of cognition. 8 This fact could justify the role of hippocampal atrophy as a predictor marker for the risk of developing AD within mild cognitive impairment (MCI) population. How- ever, a reduced hippocampus was also found in other causes of dementia. 9,10 This could be understood as the fact that the residual hippocampal volume reflects a residual number of neurons, but not the etiology of the process, which is actually damaging the neurons. The problem of early diagnosis of AD is so relevant for the scientific community that the so-called ‘‘transitional stage’’ between normal ageing and dementia has received increasing attention. MCI is one of the terms used to describe such transitional stage. Although all MCIs will not develop dementia, they present an increased risk of progression. Even though various criteria for MCI diag- nosis have been used in prospective studies, the estimation of the conversion rate from MCI to dementia was 6% to 15% per year, whereas the risk for healthy controls to convert to dementia is 1% to 2%. 11 Several methods are sensitive for MCI, including MRI, positron emission tomography (PET), single photon emission computed tomography (SPECT), quantitative electroencephalography (qEEG), and MEG. The measure of hippocampal volume with MRI is well standardized. Cerebral and hippocampal atrophy can occur several years before a patient develops AD and is also present in preclinical AD. 12 The individual classification on Copyright r 2010 by Lippincott Williams & Wilkins Received for publication December 5, 2008; accepted April 15, 2009. From the *Servicio de Geriatrı´a; zServicio de Radiologı´a; yServicio de Medicina Preventiva y Epidemiologı´a, Hospital Clı´nico San Carlos; and wCentro de Magnetoencefalografı´a Dr Pe´ rez-Modrego, Uni- versidad Complutense de Madrid, Madrid, Spain. Supported by Fundacio´n Mutua Madrilen˜a and by the FIS project PI-061089. Reprints: Toma´s Ortiz, MD, PhD, Facultad de Medicina, Centro de Magnetoencefalografı´a Dr Pe´rez-Modrego, Pabello´ n 8, Universi- dad Complutense de Madrid, 28040, Madrid, Spain (e-mail: tortiz@med.ucm.es). ORIGINAL ARTICLE Alzheimer Dis Assoc Disord  Volume 24, Number 1, January–March 2010 www.alzheimerjournal.com | 1