Quantitative analysis of electroencephalography in patients with Alzheimer's disease and mild cognitive impairment

Poster Presentations P3 P3-065

BLOOD-BASED MICROCIRCULATION MARKERS IN ALZHEIMER’S DISEASE: DIAGNOSTIC VALUE OF CT-PROET-1 IN PATIENTS WITH AMNESTIC MILD COGNITIVE IMPAIRMENT

Philine Schneider1, Sabrina Putz1, Oliver Hartmann2, Frauke Hein2, Andreas Bergmann2, Harald Hampel3, Katharina Buerger1, 1Ludwig-Maximilian University Munich, Munich, Germany; 2BRAHMS AG, Hennigsdorf, Germany; 3Trinity College Dublin, Dublin, Ireland. Contact e-mail: Philine. [email protected] Background: There is an urgent need for blood-based biological markers of Alzheimer’s disease (AD), particularly in its pre-dementia stage of mild cognitive impairment (MCI). Cardiovascular risk factors and circulatory dysfunction are associated with AD pathogenesis. The pro-hormone fragments C-terminal endothelin-1 precursor fragment (CT-proET-1), midregional pro-adrenomedullin (MR-proADM), and midregional pro-atrial natriuretic peptide (MR-proANP), are novel blood-based biological markers for circulatory function and an alteration has recently been shown in AD (Buerger K et al., Biol. Psychiatry, in press). We investigated these blood-based (micro-) circulation markers in the diagnosis of the high risk group of amnestic MCI. Methods: We prospectively recruited a volunteer cohort of 51 patients with amnestic MCI and 61 healthy age-matched controls (HC) (mean age 71.2 years). CT-proET-1, MR-proADM, and MR-proANP were analysed in plasma using sandwich luminescence immunoassays. Concentrations of the plasma markers were compared between the two groups by use of analysis of variance (ANOVA). Results: In amnestic MCI patients, plasma concentrations of CT-proET-1 were significantly decreased (p<0.0001) compared to HC subjects. MR-proADM and MR-proANP levels were not significantly altered in amnestic MCI. Amnestic MCI patients could be discriminated from HC with a specificity of 90.2% and a sensitivity of 46.9% based on cut-off values of 47 pmol/L for CT-proET-1. At a cut-off of 53.6 pmol/L, specificity was 82.0% and sensitivity was 57.8%. Conclusions: These findings extend our recent data that report altered expression of (micro-) circulation parameters in AD. We show here alterations even in amnestic MCI, a high-risk group of AD. CT-proET-1, the pro-hormone of Endothelin-1, which acts as a vasoconstrictor on the vasculature, yielded the highest diagnostic accuracy. These study results support the hypothesis of a disturbed (micro-) vascular homeostasis even in the early, pre-dementia MCI stage of AD. MCI patients will be followed for further evaluation of the biomarker, particularly in terms of prediction of AD in amnestic MCI subjects. P3-066

ANALYSIS OF EEG GAMMA BAND OSCILLATIONS IN PROGRESSIVE MILD COGNITIVE IMPAIRMENT INDICATES IMPAIRED ACTIVATION OF ATTENTION PROCESSES

Gabriel Gold1, Pascal Missonnier2, Agnes Michon2, Lara Fazio-Costa1, Francois R. Herrmann1, Panteleimon Giannakopoulos2,3, 1University Hospitals of Geneva, Department of Geriatrics and Rehabilitation, ThonexGeneve, Switzerland; 2University Hospitals of Geneva, Department of Psychiatry, Thonex- Geneve, Switzerland; 3University Hospitals of Lausanne, Prilly, Switzerland. Contact e-mail: [email protected] Background: EEG gamma band high frequency (30-100Hz) most likely reflects neural activity for synchronization of cortical networks involved in short term memory and attentional processes. Methods: We performed baseline assessment of the temporal evolution of gamma band power in 17 elderly controls (EC) and 29 longitudinally followed-up MCI cases during a pure attentional detection task compared to a 2-back working memory task. Based on phase diagrams, multiple linear regression models were built to explore the relationship between cognitive status and gamma oscillation values after adjusting for gamma values at previous time lags. In addition, fractal dimension was used to obtain an individual measure of phase diagram complexity in stable (SMCI) and progressive (PMCI) cases. Based on one year cognitive follow-up, 16 individuals were classified as PMCI and 13 as SMCI. Results: Gamma band power at rest did not differ between the three groups. In contrast, when adjusted for gamma value at lag -14 and -15 milliseconds, significant group differences were found between SMCI and EC for detection and

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2-back. This was also the case between PMCI and SMCI cases at lags -2 and -3 milliseconds. The fractal dimension of phase diagrams was significantly higher in PMCI compared to SMCI cases. Conclusions: The progression of cognitive decline in MCI is associated with EEG evidence of time binding deficits that occur during the activation of selective attention processes. P3-067

QUALITATIVE ANALYSES OF CLOCK DRAWINGS IN MILD COGNITIVE IMPAIRMENT

Seon-Young Ryu1, Sang-Bong Lee1, In-Uk Song1, Yeong-In Kim2, KwangSoo Lee2, 1The Catholic University of Korea, College of Medicine, Daejeon, Republic of Korea; 2The Catholic University of Korea, College of Medicine, Seoul, Republic of Korea. Contact e-mail: [email protected] Background: The diagnosis of cognitive deficits at an early stage such as mild cognitive impairment (MCI) is an issue of growing concern. The clock drawing test (CDT) provides a simple and reliable measure of a comprehensive range of cognitive functions. There are many studies about the CDT as a convenient screening instrument for dementia, but few studies examining the utility of the CDT in MCI. Objectives: The purpose of this study is to examine the usefulness of the CDT including quantitative and qualitative analyses as a screening method for MCI. Methods: We analysed 58 subjects with MCI among the people who visited the outpatient clinic complaining the memory impairments. The CDT was scored by 3 different scoring methods (Freedman, modified Shulman, and Rouleau) and also anaylsed about the qualitative error types (Rouleau’s criteria). Results: The subjects were 25 women and 33 men; their mean age was 68.03 years (69.51) (range 46 - 82). The mean MMSE was 25.506 2.87. The mean CDT scores by each scoring method were Freedman 13.33 6 2.20, Shulman 1.95 6 0.88, Rouleau 8.67 6 1.32. In specific error types, 23 among 58 cases showed qualitative errors more than one (maximum error numbers: 3). The planning deficit and nonspecific spatial error were the most frequent (9 of 58 cases, respectively), followed by the conceptual deficit and size of the clock (6 of 58 cases, respectively). Among 58 cases, there were no error types of perseveration or neglect of left hemisphere. All correlations between CDT scoring methods were statistically significant (r¼0.781-0.893, p<0.01). Conclusions: Although there is the limit due to the small sample size, the most frequent qualitative errors among the subjects with MCI were planning deficit and nonspecific spatial errors, followed by the conceptual deficit and size of the clock. The planning deficit or nonspecific spatial errors among the qualitative errors could need the more careful examination than other qualitative errors. Therefore it would be necessary to do more careful analysis to get more information from the qualitative analysis in MCI. P3-068

QUANTITATIVE ANALYSIS OF ELECTROENCEPHALOGRAPHY IN PATIENTS WITH ALZHEIMER’S DISEASE AND MILD COGNITIVE IMPAIRMENT

Jee Hoon Roh1, Moon Ho Park2, Kun-Woo Park2, Dae-Hee Lee2, Deokwon Ko2, Ki-Young Jung2, 1Samsung Medical Center, Seoul, Republic of Korea; 2Korea University Medical Center, Seoul, Republic of Korea. Contact e-mail: [email protected] Background: Slowing of EEG rhythms has been a consistent finding in dementia studies. However, brain regions in which the quantitative EEG data shows prominent changes are not well known. In addition, the relationship between quantitative EEG analysis and neuropsychological tests is not fully understood. This study tried to find out whether healthy controls, amnestic MCI (aMCI) patients, and AD patients exhibit regional differences as well as frequency differences in the low resolution brain electromagnetic tomography (LORETA) analysis, and whether there is a correlation between LORETA current density and neuropsychological tests. Methods: Forty-one patients with AD, 38 patients with aMCI, and 39 healthy controls were enrolled. All subjects underwent routine scalp EEG and neuropsychological tests. Repeated measures analysis of variance (ANOVA) was performed to evaluate differences in LORETA among the three groups in terms of region and frequency. After selecting regions, in which LORETA values showed

Poster Presentations P3

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increasing or decreasing patterns along the course of disease progression, the correlation between LORETA current density and each neuropsychological test score was analyzed. Results: The theta band LORETA current density in the temporal, limbic, parietal, and corpus callosum/cingulate gyrus regions increased, whereas the alpha band current density in the temporal, parietal, and corpus callosum/cingulate gyrus regions and beta 2 band current density in the frontal region decreased along the continuum of disease progression. The theta band LORETA current density in the temporal, limbic, and corpus callosum/cingulate gyrus regions was negatively correlated with verbal word memory, constructional memory recall, and verbal fluency task. The parietal theta and corpus callosum/cingulate gyrus alpha band current density was correlated with verbal word memory. There was also a correlation between constructional memory registration and limbic theta band current density (p < 0.01). Conclusions: Quantitative EEG analysis showed a consecutive increase in low frequency bands and a decreasing pattern in high frequency bands along the course of disease progression in selected regions of the brain. The LORETA current density in selected regions showing consecutive changes was correlated with neuropsychological test scores. These findings suggest that quantitative EEG findings can be helpful in discriminating among healthy subjects, aMCI patients, and AD patients. P3-069

GREY MATTER VOLUME LOSS IN MEDIAL AND ANTERIOR TEMPORAL REGIONS MAY EXPLAIN EXCESSIVE LEXICAL SEMANTIC DECLINE IN MCI APOE E4 CARRIERS

Roberta Biundo, William J. McGeown, Michael F. Shanks, Annalena Venneri, University of Hull, Hull, United Kingdom. Contact e-mail: [email protected] Background: Patients with early Alzheimer’s disease (AD) show marked semantic declines. For example, words produced in a semantic fluency task are earlier acquired and more typical of their category. Age of acquisition and typicality effects correlate strongly with medial temporal atrophy and discriminate normal from abnormal cognitive decline. In the preclinical amnestic mild cognitive impairment (aMCI) stage, individuals who carry the APOE4 mutation (a risk factor for AD) also produce words which are earlier acquired than those of controls and non carriers. The purpose of this study was to test the relationships between APOE status, semantic competency and grey matter volume in the brain of a group of older adults with and without mild cognitive impairment. Methods: Thirty older adults (18 amnestic MCI and 12 controls) were tested with a semantic fluency task (two categories: animals and fruits) and their APOE status determined. 3D structural MRI brain scans were acquired. Grey matter segments extracted from 3D MRIs were entered into a multiple regression with genotype and age of acquisition values from the semantic fluency task using SPM5. Results: There was a significant negative correlation between APOE status and grey matter volumes in medial temporal areas and anterior cingulate regions, with greater atrophy in carriers of the 4 allele. Age of acquisition values from the semantic fluency task also correlated significantly with volume loss in the anterior part of the hippocampus and temporal region. Conclusions: Poorer semantic abilities in APOE 4 carriers with MCI seem likely to follow from more marked grey matter volume loss in medial and anterior temporal regions. The early and excessive semantic deterioration observed in MCI APOE 4 carriers might, therefore, be due to the greater neuropathogical burden associated with the presence of the APOE 4 allele in those neural structures which are essential for efficient semantic retrieval from long term memory. P3-070

EARLY DETECTION AND DIFFERENTIATION OF AMNESTIC AND NONAMNESTIC MILD COGNITIVE IMPAIRMENT (MCI)

Stuart Zola1,2, Cecelia Manzanares1, Melinda K. Higgins1, 1Yerkes National Primate Research Center, Emory Alzheimer’s Disease Research Center, Emory University, Atlanta, GA, USA; 2Veterans Administration Medical Center, Atlanta, GA, USA. Contact e-mail: [email protected] Background: The diagnosis of mild cognitive impairment (MCI) can refer to individuals who have memory loss but relatively preserved other cognitive abilities, (amnestic MCI, aMCI), or individuals who have relatively intact

memory but impaired abilities in other cognitive domains, e.g., executive function (nonamnestic MCI, naMCI). Individuals in both populations can be at high risk for dementia of different forms, i.e., Alzheimer’s Disease, or subcortical dementias, respectively. We report preliminary findings of a dissociation in performance between individuals with aMCI and individuals with naMCI using a behavioral task shown to be sensitive to aMCI, that is, the preferential looking task combined with noninvasive infrared eye-tracking. Methods: A new picture and a recently presented picture are presented side-by-side, and a subject’s spontaneous tendency to look at the new picture is measured using eye-tracking. Normal individuals typically look at the new picture about two-thirds of the viewing time. We used two delay intervals between initial viewing of a picture and the preferential looking component of the task: 2 sec, where the challenge to memory is minimal; and 2 min, where the hippocampal memory system is actively engaged. Results: Eye-tracking data were submitted to ANOVA and ANCOVA (Analysis of Covariance). No significant differences were found between the groups at the 2-sec delay interval (ANOVA). Taking into account within-subject performance at the 2-sec delay (ANCOVA), significant differences were found between groups at the 2-min delay: The aMCI group looked at the novel stimulus only 60.9% of the time, which was different from the NC (control) group (68.2% viewing time; p ¼ .001), and also different from the naMCI group (66.6% viewing time; p ¼ .019). The naMCI and NC groups did not differ (p>.050). Conclusions: The eye-tracking task successfully dissociated the aMCI patients, who did not remember well which pictures had been recently viewed after only a 2-min delay, and the naMCI patients, who performed normally at 2 min. These findings suggest a dissociation in the groups’ underlying neurology. Additionally, an important next question is whether this task can accurately predict individual aMCI and naMCI patients prone to particular dementias, so that specific interventions could occur earlier than is now possible. P3-071

RELATION BETWEEN APOE 4 ALLELE AND MCI IS MODULATED BY GEOGRAPHICAL REGION: RESULTS FROM THE DESCRIPA STUDY

Jocke Norberg1, Ove Almkvist1, Caroline Graff1, Giovanni B. Frisoni2, Lutz Froelich3, Harald Hampel4, Roy Jones5, Patrick Kehoe6, Lennart Minthon7, Flavio Nobili8, Marcel Olde-Rikkert9, AnneSophie Rigaud10, Hilkka Soininen11, Luiza Spiru12, Magda Tsolaki13, Bruno Vellas14, Lyzel Elias-Sonnenschein15, Philip Scheltens16, LarsOlof Wahlund1, Frans R. J. Verhey15, Pieter Jelle Visser15,16, 1Karolinska Institute, Stockholm, Sweden; 2IRCCS Fatebenefratelli, Brescia, Italy; 3 Zentralinstitut fu¨r Seelische Gesundheit, Mannheim, Germany; 4Trinity College Dublin, Dublin, Ireland; 5The Research Institute for the Care of Older People, Bath, United Kingdom; 6University of Bristol, Bristol, United Kingdom; 7Department of Clinical Sciences Malmo¨, Malmo¨, Sweden; 8 University of Genoa, Genoa, Italy; 9Radboud University Medical Centre, Nijmegen, Netherlands; 10Hopital Broca, Paris, France; 11University Hospital of Kuopio, Kuopio, Finland; 12"Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania; 13Aristotle University of Thessaloniki, Thessaloniki, Greece; 14Toulouse University Hospital, Toulouse, France; 15 University of Maastricht, Maastricht, Netherlands; 16VU University Medical Centre, Amsterdam, Netherlands. Contact e-mail: pj.visser@np. unimaas.nl Background: The APOE e4 allele is a known risk factor for Alzheimer disease (AD). The allele has a North-South gradient across Europe. Previous studies have shown that AD is preceded by subjective cognitive impairment (SCI) and mild cognitive impairment (MCI), specifically by the amnestic subtype of MCI. The aim of the present study was to investigate the association of APOE e4 with SCI, non-amnestic MCI, and amnestic MCI, in different European regions (North, middle and South). Methods: Subjects with SCI (n ¼ 130), amnestic MCI (n¼ 256) and non-amnestic MCI (n¼ 134) were selected from the DESCRIPA project, a European multi-centre study performed in a memory clinic setting. Diagnoses of SCI, non-amnestic MCI and amnestic MCI were made based on neuropsychological test performance. Results: The prevalence of APOE e4 carriers was 62.7% in the Northern region, 42.1% in the middle region, and 33.2% in the Southern region. In the combined sample, the prevalence of APOE e4 carriers was 40% among subjects with SCI, 36.6%